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Body mass index, waist circumference, and risk of hearing loss: a meta-analysis and systematic review of observational study.
Yang JR, Hidayat K, Chen CL, Li YH, Xu JY, Qin LQ.
Environ Health Prev Med. 2020 Jun 26;25(1):25. doi: 10.1186/s12199-020-00862-9.
PMID: 32590951 Review.
Background: Emerging evidence implicates excess weight as a potential risk factor for hearing loss. However, this association remained inconclusive. Therefore, we aimed to systematically and quantitatively review the published observational study on the association between body mass index (BMI) or waist circumference (WC) and hearing loss.
Methods: The odds ratios (ORs) or relative risks (RRs) with their 95% confidence intervals (CIs) were pooled under a random-effects model. Fourteen observational studies were eligible for the inclusion in the final analysis.
Results: In the meta-analysis of cross-sectional studies, the ORs for prevalent hearing loss were 1.10 (95% CI 0.88, 1.38) underweight, 1.14 (95% CI 0.99, 1.32) for overweight, OR 1.40 (95% CI 1.14, 1.72) for obesity, 1.14 (95% CI 1.04, 1.24) for each 5 kg/m2 increase in BMI, and 1.22 (95% CO 0.88. 1.68) for higher WC. In the meta-analysis of longitudinal studies, the RRs were 0.96 (95% CI 0.52, 1.79) for underweight, 1.15 (95% CI 1.04, 1.27) for overweight, 1.38 (95% CI 1.07, 1.79) for obesity, 1.15 (95% CI 1.01, 1.30) for each 5 kg/m2 increase in BMI, and 1.11 (95% CI 1.01, 1.22) for higher WC.
Conclusions: In summary, our findings add weight to the evidence that elevated BMI and higher WC may be positively associated with the risk of hearing loss.
Keywords: Adiposity; Body mass index; Hearing loss; Obesity; Overweight; Waist circumference.

In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.
Zhang XJ, Qin JJ, Cheng X, Shen L, Zhao YC, Yuan Y, Lei F, Chen MM, Yang H, Bai L, Song X, Lin L, Xia M, Zhou F, Zhou J, She ZG, Zhu L, Ma X, Xu Q, Ye P, Chen G, Liu L, Mao W, Yan Y, Xiao B, Lu Z, Peng G, Liu M, Yang J, Yang L, Zhang C, Lu H, Xia X, Wang D, Liao X, Wei X, Zhang BH, Zhang X, Yang J, Zhao GN, Zhang P, Liu PP, Loomba R, Ji YX, Xia J, Wang Y, Cai J, Guo J, Li H.
Cell Metab. 2020 Jun 24:S1550-4131(20)30316-8. doi: 10.1016/j.cmet.2020.06.015. Online ahead of print.
PMID: 32592657
Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.
Keywords: ACEi/ARB; COVID-19; SARS-COV-2; mortality; statin.

An Insulin-Sensitive Circular RNA that Regulates Lifespan in Drosophila.
Weigelt CM, Sehgal R, Tain LS, Cheng J, Eßer J, Pahl A, Dieterich C, Grönke S, Partridge L.
Mol Cell. 2020 Jun 19:S1097-2765(20)30396-8. doi: 10.1016/j.molcel.2020.06.011. Online ahead of print.
PMID: 32592682
Circular RNAs (circRNAs) are abundant and accumulate with age in neurons of diverse species. However, only few circRNAs have been functionally characterized, and their role during aging has not been addressed. Here, we use transcriptome profiling during aging and find that accumulation of circRNAs is slowed down in long-lived insulin mutant flies. Next, we characterize the in vivo function of a circRNA generated by the sulfateless gene (circSfl), which is consistently upregulated, particularly in the brain and muscle, of diverse long-lived insulin mutants. Strikingly, lifespan extension of insulin mutants is dependent on circSfl, and overexpression of circSfl alone is sufficient to extend the lifespan. Moreover, circSfl is translated into a protein that shares the N terminus and potentially some functions with the full-length Sfl protein encoded by the host gene. Our study demonstrates that insulin signaling affects global circRNA accumulation and reveals an important role of circSfl during aging in vivo.
Keywords: Drosophila; ageing; alternative splicing; backsplicing; circRNA; heparan sulfate; insulin; longevity; non-coding RNAs; sulfateless.

Denosumab, raloxifene, romosozumab and teriparatide to prevent osteoporotic fragility fractures: a systematic review and economic evaluation.
Davis S, Simpson E, Hamilton J, James MM, Rawdin A, Wong R, Goka E, Gittoes N, Selby P.
Health Technol Assess. 2020 Jun;24(29):1-314. doi: 10.3310/hta24290.
PMID: 32588816
Background: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture.
Objectives: The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo®; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture.
Data sources: For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018.
Review methods: A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty.
Results: Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0-33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories.
Limitations: The incremental cost-effectiveness ratios are uncertain for very high-risk patients.
Conclusions: Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000-30,000 per quality-adjusted life-year.

Effect of glucose and sucrose on cognition in healthy humans: a systematic review and meta-analysis of interventional studies.
García CR, Piernas C, Martínez-Rodríguez A, Hernández-Morante JJ.
Nutr Rev. 2020 Jun 25:nuaa036. doi: 10.1093/nutrit/nuaa036. Online ahead of print.
PMID: 32585003
Context: Evidence suggests that plasma glucose levels may influence cognitive performance, but this has not been systematically reviewed and quantified.
Objective: The aim of this review was to investigate the potential effects of glucose and sucrose, compared with placebo, on cognition in healthy humans.
Data sources: The electronic databases PubMed and Web of Science were searched up to December 2019. Reference lists of selected articles were checked manually.
Study selection: Randomized controlled trials or crossover trials that compared glucose or sucrose with placebo for effects on cognition were eligible.
Data extraction: Potentially eligible articles were selected independently by 2 authors. Risk of bias was assessed through the Cochrane Collaboration tool. Standardized mean differences (SMDs) were obtained from random-effects meta-analyses for a subsample of studies that reported the same outcomes.
Results: Thirty-seven trials were identified, of which 35 investigated the effect of glucose consumption compared with placebo on cognition. Two studies found no effect of glucose on cognition, while the others found mixed results. Only 3 of the 37 studies investigated the effects of sucrose intake, reporting mixed results. Meta-analyses revealed a significantly positive effect of glucose compared with control, but only when a verbal performance test (immediate word recall) was used in parallel-design studies (SMD = 0.61; 95%CI, 0.20-1.02; I2 = 0%). Twenty-four studies were classified as having high risk of bias for the selection procedure.
Conclusions: A limited body of evidence shows a beneficial effect of glucose in individuals performing immediate verbal tasks. High-quality trials with standardized cognitive measurements are needed to better establish the effect of glucose or sucrose on cognition.
Keywords: cognition; executive functions; glucose; sucrose; sugar.

Whole milk consumption is associated with lower risk of coronary artery calcification progression: evidences from the Multi-Ethnic Study of Atherosclerosis.
Ghosh S, He W, Gao J, Luo D, Wang J, Chen J, Huang H.
Eur J Nutr. 2020 Jun 24. doi: 10.1007/s00394-020-02301-5. Online ahead of print.
PMID: 32583016
Purpose: Coronary artery calcification (CAC) progression is a strong predictor of cardiovascular disease (CVD) morbidity and mortality. However, the association between whole milk and CAC progression remains unknown. Recent studies highlighted beneficial effects of short chain fatty acids (SCFA) from whole milk on CVD. In this study, we attempted to investigate the relationship between whole milk consumption and CAC progression, and the potential effect of SCFA in it.
Methods: We analyzed a population-based cohort with 5273 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who completed a dietary questionnaire at baseline. CAC was measured at baseline and subsequent follow-up examinations by multi-detector computed tomography (MDCT) scans with Agatston scores. CAC progression was defined as increased CAC scores in the follow-up from the baseline exam.
Results: Participants consuming whole milk exhibited lower baseline CAC and CAC progression than those who never/rarely consumed whole milk (P < 0.001 and P = 0.010, respectively). Moreover, multivariable logistic regression analysis demonstrated that whole milk intake was independently associated with lower CAC progression (OR 0.765; 95% CI 0.600-0.977; P = 0.032), especially in males, participants with age ≤ 64 years and with body mass index (BMI) ≤ 25 kg/m2. Mediation analysis further showed that caproic acid, one kind of SCFA, partly mediated protective effects of whole milk on CAC progression.
Conclusions: Self-reported whole milk consumption was inversely associated with CAC progression in community-dwelling participants, especially in those at relatively low cardiovascular risks. The beneficial effect was partially mediated by SCFA. Therefore, whole milk can be incorporated into part of a cardio-protective diet. Regarding this, future studies may target SCFA to provide insight into more mechanistic views.
Keywords: Cardiovascular disease; Coronary artery calcification; Short chain fatty acids; Whole milk.

The Effect of Caffeine on the Risk and Progression of Parkinson's Disease: A Meta-Analysis.
Hong CT, Chan L, Bai CH.
Nutrients. 2020 Jun 22;12(6):E1860. doi: 10.3390/nu12061860.
PMID: 32580456
Coffee and caffeine are speculated to be associated with the reduced risk of Parkinson's disease (PD). The present study aimed to investigate the disease-modifying potential of caffeine on PD, either for healthy people or patients, through a meta-analysis. The electronic databases were searched using terms related to PD and coffee and caffeinated food products. Articles were included only upon fulfillment of clear diagnostic criteria for PD and details regarding their caffeine content. Reference lists of relevant articles were reviewed to identify eligible studies not shortlisted using these terms. In total, the present study enrolled 13 studies, nine were categorized into a healthy cohort and the rest into a PD cohort. The individuals in the healthy cohort with regular caffeine consumption had a significantly lower risk of PD during follow-up evaluation (hazard ratio (HR) = 0.797, 95% CI = 0.748-0.849, p < 0.001). The outcomes of disease progression in PD cohorts included dyskinesia, motor fluctuation, symptom onset, and levodopa initiation. Individuals consuming caffeine presented a significantly lower rate of PD progression (HR = 0.834, 95% CI = 0.707-0.984, p = 0.03). In conclusion, caffeine modified disease risk and progression in PD, among both healthy individuals or those with PD. Potential biological benefits, such as those obtained from adenosine 2A receptor antagonism, may require further investigation for designing new drugs.
Keywords: Parkinson’s disease; caffeine; meta-analysis; progression; risk.

Hypertension is associated with oral, laryngeal, and esophageal cancer: a nationwide population-based study.
Seo JH, Kim YD, Park CS, Han KD, Joo YH.
Sci Rep. 2020 Jun 24;10(1):10291. doi: 10.1038/s41598-020-67329-3.
PMID: 32581314
Several studies have reported an association between hypertension and upper aerodigestive tract cancer, but no large-scale, population-based studies have been conducted to confirm this.The aim of this study was to explore the association between hypertension and risk of upper aerodigestive tract cancer in Koreans. Participants who underwent a national health screening examination from January 1 to December 31, 2009 (n = 9,746,606) were enrolled. We assessed the development of oral, laryngeal, or esophageal cancer until 2016 using records from the Korean Health Insurance claims database during the study period. During the seven-year follow-up period, 6,062, 2,658, and 4,752 subjects were newly diagnosed with oral, laryngeal, and esophageal cancer, respectively. Participants with metabolic syndrome had the highest risk of developing oral cancer (hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.03-1.16), laryngeal cancer (HR 1.27, 95% CI 1.17-1.38), and esophageal cancer (HR 1.11, 95% CI 1.04-1.19). Hypertension was a remarkable risk factor for each cancer (HR 1.11, 95% CI 1.04-1.17 for oral cancer; HR 1.23, 95% CI 1.13-1.33 for laryngeal cancer; HR 1.25, 95% CI 1.18-1.33 for esophageal cancer) after adjusting for age and other variables including gender, smoking status, alcohol intake, exercise, body mass index, and diabetes. Patients with untreated hypertension were at highest risk of developing oral cancer (HR 1.15; 95% CI 1.05-1.26), laryngeal cancer (HR 1.25; 95% CI 1.09-1.44), and esophageal cancer (HR 1.47; 95% CI 1.33-1.63) after adjusting for confounders. Hypertension was associated with the risk of oral, laryngeal, and esophageal cancer, despite of the lack of detailed biochemical information including the cancer cell types (squamous cell carcinoma or adenocarcinoma), cancer stage, physical findings and other medical history. Further studies are warranted to determine the reasons for this association and to establish effective interventions in this vulnerable population.

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The Performance Effect of Scheduled Carbohydrate and Caffeine Intake during Simulated Team Sport Match-Play.
Keane J, Shovlin A, Devenney S, Malone S, Young D, Coratella G, Collins K, Shortall M.
Nutrients. 2020 Jun 29;12(7):E1926. doi: 10.3390/nu12071926.
PMID: 32610573
The aim of the current investigation was to identify the effects of scheduled carbohydrate (CHO) and caffeine (CAF) supplementation on simulated team sport match-play performance. Ten male hurling players completed three hurling match-play simulation protocols (HSP) performed 7 days apart in a double-blind, randomized design. Supplementation included CHO, CHO + CAF, and placebo (PLA). In a randomized order, participants ingested either a 6% CHO solution, a PLA solution of similar taste, or a combined intake of 6% CHO solution + 200 mg CAF capsule. At specific time points (Pre-0 min; half time (HT)-30 min; full time (FT)-60 min), participants completed a repeated sprint protocol (RAST; 12 × 20 m). Physiological [% maximal oxygen uptake (%VO2max), % mean oxygen uptake (%VO2mean), % maximal heart rate (%HRmax), % mean heart rate (%HRmean), respiratory exchange ratio (RER), and blood lactate (BLa)] and performance [(best sprint time (RSAbest), mean sprint time (RSAmean), and rate of perceived exertion (RPE)] variables were monitored throughout each simulation. Non-significant differences were observed between supplement trials (CHO, CHO + CAF, and PLA) for BLa (η2 = 0.001, small), %VO2max (η2 = 0.001, small), %VO2mean (η2 = 0.004, small), %HRmax (η2 = 0.007, small), %HRmean (η2 = 0.018, small), RER (η2 = 0.007, small), RPE (η2 = 0.007, small), and RSAbest (η2 = 0.050, small). RSAmean performance significantly improved in CHO + CAF trials compared to PLA, with sprint times significantly improved from Pre to FT also (η2 = 0.135, medium). A significant difference was observed in BLa between time points (Pre, HT, and FT) (η2 = 0.884, large) in % HRmax (η2 = 0.202, medium), %HRmean (η2 = 0.477, large), and RER (η2 = 0.554, large) across halves and in RPE across time points (η2 = 0.670, large). Our data provide novel data regarding the effects of CHO and CAF supplementation on team sport performance, with co-ingestion of CHO + CAF reducing the decrement in repeated sprint performance compared to PLA.
Keywords: aerobic performance; ergogenic aids; internal load; repeated sprint-ability; team sports.

Caffeine-Containing, Adaptogenic-Rich Drink Modulates the Effects of Caffeine on Mental Performance and Cognitive Parameters: A Double-Blinded, Placebo-Controlled, Randomized Trial.
Boolani A, Fuller DT, Mondal S, Wilkinson T, Darie CC, Gumpricht E.
Nutrients. 2020 Jun 29;12(7):E1922. doi: 10.3390/nu12071922.
PMID: 32610481
Using a placebo-controlled, double-blinded, within-participants, randomized, cross-over design, we examined the neurocognitive effects of a: (a) caffeine-containing, adaptogenic herbal-rich natural energy shot (e+ shot), (b) a matched caffeine-containing shot (caffeine), and, (c) a placebo. Participants (n = 30) were low consumers of caffeine without elevated feelings of energy. Before and three times after beverage consumption, a 27-min battery was used to assess motivation to perform cognitive tasks, mood, attention ((serial subtractions of 3 (SS3) and 7 (SS7), the continuous performance task (CPT), and the rapid visual input processing tasks)), heart rate (HR), blood pressure (BP), and motor coordination (nine-hole peg test) with a 10-min break between each post-consumption battery. The procedure was repeated for each beverage for each participant at least 48 h apart and within 30 min the same time of day using a random group assignment with blinding of researchers and subjects. To evaluate for changes in outcomes, a Treatment × Time analysis of covariance controlling for hours of prior night's sleep was used. Analysis of all outcomes and all treatment comparisons indicated that compared to placebo, both e+ shot ( Δ ¯ &nbsp; = 2.60; η2 = 0.098) and caffeine ( Δ ¯ &nbsp; = 5.30, η2 = 0.098) increased systolic BP 30 min post consumption (still within normal healthy ranges). The caffeine beverage also led to an improvement in most cognitive measures and moods 30-min post-consumption with improvements tapering at 69 and 108 min, while e+ shot noted more steady improvements with no significant differences between beverages on most cognitive and mood measures at 69 and 108 min. However, compared to caffeine, e+ shot noted a significant increase in reaction time at 108 min, while caffeine noted a small change in the opposite direction. No side-effects were reported by any intervention. These results suggest that the specific blend of adaptogens in e+ shot may modulate the neurocognitive effects of caffeine on mood, and cognition.
Keywords: adaptogens; caffeine; cognition; energy; fatigue; mood.

The Influence of Different Foods and Food Ingredients on Acute Postprandial Triglyceride Response: A Systematic Literature Review and Meta-Analysis of Randomized Controlled Trials.
Lee DPS, Low JHM, Chen JR, Zimmermann D, Actis-Goretta L, Kim JE.
Adv Nutr. 2020 Jul 1:nmaa074. doi: 10.1093/advances/nmaa074. Online ahead of print.
PMID: 32609800
The use of postprandial triglyceride (ppTG) as a cardiovascular disease risk indicator has gained recent popularity. However, the influence of different foods or food ingredients on the ppTG response has not been comprehensively characterized. A systematic literature review and meta-analysis was conducted to assess the effects of foods or food ingredients on the ppTG response. PubMed, MEDLINE, Cochrane, and CINAHL databases were searched for relevant acute (<24-h) randomized controlled trials published up to September 2018. Based on our selection criteria, 179 relevant trials (366 comparisons) were identified and systematically compiled into distinct food or food ingredient categories. A ppTG-lowering effect was noted for soluble fiber (Hedges' giAUC = -0.72; 95% CI: -1.33, -0.11), sodium bicarbonate mineral water (Hedges' gAUC = -0.42; 95% CI: -0.79, -0.04), diacylglycerol oil (Hedges' giAUC = -0.38; 95% CI: -0.75, -0.00), and whey protein when it was contrasted with other proteins. The fats group showed significant but opposite effects depending on the outcome measure used (Hedges' giAUC = -0.32; 95% CI: -0.61, -0.03; and Hedges' gAUC = 0.16; 95% CI: 0.06, 0.26). Data for other important food groups (nuts, vegetables, and polyphenols) were also assessed but of limited availability. Assessing for oral fat tolerance test (OFTT) recommendation compliance, most trials were ≥4 h long but lacked a sufficiently high fat challenge. iAUC and AUC were more common measures of ppTG. Overall, our analyses indicate that the effects on ppTG by different food groups are diverse, largely influenced by the type of food or food ingredient within the same group. The type of ppTG measurement can also influence the response.
Keywords: food; ingredient; lipemia; oral fat tolerance test recommendation; postprandial; triglyceride; triglyceridemia.

Lifespan-extending interventions enhance lipid-supported mitochondrial respiration in Caenorhabditis elegans.
Macedo F, Romanatto T, Gomes de Assis C, Buis A, Kowaltowski AJ, Aguilaniu H, Marques da Cunha F.
FASEB J. 2020 Jul 1. doi: 10.1096/fj.201901880R. Online ahead of print.
PMID: 32609395
Dietary restriction and reduced reproduction have been linked to long lifespans in the vast majority of species tested. Although decreased mitochondrial mass and/or function are hallmarks of aging, little is known about the mechanisms by which these organelles contribute to physiological aging or to the effects of lifespan-extending interventions, particularly with respect to oxidative phosphorylation and energy production. Here, we employed the nematode Caenorhabditis elegans to examine the effects of inhibition of germline proliferation and dietary restriction, both of which extend the lifespan of C. elegans, on mitochondrial respiratory activity in whole animals and isolated organelles. We found that oxygen consumption rates and mitochondrial mass were reduced in wild-type (WT) C. elegans subjected to bacterial deprivation (BD) compared with animals fed ad libitum (AL). In contrast, BD decreased the rate of oxygen uptake but not mitochondrial mass in germline-less glp-1(e2144ts) mutants. Interestingly, mitochondria isolated from animals subjected to BD and/or inhibition of germline proliferation showed no differences in complex I-mediated respiratory activity compared to control mitochondria, whereas both interventions enhanced the efficiency with which mitochondria utilized lipids as respiratory substrates. Notably, the combination of BD and inhibition of germline proliferation further increased mitochondrial lipid oxidation compared to either intervention alone. We also detected a striking correlation between lifespan extension in response to BD and/or inhibition of germline proliferation and the capacity of C. elegans to generate ATP from lipids. Our results thus suggest that the ability to oxidize lipids may be determinant in enhanced longevity.
Keywords: C. elegans; dietary restriction; lipid oxidation; longevity; mitochondrial metabolism.

Dietary Factors and Risk of Chronic Obstructive Pulmonary Disease: a Systemic Review and Meta-Analysis.
Seyedrezazadeh E, Moghaddam MP, Ansarin K, Asghari Jafarabadi M, Sharifi A, Sharma S, Kolahdooz F.
Tanaffos. 2019 Apr;18(4):294-309.
PMID: 32607110 Free PMC article. Review.
Background: The relationship between dietary pattern and the risk of chronic obstructive pulmonary disease (COPD) has been described; however, the exclusive role of dietary factors remains controversial. Hence, we conducted this systematic meta-analysis to clarify the role of some nutrients and antioxidant vitamins in the risk of COPD.
Materials and methods: PubMed, Embase, and Scopus databases were searched for studies evaluating the associations between COPD outcome measures, symptoms, and mortality, and intake of fruits and vegetables, fiber, fish, n-3 or n-6 fatty acids, and antioxidant vitamins in adults. The random-effect model meta-analyses were used to pool the results.
Results: Ten cohort, six case-control, and 20 cross-sectional studies were identified. The pooled relative risks (RRs) of the COPD and confidence intervals (CIs) for the highest intake group compared with the lowest intake group were 0.74 (95% CI: 0.65-0.85) for fruit, 0.65 (95% CI: 0.55-0.78) for dietary fiber, 0.71 (95% CI: 0.58-0.85) for fish, and 0.89 (95% CI: 0.76-0.99) for vitamin C. No association was observed between the risk of COPD and the intake of vegetables, n-3 fatty acids, vitamin E, and β-carotene; however, it was associated with n-6 fatty acids 1.06 (95% CI: 0.87-1.30).
Conclusion: The results suggested that a higher intake of fruits, probably dietary fiber, and fish reduce the risk of COPD.
Keywords: Antioxidant Vitamins; COPD; Dietary Fiber; Fatty Acids; Fruit; Vegetables.

Clinical determinants of low handgrip strength and its decline in the oldest old: the Leiden 85-plus Study.
Ling CHY, Gussekloo J, Trompet S, Meskers CGM, Maier AB.
Aging Clin Exp Res. 2020 Jun 30. doi: 10.1007/s40520-020-01639-4. Online ahead of print.
PMID: 32607865
Background: Age-related decline in muscle strength, dynapenia, is linked to serious adverse health outcomes. Evidence on the determinants of muscle strength decline in the oldest old is lacking.
Aims: To identify clinical variables associated with handgrip strength and its change over a 4-year period in an oldest old cohort.
Methods: We included 555 participants from the Leiden 85-plus Study, a prospective population-based study of 85-year-old inhabitants of Leiden, the Netherlands. Handgrip strength was assessed at age 85 and 89 years. Anthropometry, mental status, functional performance, and biochemical variables were obtained at baselines. Significant univariates were included into multivariable regression models to extract the final predictive variables.
Results: Handgrip strength for men and women at age 85 years was 30.6 kg (SD 8.2) and 18.7 kg (SD, 5.5), respectively. In the cross-sectional analysis, body height and weight were positively associated with handgrip strength in both genders. Higher functional performance was associated with stronger handgrip strength in women. Mean absolute handgrip strength decline over 4 years was greater for men than women (- 6.1 kg (SD, 5.2) vs. - 3.4 kg (SD, 4.1), p < 0.001). Men with better baseline cognitive functioning had smaller decline in handgrip strength.
Conclusions: This study further strengthens evidence linking functional and cognitive performances to muscle strength in the oldest old. Future research is needed to ascertain causality and determine if these markers represent potential targets for intervention.
Keywords: Cognitive function; Muscle strength; Physical fitness; Sex differences.

Dietary Methionine Restriction Ameliorated Fat Accumulation, Systemic Inflammation, and Increased Energy Metabolism by Altering Gut Microbiota in Middle-aged Mice Administered Different Fat Diets.
Wu G, Shi Y, Han L, Feng C, Ge Y, Yu Y, Tang X, Cheng X, Sun J, Le GW.
J Agric Food Chem. 2020 Jun 27. doi: 10.1021/acs.jafc.0c02965. Online ahead of print.
PMID: 32597175
Diet greatly influences gut microbiota. Dietary methionine restriction (MR) prevents and ameliorates age-related or high-fat induced diseases, and prolongs life-span. This study aimed to reveal the impact of MR on gut microbiota in middle-aged mice with low-, medium-, high-fat diets. C57BL/6J mice were randomly divided into six groups with different MR and fat-content diets. Multiple indicators of intestinal function, fat accumulation, energy consumption, and inflammation were measured. 16S rRNA gene sequencing was used to analyze cecal microbiota. Our results indicated that MR considerably dropped the concentrations of lipopolysaccharides (LPS) and increased short-chain fatty acids (SCFAs) by upregulating the abundance of Corynebacterium and SCFAs-producing bacterium Bacteroides, Faecalibaculum, Roseburia, and downregulating the LPS-producing or pro-inflammatory bacterium Desulfovibrio and Escherichia-Shigella. These variations upon MR irrespective of fat content contributed to reducing fat accumulation, systemic inflammation, heat production, and strengthening the intestinal mucosal immunity barrier by LPS/LBP/CD14/TLR4 signal pathway in middle-aged mice.

Omega-3 Fatty Acid Supplements for the Prevention of Cardiovascular Disease.
Lan M, Nguyen T, Gray S.
Sr Care Pharm. 2020 Jul 1;35(7):318-323. doi: 10.4140/TCP.n.2020.318..
PMID: 32600510
In the United States, cardiovascular disease (CVD) is the most common cause of death in older people. The use of omega-3 fatty acid supplements (nonprescription) is common in older people, despite the conflicting evidence regarding the benefits of supplements in CVD. The 2017 American Heart Association science advisory on omega-3 fatty acid supplements suggested that it is reasonable to use omega-3 fatty acids for secondary prevention in people with coronary heart disease and heart failure. This article reviewed large meta-analyses and clinical trials published since the science advisory. Two metaanalyses concluded that these supplements were not effective for secondary or primary prevention of CVD. Two large randomized, placebo-controlled clinical trials, one in people with diabetes mellitus, evaluated omega-3 fatty acid supplements for primary prevention and reported no benefit. Taken together, these findings do not support the routine dietary supplementation with omega-3 fatty acids to prevent cardiovascular events.

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Glycemic index, glycemic load, and risk of coronary heart disease: a pan-European cohort study.
Sieri S, Agnoli C, Grioni S, Weiderpass E, Mattiello A, Sluijs I, Sanchez MJ, Jakobsen MU, Sweeting M, van der Schouw YT, Nilsson LM, Wennberg P, Katzke VA, Kühn T, Overvad K, Tong TYN, Conchi MI, Quirós JR, García-Torrecillas JM, Mokoroa O, Gómez JH, Tjønneland A, Sonestedt E, Trichopoulou A, Karakatsani A, Valanou E, Boer JMA, Verschuren WMM, Boutron-Ruault MC, Fagherazzi G, Madika AL, Bergmann MM, Schulze MB, Ferrari P, Freisling H, Lennon H, Sacerdote C, Masala G, Tumino R, Riboli E, Wareham NJ, Danesh J, Forouhi NG, Butterworth AS, Krogh V.
Am J Clin Nutr. 2020 Jul 3:nqaa157. doi: 10.1093/ajcn/nqaa157. Online ahead of print.
PMID: 32619242
Background: High carbohydrate intake raises blood triglycerides, glucose, and insulin; reduces HDLs; and may increase risk of coronary heart disease (CHD). Epidemiological studies indicate that high dietary glycemic index (GI) and glycemic load (GL) are associated with increased CHD risk.
Objectives: The aim of this study was to determine whether dietary GI, GL, and available carbohydrates are associated with CHD risk in both sexes.
Methods: This large prospective study-the European Prospective Investigation into Cancer and Nutrition-consisted of 338,325 participants who completed a dietary questionnaire. HRs with 95% CIs for a CHD event, in relation to intake of GI, GL, and carbohydrates, were estimated using covariate-adjusted Cox proportional hazard models.
Results: After 12.8 y (median), 6378 participants had experienced a CHD event. High GL was associated with greater CHD risk [HR 1.16 (95% CI: 1.02, 1.31) highest vs. lowest quintile, p-trend 0.035; HR 1.18 (95% CI: 1.07, 1.29) per 50 g/day of GL intake]. The association between GL and CHD risk was evident in subjects with BMI (in kg/m2) ≥25 [HR: 1.22 (95% CI: 1.11, 1.35) per 50 g/d] but not in those with BMI <25 [HR: 1.09 (95% CI: 0.98, 1.22) per 50 g/d) (P-interaction = 0.022). The GL-CHD association did not differ between men [HR: 1.19 (95% CI: 1.08, 1.30) per 50 g/d] and women [HR: 1.22 (95% CI: 1.07, 1.40) per 50 g/d] (test for interaction not significant). GI was associated with CHD risk only in the continuous model [HR: 1.04 (95% CI: 1.00, 1.08) per 5 units/d]. High available carbohydrate was associated with greater CHD risk [HR: 1.11 (95% CI: 1.03, 1.18) per 50 g/d]. High sugar intake was associated with greater CHD risk [HR: 1.09 (95% CI: 1.02, 1.17) per 50 g/d].
Conclusions: This large pan-European study provides robust additional support for the hypothesis that a diet that induces a high glucose response is associated with greater CHD risk.
Keywords: EPIC study; EPIC-CVD study; cohort study; coronary heart disease; glycemic index; glycemic load.

Whole grain and dietary fiber intake and risk of colorectal cancer in the NIH-AARP Diet and Health Study cohort.
Hullings AG, Sinha R, Liao LM, Freedman ND, Graubard BI, Loftfield E.
Am J Clin Nutr. 2020 Jul 3:nqaa161. doi: 10.1093/ajcn/nqaa161. Online ahead of print.
PMID: 32619213
Background: Whole grains and other foods containing fiber are thought to be inversely related to colorectal cancer (CRC). However, whether these associations reflect fiber or fiber source remains unclear.
Objectives: We evaluated associations of whole grain and dietary fiber intake with CRC risk in the large NIH-AARP Diet and Health Study.
Methods: We used Cox proportional hazard models to estimate HRs and 95% CIs for whole grain and dietary fiber intake and risk of CRC among 478,994 US adults, aged 50-71 y. Diet was assessed using a self-administered FFQ at baseline in 1995-1996, and 10,200 incident CRC cases occurred over 16 y and 6,464,527 person-years of follow-up. We used 24-h dietary recall data, collected on a subset of participants, to evaluate the impact of measurement error on risk estimates.
Results: After multivariable adjustment for potential confounders, including folate, we observed an inverse association for intake of whole grains (HRQ5 vs.Q1 : 0.84; 95% CI: 0.79, 0.90; P-trend < 0.001), but not dietary fiber (HRQ5 vs. Q1: 0.96; 95% CI: 0.88, 1.04; P-trend = 0.40), with CRC incidence. Intake of whole grains was inversely associated with all CRC cancer subsites, particularly rectal cancer (HRQ5 vs. Q1: 0.76; 95% CI: 0.67, 0.87; P-trend < 0.001). Fiber from grains, but not other sources, was associated with lower incidence of CRC (HRQ5 vs. Q1: 0.89; 95% CI: 0.83, 0.96; P-trend < 0.001), particularly distal colon (HRQ5 vs. Q1: 0.84; 95% CI: 0.73, 0.96; P-trend = 0.005) and rectal cancer (HRQ5 vs. Q1: 0.77; 95% CI: 0.66, 0.88; P-trend < 0.001).
Conclusions: Dietary guidance for CRC prevention should focus on intake of whole grains as a source of fiber.
Keywords: colon cancer; colorectal cancer; diet; dietary fiber; epidemiology; rectal cancer; whole grains.

Vitamin D status and risk of all-cause and cause-specific mortality in a large cohort: results from the UK Biobank.
Fan X, Wang J, Song M, Giovannucci EL, Ma H, Jin G, Hu Z, Shen H, Hang D.
J Clin Endocrinol Metab. 2020 Jul 4:dgaa432. doi: 10.1210/clinem/dgaa432. Online ahead of print.
PMID: 32620963
Context: Although an inverse association between vitamin D status and mortality has been reported in observational studies, the precise association shape and optimal vitamin D status remain undetermined.
Objective: To investigate the association between vitamin D status and risk of all-cause and cause-specific mortality, and estimate optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations.
Design: Prospective cohort study.
Setting: UK Biobank.
Participants: 365,530 participants who had serum 25(OH)D measurements and no history of cardiovascular disease (CVD), cancer, or diabetes at baseline (2006-2010).
Main outcome measures: All-cause and cause-specific mortality.
Results: During a median follow-up of 8.9 (interquartile range: 8.3-9.5) years, 10,175 deaths occurred, including 1841 (18.1%) due to CVD and 5737 (56.4%) due to cancer. The multivariate analyses revealed non-linear inverse associations, with a decrease in mortality risk appearing to level off at 60 nmol/L of 25(OH)D for all-cause and CVD deaths, and at 45 nmol/L for cancer deaths. Compared to participants with 25(OH)D concentrations below the cutoffs, those with higher concentrations had a 17% lower risk for all-cause mortality (HR: 0.83, 95% CI: 0.79-0.86), 23% lower risk for CVD mortality (HR: 0.77, 95% CI: 0.68-0.86), and 11% lower risk for cancer mortality (HR: 0.89, 95% CI: 0.84-0.95).
Conclusions: Higher 25(OH)D concentrations are non-linearly associated with lower risk of all-cause, CVD, and cancer mortality. The thresholds of 45-60 nmol/L might represent an intervention target to reduce the overall risk of premature death, which needs further confirmation in large clinical trials.
Keywords: 25-hydroxyvitamin D; cancer; cardiovascular disease; mortality; vitamin D.

24-h ambulatory blood pressure versus clinic blood pressure as predictors of cardiovascular risk: a systematic review and meta-analysis of prospective studies.
Fan H, Onakpoya IJ, Heneghan CJ.
J Hypertens. 2020 Jun 25. doi: 10.1097/HJH.0000000000002500. Online ahead of print.
PMID: 32618886
Background: There is uncertainty about the usefulness of ambulatory blood pressure (ABP) in predicting cardiovascular disease (CVD) risk. Our objective was to compare the prognostic value of ABP versus clinic blood pressure (BP) in CVD.
Methods: We conducted electronic searches on Medline, Embase, and the Cochrane library up to July 2018. We included prospective longitudinal studies that compared 24-h ABP with clinic BP measurement in adults. Our main outcomes were all-cause mortality, CVD mortality, and/or CVD events. We assessed study quality based on four domains and pooled data using a random effects model of STATA for meta-analyses.
Results: We included 13 studies comprising 81 736 participants. The overall quality of the studies was moderate. Both systolic and diastolic 24-h ABP as well as systolic clinic BP significantly predicted all-cause mortality, CVD mortality, and CVD events. Systolic 24-h ABP was significantly better than systolic clinic BP at predicting future risk of CVD events: combined hazard ratio for 24-h ABP = 1.27 (95% confidence interval 1.21-1.34) per 10 mmHg increase in SBP compared with 1.13 (1.06-1.21) for clinic BP (interaction test P = 0.02). After adjusting for clinic BP, both systolic and diastolic 24-h ABP measurements were significantly better than their corresponding clinic measurements at predicting all-cause mortality, CVD mortality, and CVD events (P = 0.001 and P = 0.000, respectively).
Conclusion: Systolic 24-h ABP is a better predictor of future CVD events than systolic clinic BP. Future studies should incorporate the use of individual patient data to assess the prognostic value of 24-h ABP.

Association of Body Mass Index with the Risk of Incident Type 2 Diabetes, Cardiovascular Disease, and All-Cause Mortality: A Community-Based Prospective Study.
Bae JC, Cho NH, Kim JH, Hur KY, Jin SM, Lee MK.
Endocrinol Metab (Seoul). 2020 Jun;35(2):416-424. doi: 10.3803/EnM.2020.35.2.416. Epub 2020 Jun 24.
PMID: 32615726
Background: Type 2 diabetes and cardiovascular disease (CVD) are the most important sequelae of obesity and the leading cause of death. We evaluated the association between body mass index (BMI) and the risk of incident type 2 diabetes, CVD, and all-cause mortality in a prospective study of a Korean population.
Methods: The shapes of the associations were modeled by restricted cubic splines regression analysis. After categorizing all subjects (n=8,900) into octiles based on their BMI levels, we estimated the hazard ratio (HR) for the association of categorized BMI levels with the risk of incident CVD and type 2 diabetes using a Cox's proportional hazard analysis.
Results: The mean age of participants was 52 years and 48% were men. Of the subjects at baseline, 39.0% of men and 45.6% of women were classified as obese (BMI ≥25 kg/m2). Over a mean follow-up of 8.1 years, CVD events occurred in 509 participants; 436 died; and 1,258 subjects developed type 2 diabetes. The increased risk of incident diabetes began to be significant at BMI 23 to 24 kg/m2 in both sexes (HR, 1.8). For CVD events, the risk began to increase significantly at BMI 26 to 28 kg/m2 (HR, 1.6). We found a reverse J-shaped relationship between BMI and all-cause mortality, with an increased risk among individuals with BMI values in lower range (BMI &lt;21 kg/m2).
Conclusion: These results suggest that the BMI cut-off points for observed risk were varied depending on the diseases and that the BMI classification of obesity need to be revised to reflect differential risk of obesity-related diseases.
Keywords: Cardiovascular diseases; Diabetes mellitus; Obesity; Body mass index.

Dietary betaine intake is associated with skeletal muscle mass change over three years in middle-aged adults: the Guangzhou Nutrition and Health Study.
Long JA, Zhong RH, Chen S, Wang F, Luo Y, Lu XT, Yishake D, Chen YM, Fang AP, Zhu HL.
Br J Nutr. 2020 Jul 3:1-21. doi: 10.1017/S0007114520002433. Online ahead of print.
PMID: 32616104
A higher dietary intake or serum concentration of betaine has been associated with greater lean body mass in middle-aged and older adults. However, it remains unknown whether betaine intake is associated with age-related loss of skeletal muscle mass (SMM). We assessed the association between dietary betaine intake and relative changes in SMM after 3 year in middle-aged adults. A total of 1242 participants aged 41-60 years from the Guangzhou Nutrition and Health Study (GNHS) 2011-2013 and 2014-2017 with body composition measurements by dual-energy x-ray absorptiometry were included. A face-to-face questionnaire was used to collect general baseline information. After adjustment for potential confounders, multiple linear regression found that energy-adjusted dietary betaine intake was significantly and positively associated with relative changes (i.e., percentage loss or increase) in SMM of legs, limbs, and appendicular skeletal mass index (ASMI) over 3-year follow-up [β(SE): 0.322 (0.157), 0.309 (0.142), and 0.303 (0.145), respectively; P < 0.05]. The ANCOVA models revealed that participants in the highest betaine tertile had significantly less loss in SMM of limbs and ASMI and more increase in SMM of legs over 3 years of follow-up, compared with those in the bottom betaine tertile (all P-trend < 0.05). In conclusion, our findings suggest that elevated higher dietary betaine intake may be associated with less loss of SMM of legs, limbs and ASMI in middle-aged adults.
Keywords: dietary betaine; longitudinal change; prospective cohort study; skeletal muscle index; skeletal muscle mass.

Dietary and circulating fatty acids and ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition.
Yammine S, Huybrechts I, Biessy C, Dossus L, Aglago EK, Naudin S, Ferrari P, Weiderpass E, Tjonneland A, Hansen L, Overvad K, Romana Mancini F, Boutron-Ruault MC, Kvaskoff M, Fortner RT, Kaaks R, Schulze MB, Boing H, Trichopoulou A, Karakatsani A, La Vecchia C, Benetou V, Masala G, Krogh V, Mattiello A, Macciotta A, Gram IT, Skeie G, Quiros Garcia JR, Agudo A, Sanchez-Perez MJ, Chirlaque MD, Ardanaz E, Gil L, Sartor H, Drake I, Idahl A, Lundin EA, Aune D, Ward HA, Merritt MA, Allen NE, Gunter MJ, Chajes V.
Cancer Epidemiol Biomarkers Prev. 2020 Jul 2:cebp.1477.2019. doi: 10.1158/1055-9965.EPI-19-1477. Online ahead of print.
PMID: 32616494
Background: Fatty acids impact obesity, estrogens and inflammation, risk factors for ovarian cancer. Few epidemiological studies have investigated the association of fatty acids with ovarian cancer.
Methods: Within the European Prospective Investigation into Cancer and nutrition, 1,486 incident ovarian cancer cases were identified. Cox Proportional Hazard models with adjustment for ovarian cancer risk factors were used to estimate hazard ratios of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate odds ratios of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis.
Results: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid (Hazard Ratio comparing 5th with 1st quintileQ5-Q1=1.29; 95% CI=1.03-1.62; ptrend=0.02, q-value=0.06). Dietary intakes of n-6 linoleic acid (HRQ5-Q1=1.10; 95% CI=1.01-1.21; ptrend=0.03) and n-3 α-linolenic acid (HRQ5-Q1=1.18; 95% CI=1.05-1.34; ptrend=0.007) from deep frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (Odds Ratio comparing 3rd with 1st tertileT3-T1 = 1.39; 95% CI=0.99-1.94; ptrend=0.06) and α-linolenic acids (ORT3-T1=1.30; 95% CI=0.98-1.72; ptrend=0.06).
Conclusions: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep frying fat, may be associated with greater risk of ovarian cancer.
Impact: If causal, eliminating industrial trans fatty acids could offer a straightforward public health action for reducing ovarian cancer.

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Association of Rapid Eye Movement Sleep With Mortality in Middle-aged and Older Adults.
Leary EB, Watson KT, Ancoli-Israel S, Redline S, Yaffe K, Ravelo LA, Peppard PE, Zou J, Goodman SN, Mignot E, Stone KL.
JAMA Neurol. 2020 Jul 6. doi: 10.1001/jamaneurol.2020.2108. Online ahead of print.
PMID: 32628261
Importance: Rapid eye movement (REM) sleep has been linked with health outcomes, but little is known about the relationship between REM sleep and mortality.
Objective: To investigate whether REM sleep is associated with greater risk of mortality in 2 independent cohorts and to explore whether another sleep stage could be driving the findings.
Design, setting, and participants: This multicenter population-based cross-sectional study used data from the Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study and Wisconsin Sleep Cohort (WSC). MrOS participants were recruited from December 2003 to March 2005, and WSC began in 1988. MrOS and WSC participants who had REM sleep and mortality data were included. Analysis began May 2018 and ended December 2019.
Main outcomes and measures: All-cause and cause-specific mortality confirmed with death certificates.
Results: The MrOS cohort included 2675 individuals (2675 men [100%]; mean [SD] age, 76.3 [5.5] years) and was followed up for a median (interquartile range) of 12.1 (7.8-13.2) years. The WSC cohort included 1386 individuals (753 men [54.3%]; mean [SD] age, 51.5 [8.5] years) and was followed up for a median (interquartile range) of 20.8 (17.9-22.4) years. MrOS participants had a 13% higher mortality rate for every 5% reduction in REM sleep (percentage REM sleep SD = 6.6%) after adjusting for multiple demographic, sleep, and health covariates (age-adjusted hazard ratio, 1.12; fully adjusted hazard ratio, 1.13; 95% CI, 1.08-1.19). Results were similar for cardiovascular and other causes of death. Possible threshold effects were seen on the Kaplan-Meier curves, particularly for cancer; individuals with less than 15% REM sleep had a higher mortality rate compared with individuals with 15% or more for each mortality outcome with odds ratios ranging from 1.20 to 1.35. Findings were replicated in the WSC cohort despite younger age, inclusion of women, and longer follow-up (hazard ratio, 1.13; 95% CI, 1.08-1.19). A random forest model identified REM sleep as the most important sleep stage associated with survival.
Conclusions and relevance: Decreased percentage REM sleep was associated with greater risk of all-cause, cardiovascular, and other noncancer-related mortality in 2 independent cohorts.

Helicobacter pylori eradication for the prevention of gastric neoplasia.
Ford AC, Yuan Y, Forman D, Hunt R, Moayyedi P.
Cochrane Database Syst Rev. 2020 Jul 6;7:CD005583. doi: 10.1002/14651858.CD005583.pub3.
PMID: 32628791 Review.
Background: Gastric cancer is the third most common cause of cancer death worldwide. Individuals infected with Helicobacter pylori have a higher likelihood of developing gastric cancer than individuals who are not infected. Eradication of H. pylori in healthy asymptomatic individuals in the general population may reduce the incidence of gastric cancer, but the magnitude of this effect is unclear.
Objectives: To assess the effectiveness of eradication of H. pylori in healthy asymptomatic individuals in the general population in reducing the incidence of gastric cancer.
Search methods: We identified trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1), MEDLINE (1946 to February 2020), and EMBASE (1974 to February 2020). We handsearched reference lists from trials selected by electronic searching to identify further relevant trials. We handsearched published abstracts from conference proceedings from the United European Gastroenterology Week (published in Gut) and Digestive Disease Week (published in Gastroenterology) between 2001 and 2019. We contacted members of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Review Group and experts in the field and asked them to provide details of outstanding clinical trials and any relevant unpublished materials.
Selection criteria: We analysed randomised controlled trials comparing at least one week of H. pylori therapy with placebo or no treatment in preventing subsequent development of gastric cancer in otherwise healthy and asymptomatic H. pylori-positive adults. Trials had to follow up participants for at least two years and needed to have at least two participants with gastric cancer as an outcome. We defined gastric cancer as any gastric adenocarcinoma, including intestinal (differentiated) or diffuse (undifferentiated) type, with or without specified histology.
Data collection and analysis: We collected data on incidence of gastric cancer, incidence of oesophageal cancer, deaths from gastric cancer, deaths from any cause, and adverse effects arising due to therapy.
Main results: Six trials met all our eligibility criteria and provided extractable data in the previous version. Following our updated search, one new RCT was identified, meaning that seven trials were included in this updated review. In addition, one previously included trial provided fully published data out to 10 years, and another previously included trial provided fully published data out to 22 years of follow-up. Four trials were at low risk of bias, one trial was at unclear risk, and two trials were at high risk of bias. Six trials were conducted in Asian populations. In preventing development of subsequent gastric cancer, H. pylori eradication therapy was superior to placebo or no treatment (RR 0.54, 95% confidence interval (CI) 0.40 to 0.72, 7 trials, 8323 participants, moderate certainty evidence). Only two trials reported the effect of eradication of H. pylori on the development of subsequent oesophageal cancer. Sixteen (0.8%) of 1947 participants assigned to eradication therapy subsequently developed oesophageal cancer compared with 13 (0.7%) of 1941 participants allocated to placebo (RR 1.22, 95% CI 0.59 to 2.54, moderate certainty evidence). H. pylori eradication reduced mortality from gastric cancer compared with placebo or no treatment (RR 0.61, 95% CI 0.40 to 0.92, 4 trials, 6301 participants, moderate certainty evidence). There was little or no evidence in all-cause mortality (RR 0.97, 95% CI 0.85 to 1.12, 5 trials, 7079 participants, moderate certainty evidence). Adverse events data were poorly reported.
Authors' conclusions: We found moderate certainty evidence that searching for and eradicating H. pylori reduces the incidence of gastric cancer and death from gastric cancer in healthy asymptomatic infected Asian individuals, but we cannot necessarily extrapolate this data to other populations.

Relationships between serum uric acid concentrations, uric acid lowering medications, and vertebral fracture in community-dwelling elderly Japanese men: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Cohort Study.
Iki M, Yura A, Fujita Y, Kouda K, Tachiki T, Tamaki J, Sato Y, Moon JS, Hamada M, Kajita E, Okamoto N, Kurumatani N.
Bone. 2020 Jul 2:115519. doi: 10.1016/j.bone.2020.115519. Online ahead of print.
PMID: 32622874
Purpose: The association between serum concentrations of uric acid (UA), a potent endogenous antioxidant, and fracture risk has not yet been examined for morphometric vertebral fracture (VF). This study aimed to determine whether serum UA concentrations are associated with risks of clinical osteoporotic fracture (OPF) and morphometric VF after adjusting for confounding factors including UA-lowering medications (ULMs).
Materials and methods: A total of 2012 Japanese men aged ≥65 years completed the baseline study, which included serum UA measurement and X-ray absorptiometry-based VF assessment. We conducted a follow-up study five years later to identify incident OPFs and VFs. OPF was identified through interviews. Incident VF was defined as a vertebra which showed reduction in any of its anterior, central, or posterior heights by ≥20% during follow-up, and satisfied grade one or higher fracture criteria in Genant's method on follow-up images. Bone mineral density (BMD) of the hip and spine was measured by dual-energy X-ray absorptiometry at baseline and follow-up.
Results: We identified 45 clinical OPFs from 2000 men and 39 VFs from 1530 men during a mean follow-up period of 4.3 years. Hip BMD was significantly higher in higher UA concentration groups after adjusting for age and body mass index. A significantly decreased multivariate-adjusted odds ratio (OR) of incident VF was observed for the highest quartile groups of serum UA concentrations compared with the lowest quartile group (OR: 0.17, 95% confidence interval: 0.05-0.62). This OR remained significant after further adjusting for ULM use. ULM users in the lowest quartile group of serum UA concentrations had a significantly higher incidence rate of VF compared to the other quartile groups.
Conclusions: Higher serum UA concentrations were associated with a lower risk of morphometric VF independently of ULM in Japanese elderly men. Excessive reduction of serum UA concentrations by ULM might increase VF risk.
Keywords: Gout; Morphometric vertebral fracture; Osteoporotic fracture; Population-based prospective cohort study; Serum uric acid concentration; Uric acid lowering medication.

Estimated 24-Hour Urinary Sodium Excretion and Incident Cardiovascular Disease and Mortality Among 398 628 Individuals in UK Biobank.
Elliott P, Muller DC, Schneider-Luftman D, Pazoki R, Evangelou E, Dehghan A, Neal B, Tzoulaki I.
Hypertension. 2020 Jul 6:HYPERTENSIONAHA11914302. doi: 10.1161/HYPERTENSIONAHA.119.14302. Online ahead of print.
PMID: 32623924
We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.
Keywords: blood pressure; cardiovascular diseases; mortality; risk; sodium.

Dietary Potassium Downregulates Angiotensin-I Converting Enzyme, Renin, and Angiotensin Converting Enzyme 2.
Vio CP, Gallardo P, Cespedes C, Salas D, Diaz-Elizondo J, Mendez N.
Front Pharmacol. 2020 Jun 18;11:920. doi: 10.3389/fphar.2020.00920. eCollection 2020.
PMID: 32625100 Free PMC article.
Background: The importance of dietary potassium in health and disease has been underestimated compared with that placed on dietary sodium. Larger effort has been made on reduction of sodium intake and less on the adequate dietary potassium intake, although natural food contains much more potassium than sodium. The benefits of a potassium-rich diet are known, however, the mechanism by which it exerts its preventive action, remains to be elucidated. With the hypothesis that dietary potassium reduces renal vasoconstrictor components of the renin-angiotensin system in the long-term, we studied the effect of high potassium diet on angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2.
Methods: Sprague Dawley male rats on a normal sodium diet received normal potassium (0.9%, NK) or high potassium diet (3%, HK) for 4 weeks. Urine was collected in metabolic cages for electrolytes and urinary volume measurement. Renal tissue was used to analyze angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 expression. Protein abundance analysis was done by Western blot; gene expression by mRNA levels by RT-qPCR. Renal distribution of angiotensin-I converting enzyme and renin was done by immunohistochemistry and morphometric analysis in coded samples.
Results: High potassium diet (4 weeks) reduced the levels of renin, angiotensin-I converting enzyme, and angiotensin converting enzyme 2. Angiotensin-I converting enzyme was located in the brush border of proximal tubules and with HK diet decreased the immunostaining intensity (P < 0.05), decreased the mRNA (P < 0.01) and the protein levels (P < 0.01). Renin localization was restricted to granular cells of the afferent arteriole and HK diet decreased the number of renin positive cells (P < 0.01) and renin mRNA levels (P < 0.01). High potassium intake decreased angiotensin converting enzyme 2 gene expression and protein levels (P < 0.01).No morphological abnormalities were observed in renal tissue during high potassium diet.The reduced expression of angiotensin-I converting enzyme, renin, and angiotensin converting enzyme 2 during potassium supplementation suggest that high dietary potassium intake could modulate these vasoactive enzymes and this effects can contribute to the preventive and antihypertensive effect of potassium.
Keywords: angiotensin converting enzyme 2 (ACE2); angiotensin-I converting enzyme (ACE); dietary potassium intake; immunohistochemistry; renin.

Glycemic load, dietary fiber, and added sugar and fecundability in 2 preconception cohorts.
Willis SK, Wise LA, Wesselink AK, Rothman KJ, Mikkelsen EM, Tucker KL, Trolle E, Hatch EE.
Am J Clin Nutr. 2020 Jul 1;112(1):27-38. doi: 10.1093/ajcn/nqz312.
PMID: 31901163
Background: Glycemic load (GL) reflects the quantity and quality of carbohydrates in the diet; dietary fiber and added sugar are components of GL. Few epidemiologic studies have assessed the association between these dietary factors and fecundability.
Objective: We prospectively evaluated the associations of GL, total carbohydrates, dietary fiber, and added sugar with fecundability.
Methods: Snart Foraeldre (SF) and Pregnancy Study Online (PRESTO) are parallel web-based prospective preconception cohorts of couples attempting to conceive in Denmark and North America. At baseline, female participants completed a web-based questionnaire on demographic and lifestyle factors and a validated FFQ. We calculated GL, total carbohydrate intake, total dietary fiber, carbohydrate-to-fiber ratio, and added sugar based on reported frequencies for individual foods, standard recipes for mixed foods, and average serving sizes. The analysis included 2709 SF participants and 4268 PRESTO participants. We used proportional probabilities regression models to estimate fecundability ratios (FR) and 95% CIs.
Results: Compared with an average daily GL of ≤100, FRs for an average daily GL of ≥141 were 0.89 (95% CI: 0.73, 1.08) in SF and 0.87 (95% CI: 0.77, 0.98) in PRESTO participants. Compared with consuming ≤16 g/d of dietary fiber, FRs for consuming ≥25 g/d were 0.99 (95% CI: 0.81, 1.22) in SF and 1.06 (95% CI: 0.94, 1.20) in PRESTO. Compared with a carbohydrate-to-fiber ratio of ≤8, FRs for a ratio of ≥13 were 0.86 (95% CI: 0.73, 1.01) in SF and 0.87 (95% CI: 0.78, 0.98) in PRESTO. Compared with ≤27 g/d of added sugar, FRs for ≥72 g/d were 0.87 (95% CI: 0.68, 1.10) in SF and 0.86 (95% CI: 0.75, 0.99) in PRESTO participants.
Conclusions: Among women attempting to conceive in Denmark and North America, diets high in GL, carbohydrate-to-fiber ratio, and added sugar were associated with modestly reduced fecundability.
Keywords: added sugar; carbohydrate; dietary fiber; fecundability; glycemic load; time-to-pregnancy.
Carbohydrates and fertility: just the tip of the (fertility) iceberg.
Chavarro JE.
Am J Clin Nutr. 2020 Jul 1;112(1):1-2. doi: 10.1093/ajcn/nqaa039.
PMID: 32119733 No abstract available.

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Thyroid function and risk of all-cause and cardiovascular mortality: a prospective population-based cohort study.
Groothof D, Flores-Guerrero JL, Nolte IM, Bouma HR, Gruppen EG, Bano A, Post A, Kootstra-Ros JE, Hak E, Bos JHJ, de Borst MH, Gans ROB, Links TP, Dullaart RPF, Bakker SJL.
Endocrine. 2020 Jul 6. doi: 10.1007/s12020-020-02397-z. Online ahead of print.
PMID: 32632723
Purpose: Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality.
Methods: We included community-dwelling individuals aged 28-75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors.
Results: Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92-1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (<72 years) participants (1.31, 1.00-1.72) and decreased risk in elderly (≥72 years) (0.77, 0.56-1.06). Higher free thyroxine (FT4) was associated with all-cause mortality (1.18, 1.07-1.30) and with cardiovascular mortality only in elderly (1.61, 1.19-2.18), but not in younger participants (1.03, 0.78-1.34). Higher free triiodothyronine (FT3) was associated with all-cause mortality in females only (1.18, 1.02-1.35). FT3 was not associated with cardiovascular mortality (0.91, 0.70-1.18).
Conclusions: Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.
Keywords: Biomarker; Cohort study; Euthyroid; General population; Mortality risk; Thyroid function.

Association of Statin Use With All-Cause and Cardiovascular Mortality in US Veterans 75 Years and Older.
Orkaby AR, Driver JA, Ho YL, Lu B, Costa L, Honerlaw J, Galloway A, Vassy JL, Forman DE, Gaziano JM, Gagnon DR, Wilson PWF, Cho K, Djousse L.
JAMA. 2020 Jul 7;324(1):68-78. doi: 10.1001/jama.2020.7848.
PMID: 32633800
Importance: Data are limited regarding statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults 75 years and older.
Objective: To evaluate the role of statin use for mortality and primary prevention of ASCVD in veterans 75 years and older.
Design, setting, and participants: Retrospective cohort study that used Veterans Health Administration (VHA) data on adults 75 years and older, free of ASCVD, and with a clinical visit in 2002-2012. Follow-up continued through December 31, 2016. All data were linked to Medicare and Medicaid claims and pharmaceutical data. A new-user design was used, excluding those with any prior statin use. Cox proportional hazards models were fit to evaluate the association of statin use with outcomes. Analyses were conducted using propensity score overlap weighting to balance baseline characteristics.
Exposures: Any new statin prescription.
Main outcomes and measures: The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included a composite of ASCVD events (myocardial infarction, ischemic stroke, and revascularization with coronary artery bypass graft surgery or percutaneous coronary intervention).
Results: Of 326 981 eligible veterans (mean [SD] age, 81.1 [4.1] years; 97% men; 91% white), 57 178 (17.5%) newly initiated statins during the study period. During a mean follow-up of 6.8 (SD, 3.9) years, a total 206 902 deaths occurred including 53 296 cardiovascular deaths, with 78.7 and 98.2 total deaths/1000 person-years among statin users and nonusers, respectively (weighted incidence rate difference [IRD]/1000 person-years, -19.5 [95% CI, -20.4 to -18.5]). There were 22.6 and 25.7 cardiovascular deaths per 1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -3.1 [95 CI, -3.6 to -2.6]). For the composite ASCVD outcome there were 123 379 events, with 66.3 and 70.4 events/1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, -4.1 [95% CI, -5.1 to -3.0]). After propensity score overlap weighting was applied, the hazard ratio was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers.
Conclusions and relevance: Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all-cause and cardiovascular mortality. Further research, including from randomized clinical trials, is needed to more definitively determine the role of statin therapy in older adults for primary prevention of ASCVD.

A Comparison of Mortality-related Risk Factors of COVID-19, SARS, and MERS: A Systematic Review and Meta-analysis.
Lu L, Zhong W, Bian Z, Li Z, Zhang K, Liang B, Zhong Y, Hu M, Lin L, Liu J, Lin X, Huang Y, Jiang J, Yang X, Zhang X, Huang Z.
J Infect. 2020 Jul 4:S0163-4453(20)30460-6. doi: 10.1016/j.jinf.2020.07.002. Online ahead of print.
PMID: 32634459 Review.
Objective: Coronavirus Disease 2019 (COVID-19) is a pandemic. This systematic review compares mortality risk factors including clinical, demographic and laboratory features of COVID-19, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The aim is to provide new strategies for COVID-19 prevention and treatment.
Methods: We performed a systematic review with meta-analysis, using five databases to compare the predictors of death for COVID-19, SARS and MERS. A random-effects model meta-analysis calculated odds ratios (OR) and 95% confidence intervals (95% CI).
Results: 845 articles up through 11/4/2020 were retrieved, but only 28 studies were included in this meta-analysis. The results showed that males had a higher likelihood of death than females (OR = 1.82, 95% CI 1.56-2.13). Age (OR = 7.86, 95% CI 5.46-11.29), diabetes comorbidity (OR = 3.73, 95% CI 2.35-5.90), chronic lung disease (OR = 3.43, 95% CI 1.80-6.52) and hypertension (OR = 3.38, 95% CI 2.45-4.67) were the mortality risk factors. The laboratory indicators lactic dehydrogenase (OR = 37.52, 95% CI 24.68-57.03), C-reactive protein (OR = 12.11, 95% CI 5.24-27.98), and neutrophils (OR = 17.56, 95% CI 10.67-28.90) had stronger correlations with COVID-19 mortality than with SARS or MERS mortality. Consolidation and ground-glass opacity imaging features were similar among COVID-19, SARS, and MERS patients.
Conclusions: COVID-19's mortality factors are similar to those of SARS and MERS. Age and laboratory indicators could be effective predictors of COVID-19 mortality outcomes.
Keywords: COVID-19; MERS; Meta-analysis; Mortality; Risk factors; SARS.

Effect of cinnamon on migraine attacks and inflammatory markers: A randomized double-blind placebo-controlled trial.
Zareie A, Sahebkar A, Khorvash F, Bagherniya M, Hasanzadeh A, Askari G.
Phytother Res. 2020 Jul 7. doi: 10.1002/ptr.6721. Online ahead of print.
PMID: 32638445
Migraine is the most common type of primary headaches. Increased levels of interleukin-6 (IL-6), calcitonin-gene-related peptide (CGRP) and nitric oxide (NO) lead to inflammation and neurogenic pain. Cinnamon has anti-inflammatory and neuroprotective properties. Thus, the aim of this study was to assess the effect of cinnamon on migraine attacks and inflammatory status. Fifty patients with migraine were randomized to receive either cinnamon powder (three capsules/day each containing 600 mg of cinnamon) or three placebo capsules/day each containing 100 mg of corn starch (control group) for 2 months. Serum levels of IL-6, CGRP and NO were measured at baseline and at the end of the study. The frequency, severity and duration of pain attacks were also recorded using questionnaire. Serum concentrations of IL-6 and NO were significantly reduced in the cinnamon group compared with the control group (p < .05). However, serum levels of CGRP remained unchanged in both groups. The frequency, severity and duration of migraine attacks were significantly decreased in the cinnamon group compared with the control group. Cinnamon supplementation reduced inflammation as well as frequency, severity and duration of headache in patients with migraine. Cinnamon could be regarded as a safe supplement to relieve pain and other complications of migraine.
Keywords: calcitonin-gene-related; cinnamon; interleukin-6; migraine; nitric oxide.

Dietary Fatty Acids and Colorectal Cancer Risk in Men: A Report from the Shanghai Men's Health Study and a Meta-Analysis.
Nguyen S, Li H, Yu D, Cai H, Gao J, Gao Y, Luu H, Tran H, Xiang YB, Zheng W, Shu XO.
Int J Cancer. 2020 Jul 7. doi: 10.1002/ijc.33196. Online ahead of print.
PMID: 32638381
Evidence from animal models suggests that dietary fatty acids have both anticancer and tumor-promoting effects. Whether dietary fatty acids are associated with colorectal cancer (CRC) in humans remains inconclusive. We investigated associations between dietary fatty acids and risk of CRC among 59,986 men who participated in the Shanghai Men's Health Study (SMHS), an ongoing population-based prospective cohort study. We identified 876 incident CRC cases in the SMHS during a mean follow-up of 9.8 years. Associations between dietary fatty acid intake and CRC risk were evaluated by Cox proportional hazard regression analyses. Consumption of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids was not significantly associated with CRC risk. Multivariate hazard ratios (HR) and respective 95% confidence intervals (CI) for quartile 4 vs. quartile 1 were 0.92 (0.74-1.14; Ptrend =0.47) for SFA, 0.95 (0.79-1.16; Ptrend =0.74) for MUFA and 1.18 (0.95-1.46; Ptrend =0.21) for PUFA. No significant association was found for total n-6 PUFA and total n-3 PUFA. Additionally, we performed a meta-analysis to summarize results from the present study and 28 reports from 26 additional cohorts, which supported the overall null association between dietary fatty acid intake and CRC risk among men. Docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA) were associated with 11-12% reduced risk, and linoleic acid (LA) a 19% increased risk, of CRC in the meta-analysis of combined sexes. In conclusion, this population-based prospective study and meta-analysis of cohort studies found little evidence that dietary fatty acid intake was associated with risk of CRC in men.
Keywords: Colorectal cancer; Dietary fatty acid; Meta-analysis; Prospective cohort study.

Hypertension and changes in cognitive function in a Mediterranean population.
Razquin C, Menéndez-Acebal C, Cervantes S, Martínez-González MA, Vázquez-Ruiz Z, Martínez-González J, Guillén-Grima F, Toledo E.
Nutr Neurosci. 2020 Jul 7:1-9. doi: 10.1080/1028415X.2020.1788773. Online ahead of print.
PMID: 32635835
Background: Severe cognitive decline is one of the major public health problems in developed countries. Finding modifiable risk factors could become essential to develop strategies to prevent or delay dementia progression and stop its rising incidence. Objective: Our aim was to investigate the association between hypertension and cognitive function and to assess whether better adherence to the Mediterranean diet may modify this association. Methods: A subsample of 764 participants from the 'Seguimiento Universidad de Navarra' (SUN) cohort older than 55 years was evaluated with the Spanish Telephone Interview for Cognitive Status (TICS-m) at two-time points, separated by 6 years. Multivariable-adjusted linear regression models were used to prospectively assess the association between hypertension -also according to adherence to the Mediterranean diet- and 6-y changes in cognitive function. Results: The adjusted between-group difference in the 6-year change of the TICS-m score between hypertensive participants and their non-hypertensive counterparts was -0.36 (95% CI -0.70, -0.02). This association was stronger among participants with a lower adherence to the Mediterranean diet [-0.62 (95% CI: -1.09, -0.15)] but the differences between hypertensive and non-hypertensive participants were no longer significant among participants with a higher baseline adherence to the Mediterranean diet. Conclusion: In this Mediterranean cohort, hypertension was inversely associated with cognitive function, but an attenuation of this detrimental association by a moderate/high adherence to the Mediterranean diet was suggested.
Keywords: Cognitive decline; Mediterranean diet; SUN cohort; cognitive function; cognitive screening test; dementia; hypertension; primary prevention.

C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling.
Bai J, Farias-Pereira R, Zhang Y, Jang M, Park Y, Kim KH.
Biofactors. 2020 Jul 8. doi: 10.1002/biof.1666. Online ahead of print.
PMID: 32639091
Overly active acyl-coenzyme A: cholesterol acyltransferases (ACATs) are known to contribute to the development of atherosclerosis, cancer cell proliferation and de novo lipogenesis. However, the role of ACAT in systemic lipid metabolism and its consequence of aging is unknown. Using avasimibe, a clinically proven ACAT inhibitor, and mboa-1 mutant strain, a homologous to mammalian ACAT, herein, we found that Ava treatment and mboa-1 mutant exhibited a decreased fat accumulation during feeding and increased lipolysis with extended lifespan of C. elegans during fasting. Our study highlights the essential role of ACAT inhibitor and mboa-1 in fat mobilization and the survival of C. elegans in fasting through the modulation of the genes involved in lipolysis and insulin/IGF-1 signaling.
Keywords: C. elegans; MBOA-1; avasimibe; fasting; lifespan.

Impact of Influenza Vaccination on Mortality in the Oldest Old: A Propensity Score-Matched Cohort Study.
Walzer P, Estève C, Barben J, Menu D, Cuenot C, Manckoundia P, Putot A.
Vaccines (Basel). 2020 Jul 3;8(3):E356. doi: 10.3390/vaccines8030356.
PMID: 32635210
Influenza remains a major cause of illness and death in geriatric populations. While the influenza vaccine has successfully reduced morbidity and mortality, its effectiveness is suspected to decrease with age. The aim of this study was to assess the impact of influenza vaccination on all-cause mortality in very old ambulatory subjects. We conducted a prospective cohort study from 1 July 2016 to 31 June 2017 in a large unselected ambulatory population aged over 80 years. We compared all-cause mortality in vaccinated versus unvaccinated subjects after propensity-score matching, to control for age, sex and comorbidities. Among the 9149 patients included, with mean age 86 years, 4380 (47.9%) were vaccinated against influenza. In total, 5253 (57.4%) had at least one chronic disease. The most commonly vaccinated patients were those with chronic respiratory failure (76.3%) and the least commonly vaccinated were those suffering from Parkinson's disease (28.5%). Overall, 2084 patients (22.8%) died during the study. After propensity score matching, the mortality was evaluated at 20.9% in the vaccinated group and 23.9% in the unvaccinated group (OR = 0.84 [0.75-0.93], p = 0.001). This decrease in mortality in the vaccinated group persisted whatever the age and Charlson Comorbidity index. In conclusion, nearly a half of this ambulatory elderly population received Influenza vaccine. After adjustment on comorbidities, influenza vaccination was associated with a significant decrease in all-cause mortality, even in the eldest multimorbid population. Improving immunization coverage in this frail older population is urgently needed.
Keywords: comorbidities; elderly; flu; influenza; influenza vaccination; mortality; multimorbidity.

Nutritional Aspects of Spermidine.
Madeo F, Hofer SJ, Pendl T, Bauer MA, Eisenberg T, Carmona-Gutierrez D, Kroemer G.
Annu Rev Nutr. 2020 Jul 7. doi: 10.1146/annurev-nutr-120419-015419. Online ahead of print.
PMID: 32634331
Natural polyamines (spermidine and spermine) are small, positively charged molecules that are ubiquitously found within organisms and cells. They exert numerous (intra)cellular functions and have been implicated to protect against several age-related diseases. Although polyamine levels decline in a complex age-dependent, tissue-, and cell type-specific manner, they are maintained in healthy nonagenarians and centenarians. Increased polyamine levels, including through enhanced dietary intake, have been consistently linked to improved health and reduced overall mortality. In preclinical models, dietary supplementation with spermidine prolongs life span and health span. In this review, we highlight salient aspects of nutritional polyamine intake and summarize the current knowledge of organismal and cellular uptake and distribution of dietary (and gastrointestinal) polyamines and their impact on human health. We further summarize clinical and epidemiological studies of dietary polyamines. 

Integrated metabolomics reveals altered lipid metabolism in adipose tissue in a model of extreme longevity.
Darcy J, Fang Y, McFadden S, Lynes MD, Leiria LO, Dreyfuss JM, Bussburg V, Tolstikov V, Greenwood B, Narain NR, Kiebish MA, Bartke A, Tseng YH.
Geroscience. 2020 Jul 6. doi: 10.1007/s11357-020-00221-0. Online ahead of print.
PMID: 32632845
Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally long-lived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice. We observed distinct lipid profiles in brown versus white adipose tissue of Ames dwarf mice that are consistent with increased thermogenesis and insulin sensitivity, such as increased cardiolipin and decreased ceramide concentrations. Moreover, we identified 5-hydroxyeicosapentaenoic acid (5-HEPE), an ω-3 fatty acid metabolite, to be increased in Ames dwarf brown adipose tissue (BAT), as well as in circulation. Importantly, 5-HEPE is increased in other models of BAT activation and is negatively correlated with body weight, insulin resistance, and circulating triglyceride concentrations in humans. Together, these data represent a novel lipid signature of adipose tissue in a mouse model of extreme longevity.
Keywords: Aging; Ames dwarf; Beige adipose tissue; Brown adipose tissue; Lipidomics; Metabolomics; Thermogenesis.

Health benefits of xylitol.
Gasmi Benahmed A, Gasmi A, Arshad M, Shanaida M, Lysiuk R, Peana M, Pshyk-Titko I, Adamiv S, Shanaida Y, Bjørklund G.
Appl Microbiol Biotechnol. 2020 Jul 7. doi: 10.1007/s00253-020-10708-7. Online ahead of print.
PMID: 32638045 Review.
Many diseases, including caries, chronic inflammatory diseases, diabetes, and obesity, are associated with uncontrolled sugar consumption. Artificial sweeteners are commonly used in food and pharmaceutical industries as sugar substitutes for the prevention of several dental and body diseases; they also have a favorable impact on body weight as they may help to restrict simple sugar consumption. Xylitol is a sugar alcohol that is commonly used as a sweetener. It can be found naturally or artificially prepared mainly from plant materials chemically or by fermentation of hemicelluloses from agricultural biomass by yeast or bacteria strains. This polyol has a significant antiplaque effect on teeth surface and can reduce the gingival inflammation; it is being used as a preventive agent for dental caries due to decreasing the growth levels of pathogenic Streptococcus mutans and Streptococcus sangui at the very early stages. Xylitol can bind with calcium ion leading to consequent remineralization of teeth enamel; it is also able to prevent osteoporosis. This polyol can treat respiratory tract and middle ear diseases due to its antibacterial and anti-inflammatory potential and prevent some diseases which cannot be cured through antibiotics or surgery. Xylitol can reduce constipation, diabetes, obesity, and other body syndromes or illnesses; it has also revealed its stimulating effect on digestion and immune system. However, it can produce some side effects such as irritable bowel syndrome, diarrhea, nephrolithiasis, etc., when consumed in excessive amounts. Different vehicles are used for delivering the xylitol into the human body, but chewing gums occupy a leading position. The present review is devoted to comprehensive analyses of the positive and negative effects of this polyol on human health.Key Points• The health benefits of xylitol are not limited to oral hygiene.• Xylitol efficiently stimulates the immune system, digestion, lipid and bone metabolism.• Xylitol helps in glycemic and obesity control; reduces ear and respiratory infections.• Xylitol treats diseases that cannot be cured through antibiotics or by surgery.
Keywords: Artificial sweetener; Caries; Health care; Metabolic disease; Oral microbiota; Preventive effect; Xylitol.

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Association of Major Food Sources of Fructose-Containing Sugars With Incident Metabolic Syndrome: A Systematic Review and Meta-analysis.
Semnani-Azad Z, Khan TA, Blanco Mejia S, de Souza RJ, Leiter LA, Kendall CWC, Hanley AJ, Sievenpiper JL.
JAMA Netw Open. 2020 Jul 1;3(7):e209993. doi: 10.1001/jamanetworkopen.2020.9993.
PMID: 32644139
Importance: Sugar-sweetened beverages (SSBs) are associated with increased risk of metabolic syndrome (MetS). However, the role of other important food sources of fructose-containing sugars in the development of MetS remains unclear.
Objective: To examine the association of major food sources of fructose-containing sugars with incident MetS.
Data sources: MEDLINE, Embase, and Cochrane Library were searched from database inception to March 24, 2020, in addition to manual searches of reference lists from included studies using the following search terms: sugar-sweetened beverages, fruit drink, yogurt, metabolic syndrome, and prospective study.
Study selection: Inclusion criteria included prospective cohort studies of 1 year or longer that investigated the association of important food sources of fructose-containing sugars with incident MetS in participants free of MetS at the start of the study.
Data extraction and synthesis: Study quality was assessed using the Newcastle-Ottawa Scale. Extreme quantile risk estimates for each food source with MetS incidence were pooled using a random-effects meta-analysis. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Dose-response analyses were performed using a 1-stage linear mixed-effects model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.
Main outcomes and measures: Pooled risk ratio (RR) of incident MetS (pairwise and dose response).
Results: Thirteen prospective cohort studies (49 591 participants [median age, 51 years; range, 6-90 years]; 14 205 with MetS) that assessed 8 fructose-containing foods and MetS were included. An adverse linear dose-response association for SSBs (RR for 355 mL/d, 1.14; 95% CI, 1.05-1.23) and an L-shaped protective dose-response association for yogurt (RR for 85 g/d, 0.66; 95% CI, 0.58-0.76) and fruit (RR for 80 g/d, 0.82; 95% CI, 0.78-0.86) was found. Fruit juices (mixed and 100%) had a U-shaped dose-response association with protection at moderate doses (mixed fruit juice: RR for 125 mL/d, 0.58; 95% CI, 0.42-0.79; 100% fruit juice: RR for 125 mL/d, 0.77; 95% CI, 0.61-0.97). Honey, ice cream, and confectionary had no association with MetS incidence. The certainty of the evidence was moderate for SSBs, yogurt, fruit, mixed fruit juice, and 100% fruit juice and very low for all other food sources.
Conclusions and relevance: The findings of this meta-analysis suggest that the adverse association of SSBs with MetS does not extend to other food sources of fructose-containing sugars, with a protective association for yogurt and fruit throughout the dose range and for 100% fruit juice and mixed fruit juices at moderate doses. Therefore, current policies and guidelines on the need to limit sources of free sugars may need to be reexamined.

Effects of α-linolenic acid intake on blood lipid profiles:a systematic review and meta-analysis of randomized controlled trials.
Yue H, Qiu B, Jia M, Liu W, Guo XF, Li N, Xu ZX, Du FL, Xu T, Li D.
Crit Rev Food Sci Nutr. 2020 Jul 9:1-17. doi: 10.1080/10408398.2020.1790496. Online ahead of print.
PMID: 32643951
To investigate the effect of ALA intake on blood lipid profiles, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein (VLDL-C) and ratio of TC to HDL-C. We systematically searched randomized controlled trials of ALA intervention on PubMed, Embase, Cochrane library and related references up to March 2018. The final values were calculated as weighted mean difference (WMD) by using a random effects model. Subgroup analysis and meta-regression were used to explore the source of heterogeneity. Generalized least square was performed for dose-response analysis. Forty-seven studies with 1305 individuals in the ALA arm and 1325 individuals in the control arm were identified. Compared with control group, dietary intake of ALA significantly reduced the concentrations of TG (WMD -0.101 mmol/L; 95% CI: -0.158 to -0.044 mmol/L; P = 0.001), TC (WMD -0.140 mmol/L; 95% CI: -0.224 to -0.056 mmol/L; P = 0.001), LDL-C (WMD -0.131 mmol/L; 95% CI: -0.191 to -0.071 mmol/L; P < 0.001), VLDL-C (WMD -0.121 mmol/L; 95% CI: -0.170 to -0.073 mmol/L; P < 0.001), TC/HDL-C ratio (WMD -0.165 mmol/L; 95% CI: -0.317 to -0.013 mmol/L; P = 0.033) and LDL-C/HDL-C ratio (WMD -0.158 mmol/L; 95% CI: -0.291 to -0.025 mmol/L; P = 0.02). There is no effect of ALA intake on HDL-C (WMD 0.008 mmol/L; 95% CI: -0.018 to 0.034 mmol/L; P = 0.541). Dose-response analysis indicated that 1 g per day increment of ALA was associated with a 0.0016 mmol/L, 0.0071 mmol/L, 0.0015 and 0.0061 mmol/L reduction in TG (95% CI: -0.0029 to -0.0002 mmol/L), TC (95% CI: -0.0085 to -0.0058 mmol/L), HDL-C (95% CI: -0.0020 to -0.0011 mmol/L) and LDL-C (95% CI: -0.0073 to -0.0049 mmol/L) levels, respectively. The effects of ALA intake on TG, TC and LDL-C concentrations were more obvious among Asian participants, and also more obvious on patients with hyperlipidemia or hyperglycemia compared to healthy individuals. Dietary ALA intervention improves blood lipid profiles by decreasing levels of TG, TC, LDL and VLDL-C. Our findings add to the evidence that increasing ALA intake could potentially prevent risk of cardiovascular diseases.
Keywords: Alpha-linolenic acid; blood lipid profiles; meta-analysis; randomized controlled trials.

The association of blood pressure with physical frailty and cognitive function in community-dwelling septuagenarians, octogenarians, and nonagenarians: the SONIC study.
Kabayama M, Kamide K, Gondo Y, Masui Y, Nakagawa T, Ogawa M, Yasumoto S, Ryuno H, Akagi Y, Kiyoshige E, Godai K, Sugimoto K, Akasaka H, Takami Y, Takeya Y, Yamamoto K, Ikebe K, Inagaki H, Martin P, Arai Y, Ishizaki T, Rakugi H; SONIC study group.
Hypertens Res. 2020 Jul 8. doi: 10.1038/s41440-020-0499-9. Online ahead of print.
PMID: 32641853
We investigated the association of systolic blood pressure (SBP) level with physical frailty and cognitive function in community-dwelling older Japanese. Using the 'Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians' survey as the baseline, we performed a cross-sectional analysis of people aged 70 ± 1 (n = 1000), 80 ± 1 (n = 978), and 90 ± 1 (n = 272) years. Medical histories and medications were collected via interviews conducted by medical professionals. Blood pressure (BP), grip strength, gait speed, and cognitive function were examined on site. Trend analysis and multiple regression analysis were used to determine the association of the SBP level with physical frailty and cognitive function. The principal finding was that the association of SBP with physical frailty and cognitive function varied depending on characteristics such as age, physical and cognitive function, and antihypertensive medication use. A lower SBP level was associated with a higher prevalence of physical frailty only among 80-year-olds who were on antihypertensive medication. A significant association was found between higher SBP and lower cognitive function among 70-year-olds, while among 90-year-olds, the opposite was found. No association was found among participants who were 80 years old or among participants of all ages without antihypertensive medication. Our finding that an inverted association between SBP and geriatric syndrome exists suggests that the treatment of older patients must be individualized to prevent geriatric syndrome.
Keywords: Blood pressure; Cognitive function; Community-dwelling older population; Hypertension; Physical frailty.

Intake of whole grain foods and risk of type 2 diabetes: results from three prospective cohort studies.
Hu Y, Ding M, Sampson L, Willett WC, Manson JE, Wang M, Rosner B, Hu FB, Sun Q.
BMJ. 2020 Jul 8;370:m2206. doi: 10.1136/bmj.m2206.
PMID: 32641435
Objective: To examine the associations between the intake of total and individual whole grain foods and the risk of type 2 diabetes.
Design: Prospective cohort studies.
Setting: Nurses' Health Study (1984-2014), Nurses' Health Study II (1991-2017), and Health Professionals Follow-Up Study (1986-2016), United States.
Participants: 158 259 women and 36 525 men who did not have type 2 diabetes, cardiovascular disease, or cancer at baseline.
Main outcome measures: Self-reports of incident type 2 diabetes by participants identified through follow-up questionnaires and confirmed by a validated supplementary questionnaire.
Results: During 4 618 796 person years of follow-up, 18 629 participants with type 2 diabetes were identified. Total whole grain consumption was categorized into five equal groups of servings a day for the three cohorts. After adjusting for lifestyle and dietary risk factors for diabetes, participants in the highest category for total whole grain consumption had a 29% (95% confidence interval 26% to 33%) lower rate of type 2 diabetes compared with those in the lowest category. For individual whole grain foods, pooled hazard ratios (95% confidence intervals) for type 2 diabetes in participants consuming one or more servings a day compared with those consuming less than one serving a month were 0.81 (0.77 to 0.86) for whole grain cold breakfast cereal, 0.79 (0.75 to 0.83) for dark bread, and 1.08 (1.00 to 1.17) for popcorn. For other individual whole grains with lower average intake levels, comparing consumption of two or more servings a week with less than one serving a month, the pooled hazard ratios (95% confidence intervals) were 0.79 (0.75 to 0.83) for oatmeal, 0.88 (0.82 to 0.94) for brown rice, 0.85 (0.80 to 0.90) for added bran, and 0.88 (0.78 to 0.98) for wheat germ. Spline regression showed a non-linear dose-response association between total whole grain intake and the risk of type 2 diabetes where the rate reduction slightly plateaued at more than two servings a day (P<0.001 for curvature). For whole grain cold breakfast cereal and dark bread, the rate reduction plateaued at about 0.5 servings a day. For consumption of popcorn, a J shaped association was found where the rate of type 2 diabetes was not significantly raised until consumption exceeded about one serving a day. The association between higher total whole grain intake and lower risk of type 2 diabetes was stronger in individuals who were lean than in those who were overweight or obese (P=0.003 for interaction), and the associations did not vary significantly across levels of physical activity, family history of diabetes, or smoking status.
Conclusion: Higher consumption of total whole grains and several commonly eaten whole grain foods, including whole grain breakfast cereal, oatmeal, dark bread, brown rice, added bran, and wheat germ, was significantly associated with a lower risk of type 2 diabetes. These findings provide further support for the current recommendations of increasing whole grain consumption as part of a healthy diet for the prevention of type 2 diabetes.

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Dietary and lifestyle factors for primary prevention of nephrolithiasis: a systematic review and meta-analysis.
Lin BB, Lin ME, Huang RH, Hong YK, Lin BL, He XJ.
BMC Nephrol. 2020 Jul 11;21(1):267. doi: 10.1186/s12882-020-01925-3.
PMID: 32652950
Background: Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis.
Methods: PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible.
Results: Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27-1.52), dietary sodium (1.38, 1.21-1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51-0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64-0.75), alcohol (0.69, 0.56-0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76-0.90), and potassium. Vitamin D (1.22, 1.01-1.49) and calcium (1.16, 1.00-1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk.
Conclusions: Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.
Keywords: Diet; Epidemiology; Meta-analysis; Nephrolithiasis; Obesity; Systematic review.

Association of dietary nitrate intake with retinal microvascular structure in older adults.
Gopinath B, Liew G, Lewis JR, Blekkenhorst LC, Bondonno C, Burlutsky G, Hodgson JM, Mitchell P.
Eur J Nutr. 2020 Aug;59(5):2057-2063. doi: 10.1007/s00394-019-02055-9. Epub 2019 Jul 15.
PMID: 31309281

Association of dietary nitrate intake with retinal microvascular structure in older adults.
Gopinath B, Liew G, Lewis JR, Blekkenhorst LC, Bondonno C, Burlutsky G, Hodgson JM, Mitchell P.
Eur J Nutr. 2020 Aug;59(5):2057-2063. doi: 10.1007/s00394-019-02055-9. Epub 2019 Jul 15.
PMID: 31309281
Purpose: Existing research suggests that changes to retinal vascular caliber reflect nitric oxide (NO)-dependent endothelial dysfunction. Dietary nitrate is an important source of NO; however, studies on the link between dietary nitrate intake and retinal microvasculature are lacking. We aimed to assess the cross-sectional association between intake of dietary nitrate (from vegetable and non-vegetable sources) and retinal arteriolar and venular caliber among older adults.
Methods: Participants from the Blue Mountains Eye Study aged 49+ years with complete data at baseline on diet and retinal vessel measures were analyzed (n = 2813). Dietary intake was assessed using a validated semi-quantitative food-frequency questionnaire. Nitrate intake from vegetable and non-vegetable sources was estimated using a validated comprehensive database and other published data where necessary. Fundus photographs were taken and retinal vascular caliber measured using validated computer-assisted techniques and summarized.
Results: Participants in the lowest versus highest tertile of vegetable nitrate intake had significantly narrower retinal arterioles: 186.2 ± 0.48 versus 187.6 ± 0.48 µm (multivariable-adjusted p = 0.04). After multivariable adjustment, each 10-unit higher intake of total nitrate and vegetable nitrate was associated with 0.089 ± 0.004 and 0.090 ± 0.004 µm wider retinal arteriolar caliber, respectively, both p = 0.03. Each 10-unit higher vegetable nitrate intake was associated with 0.092 ± 0.005 µm narrower retinal venules (p = 0.05).
Conclusion: Intake of dietary nitrate, particularly from vegetable sources, was associated with beneficial variations in both retinal arteriolar and venular caliber among older adults. Further research into associations between dietary nitrate and the retinal microvasculature could allow for greater understanding and possible prevention of clinical cardiovascular events.
Keywords: Blue Mountains Eye Study; Nitrate; Nitric oxide; Older adults; Retinal vascular caliber

Exercising your mind.
Ansere VA, Freeman WM.
Science. 2020 Jul 10;369(6500):144-145. doi: 10.1126/science.abc8830.
PMID: 32646988 No abstract available.
Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain.
Horowitz AM, Fan X, Bieri G, Smith LK, Sanchez-Diaz CI, Schroer AB, Gontier G, Casaletto KB, Kramer JH, Williams KE, Villeda SA.
Science. 2020 Jul 10;369(6500):167-173. doi: 10.1126/science.aaw2622.
PMID: 32646997
Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

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Overweight and obesity could not predicate all-cause mortality in metabolically healthy individuals.
Tian Q, Wang A, Zuo Y, Chen S, Hou H, Wang W, Wu S, Wang Y.
JCI Insight. 2020 Jul 14:136982. doi: 10.1172/jci.insight.136982. Online ahead of print.
PMID: 32663197
Background: Metabolically healthy obesity (MHO) and metabolically healthy overweight (MH-OW) have been suggested to be an important and emerging phenotype with an increased risk of cardiovascular disease (CVD). However, whether MHO and MH-OW are associated with all-cause mortality remains inconsistent.
Methods: The association of MHO and MH-OW and all-cause mortality was determined in China community-based prospective cohort study (Kailuan Study) including 93,272 adults at baseline. Data were analyzed from 2006 to 2017. Participants were categorized into six mutually exclusive groups according to the body mass index (BMI) and metabolic syndrome (MetS) status. The primary outcome is all-cause death, whereas accidental deaths were excluded.
Results: During a median follow-up of 11.04 years (interquartile range: 10.74-11.22 years), 8,977 deaths occurred. Compared to healthy participants with normal BMI (MH-NW), MH-OW had lowest risk of all-cause mortality (multivariate-adjusted hazard ratio [aHR]: 0.926; 95% confidence interval [CI]: 0.861 to 0.997), whereas there was no increased or decreased risk for MHO (aHR: 1.009; 95% CI: 0.886 to 1.148). Stratified analyses and sensitivity analyses further validated that nonsignificant association between MHO and all-cause mortality.
Conclusions: Overweight and obesity do not predicate increased risk of all-cause mortality in metabolic healthy Chinese individuals.
Keywords: Epidemiology; Medical statistics; Metabolism; Obesity.

Effects of Dietary Carbohydrate Content on Circulating Metabolic Fuel Availability in the Postprandial State.
Shimy KJ, Feldman HA, Klein GL, Bielak L, Ebbeling CB, Ludwig DS.
J Endocr Soc. 2020 May 26;4(7):bvaa062. doi: 10.1210/jendso/bvaa062. eCollection 2020 Jul 1.
PMID: 32666008 Free PMC article.
Context: According to the carbohydrate-insulin model of obesity, an elevated insulin-to-glucagon ratio in response to a high-carbohydrate diet directs metabolic fuels toward storage, resulting in lower circulating energy.
Objective: To determine differences in total circulating energy post-meal related to dietary carbohydrate.
Design: Ancillary study within the Framingham State Food Study.
Setting: University community.
Participants: 29 adults (aged 20 to 65 years) with overweight or obesity (body mass index ≥25 kg/m2).
Intervention: After achieving 10% to 14% weight loss on a run-in diet, participants were randomized to weight-loss-maintenance test diets varying in carbohydrate content (high-carbohydrate, 60% of total energy, n = 11; moderate-carbohydrate, 40%, n = 8; low-carbohydrate, 20%, n = 10) and controlled for protein (20%). During 24-hour metabolic ward admissions between 10 and 15 weeks on the test diets, metabolic fuels and hormones were measured.
Main outcome measure: Energy availability (EA) based on energy content of blood glucose, beta-hydroxybutyrate, and free fatty acids, in the late postprandial period (180 to 300 minutes). Insulin at 30 minutes into the test meal (Meal Insulin-30) was measured as an effect modifier.
Results: Insulin-to-glucagon ratio was 7-fold higher in participants on the high- vs low-carbohydrate diet (2.5 and 0.36, respectively). Late postprandial EA was 0.58 kcal/L lower on the high- vs low-carbohydrate diet (P < 0.0001), primarily related to suppression of free fatty acids. Early postprandial EA (30 to 180 minutes) declined fastest in the high-carbohydrate group, and Meal Insulin-30 modified this diet effect.
Conclusions: During weight-loss maintenance on a high-carbohydrate diet, late postprandial EA is reduced, consistent with the carbohydrate-insulin model.
Keywords: beta-hydroxybutyrate; carbohydrate; fatty acids; glucose; insulin; obesity.

The Effect of Lactobacillus acidophilus YT1 (MENOLACTO) on Improving Menopausal Symptoms: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.
Lim EY, Lee SY, Shin HS, Lee J, Nam YD, Lee DO, Lee JY, Yeon SH, Son RH, Park CL, Heo YH, Kim YT.
J Clin Med. 2020 Jul 9;9(7):E2173. doi: 10.3390/jcm9072173.
PMID: 32660010
This study evaluated the efficacy of Lactobacillus acidophilus YT1 (MENOLACTO) for alleviating menopausal symptoms. This study was a multi-center, randomized, double-blinded, placebo-controlled clinical trial involving female subjects (ages: 40-60 years) with menopausal symptoms and a Kupperman index (KMI) score ≥ 20. Subjects were administered 1 × 108 CFU/day MENOLACTO or placebo, with the primary endpoint being total KMI score, and the effect of secondary endpoints on alleviating menopausal symptoms according to individual categories of the modified KMI, as well as a quality of life questionnaire (MENQOL questionnaire). After 12 weeks, total KMI scores decreased significantly, demonstrating improved menopausal symptoms relative to placebo along with improved modified KMI scores. Additionally, quality of life, according to the MENQOL questionnaire, significantly improved in all four symptoms-physical, psychosocial, vasomotor, and sexual symptoms. Moreover, we observed no significant difference between the two groups or significant changes in blood follicle-stimulating hormone and estradiol levels or endometrial thickness. These results demonstrated that MENOLACTO alleviated menopausal symptoms without notable side effects and improved quality of life, suggesting its efficacy as an alternative supplement to alleviate menopausal symptoms in women ineligible for hormonal therapy.
Keywords: Kupperman index; Lactobacillus acidophilus YT1; MENOLACTO; clinical trial; menopausal symptoms.

Participation in specific leisure-time activities and mortality risk among U.S. adults.
Porter AK, Cuthbertson CC, Evenson KR.
Ann Epidemiol. 2020 Jun 18:S1047-2797(20)30203-9. doi: 10.1016/j.annepidem.2020.06.006. Online ahead of print.
PMID: 32660884
Purpose: This prospective cohort study examined the association between specific leisure-time activity and mortality risk.
Methods: Data are from 1999 to 2006 U.S. National Health and Nutrition Examination Surveys and included adults followed through December 31, 2015 (n = 17,938, representing 191,463,892 U.S. adults). Participants reported specific leisure-time activities performed at moderate-to-vigorous intensity. Walking, bicycling, running, dance, golf, stretching, and weightlifting were examined. Cox proportional hazards models (adjusted hazard ratios [aHRs]; 95% confidence intervals [CIs]) assessed the association of individual activities with the risk of all-cause mortality, CVD mortality, and cancer mortality.
Results: Over a median follow-up of 11.9 years, 3799 deaths occurred. Any leisure-time walking ([aHR], 0.73; 95% CI, 0.66-0.82), bicycling (aHR, 0.73, 95% CI, 0.59-0.91), and running (aHR, 0.70; 95% CI, 0.59-0.84) were associated with lower all-cause mortality compared with no participation in the specific activity. Dance, golf, stretching, and weightlifting were not associated with mortality. Comparable results were observed when activities were categorized as none, less than 60 min/wk, or 60 minutes or more/wk. Walking and running were similarly associated with the risk of CVD mortality.
Conclusions: Participating in moderate-to-vigorous walking, bicycling, or running may be particularly beneficial for health and longevity.
Keywords: Bicycling; Cardiovascular disease; Neoplasms; Physical activity; Running; Sport; Walking.

Association Between Plant and Animal Protein Intake and Overall and Cause-Specific Mortality.
Huang J, Liao LM, Weinstein SJ, Sinha R, Graubard BI, Albanes D.
JAMA Intern Med. 2020 Jul 13. doi: 10.1001/jamainternmed.2020.2790. Online ahead of print.
PMID: 32658243
Importance: Although emphasis has recently been placed on the importance of high-protein diets to overall health, a comprehensive analysis of long-term cause-specific mortality in association with the intake of plant protein and animal protein has not been reported.
Objective: To examine the associations between overall mortality and cause-specific mortality and plant protein intake.
Design, setting, and participants: This prospective cohort study analyzed data from 416 104 men and women in the US National Institutes of Health-AARP Diet and Health Study from 1995 to 2011. Data were analyzed from October 2018 through April 2020.
Exposures: Validated baseline food frequency questionnaire dietary information, including intake of plant protein and animal protein.
Main outcomes and measures: Hazard ratios and 16-year absolute risk differences for overall mortality and cause-specific mortality.
Results: The final analytic cohort included 237 036 men (57%) and 179 068 women. Their overall median (SD) ages were 62.2 (5.4) years for men and 62.0 (5.4) years for women. Based on 6 009 748 person-years of observation, 77 614 deaths (18.7%; 49 297 men and 28 317 women) were analyzed. Adjusting for several important clinical and other risk factors, greater dietary plant protein intake was associated with reduced overall mortality in both sexes (hazard ratio per 1 SD was 0.95 [95% CI, 0.94-0.97] for men and 0.95 [95% CI, 0.93-0.96] for women; adjusted absolute risk difference per 1 SD was -0.36% [95% CI, -0.48% to -0.25%] for men and -0.33% [95% CI, -0.48% to -0.21%] for women; hazard ratio per 10 g/1000 kcal was 0.88 [95% CI, 0.84-0.91] for men and 0.86 [95% CI, 0.82-0.90] for women; adjusted absolute risk difference per 10 g/1000 kcal was -0.95% [95% CI, -1.3% to -0.68%] for men and -0.86% [95% CI, -1.3% to -0.55%] for women; all P < .001). The association between plant protein intake and overall mortality was similar across the subgroups of smoking status, diabetes, fruit consumption, vitamin supplement use, and self-reported health status. Replacement of 3% energy from animal protein with plant protein was inversely associated with overall mortality (risk decreased 10% in both men and women) and cardiovascular disease mortality (11% lower risk in men and 12% lower risk in women). In particular, the lower overall mortality was attributable primarily to substitution of plant protein for egg protein (24% lower risk in men and 21% lower risk in women) and red meat protein (13% lower risk in men and 15% lower risk in women).
Conclusions and relevance: In this large prospective cohort, higher plant protein intake was associated with small reductions in risk of overall and cardiovascular disease mortality. Our findings provide evidence that dietary modification in choice of protein sources may influence health and longevity.

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Link Between Dietary Sodium Intake, Cognitive Function, and Dementia Risk in Middle-Aged and Older Adults: A Systematic Review.
Mohan D, Yap KH, Reidpath D, Soh YC, McGrattan A, Stephan BCM, Robinson L, Chaiyakunapruk N, Siervo M; DePEC team.
J Alzheimers Dis. 2020 Jul 13. doi: 10.3233/JAD-191339. Online ahead of print.
PMID: 32675410
Background: A key focus for dementia risk-reduction is the prevention of socio-demographic, lifestyle, and nutritional risk factors. High sodium intake is associated with hypertension and cardiovascular disease (both are linked to dementia), generating numerous recommendations for salt reduction to improve cardiovascular health.
Objective: This systematic review aimed to assess, in middle- and older-aged people, the relationship between dietary sodium intake and cognitive outcomes including cognitive function, risk of cognitive decline, or dementia.
Methods: Six databases (PubMed, EMBASE, CINAHL, Psych info, Web of Science, and Cochrane Library) were searched from inception to 1 March 2020. Data extraction included information on study design, population characteristics, sodium reduction strategy (trials) or assessment of dietary sodium intake (observational studies), measurement of cognitive function or dementia, and summary of main results. Risk-of-bias assessments were performed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tool.
Results: Fifteen studies met the inclusion criteria including one clinical trial, six cohorts, and eight cross-sectional studies. Studies reported mixed associations between sodium levels and cognition. Results from the only clinical trial showed that a lower sodium intake was associated with improved cognition over six months. In analysis restricted to only high-quality studies, three out of four studies found that higher sodium intake was associated with impaired cognitive function.
Conclusion: There is some evidence that high salt intake is associated with poor cognition. However, findings are mixed, likely due to poor methodological quality, and heterogeneous dietary, analytical, and cognitive assessment methods and design of the studies. Reduced sodium intake may be a potential target for intervention. High quality prospective studies and clinical trials are needed.
Keywords: Cognitive dysfunction; dementia; salt; sodium; systematic review.

The effect of caloric restriction on blood pressure and cardiovascular function: A systematic review and meta-analysis of randomized controlled trials.
Kirkham AA, Beka V, Prado CM.
Clin Nutr. 2020 Jul 1:S0261-5614(20)30340-X. doi: 10.1016/j.clnu.2020.06.029. Online ahead of print.
PMID: 32675017
Background & aims: Preclinical evidence suggests that caloric restriction is an effective therapy for a number of cardiovascular insults. Whether caloric restriction has cardio-protective effects in humans is not well understood. The aim was to systematically review and meta-analyze human randomized control trials (RCTs) testing the effect of caloric restriction on blood pressure (BP) and cardiovascular function.
Methods: A systematic review was performed using Medline, EMBASE, CINAHL (up to June 2017) to search for RCTs of adults receiving a calorie-restricted intervention versus a control/standard diet. Random-effect meta-analyses were performed to calculate weighted mean difference and 95% CI.
Results: Thirty-two RCTs with 1722 participants assessing BP (n = 29 studies), heart rate (n = 10), VO2peak (n = 8), muscle sympathetic nerve activity (MSNA, n = 4), and endothelial function (n = 4) were included. Calorie-restricted interventions lasting 1-4 weeks had the largest effect on systolic (-5.5 mmHg, p < 0.001, 95% CI: -3.8, -7.1) and diastolic (-2.9 mmHg, p = 0.005, 95% CI: -5.0, -0.9) BP, but no effect on HR. Interventions lasting 1.5-6 months had similar effects on BP, and reduced HR (-4.4 beats/minute, p < 0.001, 95% CI: -6.1,-2.8). Relative VO2peak improved (1.8 mL/kg/min, p < 0.001, 95% CI: 1.3, 2.2). There were also potential positive effects on MSNA and endothelial function.
Conclusions: The effect of 1-4 weeks of calorie restriction on BP was similar to that expected with medications, and larger than that reported for other lifestyle interventions or supplements. Cardiovascular risk could be further reduced by caloric restriction lasting up to six months to lower heart rate and improve VO2peak.
Keywords: Blood pressure; Calorie restriction; Cardiorespiratory fitness; Cardiovascular risk; Meta-analysis; Systematic review.

Resistant starch supplementation increases crypt cell proliferative state in the rectal mucosa of older healthy participants.
Malcomson FC, Willis ND, McCallum I, Xie L, Ouwehand AC, Stowell JD, Kelly S, Bradburn DM, Belshaw NJ, Johnson IT, Mathers JC.
Br J Nutr. 2020 Aug 28;124(4):374-385. doi: 10.1017/S0007114520001312. Epub 2020 Apr 13.
PMID: 32279690
There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.
Keywords: Apoptosis; Colorectal cancer risk; Crypt cell proliferation; Dietary fibre; Polydextrose; Resistant starch.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.
Caffa I, Spagnolo V, Vernieri C, Valdemarin F, Becherini P, Wei M, Brandhorst S, Zucal C, Driehuis E, Ferrando L, Piacente F, Tagliafico A, Cilli M, Mastracci L, Vellone VG, Piazza S, Cremonini AL, Gradaschi R, Mantero C, Passalacqua M, Ballestrero A, Zoppoli G, Cea M, Arrighi A, Odetti P, Monacelli F, Salvadori G, Cortellino S, Clevers H, De Braud F, Sukkar SG, Provenzani A, Longo VD, Nencioni A.
Nature. 2020 Jul 15. doi: 10.1038/s41586-020-2502-7. Online ahead of print.
PMID: 32669709
Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Dietary iron intake and risk of death due to cardiovascular diseases: A systematic review and dose-response meta-analysis of prospective cohort studies.
Han M, Guan L, Ren Y, Zhao Y, Liu D, Zhang D, Liu L, Liu F, Chen X, Cheng C, Li Q, Guo C, Zhou Q, Tian G, Qie R, Huang S, Wu X, Liu Y, Li H, Sun X, Zhang M, Hu D, Lu J.
Asia Pac J Clin Nutr. 2020;29(2):309-321. doi: 10.6133/apjcn.202007_29(2).0014.
PMID: 32674239
Background and objectives: Many studies have investigated the association between dietary iron intake and death due to cardiovascular disease (CVD), but the results were inconsistent. We performed a dose-response meta- analysis to quantitatively assess the risk of CVD mortality with dietary intake of iron (total iron, heme iron, and non-heme iron).
Methods and study design: PubMed and Embase databases were searched for articles published up to February 21, 2019. Prospective cohort studies were included if reporting relative risks (RRs) and 95% confidence intervals (CIs) for risk of CVD mortality associated with dietary iron intake. Restricted cubic splines were used to model the dose-response association.
Results: We included eight articles (19 studies including 720,427 participants [46,045 deaths due to CVD]) in the meta-analysis. When comparing the highest versus lowest level of dietary heme iron intake, the pooled RR for CVD mortality was 1.19 (95% CI, 1.01-1.39). With a 1-mg/day increase in dietary heme iron intake, the pooled RR for death due to CVD, stroke, coronary heart disease, and myocardial infarction were 1.25 (95% CI, 1.17-1.33), 1.17 (1.04-1.32), 1.25 (0.70-2.22), and 1.17 (0.55-2.50) respectively. The association between dietary iron intake and CVD mortality was linear (pnonlinearity> 0.05).
Conclusions: Higher dietary intake of heme iron was associated with a greater risk of CVD mortality. Reducing consumption of heme iron may help to prevent premature death due to CVD.

Acute glycemic and insulinemic effects of low-energy sweeteners: a systematic review and meta-analysis of randomized controlled trials.
Greyling A, Appleton KM, Raben A, Mela DJ.
Am J Clin Nutr. 2020 Jul 16:nqaa167. doi: 10.1093/ajcn/nqaa167. Online ahead of print.
PMID: 32672338
Background: It has been suggested that low-energy sweeteners (LES) may be associated with an increased risk of metabolic diseases, possibly due to stimulation of glucose-responsive mechanisms.
Objective: We conducted a systematic review and meta-analysis of human intervention studies examining the acute effect of LES intake on postprandial glucose (PPG) and postprandial insulin (PPI) responses, in order to comprehensively and objectively quantify these relations.
Methods: We systematically searched the Medline, OVID FSTA, and SCOPUS databases until January 2020. Randomized controlled trials comparing acute postprandial effects on PPG and/or PPI after exposure to LES, either alone, with a meal, or with other nutrient-containing preloads to the same intervention without LES were eligible for inclusion. PPG and PPI responses were calculated as mean incremental area under the curve divided by time. Meta-analyses were performed using random effects models with inverse variance weighing.
Results: Twenty-six papers (34 PPG trials and 29 PPI trials) were included. There were no reports of statistically significant differences in the effects of LES on PPG and PPI responses compared with control interventions. Pooled effects of LES intake on the mean change difference in PPG and PPI were -0.02 mmol/L (95% CI: -0.09, 0.05) and -2.39 pmol/L (95% CI: -11.83, 7.05), respectively. The results did not appreciably differ by the type or dose of LES consumed, cointervention type, or fasting glucose and insulin levels. Among patients with type 2 diabetes, the mean change difference indicated a smaller PPG response after exposure to LES compared with the control (-0.3 mmol/L; 95% CI: -0.53, -0.07).
Conclusions: Ingestion of LES, administered alone or in combination with a nutrient-containing preload, has no acute effects on the mean change in postprandial glycemic or insulinemic responses compared with a control intervention. Apart from a small beneficial effect on PPG (-0.3 mmol/L) in studies enrolling patients with type 2 diabetes, the effects did not differ by type or dose of LES, or fasting glucose or insulin levels. This review and meta-analysis was registered at PROSPERO as CRD42018099608.
Keywords: artificial sweeteners; diabetes; glucose; insulin; noncaloric sweeteners; nonnutritive sweeteners; postprandial.

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The effect of a split portion of flaxseed on 24-h blood glucose response.
Almehmadi A, Lightowler H, Chohan M, Clegg ME.
Eur J Nutr. 2020 Jul 22. doi: 10.1007/s00394-020-02333-x. Online ahead of print.
PMID: 32699911
Purpose: Flaxseed can be effective at lowering and stabilising blood glucose responses. The aim of this study was to determine whether flaxseed could lower blood glucose response more effectively when consumed as a single portion of 30 g, or a split portion consumed three times per day (10 g flaxseed per portion).
Methods: The study was a randomised, repeated measures, cross-over design. Fifteen healthy participants consumed either (1) three flaxseed muffins containing a total of 30 g of flaxseed once in the morning, (2) three flaxseed muffins consumed at three different timepoints across the day (10 g flaxseed per muffin) or (3) three control muffins consumed at three different timepoints across the day (0 g flaxseed). The 24-h blood glucose response was measured using a continuous glucose monitor.
Results: The results of this study demonstrated that flaxseed muffins given three times a day were effective at lowering and maintaining blood glucose levels over 24 h, compared to the control muffins and that both flaxseed treatments resulting in a lower blood glucose iAUC during the night.
Conclusion: The results of this study indicated that adding flaxseed to a daily diet produced a lower glucose profile over 24 h in a free-living context compared to the control muffins.
Keywords: 24 blood glucose profile; Blood glucose; Blood glucose incremental area under the curve (iAUC); Continuous glucose monitor; Flaxseed; Linseed.

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.
Colicino E, Marioni R, Ward-Caviness C, Gondalia R, Guan W, Chen B, Tsai PC, Huan T, Xu G, Golareh A, Schwartz J, Vokonas P, Just A, Starr JM, McRae AF, Wray NR, Visscher PM, Bressler J, Zhang W, Tanaka T, Moore AZ, Pilling LC, Zhang G, Stewart JD, Li Y, Hou L, Castillo-Fernandez J, Spector T, Kiel DP, Murabito JM, Liu C, Mendelson M, Assimes T, Absher D, Tsaho PS, Lu AT, Ferrucci L, Wilson R, Waldenberger M, Prokisch H, Bandinelli S, Bell JT, Levy D, Deary IJ, Horvath S, Pankow J, Peters A, Whitsel EA, Baccarelli A.
Aging (Albany NY). 2020 Jul 22;12. doi: 10.18632/aging.103408. Online ahead of print.
PMID: 32697766
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
Keywords: 450K; DNA methylation; aging; all-cause mortality; epigenome-wide association studies.

Dietary intake of total, animal, and plant proteins and risk of all cause, cardiovascular, and cancer mortality: systematic review and dose-response meta-analysis of prospective cohort studies.
Naghshi S, Sadeghi O, Willett WC, Esmaillzadeh A.
BMJ. 2020 Jul 22;370:m2412. doi: 10.1136/bmj.m2412.
PMID: 32699048
Objective: To examine and quantify the potential dose-response relation between intake of total, animal, and plant protein and the risk of mortality from all causes, cardiovascular disease, and cancer.
Design: Systematic review and meta-analysis of prospective cohort studies.
Data sources: PubMed, Scopus, and ISI Web of Science until December 2019, and references of retrieved relevant articles.
Study selection: Prospective cohort studies that reported the risk estimates for all cause, cardiovascular, and cancer mortality in adults aged 18 or older.
Data synthesis: Random effects models were used to calculate pooled effect sizes and 95% confidence intervals for the highest versus lowest categories of protein intake and to incorporate variation between studies. Linear and non-linear dose-response analyses were done to evaluate the dose-response relations between protein intake and mortality.
Results: 32 prospective cohort studies were included in the systematic review and 31 in the meta-analysis. During the follow-up period of 3.5 to 32 years, 113 039 deaths (16 429‬ from cardiovascular disease and 22 303‬ from cancer) occurred among 715 128 participants. Intake of total protein was associated with a lower risk of all cause mortality (pooled effect size 0.94, 95% confidence interval 0.89 to 0.99, I2=58.4%, P<0.001). Intake of plant protein was significantly associated with a lower risk of all cause mortality (pooled effect size 0.92, 95% confidence interval 0.87 to 0.97, I2=57.5%, P=0.003) and cardiovascular disease mortality (pooled hazard ratio 0.88, 95% confidence interval 0.80 to 0.96, I2=63.7%, P=0.001), but not with cancer mortality. Intake of total and animal protein was not significantly associated with risk of cardiovascular disease and cancer mortality. A dose-response analysis showed a significant inverse dose-response association between intake of plant protein and all cause mortality (P=0.05 for non-linearity). An additional 3% energy from plant proteins a day was associated with a 5% lower risk of death from all causes.
Conclusions: Higher intake of total protein was associated with a lower risk of all cause mortality, and intake of plant protein was associated with a lower risk of all cause and cardiovascular disease mortality. Replacement of foods high in animal protein with plant protein sources could be associated with longevity.

Predicting resistance to amyloid-beta deposition and cognitive resilience in the oldest-old.
Snitz BE, Chang Y, Tudorascu DL, Lopez OL, Lopresti BJ, DeKosky ST, Carlson MC, Cohen AD, Kamboh MI, Aizenstein HJ, Klunk WE, Kuller LH.
Neurology. 2020 Jul 22:10.1212/WNL.0000000000010239. doi: 10.1212/WNL.0000000000010239. Online ahead of print.
PMID: 32699143
Objective: To explore long-term predictors of avoiding amyloid-beta (Aβ) deposition and maintaining unimpaired cognition as outcomes in the oldest old.
Methods: In a longitudinal observational cohort study, N=100 former participants of the Ginkgo Evaluation of Memory Study (GEMS; 2000-2008) completed biannual Pittsburgh Compound B (PiB)-PET imaging and annual clinical-cognitive evaluations beginning in 2010. Most recent Aβ status and cognitive status were selected for each participant. Longitudinal outcomes included change in serial Aβ and cognitive tests. Baseline predictors from GEMS included neuropsychological tests, daily functioning, APOE genotype, lifestyle variables, occupational measures, health history, sleep, subjective memory, physical and cognitive activities, depressive symptoms, physical performance and health indices, among others.
Results: Mean age at last cognitive evaluation was 92.0 years (range 86-100). Mean follow-up time from baseline to last measured Aβ status was 12.3 (SD 1.9) years and to last cognitive evaluation was 14.1 (SD 1.9) years. The APOE*2 allele predicted last Aβ status (n=34 Aβ-negative vs. n=66 Aβ-positive). Baseline cognition predicted cognitive status (n=30 unimpaired vs. n=70 impaired). Predictors of cognitive status among Aβ-positive participants only (n=14 normal cognition vs. n=52 impaired) were baseline cognitive test scores and smoking history. Baseline pulse pressure predicted longitudinal Aβ increase; paid work engagement and life satisfaction predicted less cognitive decline.
Conclusions: The APOE*2 allele and lower pulse pressure predicts resistance to Aβ deposition in advanced aging. Cognitive test scores 14 years prior, likely reflecting premorbid abilities, predict cognitive status and maintenance of unimpaired cognition in the presence of Aβ. Several lifestyle factors appear protective.

Intermittent Fasting and Metabolic Health: From Religious Fast to Time-Restricted Feeding.
Hoddy KK, Marlatt KL, Çetinkaya H, Ravussin E.
Obesity (Silver Spring). 2020 Jul;28 Suppl 1:S29-S37. doi: 10.1002/oby.22829.
PMID: 32700827 Review.
Over the past 10 to 15 years, intermittent fasting has emerged as an unconventional approach to reduce body weight and improve metabolic health beyond simple calorie restriction. In this review, we summarize findings related to Ramadan and Sunnah fasting. We then discuss the role of caloric restriction not only as an intervention for weight control, but importantly, as a strategy for healthy aging and longevity. Finally, we review the four most common intermittent fasting (IF) strategies used to date for weight management and to improve cardiometabolic health. Weight loss is common after IF but does not appear to be different than daily caloric restriction when compared directly. IF may also provide additional cardiometabolic benefit, such as insulin sensitization, that is independent from weight loss. While no specific fasting regimen stands out as superior at this time, there is indeed heterogeneity in responses to these different IF diets. This suggests that one dietary regimen may not be ideally suited for every individual. Future studies should consider strategies for tailoring dietary prescriptions, including IF, based on advanced phenotyping and genotyping prior to diet initiation.

Seasonal Blood Pressure Variation: A Neglected Confounder in Clinical Hypertension Research and Practice.
Stergiou GS, Palatini P, Kollias A, Kyriakoulis KG, Myers M, O'Brien E, Parati G, Modesti PA.
Am J Hypertens. 2020 Jul 18;33(7):595-596. doi: 10.1093/ajh/hpaa056.
PMID: 32298406 No abstract available.
Accounting for Blood Pressure Seasonality Alters Evaluation of Practice-Level Blood Pressure Control Intervention.
Gepts T, Nguyen AM, Cleland C, Wu W, Pham-Singer H, Shelley D.
Am J Hypertens. 2020 Mar 13;33(3):220-222. doi: 10.1093/ajh/hpz179.
PMID: 31711219
Background: Despite the large body of literature evaluating interventions to improve hypertension management, few studies have addressed seasonal variation in blood pressure (BP) control. This underreported phenomenon has implications for interpreting study findings and informing clinical care. We share a methodology that accounts for BP seasonality, presented through a case study-HealthyHearts NYC, an intervention aimed at increasing adherence to the Million Hearts BP control evidence-based guidelines in primary care practices.
Methods: We used a randomized stepped-wedge design (n = 257 practices). Each intervention included 13 visits from practice facilitators trained in improving practice-level BP control over 12 months. Two models were used to assess the intervention effect-one that did not account for seasonality (model 1) and one that did (model 2). Model 2 was a re-specification of model 1 to include our proposed two fixed-effects terms to address BP seasonality.
Results: Model 1 showed a significant negative association between the intervention and BP control (IRR = 0.98, 95% CI = 0.96-0.99, P ≤ 0.05). In contrast, Model 2, which did address seasonality, showed no intervention effect on BP control (IRR = 0.99, 95% CI = 0.97-1.01, P = 0.19).
Conclusions: These findings reveal that analyses that do not account for BP seasonality may not present an accurate picture of intervention effects. In our case study, accounting for BP seasonality turned a negative association into a null association. We recommend that when evaluating BP control, studies compare outcome measures across similar seasons and that the measurement period last long enough to account for seasonal effects.
Keywords: blood pressure; hypertension; seasonality.
Seasonal Variation of Home Blood Pressure and Its Association With Target Organ Damage: The J-HOP Study (Japan Morning Surge-Home Blood Pressure).
Narita K, Hoshide S, Fujiwara T, Kanegae H, Kario K.
Am J Hypertens. 2020 Jul 18;33(7):620-628. doi: 10.1093/ajh/hpaa027.
PMID: 32202625
Background: Although seasonal variation of home blood pressure (BP) has been reported to be higher in winter, seasonal difference in home BP (HBP) and its association with target organ damage (TOD) remains unclear.
Methods: This is a cross-sectional study using the dataset from the Japan Morning Surge-Home Blood Pressure (J-HOP) study to assess seasonal differences in HBP, prevalence of masked hypertension, and association of HBP with TOD. The J-HOP study is a nationwide, multicenter prospective study whose participants with cardiovascular risks underwent morning and evening HBP measurements for a 14-day period in 71 institutions throughout Japan. Urine albumin-creatinine ratio (UACR) and serum-B-type natriuretic peptide (BNP) were obtained at enrollment.
Results: Among 4,267 participants (mean age, 64.9 ± 10.9 years; 46.9% male; 91.4% hypertensives), 1,060, 979, 1,224, and 1,004 participants were enrolled in spring, summer, autumn, and winter, respectively. Morning and evening home systolic/diastolic BP levels, and prevalence of masked hypertension (office BP <140/90 mm Hg and HBP ≥135/85 mm Hg) were significantly lower in summer than other seasons after adjustment for covariates. When we assessed the interaction between BP parameters and each season for an association with TOD, we found the association between morning home diastolic BP and each of UACR and BNP was stronger in winter than other seasons (both P for interaction <0.05).
Conclusions: In this study, we revealed that the prevalence of masked hypertension was higher in other seasons than in summer and found a notable association between morning home diastolic BP and TOD in winter.
Keywords: blood pressure; home blood pressure; hypertension; masked hypertension; seasonal variation; target organ damage.

Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the URic acid Right for heArt Health study.
Muiesan ML, Salvetti M, Virdis A, Masi S, Casiglia E, Tikhonoff V, Barbagallo CM, Bombelli M, Cicero AFG, Cirillo M, Cirillo P, Desideri G, D'Eliak L, Ferri C, Galletti F, Gesualdo L, Giannattasio C, Iaccarino G, Mallamaci F, Maloberti A, Mazza A, Nazzaro P, Palatini P, Parati G, Pontremoli R, Rattazzi M, Rivasi G, Tocci G, Ungar A, Verdecchia P, Viazzi F, Volpe M, Grassi G, Borghi C; from the Working Group on Uric Acid, Cardiovascular Risk of the Italian Society of Hypertension.
J Hypertens. 2020 Jul 15. doi: 10.1097/HJH.0000000000002589. Online ahead of print.
PMID: 32694342
Objective: To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension.
Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, cohort study involving data on individuals aged 18-95 years, recruited on a community basis from all regions of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 128 ± 65 months. Incident heart failure was defined on the basis of International Classification of Diseases Tenth Revision codes and double-checked with general practitioners and hospital files. Multivariate Cox regression models having fatal and morbid heart failure as dependent variables, adjusted for sex, age, SBP, diabetes, estimated glomerular filtration rate, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol, previous diagnosis of heart failure and use of diuretics as possible confounders, were used to search for an association between SUA as a continuous variable and heart failure. By means of receiver operating characteristic curves, two prognostic cut-off values (one for all heart failure and one for fatal heart failure) were identified as able to discriminate between individuals doomed to develop the event. These cut-off values were used as independent predictors to divide individuals according to prognostic cut-off values in a multivariate Cox models, adjusted for confounders.
Results: A total of 21 386 individuals were included in the analysis. In Cox analyses, SUA as a continuous variable was a significant predictor of all [hazard ratio 1.29 (1.23-1.359), P < 0.0001] and fatal [hazard ratio 1.268 (1.121-1.35), P < 0.0001] incident heart failure. Cut-off values of SUA able to discriminate all and fatal heart failure status were identified by mean of receiver operating characteristic curves in the whole database: SUA more than 5.34 mg/dl (confidence interval 4.37-5.6, sensitivity 52.32, specificity 63.96, P < 0.0001) was the univariate prognostic cut-off value for all heart failure, whereas SUA more than 4.89 mg/dl (confidence interval 4.78-5.78, sensitivity 68.29, specificity 49.11, P < 0.0001) for fatal heart failure. The cut-off for all heart failure and the cut-off value for fatal heart failure were accepted as independent predictors in the Cox analysis models, the hazard ratios being 1.645 (1.284-2.109, P < 0.0001) for all heart failure and 1.645 (1.284-2.109, P < 0.0001) for fatal heart failure, respectively.
Conclusion: The results of the current study confirm that SUA is an independent risk factor for all heart failure and fatal heart failure, after adjusting for potential confounding variables and demonstrate that a prognostic cut-off value can be identified for all heart failure (>5.34 mg/dl) and for fatal heart failure (>4.89 mg/dl).

The impact of time-updated resting heart rate on cause-specific mortality in a random middle-aged male population: a lifetime follow-up.
Cui X, Mandalenakis Z, Thunström E, Fu M, Svärdsudd K, Hansson PO.
Clin Res Cardiol. 2020 Jul 21. doi: 10.1007/s00392-020-01714-w. Online ahead of print.
PMID: 32696079
Background: A high resting heart rate (RHR) is associated with an increase in adverse events. However, the long-term prognostic value in a general population is unclear. We aimed to investigate the impact of RHR, based on both baseline and time-updated values, on mortality in a middle-aged male cohort.
Methods: A random population sample of 852 men, all born in 1913, was followed from age 50 until age 98, with repeated examinations including RHR over a period of 48 years. The impact of baseline and time-updated RHR on cause-specific mortality was assessed using Cox proportional hazard models and cubic spline models.
Results: A baseline RHR of ≥ 90 beats per minute (bpm) was associated with higher all-cause mortality, as compared with an RHR of 60-70 bpm (hazard ratio

1.60, 95% confidence interval [CI] 1.17-2.19, P = 0.003), but not with cardiovascular (CV) mortality. A time-updated RHR of < 60 bpm (HR 1.41, 95% CI 1.07-1.85, P = 0.014) and a time-updated RHR of 70-80 bpm (HR 1.34, 95% CI 1.02-1.75, P = 0.036) were both associated with higher CV mortality as compared with an RHR of 60-70 bpm after multivariable adjustment. Analyses using cubic spline models confirmed that the association of time-updated RHR with all-cause and CV mortality complied with a U-shaped curve with 60 bpm as a reference.
Conclusion: In this middle-aged male cohort, a time-updated RHR of 60-70 bpm was associated with the lowest CV mortality, suggesting that a time-updated RHR could be a useful long-term prognostic index in the general population.
Keywords: Cohort study; General population; Heart rate; Mortality.

Association between Excessive Daytime Sleepiness and Risk of Cardiovascular Disease and All-Cause Mortality: A Systematic Review and Meta-Analysis of Longitudinal Cohort Studies.
Wang L, Liu Q, Heizhati M, Yao X, Luo Q, Li N.
J Am Med Dir Assoc. 2020 Jul 18:S1525-8610(20)30426-6. doi: 10.1016/j.jamda.2020.05.023. Online ahead of print.
PMID: 32693994
Objective: Excessive daytime sleepiness (EDS) is a prevalent phenomenon in adults, and although cohort studies have reported an association between EDS and adverse health outcomes, the results are inconclusive. This meta-analysis summarizes the evidence from longitudinal cohort studies on the relationship between EDS and the risk of cardiovascular disease (CVD) or all-cause mortality.
Design: A meta-analysis of prospective cohort studies was conducted.
Setting and participants: We searched for relevant longitudinal cohort studies published through September 2019 using Web of Science, PubMed, Medline, and SciELO.
Measures: The relative risk (RR) of EDS was pooled in random-effects or fixed-effects meta-analyses. Subgroup, sensitivity, and meta-regression analyses were performed to identify heterogeneous sources. Publication bias was assessed using the Begg and Egger tests.
Results: Seventeen studies (153,909 participants) were included. The mean follow-up was 5.4 (range, 2-13.8) years. The pooled relative risks of EDS were 1.28 [95% confidence interval (CI) 1.09-1.50] for total CVD events, 1.28 (95% CI 1.12-1.46) for coronary heart disease (CHD), 1.52 (95% CI 1.10-2.12) for stroke, 1.47 (95% CI 1.09-1.98) for CVD mortality, and 1.23 (95% CI 1.13-1.33) for all-cause mortality. Subgroup analyses by mean age, region, follow-up time, EDS assessment method, and year of publication yielded similar results.
Conclusions and implications: EDS is a modest but statistically significant predictor for CVD events, coronary heart disease, stroke, and CVD and all-cause mortality. However, its prognostic value warrants further investigation to identify those at highest risk of mortality and in need of intervention to improve outcomes.
Keywords: Daytime sleepiness; cardiovascular risk; meta-analysis; mortality.

Low cholesterol levels are associated with a high mortality risk in older adults without statins therapy: An externally validated cohort study.
Turusheva A, Vaes B, Degryse JM, Frolova E.
Arch Gerontol Geriatr. 2020 Jul 11;90:104180. doi: 10.1016/j.archger.2020.104180. Online ahead of print.
PMID: 32688205
Background: The relationship of total cholesterol (TC) levels with mortality among older adults without statin therapy has not been fully studied.
Aims: To examine the relationship between TC and all-cause mortality in adults aged 65 years and older in Russia without statin therapy.
Methods: This was a population-based prospective cohort study of community-dwelling people aged 65 years and older in Russia. Data from 379 individuals on cardiovascular risk factors; comorbidities; cognitive, physical and autonomous function; lipid panel; B-type natriuretic peptide; C-reactive protein; and others were collected through interviews, clinical examinations, and laboratory tests. The total follow-up time was 3 years. Cox proportional hazards models for all-cause mortality, C-statistics, internal validation and external validation using the Belgian population from the BELFRAIL study were performed.
Results: A U-shaped association between the TC level and all-cause mortality was identified. Older adults without statin therapy and with low/high TC levels were at higher risk for mortality even after adjustment for covariates, with a hazard ratio (HR) of 5.78 (1.96-17.03) for TC < 5.4 mmol/L and an HR of 6.24 (1.69-22.94) for TC levels > 7.2 mmol/L. The association between low TC and all-cause mortality was confirmed in an external population of adults 80 years and older.
Conclusion: The TC level range associated with the lowest mortality was 5.4-7.2 mmol/L, irrespective of concomitant diseases or health status. The association between low TC levels and a high risk of all-cause mortality was confirmed in a Belgian cohort of adults 80 years and older.
Keywords: Mortality; Older adults; Population study; Total cholesterol.

Associations between age-related changes in bone microstructure and strength and dietary acid load in a cohort of community-dwelling, healthy men and postmenopausal women.
Papageorgiou M, Merminod F, Chevalley T, van Rietbergen B, Ferrari S, Rizzoli R, Biver E.
Am J Clin Nutr. 2020 Jul 17:nqaa191. doi: 10.1093/ajcn/nqaa191. Online ahead of print.
PMID: 32678420
Background: The importance of dietary acid load (DAL) in the pathogenesis of osteoporosis is still debated. Age-related changes in bone microstructure and strength in relation to DAL remain largely unexplored.
Objectives: We investigated the associations between changes in areal and volumetric bone mineral density (BMD), bone microstructure and strength, fracture risk, and DAL in a prospective cohort of 65-y-old healthy men and postmenopausal women.
Methods: Potential renal acid load (PRAL; mEq/d) was calculated as a DAL proxy to characterize participants' diet as alkaline (Alk-D; PRAL < -5), neutral (Neut-D; -5 ≤ PRAL ≤ 5), or acidic (Acid-D; PRAL >5). We measured areal BMD (aBMD) by DXA, and distal radius and tibia bone microstructure using high-resolution peripheral quantitative computed tomography, at baseline (n = 853) and after 6.1 ± 1.4 y (n = 708). Bone strength was estimated using finite element analyses at baseline and after 3.0 ± 0.5 y (n = 613). Prevalent and incident fractures were recorded.
Results: The majority of the participants (59%) had an Alk-D, while 23% had a Neut-D, and 18% an Acid-D. Baseline aBMD and bone microstructure and strength did differ or were slightly better in women or men with an Acid-D versus those consuming an Alk-D or Neut-D. Indeed, women with an Acid-D had higher trabecular number (P = 0.010 vs. Alk-D; P = 0.001 vs. Neut-D), while men had higher hip and radius aBMD (P = 0.008 and 0.024 vs. Neut-D, respectively) and radius strength (P = 0.026 vs. Neut-D). Over the follow-up, women in the Acid-D group experienced lower cortical and endocortical bone loss at the radius than did the Alk-D and Neut-D groups (cortical thickness, P = 0.008 and < 0.001; trabecular area, P = 0.001 and < 0.001, respectively). No association between fractures and PRAL was observed.
Conclusions: These null or favourable associations between baseline values or changes in aBMD, bone microstructure and strength, and DAL in this cohort of 65-y-old healthy individuals do not support adverse DAL-mediated effects on bone.
Keywords: acid-ash theory; bone microstructure; bone mineral density; bone strength; dietary acid load; fractures; osteoporosis.

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Citrus intake and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).
Mahamat-Saleh Y, Cervenka I, Al-Rahmoun M, Mancini FR, Severi G, Ghiasvand R, Veierod MB, Caini S, Palli D, Botteri E, Sacerdote C, Ricceri F, Trichopoulou A, Peppa E, La Vecchia C, Overvad K, Dahm CC, Olsen A, Tjønneland A, Perez-Cornago A, Jakszyn P, Grioni S, Schulze MB, Skeie G, Lasheras C, Colorado-Yohar S, Rodríguez-Barranco M, Kühn T, Katzke VA, Amiano P, Tumino R, Panico S, Ezponda A, Sonestedt E, Scalbert A, Weiderpass E, Boutron-Ruault MC, Kvaskoff M.
Eur J Epidemiol. 2020 Jul 24. doi: 10.1007/s10654-020-00666-9. Online ahead of print.
PMID: 32710289
Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose-response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03-1.18 in the highest vs. lowest quartile; Ptrend = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02-1.20, Ptrend = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04-1.47, Ptrend = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01-1.16, Ptrend = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02-1.48; Ptrend = 0.01), although with no heterogeneity across skin cancer types (Phomogeneity = 0.21). Citrus juice was positively associated with skin cancer risk (Ptrend = 0.004), particularly with BCC (Ptrend = 0.008) and SCC (Ptrend = 0.004), but not with melanoma (Phomogeneity = 0.02). Our study suggests moderate positive linear dose-response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.
Keywords: Citrus; Cohort studies; Cutaneous melanoma; Epidemiology; Keratinocyte cancers.

Co-Administration of Iron and a Bioavailable Curcumin Supplement Increases Serum BDNF Levels in Healthy Adults.
Tiekou Lorinczova H, Fitzsimons O, Mursaleen L, Renshaw D, Begum G, Zariwala MG.
Antioxidants (Basel). 2020 Jul 22;9(8):E645. doi: 10.3390/antiox9080645.
PMID: 32707771
Brain-derived neurotrophic factor (BDNF) is key for the maintenance of normal neuronal function and energy homeostasis and has been suggested to improve cognitive function, including learning and memory. Iron and the antioxidant curcumin have been shown to influence BDNF homeostasis. This 6-week, double blind, randomized, placebo-controlled study examined the effects of oral iron supplementation at low (18 mg) and high (65 mg) ferrous (FS) iron dosages, compared to a combination of these iron doses with a bioavailable formulated form of curcumin (HydroCurcTM; 500 mg) on BDNF levels in a healthy adult cohort of 155 male (26.42 years ± 0.55) and female (25.82 years ± 0.54) participants. Participants were randomly allocated to five different treatment groups: both iron and curcumin placebo (FS0+Plac), low dose iron and curcumin placebo (FS18+Plac), low dose iron and curcumin (FS18+Curc), high dose iron and curcumin placebo (FS65+Plac) and high dose iron and curcumin (FS65+Curc). Results showed a significant increase in BDNF over time (26%) in the FS18+Curc group (p = 0.024), and at end-point between FS18+Curc and FS18+Plac groups (35%, p = 0.042), demonstrating for the first time that the combination with curcumin, rather than iron supplementation alone, results in increased serum BDNF. The addition of curcumin to iron supplementation may therefore provide a novel approach to further enhance the benefits associated with increased BDNF levels.
Keywords: BDNF (brain-derived neurotrophic factor); antioxidant capability; brain function; curcumin; ferrous sulphate; iron; supplementation.

Serum Vitamin D Levels and Risk of Liver Cancer: A Systematic Review and Dose-Response Meta-Analysis of Cohort Studies.
Zhang Y, Jiang X, Li X, Găman MA, Kord-Varkaneh H, Rahmani J, Salehi-Sahlabadi A, Day AS, Xu Y.
Nutr Cancer. 2020 Jul 24:1-9. doi: 10.1080/01635581.2020.1797127. Online ahead of print.
PMID: 32705896
Data regarding the relationship between serum vitamin D levels and the risk of liver cancer are conflicting. Therefore, we performed a systematic review and dose-response meta-analysis of all available data of cohort studies on the association of 25-OH-vitamin-D levels with the risk of hepatocellular carcinoma. We conducted a systematic search in PubMed-MEDLINE, Scopus, Cochrane and Web of Science databases for prospective observational studies conducted on the general population from inception to May 2019. Six studies provided data from 6357 participants. According to the pooled HR, the subjects with the highest serum concentrations of vitamin D had a 47% lower risk of liver cancer vs. the subjects with the lowest serum concentrations of vitamin D (pooled HR: 0.53, 95% CI: 0.41-0.68; P < 0.001). There was no significant heterogeneity among the studies (P = 0.431, I2 = 0.0). The pooled HR from the random-effects dose-response model indicated an indirect significant linear association between vitamin D and the risk of liver cancer (coef = -0.017, P < 0.001). However, there was no significant nonlinear dose-response association between serum vitamin D and the risk of liver cancer (coef = -0.0001, P = 0.342). The evidence from this meta-analysis suggests that there may be an inverse relationship between serum vitamin D levels and the risk of liver cancer.

Dose-response Association between C-Reactive Protein and Risk of All-Cause and Cause-Specific Mortality: A Systematic Review and Meta-Analysis of Cohort Studies.
Ni P, Yu M, Zhang R, Cheng C, He M, Wang H, Chen S, Duan G.
Ann Epidemiol. 2020 Jul 20:S1047-2797(20)30265-9. doi: 10.1016/j.annepidem.2020.07.005. Online ahead of print.
PMID: 32702432 Review.
Purpose: To quantitatively assess the association between CRP and all-cause, cardiovascular disease (CVD), and cancer mortality, a dose-response meta-analysis was performed on data from cohort studies in general population.
Methods: The published relevant articles were searched for in PubMed, Web of Science, and Embase until September 21, 2019. The pooled relative risk (RR) was estimated by random effects of generalized least square regression models. The dose-response relationship was modeled using restricted cubic splines.
Results: Twenty-two articles were screened for the meta-analysis. Compared with the low CRP group, the pooled RR in the moderate CRP group was 1.30 (95% CI, 1.20-1.41) for all-cause mortality, 1.43 (95% CI, 1.22-1.68) for CVD mortality; the pooled RR in the high CRP group was 1.75 (95% CI, 1.59-1.92) for all-cause mortality, 2.02 (95% CI, 1.70-2.41) for CVD mortality, and 1.32 (95% CI, 1.21-1.45) for cancer mortality.
Conclusions: This meta-analysis demonstrated the relationships between CRP and mortality were nonlinear for all-cause and CVD mortality, and were linear for cancer and non-cardiovascular mortality.
Keywords: C-reactive protein; Cohort studies; Meta-analysis; all-cause mortality; cardiovascular mortality.

Coffee consumption and overall and cause-specific mortality: the Norwegian Women and Cancer Study (NOWAC).
Lukic M, Barnung RB, Skeie G, Olsen KS, Braaten T.
Eur J Epidemiol. 2020 Jul 23. doi: 10.1007/s10654-020-00664-x. Online ahead of print.
PMID: 32705499
Coffee consumption has previously been reported to reduce overall and cause-specific mortality. We aimed to further investigate this association by coffee brewing methods and in a population with heavy coffee consumers. The information on total, filtered, instant, and boiled coffee consumption from self-administered questionnaires was available from 117,228 women in the Norwegian Women and Cancer (NOWAC) Study. We used flexible parametric survival models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause, cardiovascular, and cancer mortality by total coffee consumption and brewing methods, and adjusted for smoking status, number of pack-years, age at smoking initiation, alcohol consumption, body mass index, physical activity, and duration of education. During 3.2 million person-years of follow-up, a total of 16,106 deaths occurred. Compared to light coffee consumers (≤ 1 cup/day), we found a statistically significant inverse association with high-moderate total coffee consumption (more than 4 and up to 6 cups/day, HR 0.89; 95% CI 0.83-0.94) and all-cause mortality. The adverse association between heavy filtered coffee consumption (> 6 cups/day) and all-cause mortality observed in the entire sample (HR 1.09; 95% CI 1.01-1.17) was not found in never smokers (HR 0.85; 95% CI 0.70-1.05). During the follow-up, both high-moderate total and filtered coffee consumption were inversely associated with the risk of cardiovascular mortality (HR 0.79; 95% CI 0.67-0.94; HR 0.80; 95% CI 0.67-0.94, respectively). The association was stronger in the analyses of never smokers (> 6 cups of filtered coffee/day HR 0.20; 95% CI 0.08-0.56). The consumption of more than 6 cups/day of filtered, instant, and coffee overall was found to increase the risk of cancer deaths during the follow-up. However, these associations were not statistically significant in the subgroup analyses of never smokers. The data from the NOWAC study indicate that the consumption of filtered coffee reduces the risk of cardiovascular deaths. The observed adverse association between coffee consumption and cancer mortality is most likely due to residual confounding by smoking.
Keywords: Cancer mortality; Cardiovascular mortality; Coffee; Mortality; Prospective cohort study.

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Comparison between the impact of fermented and unfermented soy intake on the risk of liver cancer: the JPHC Study.
Abe SK, Sawada N, Ishihara J, Takachi R, Mori N, Yamaji T, Shimazu T, Goto A, Iwasaki M, Inoue M, Tsugane S; JPHC Study Group.
Eur J Nutr. 2020 Jul 27. doi: 10.1007/s00394-020-02335-9. Online ahead of print.
PMID: 32719984
Purpose: The aim of this study was to compare the impact of fermented and unfermented soy intake, based on the following soy-derived products: tofu, soymilk, natto, and miso, on the risk of liver cancer among Japanese adults.
Methods: 75,089 Participants of the Japan Public Health Center-based Prospective Study (JPHC Study) were followed from the time of the 5-year follow-up questionnaire until the end of 2012-2013. Subjects with available data on hepatitis B virus (HBV) and hepatitis C virus (HCV) infection status from blood samples (n = 14,016) and those who were anti-HCV antibody (anti-HCV) or hepatitis B virus antigen (HBsAg) positive (n = 1033) were also analyzed separately. Cox proportional hazard models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).
Results: During 1,145,453 person-years, 534 newly diagnosed cases of liver cancer were identified in the JPHC Study. For miso intake among men, the multivariate-adjusted highest versus lowest quartile HR was 0.65 (95% CI, 0.48-0.89); p for trend = 0.006. Results were similar in those who were anti-HCV or HBsAg positive, 0.24 (0.08-0.70); p for trend = 0.004 highest versus lowest tertile. For the sub-analysis among only participants with known hepatitis infection status and HCV and HBsAg adjustment, a similar association was observed. In the multivariate complete cohort analysis, among women, the highest intake of fried tofu was inversely associated with the risk of liver cancer, HR = 0.45 (0.26-0.80); p for trend = 0.014.
Conclusions: We observed no association between total soy intake, fermented and unfermented, and risk of liver cancer, and only an inverse association between miso intake and liver cancer among men.
Keywords: Cohort study; Japan; Liver cancer; Soy.

Alcohol Consumption and the Risk of Prostate Cancer: A Dose-Response Meta-Analysis.
Hong S, Khil H, Lee DH, Keum N, Giovannucci EL.
Nutrients. 2020 Jul 23;12(8):E2188. doi: 10.3390/nu12082188.
PMID: 32717903
Alcohol is widely consumed and is known as a major risk factor for several types of cancers. Yet, it is unclear whether alcohol consumption is associated with the risk of prostate cancer (PCa) or not. We conducted linear and non-linear dose-response meta-analyses of cohort studies on alcohol consumption and PCa risk by types of alcohol (total, wine, beer, and liquor) and PCa (non-aggressive and aggressive). Pubmed and Embase were searched through April 2020 to identify relevant studies. Summary relative risk (RR) and 95% confidence interval (CI) were estimated using a random-effects model. For non-aggressive PCa, by alcohol type, the risk increased linearly with liquor (RR per 14 g/day intake (alcohol content in standard drink) being 1.04 (95% CI = 1.02-1.06, I2 = 0%, three studies) and non-linearly with beer (Pnon-linearity = 0.045, four studies), with increased risk observed in the lower range (RR = 1.03, 95% CI = 1.01-1.05; 14 g/day), with 1.05 (95% CI = 1.01-1.08) at 28 g/day. Wine was not significantly associated with the risk of non-aggressive PCa. For aggressive PCa, a non-linear relationship of diverse shapes was indicated for all types of alcohol in the sensitivity analysis. Compared to non-drinking, a significant positive association was more apparent at lower dose for liquor (RR = 1.12, 95% CI = 1.04-1.20 at 14 g/day; RR = 1.16, 95% CI = 1.03-1.31 at 28 g/day; Pnon-linearity = 0.005, three studies) but at higher doses for wine (RR = 1.02, 95% CI = 0.90-1.16 at 28 g/day, RR = 1.35, 95% CI = 1.08-1.67 at 56 g/day; Pnon-linearity = 0.01, four studies). In contrast, decreased risks were indicated at lower doses of beer (RR = 0.85, 95% CI = 0.79-0.92 at 14 g/day; RR = 0.79, 95% CI = 0.70-0.90 at 28 g/day, Pnon-linearity < 0.001, four studies). Total alcohol consumption was not associated with both types of PCa. In this study, we found heterogeneous associations between alcohol intake and PCa by types of alcohol and PCa.
Keywords: alcohol consumption; alcohol intake; cohort study; dose-response; meta-analysis; prostate cancer.

Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP).
Gustafson DR, Bäckman K, Scarmeas N, Stern Y, Manly JJ, Mayeux R, Gu Y.
Alzheimers Dement. 2020 Jul 27. doi: 10.1002/alz.12154. Online ahead of print.
PMID: 32715635
Introduction: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk.
Methods: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models.
Results: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio {HR} = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05).
Discussion: Higher intake of DHA and EPA are protective for AD.
Keywords: Alzheimer's disease and related dementias (ADRD); DHA; EPA; cholesterol; diet; fatty acids; omega-3; risk factor.

Nocturnal whey protein ingestion impairs postprandial glucose tolerance at breakfast.
Smith ES, Adama E, Clayton K, Holbrey J, Palubiski G, Smith HA, Gonzalez JT, Betts JA.
Br J Nutr. 2020 Jul 27:1-24. doi: 10.1017/S0007114520002901. Online ahead of print.
PMID: 32713395
Poor postprandial glucose control is a risk factor for multiple health conditions. The second-meal effect refers to the progressively improved glycaemic control with repeated feedings, an effect which is achievable with protein ingestion at the initial eating occasion. The most pronounced glycaemic response each day therefore typically occurs following breakfast, so this study investigated whether ingesting protein during the night could improve glucose control at the first meal of the day. In a randomised cross-over design, fifteen adults (7 males, 8 females; age, 22 ± 3 years; BMI, 24.0 ± 2.8 kg·m-2; fasting blood glucose, 4.9 ± 0.5 mmol·L-1) woke at 0400 ± 1 h to ingest 300 ml water with or without 63 g whey protein. Participants then completed a mixed-macronutrient meal tolerance test (1 g carbohydrate·kg body mass-1, 563 ± 104 kcal,) 5 h 39 min following the nocturnal feeding. Nocturnal protein ingestion increased the glycaemic response (incremental area under curve) to breakfast by 43.5 ± 55.5 mmol•120 min•L-1 (p=0.009, d=0.94). Consistent with this effect, individual peak blood glucose concentrations were 0.6 ± 1.0 mmol·L-1 higher following breakfast when protein had been ingested (p=0.049, d=0.50). Immediately prior to breakfast, rates of lipid oxidation were 0.02 ± 0.03 g·min-1 higher (p=0.045) in the protein condition, followed by an elevated postprandial energy expenditure (0.09 ± 0.12 kcal·min-1, p=0.018). Postprandial appetite and energy intake were similar between conditions. This study reveals a paradoxical second-meal phenomenon whereby nocturnal whey protein feeding impaired subsequent glucose tolerance, whilst increasing postprandial energy expenditure.
Keywords: amino acids; carbohydrate; second-meal effect; sleep.

Chronic use of statins and acetylsalicylic acid and incidence of post-ERCP acute pancreatitis: a multicenter, prospective, cohort study.
Cárdenas-Jaén K, Archibugi L, Poropat G, Korpela T, Maisonneuve P, Aparicio JR, Udd M, Stimac D, Arcidiacono PG, De Pretis N, Valente R, Di Giulio E, Casellas JA, Kylänpää L, Hauser G, Mariani A, Gabbrielli A, Löhr M, Vanella G, Rainio M, Brozzi L, Arnelo U, Fagerström N, Capurso G, de-Madaria E.
Dig Endosc. 2020 Jul 25. doi: 10.1111/den.13801. Online ahead of print.
PMID: 32713065
Objectives: post-endoscopic retrograde cholangiopancreatography (ERCP) acute pancreatitis (PEP) is a frequent complication of this endoscopic procedure. Chronic statin intake has been linked to lower incidence and severity of acute pancreatitis (AP). Periprocedural rectal administration of non-steroidal anti-inflammatory drugs is protective against PEP, but the role of chronic acetylsalicylic-acid (ASA) treatment is unclear. We aimed to investigate whether statins and chronic ASA intake are associated with lower risk of PEP.
Methods: an international, multicenter, prospective cohort study. Consecutive patients undergoing ERCP in seven european centers were included. Patients were followed-up to detect those with PEP. Multivariate analysis by means of binary logistic regression was performed, and adjusted odds ratios (aORs) were calculated.
Results: a total of 1,150 patients were included, and 70 (6.1%) patients developed PEP. Among statins users, 8.1% developed PEP vs. 5.4% among non-users (p = 0.09). Multivariate analysis showed no association between statin use and PEP incidence (aOR 1.68 (95% CI 0.94-2.99, p = 0.08). Statin use had no effect on severity of PEP, being mild in 92.0% of statin users vs. 82.2% in non-statin users (p = 0.31). Chronic ASA use was not associated with PEP either (aOR 1.02 (95% CI 0.49-2.13), p = 0.96). Abuse of alcohol and previous endoscopic biliary sphincterotomy were protective factors against PEP, while >1 pancreatic guidewire passage, normal bilirubin values, and duration of the procedure >20 minutes, were risk factors.
Conclusions: the use of statins or ASA is not associated with a lower risk or a milder course of PEP.
Keywords: endoscopic retrograde cholangiopancreatography; hydroxymethylglutaryl-CoA reductase inhibitors; pancreatitis; prevention; salicylates.

Muscle area and density and risk of all-cause mortality: the multi-ethnic study of atherosclerosis.
Larsen B, Bellettiere J, Allison M, McClelland RL, Miljkovic I, Vella C, Ouyang P, De-Guzman KR, Criqui M, Unkart J.
Metabolism. 2020 Jul 23:154321. doi: 10.1016/j.metabol.2020.154321. Online ahead of print.
PMID: 32712219
Background: Lean muscle plays critical roles in physical functioning and metabolism. However, little is known regarding associations between muscle and mortality in adults.
Objective: The purpose was to evaluate associations between abdominal muscle quantity (area) and quality (density) with risk of all-cause mortality in a diverse cohort free of cardiovascular disease.
Design: Data were taken from the Abdominal Body Composition, Inflammation, and Cardiovascular Disease ancillary study of the Multi-Ethnic Study of Atherosclerosis prospective cohort study. Participants were adults (45-85 years) free of extant cardiovascular disease, and of Hispanic, African American, Chinese, or Caucasian descent. Of the original 6814 MESA participants, a random, representative sample (n = 1974) participated in the ancillary body composition study. Abdominal muscle area and density were measured from computed tomography scans spanning L2-L4. Muscle density was measured as attenuation in Hounsfield units, and area was quantified as cm2. Gender-stratified cox proportional hazard models assessed the risk of all-cause mortality across gender-specific quartiles of muscle area and density adjusting for confounders, with area and density entered simultaneously.
Results: At baseline, the mean age for men (n = 946) and women (n = 955) was 61.5 and 62.5 years and median follow-up time was 10.6 and 10.9 years, respectively. Muscle density was inversely associated with mortality, with the highest quartile of density showing a 73% reduction in risk for men (HR = 0.27, 95% CI = 0.14-0.51; p-trend<0.001) and 57% reduction for women (HR = 0.43, 95% CI = 0.18-1.01; p-trend = 0.04) compared to the lowest quartile when adjusting for mortality risk factors, lifestyle, BMI and visceral fat. There was no association between muscle area and all-cause mortality for men (p-trend = 0.58) or women (p-trend = 0.47).
Conclusions: Greater abdominal muscle density, but not muscle area, is associated with markedly lower risk of all-cause mortality across a decade of follow up. Muscle quality may be a powerful predictor of mortality in community dwelling adults.
Keywords: Body composition; Mortality; Muscle quality; Muscle quantity; Myosteatosis; Obesity.

Impact on Longevity of Genetic Cardiovascular Risk and Lifestyle including Red Meat Consumption.
Pereira da Silva A, Costa MDC, Aguiar L, Matos A, Gil Â, Gorjão-Clara J, Polónia J, Bicho M.
Oxid Med Cell Longev. 2020 Jun 30;2020:1305413. doi: 10.1155/2020/1305413. eCollection 2020.
PMID: 32714484 Free PMC article.
Background: Cardiovascular risk (CVR) underlies aging process and longevity. Previous work points to genetic and environmental factors associated with this risk.
Objectives: The aim of this research is to look for any CVR gene-gene and gene-multifactorial/lifestyle interactions that may impact health and disease and underlie exceptional longevity.
Methods: A case-control study involving 521 both gender individuals, 253 centenarians (100.26 ± 1.98 years), and 268 controls (67.51 ± 3.25 years), low (LCR, n = 107) and high (HCR, n = 161) CVR. Hypertension, diabetes, obesity (BMI, kg·m-2), and impaired kidney function were defined according to standard criteria. CVR was calculated using Q risk®. DNA was genotyping (ACE-rs4646994, AGT-rs4762, AGR1-rs5182, GRK4-rs2960306, GRK4-rs1024323, NOS3-rs1799983, and SLC12A3-rs13306673) through iPlex-MassARRAY®, read by MALDI-TOF mass spectrometry, and analyzed by EARTDECODE®.
Results: Antilongevity factors consisted (OR 95% CI, p < 0.05) BMI 1.558 (1.445-1.680), hypertension 2.358 (1.565-3.553), smoking habits 4.528 (2.579-7.949), diabetes 5.553 (2.889-10.675), hypercholesterolemia 1.016 (1.010-1.022), and regular consumption of red meat 22.363 (13.987-35.755). Genetic aspects particularly for HCR individuals ACE II (OR: 3.96 (1.83-8.56), p < 0.0001) and NOS3 TT (OR: 3.11 (1.70-5.70), p < 0.0001) genotypes were also risk associate. Obesity, smoking, hypercholesterolemia, and frequent consumption of red meat have an additive action to hypertension in the longevity process. There was a synergistic interaction between the endothelial NOS3 genotypes and the severity of arterial hypertension. An epistatic interaction between functional genetic variants of GRK4 and angiotensinogen was also observed.
Conclusions: Cardiovascular risk-related genetic and multifactorial or predominantly lifestyle aspects and its interactions might influence the aging process and contribute to exceptional longevity in Portuguese centenarians. Besides lifestyle, the activity of nitrite oxide synthase may be one of the main physiologic regulators of cardiovascular protection in the path of longevity.

Edited by AlPater

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Bicarbonate Unlocks the Ergogenic Action of Ketone Monoester Intake in Endurance Exercise.
Poffé C, Ramaekers M, Bogaerts S, Hespel P.
Med Sci Sports Exerc. 2020 Jul 27. doi: 10.1249/MSS.0000000000002467. Online ahead of print.
PMID: 32735112
Purpose: We recently reported that oral ketone ester (KE) intake before and during the initial 30 min of a ~3h 15 min simulated cycling race (RACE) transiently decreased blood pH and bicarbonate without affecting maximal performance in the final quarter of the event. We hypothesized that acid-base disturbances due to KE overrules the ergogenic potential of exogenous ketosis in endurance exercise.
Methods: Nine well-trained male cyclists participated in a similar RACE consisting of 3h submaximal intermittent cycling (IMT180') followed by a 15-min time-trial (TT15') preceding an all-out sprint at 175% of lactate threshold (SPRINT). In a randomized cross-over design participants received either i) 65g ketone ester (KE), ii) 300 mg/kg body weight NaHCO3 (BIC), iii) KE+BIC or iv) a control drink (CON), together with consistent 60g per h carbohydrate intake.
Results: KE ingestion transiently elevated blood D-ß-hydroxybutyrate to ~2-3 mM during the initial 2 hours of RACE (p< 0.001 vs. CON). In KE, blood pH concomitantly dropped from 7.43 to 7.36 whilst bicarbonate decreased from 25.5 to 20.5 mM (both p<0.001 vs. CON). Additional BIC resulted in 0.5 to 0.8 mM higher blood D-ß-hydroxybutyrate during the first half of IMT180' (p < 0.05 vs. KE) and increased blood bicarbonate to 31.1±1.8 mM and blood pH to 7.51±0.03 by the end of IMT180' (p<0.001 vs. KE). Mean power output during TT15' was similar between KE, BIC and CON at ~255 W, but was 5% higher in KE+BIC (p=0.02 vs. CON). Time-to-exhaustion in the sprint was similar between all conditions at ~60s (p=0.88). Gastrointestinal symptoms were similar between groups.
Discussion: Co-ingestion of oral bicarbonate and KE enhances high-intensity performance at the end of an endurance exercise event without causing gastrointestinal distress.

Metabolic perturbations prior to hepatocellular carcinoma diagnosis - Findings from a prospective observational cohort study.
Stepien M, Keski-Rahkonen P, Kiss A, Robinot N, Duarte-Salles T, Murphy N, Perlemuter G, Viallon V, Tjønneland A, Rostgaard-Hansen AL, Dahm CC, Overvad K, Boutron-Ruault MC, Mancini FR, Mahamat-Saleh Y, Aleksandrova K, Kaaks R, Kühn T, Trichopoulou A, Karakatsani A, Panico S, Tumino R, Palli D, Tagliabue G, Naccarati A, Vermeulen RCH, Bueno-de-Mesquita HB, Weiderpass E, Skeie G, Ramón Quirós J, Ardanaz E, Mokoroa O, Sala N, Sánchez MJ, Huerta JM, Winkvist A, Harlid S, Ohlsson B, Sjöberg K, Schmidt JA, Wareham N, Khaw KT, Ferrari P, Rothwell JA, Gunter M, Riboli E, Scalbert A, Jenab M.
Int J Cancer. 2020 Jul 31. doi: 10.1002/ijc.33236. Online ahead of print.
PMID: 32734650
Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective EPIC cohort (>520 000 participants,), where we identified 129 HCC cases matched 1:1 to controls. We conducted high resolution untargeted liquid chromatography-mass spectrometry based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk; 14 of which were unambiguously identified using pure reference standards. Positive HCC risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, L,L-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid, and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman, and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids, phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
Keywords: hepatocellular carcinoma; prospective observational cohort; untargeted metabolomics.

Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society.
Fontham ETH, Wolf AMD, Church TR, Etzioni R, Flowers CR, Herzig A, Guerra CE, Oeffinger KC, Shih YT, Walter LC, Kim JJ, Andrews KS, DeSantis CE, Fedewa SA, Manassaram-Baptiste D, Saslow D, Wender RC, Smith RA.
CA Cancer J Clin. 2020 Jul 30. doi: 10.3322/caac.21628. Online ahead of print.
PMID: 32729638
The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.
Keywords: cervical neoplasms; cervix neoplasms; guideline; mass screening; prevention and control.

Dietary nicotine intake and risk of Parkinson disease: a prospective study.
Ma C, Molsberry S, Li Y, Schwarzschild M, Ascherio A, Gao X.
Am J Clin Nutr. 2020 Jul 29:nqaa186. doi: 10.1093/ajcn/nqaa186. Online ahead of print.
PMID: 32725131
Background: Tobacco use was observed to be associated with a lower risk of Parkinson disease (PD) in previous epidemiologic studies, with nicotine as a potential candidate. The association between dietary nicotine and PD risk has, however, not been examined in prospective studies yet.
Objectives: We aimed to examine prospectively the association between dietary nicotine intake and subsequent PD risk among never-smokers.
Methods: The current study was based on never-smoker participants from 2 large prospective cohorts: the Nurses' Health Study (n = 31,615) and the Health Professionals Follow-up Study (n = 19,523). The studies contained information on dietary nicotine intake from 1986 from validated FFQs. Dietary nicotine intake was calculated based on consumption of peppers, tomatoes, processed tomatoes, potatoes, and tea. Incident cases of PD were identified via questionnaires and subsequently confirmed by reviewing medical records. We used Cox proportional hazard models to calculate cohort-specific HRs, and used fixed-effects models to calculate the pooled HR.
Results: During 26 y of follow-up, we identified 601 incident PD cases (296 women and 305 men). After adjusting for potential covariates, the pooled HR for the highest compared with the lowest quintile of dietary nicotine intake was 0.70 (95% CI: 0.51, 0.94). The significant inverse association was, however, only observed in women (adjusted HR: 0.64; 95% CI: 0.42, 0.96), not in men (adjusted HR: 0.77; 95% CI: 0.50, 1.20). Further adjusting for environmental tobacco smoke exposure, family history of PD, and use of ibuprofen generated similar significant results in women. Consistently, greater consumption of peppers was associated with lower risk of PD (adjusted HR for ≥5 times/wk compared with ≤3 times/mo: 0.49; 95% CI: 0.25, 0.94) in women but not in men (adjusted HR: 1.04; 95% CI: 0.57, 1.90).
Conclusions: Women with greater dietary nicotine intake had a lower risk of PD than those with lower intake.
Keywords: Parkinson disease; cohort; dietary nicotine; neurodegenerative disease; prospective study.

[Association between high vitamin B12 levels and one year mortality in older people admitted to the hospital].
Valdivia G, Navarrete C, Oñate A, Schmidt B, Fuentes R, Espejo E, Enos D, Fernandez-Bussy I, Labarca G.
Rev Med Chil. 2020 Jan;148(1):46-53. doi: 10.4067/S0034-98872020000100046.
PMID: 32730435 Spanish.
Background: Supplementation of vitamin B12 in older adults is a common practice to avoid vitamin B12 insufficiency. However, there is a paucity of information about the effects of cobalamin excess.
Aim: To asses any potential effects of high levels vitamin B12 on mortality on adults aged ≥ 65 years admitted to an internal medicine service.
Material and methods: We Prospectively studied patients admitted to an internal medicine service of an academic hospital from September 2017 to September 2018, who were able to give their consent and answer questionnaires. We tabulated age, gender, medical history, comorbidity index (Charlson), frailty score (Fried scale), admission diagnosis and blood tests performed within 48 hours of admission. The primary outcome was death by any cause in less of 30 days or after one of year follow up, determined according to death certificates.
Results: We included 93 patients aged 65 to 94 years (53% males). Fifteen patients died during the year of follow up (five within 30 days of admission). Those who died had higher cobalamin levels than survivors (1080.07 ± 788.09 and 656.68 ± 497.33 pg/mL respectively, p = 0.02). Patients who died had also a significantly lower corrected serum calcium, sodium (p = 0.04) and a medical history of chronic liver disease (p = 0.03). In the multivariable analysis, only vitamin B12 preserved the association with mortality (p = 0.009).
Conclusions: There was a significant association between high levels of cobalamin and all-cause mortality in this group of patients aged ≥ 65 years-old.

Associations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages.
Hirata T, Arai Y, Yuasa S, Abe Y, Takayama M, Sasaki T, Kunitomi A, Inagaki H, Endo M, Morinaga J, Yoshimura K, Adachi T, Oike Y, Takebayashi T, Okano H, Hirose N.
Nat Commun. 2020 Jul 30;11(1):3820. doi: 10.1038/s41467-020-17636-0.
PMID: 32732919
Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105-109 years), 288 centenarians (100-104 years), and 531 very old people (85-99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity.

Association between dietary fat intake and mortality from all-causes, cardiovascular disease, and cancer: A systematic review and meta-analysis of prospective cohort studies.
Kim Y, Je Y, Giovannucci EL.
Clin Nutr. 2020 Jul 14:S0261-5614(20)30355-1. doi: 10.1016/j.clnu.2020.07.007. Online ahead of print.
PMID: 32723506
Background & aims: The association between dietary fat and mortality remains inconsistent, and recent results for the association between dietary saturated fat and chronic disease are controversial. To quantitatively assess this association, we conducted a meta-analysis of prospective cohort studies.
Methods: The PubMed and Web of Science were searched up to February 2020. A random effects model was used.
Results: Nineteen studies including 1,013,273participants and 195,515deaths were identified. Significant inverse associations between all-cause mortality and a 5% energy increment in intakes of total (RR = 0.99; 95% CI:0.98-1.00), monounsaturated (RR = 0.98; 95% CI:0.97-0.99), and polyunsaturated fat (RR = 0.93; 95% CI:0.89-0.97) were found. A 5% increase in energy from polyunsaturated fat was associated with 5% (RR = 0.95; 95% CI:0.91-0.98) and 4% (RR = 0.96; 95% CI:0.94-0.99) lower mortality from CVD and cancer, respectively. A 1% energy increment in dietary trans-fat was associated with 6% higher risk of mortality from all-causes (RR = 1.06; 95% CI:1.01-1.10) and CVD (RR = 1.06; 95% CI:1.02-1.11). We found a non-linear association between dietary saturated fat and all-cause mortality showing a significant increased risk up to 11% of energy from saturated fat intake. The risk of cancer mortality increased by 4% for every 5% increase in energy from saturated fat (RR = 1.04; 95% CI:1.02-1.06).
Conclusions: Diets high in saturated fat were associated with higher mortality from all-causes, CVD, and cancer, whereas diets high in polyunsaturated fat were associated with lower mortality from all-causes, CVD, and cancer. Diets high in trans-fat were associated with higher mortality from all-causes and CVD. Diets high in monounsaturated fat were associated with lower all-cause mortality.
Keywords: Dietary fat; Meta-analysis; Mortality; Prospective cohort studies.

High intensity interval training combined with L-citrulline supplementation: Effects on physical performance in healthy older adults.
Buckinx F, Carvalho LP, Marcangeli V, Dulac M, Hajj Boutros G, Gouspillou G, Gaudreau P, Noirez P, Aubertin-Leheudre M.
Exp Gerontol. 2020 Jul 25:111036. doi: 10.1016/j.exger.2020.111036. Online ahead of print.
PMID: 32721549 Review.
Introduction: The aim of this study was to evaluate the effect of citrulline (CIT) supplementation combined to high intensity interval training (HIIT) on physical performance in healthy older adults.
Methods: This study is a secondary analysis from a double-blind, randomized trial. Among the participants (sedentary & inactive older adults aged over 65 yrs), 44 were non obese (BMI <30 kg/m2) and completed the intervention: Placebo + HIIT (PLA; n = 21) or CIT + HIIT (n = 23). All participants ingested either 10 g of CIT supplementation/day or placebo and followed HIIT sessions (30 min/session; cycle: 30 s > 85% of maximal heart rate (HR) and Borg scale >17/20 + 1:50 min at 65% HR and Borg scale between 13 and 16) on an elliptical device 3 times per week over a 12-week period. Body composition, muscle strength, muscle power, functional capacities (unipodal balance; self-paced and fast Timed Up and Go (nTUG; fTUG); chair test; step tests; 4-meter walking test; 6-minute walking test); dietary intake, energy expenditure and biological markers were measured pre and post-intervention. A repeated-measure analysis of variance was used to estimate time (HIIT intervention), group (PLA vs. CIT) and time*group effects.
Results: The decrease in BMI (p = 0.02) and android fat mass (p = 0.05) were significantly greater in the HIIT+CIT group than in the HIIT+PLA group. Finally, a greater increase in self-paced gait speed (nTUG) (p = 0.02) and fast-paced gait speed (fTUG) (p = 0.03) were also observed in the HIIT+CIT group than in the HIIT+PLA group.
Conclusion: CIT supplementation combined to HIIT is more effective in improving functional capacities and body composition in healthy older adults than HIIT alone.
Keywords: Aging; Body composition; Exercise; Mobility; Nutrition.

Higher plasma amyloid-beta levels are associated with a higher risk of cancer: a population-based prospective cohort study.
van der Willik KD, Ghanbari M, Fani L, Compter A, Ruiter R, Stricker BHC, Schagen SB, Ikram MA.
Cancer Epidemiol Biomarkers Prev. 2020 Jul 29:cebp.0167.2020. doi: 10.1158/1055-9965.EPI-20-0167. Online ahead of print.
PMID: 32727725
Background Various studies show an inverse relation between Alzheimer disease (AD) and cancer, but findings are likely to be biased by surveillance and survival bias. Plasma amyloid-β (Aβ) is defined as a preclinical feature of AD, with lower levels of Aβ42 being associated with a higher risk of AD. To get more insight into the biological link between AD and cancer, we investigated plasma Aβ levels in relation to the risk of cancer. Methods Between 2002 and 2005 we measured plasma Aβ40 and Aβ42 levels in 3,949 participants from the population-based Rotterdam Study. These participants were followed for the onset of cancer, all-cause dementia, death, loss to follow-up, or January 1st, 2014, whichever came first. We used Cox proportional hazard models to investigate the association between plasma Aβ40 and Aβ42 levels, and the risk of cancer. Analyses were stratified by cancer site. Results During a median (interquartile range) follow-up of 9.0 years (6.9-10.1), 560 participants were diagnosed with cancer. Higher levels of log2 plasma Aβ40 and Aβ42 were associated with a higher risk of cancer (hazard ratio per standard deviation increase for Aβ40=1.12 [95%CI=1.02;1.23] and Aβ42=1.12 [95%CI=1.03;1.23]). These effect estimates were most pronounced for hematological cancers, urinary tract cancers, and cancers of unknown primary origin. Conclusions We found that higher levels of both plasma Aβ40 and Aβ42 were associated with a higher risk of cancer. Impact Our study suggests a potential biological link between AD and cancer. The pathophysiological role of Aβ in cancer and its causality warrant further investigation.

Beaver and Naked Mole Rat Genomes Reveal Common Paths to Longevity.
Zhou X, Dou Q, Fan G, Zhang Q, Sanderford M, Kaya A, Johnson J, Karlsson EK, Tian X, Mikhalchenko A, Kumar S, Seluanov A, Zhang ZD, Gorbunova V, Liu X, Gladyshev VN.
Cell Rep. 2020 Jul 28;32(4):107949. doi: 10.1016/j.celrep.2020.107949.
PMID: 32726638
Long-lived rodents have become an attractive model for the studies on aging. To understand evolutionary paths to long life, we prepare chromosome-level genome assemblies of the two longest-lived rodents, Canadian beaver (Castor canadensis) and naked mole rat (NMR, Heterocephalus glaber), which were scaffolded with in vitro proximity ligation and chromosome conformation capture data and complemented with long-read sequencing. Our comparative genomic analyses reveal that amino acid substitutions at "disease-causing" sites are widespread in the rodent genomes and that identical substitutions in long-lived rodents are associated with common adaptive phenotypes, e.g., enhanced resistance to DNA damage and cellular stress. By employing a newly developed substitution model and likelihood ratio test, we find that energy and fatty acid metabolism pathways are enriched for signals of positive selection in both long-lived rodents. Thus, the high-quality genome resource of long-lived rodents can assist in the discovery of genetic factors that control longevity and adaptive evolution.
Keywords: aging; beaver; chromosome-level assembly; evolutionary analyses; gene expression; genome; long-lived rodents; longevity; naked mole rat; stress resistance.

The relationship between sleep duration and all-cause mortality in the older people: an updated and dose-response meta-analysis.
He M, Deng X, Zhu Y, Huan L, Niu W.
BMC Public Health. 2020 Jul 28;20(1):1179. doi: 10.1186/s12889-020-09275-3.
PMID: 32723316
Background: Short or long sleep duration is proposed as a potential risk factor for all-cause mortality in the older people, yet the results of published studies are not often reproducible.
Methods: Literature retrieval, study selection and data extraction were completed independently and in duplicate. Only prospective cohort studies were included. Effect-size estimates are expressed as hazard ratio (HR) and 95% confidence interval (CI).
Results: Summary data from 28 articles, involving a total of 95,259 older people, were meta-analyzed. Overall analyses revealed a remarkably significant association between long sleep duration and all-cause mortality (adjusted HR = 1.24, 95% CI: 1.16-1.33, P < .001), whereas only marginal significance was observed for short sleep duration (adjusted HR = 1.04; 95% CI: 1.00-1.09; P = .033). Funnel plots suggested no publication bias for short sleep duration (P = .392). The probability of publication bias was high for long sleep duration (P = .020), yet the trim-and-fill method strengthened its significance in predicting all-cause mortality. In subgroup analyses, the association of long sleep duration with all-cause mortality was statistically significant in both women (HR = 1.48; 95% CI: 1.18-1.86; P = .001) and men (HR = 1.31; 95% CI: 1.10-1.58; P = .003). By contrast, with regard to short sleep duration, statistical significance was observed in men (HR = 1.13; 95% CI: 1.04-1.24; P = .007), but not in women (HR = 1.00; 95% CI: 0.85-1.18; P = .999) (Two-sample Z test P = .099). Besides gender, geographic region, sleep survey method, baseline age and follow-up interval were identified as possible causes of between-study heterogeneity in subgroup analyses. Further dose-response regression analyses revealed that trend estimation was more obvious for long sleep duration (regression coefficient: 0.13; P < .001) than for short sleep duration (regression coefficient: 0.02; P = .046).
Conclusions: Our findings indicate a significantly increased risk of all-cause mortality associated with long sleep duration, especially in women, as well as with short sleep duration in men only.
Keywords: All-cause mortality; Meta-analysis; Older people; Sleep duration.

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The protective effect of pneumococcal vaccination on cardiovascular disease in adults: A systematic review and meta-analysis.
Marra F, Zhang A, Gillman E, Bessai K, Parhar K, Vadlamudi N.
Int J Infect Dis. 2020 Jul 28:S1201-9712(20)30582-8. doi: 10.1016/j.ijid.2020.07.038. Online ahead of print.
PMID: 32735953
Background: Epidemiological studies suggest the existence of a link between pneumococcal infection and adverse cardiovascular outcomes, such as myocardial infarction. Multiple studies have evaluated the protective effect of the 23-valent polysaccharide pneumococcal vaccination (PPV23), but results have varied. Therefore a meta-analysis was conducted to summarize available evidence on the impact of PPV23 on cardiovascular disease.
Methods: A literature search from January 1946 to September 2019 was conducted across Embase, Medline and Cochrane. All studies evaluating PPV23 compared to a control (placebo, no vaccine or another vaccine) for any cardiovascular events including myocardial infarction (MI), heart failure, cerebrovascular events were included. Risk ratios (RRs) were pooled using random effects models.
Results: Eighteen studies were included, with a total of 716,108 participants. Vaccination with PPV23 was associated with decreased risk of any cardiovascular event (RR: 0.91;95% CI: 0.84-0.99), and MI (RR of 0.88; 95% CI:0.79-0.98) in all age groups, with a significant effect in those 65 years and older, but not in the younger age group. Similarly, PPV23 vaccine was associated with significant risk reduction in all-cause mortality in all ages (RR: 0.78; 95%CI: 0.68-0.88), specifically in those aged 65 years and older (RR: 0.71; 95%CI: 0.60-0.84). A significant risk reduction in cerebrovascular disease was not observed following pneumococcal vaccination.
Conclusions: Polysaccharide pneumococcal vaccination decreases the risk for some adverse cardiovascular events, specifically acute MI in the vaccinated population, particularly for those individuals aged 65 years and older. It would be highly beneficial to vaccinate the population who is at greater risk for cardiovascular diseases.
Keywords: PPV23; Streptococcus pneumoniae; cardiovascular disease; cerebrovascular disease; coronary artery disease; death; heart failure; mortality; myocardial infarction; polysaccharide pneumococcal vaccine; stroke; vaccination.

Intakes of Folate, Vitamin B(6), and Vitamin B(12) in Relation to Diabetes Incidence Among American Young Adults: A 30-Year Follow-up Study.
Zhu J, Chen C, Lu L, Yang K, Reis J, He K.
Diabetes Care. 2020 Jul 31:dc200828. doi: 10.2337/dc20-0828. Online ahead of print.
PMID: 32737139
Objective: To prospectively examine intakes of folate, vitamin B6, and vitamin B12 in relation to diabetes incidence in a large U.S. cohort.
Research design and methods: A total of 4,704 American adults aged 18-30 years and without diabetes were enrolled in 1985-1986 and monitored until 2015-2016 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Dietary assessment was conducted by a validated dietary-history questionnaire at baseline, in 1992-1993, and in 2005-2006. The cumulative average intakes of folate, vitamin B6, and vitamin B12 were used in the analyses. Incident diabetes was ascertained by plasma glucose levels, oral glucose tolerance tests, hemoglobin A1c concentrations, and/or antidiabetic medications.
Results: During 30 years (mean 20.5 ± 8.9) of follow-up, 655 incident cases of diabetes occurred. Intake of folate, but not vitamin B6 or vitamin B12, was inversely associated with diabetes incidence after adjustment for potential confounders. Compared with the lowest quintile of total folate intake, the multivariable-adjusted hazard ratios (95% CI) in quintile 2-5 were 0.85 (0.67-1.08), 0.78 (0.60-1.02), 0.82 (0.62-1.09), and 0.70 (0.51-0.97; P trend = 0.02). Higher folate intake was also associated with lower plasma homocysteine (P trend < 0.01) and insulin (P trend < 0.01). Among supplement users, folate intake was inversely associated with serum C-reactive protein levels (P trend < 0.01).
Conclusions: Intake of folate in young adulthood was inversely associated with diabetes incidence in midlife among Americans. The observed association may be partially explained by mechanisms related to homocysteine level, insulin sensitivity, and systemic inflammation.

Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.
Makkar SR, Lipnicki DM, Crawford JD, Kochan NA, Castro-Costa E, Lima-Costa MF, Diniz BS, Brayne C, Stephan B, Matthews F, Llibre-Rodriguez JJ, Llibre-Guerra JJ, Valhuerdi-Cepero AJ, Lipton RB, Katz MJ, Zammit A, Ritchie K, Carles S, Carriere I, Scarmeas N, Yannakoulia M, Kosmidis M, Lam L, Fung A, Chan WC, Guaita A, Vaccaro R, Davin A, Kim KW, Han JW, Suh SW, Riedel-Heller SG, Roehr S, Pabst A, Ganguli M, Hughes TF, Jacobsen EP, Anstey KJ, Cherbuin N, Haan MN, Aiello AE, Dang K, Kumagai S, Narazaki K, Chen S, Ng TP, Gao Q, Nyunt MSZ, Meguro K, Yamaguchi S, Ishii H, Lobo A, Lobo Escolar E, De la Cámara C, Brodaty H, Trollor JN, Leung Y, Lo JW, Sachdev P; for Cohort Studies of Memory in an International Consortium (COSMIC).
Arch Gerontol Geriatr. 2020 Jul 13;91:104112. doi: 10.1016/j.archger.2020.104112. Online ahead of print.
PMID: 32738518
Background: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4).
Methods: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School.
Results: Compared to Elementary, Middle (HR = 0.645, P = 0.004) and High School (HR = 0.472, P < 0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HR = 1.029, P = 0.056) and was stronger in women than men (HR = 1.309, P = 0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HR = 1.047, P = 0.044), and significant among Asian (HR = 0.34, P < 0.001) and Black (HR = 0.382, P = 0.016), but not White, APOE*4 carriers.
Conclusion: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.
Keywords: Age; Ageing; Cognitive decline; Education; Ethnicity; Sex.

Dietary fiber intake and risk of type 2 diabetes in a general Japanese population: the Hisayama Study.
Kimura Y, Yoshida D, Hirakawa Y, Hata J, Honda T, Shibata M, Sakata S, Uchida K, Kitazono T, Ninomiya T.
J Diabetes Investig. 2020 Aug 1. doi: 10.1111/jdi.13377. Online ahead of print.
PMID: 32738819
Aims/introduction: The investigation of the influence of the dietary fiber intake on the incidence of type 2 diabetes in a general Japanese population.
Materials and methods: A total of 1,892 subjects aged 40-79 years without diabetes at baseline were prospectively followed up for 14 years. Glucose tolerance status of subjects was defined by a 75-g oral glucose tolerance test with the criteria of 1998 World Health Organization. Dietary fiber intake was estimated by a semiquantitative food frequency questionnaire and divided to quintile levels separately by gender. A Cox proportional hazards model was applied for computing the hazard ratios and their 95% confidence intervals for the incidence of diabetes.
Results: During the follow-up period, 280 subjects had developed diabetes. The age-adjusted cumulative diabetes incidence decreased significantly with higher total dietary fiber intake (p for trend = 0.01). Subjects in the highest quintile of total dietary fiber intake had a 0.53-times (95% CI 0.31-0.90) lower risk of developing diabetes than those in the lowest quintile after for the adjustment with potential confounding factors. Total dietary fiber intake showed moderate positive correlation to the intake of soybean and soybean products, green vegetables, and other vegetables. Similar associations with diabetes and food sources were observed for both of the soluble and insoluble dietary fiber intake.
Conclusions: The present study showed that higher dietary fiber intake was associated with a lower risk of type 2 diabetes in a general Japanese population. The intake of high dietary fiber foods may be useful for diabetes prevention.
Keywords: Type 2 diabetes; cohort study; dietary fiber.

The Deadly Quartet (Covid-19, old age, lung disease, and heart failure) explain why coronavirus-related mortality in northern Italy was so high.
Calcaterra G, Bassareo PP, Barilla F, Sergi D, Chiocchi M, Romeo F, Mehta JL.
Curr Cardiol Rev. 2020 Jul 31. doi: 10.2174/1573403X16666200731162614. Online ahead of print.
PMID: 32735524
Since its outbreak in China at the end of 2019, the new coronavirus disease (COVID-19) was characterized by both easy spreading and high mortality. The latter proved to be way more elevated in the North of Italy -with a peak of 18.4% in region Lombardia and even 31% in the city of Bergamo and surrounding county- than in the rest of the world. In an attempt of conceptualizing the reasons for a so dramatic situation, four key elements have been identified: COVID-19 itself, old age, lung disease, and heart failure. Their harmful combination has been named "The deadly quartet". The underlying risk factors, of whom a lot of them are distinctive features of the population in northern Italy, have been summarized in "unmodifiable", "partially modifiable", and "modifiable", for the sake of clarity. Up-to-date scientific evidence in this field was described in the form of a narrative and easy-to-read review.
Keywords: COVID-19; Italy; coronavirus; heart Earth's oldest material is older than earth Pandemic changes the course of human history -Anonymous Scientist and Philosopher; lung; mortality.

Prolonged fasting induces long-lasting metabolic consequences in mice.
Pedroso JAB, Wasinski F, Donato J Jr.
J Nutr Biochem. 2020 Jul 3;84:108457. doi: 10.1016/j.jnutbio.2020.108457. Online ahead of print.
PMID: 32738733
To endure prolonged fasting, animals undergo important acute physiological adjustments. However, whether severe fasting also leads to long-term metabolic adaptations is largely unknown. Forty-eight-hour fasting caused a pronounced weight loss in adult C57BL/6 male mice. Seven days of refeeding increased body adiposity to levels above baseline, whereas fasting-induced reductions in lean body mass and energy expenditure were not fully recovered. Respiratory exchange ratio and locomotor activity also remained altered. A fasting/refeeding cycle led to persistent suppression of Pomc mRNA levels and significant changes in the expression of histone deacetylases and DNA methyltransferases in the hypothalamus. Additionally, histone acetylation in the ventromedial nucleus of the hypothalamus was reduced by prolonged fasting and remained suppressed after refeeding. Mice subjected to 48-h fasting 30 days earlier exhibited higher body weight and fat mass compared to aged-matched animals that were never food-deprived. Furthermore, a previous fasting experience altered the changes in body weight, lean mass, energy expenditure and locomotor activity induced by a second cycle of fasting and refeeding. Notably, when acutely exposed to high-palatable/high-fat diet, mice that went through cumulative fasting episodes presented higher calorie intake and reduced energy expenditure and fat oxidation, compared to mice that had never been subjected to fasting. When chronically exposed to high-fat diet, mice that experienced cumulative fasting episodes showed higher gain of body and fat mass and reduced energy expenditure and calorie intake. In summary, cumulative episodes of prolonged fasting lead to hypothalamic epigenetic changes and long-lasting metabolic adaptations in mice.
Keywords: Calorie restriction; Epigenetics; Food Intake; High-fat diet; Hypothalamus; Leptin

Edited by AlPater

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Current intake levels of potatoes and all-cause mortality in China: A population-based nationwide study.
Chen X, Jiao J, Zhuang P, Wu F, Mao L, Zhang Y, Zhang Y.
Nutrition. 2020 Jun 19;81:110902. doi: 10.1016/j.nut.2020.110902. Online ahead of print.
PMID: 32739659
Objective: Current levels of potato consumption in relation to mortality in Chinese people remains unknown. The aim of this study was to investigate the intakes of total potatoes, fried potatoes, non-fried potatoes, and sweet potatoes as dietary carbohydrate sources in relation to all-cause mortality in the China Health and Nutrition Survey (CHNS).
Methods: Overall 14 117 participants ≥20 y of age were included, with a median follow-up of 14 y. The cumulative average consumption of potatoes and other foods were calculated and validated using weighing methods in combination with 3-d, 24-h dietary recalls at both household and individual levels. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models after multivariate adjustment.
Results: We documented 1007 deaths among the participants. The low and moderate intakes of total potatoes, fried potatoes, and non-fried potatoes were inversely associated with mortality. Compared with non-consumers, the intakes of total potatoes (HR, 0.48; 95% CI, 0.38-0.59), fried potatoes (HR, 0.44; 95% CI, 0.34-0.56), and non-fried potatoes (HR, 0.47; 95% CI, 0.37-0.61) at low consumption levels were most significantly related to lower mortality. Sweet potato consumption was inversely associated with mortality after full adjustment (HR, 0.82; 95% CI, 0.69-0.96) compared with non-consumers. Substituting grains and mixed beans for potatoes with equal amounts at high consumption levels strengthened the inverse associations.
Conclusion: In the CHNS, current low and moderate, but not high levels of total potato and fried/non-fried potato consumption as well as sweet potato consumption were inversely associated with all-cause mortality among Chinese people.
Keywords: China Health and Nutrition Survey; Fried/Non-fried potatoes; Mortality; Nationwide; Potatoes; Sweet potatoes.

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Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.
Stoffel NU, Uyoga MA, Mutuku FM, Frost JN, Mwasi E, Paganini D, van der Klis FRM, Malhotra IJ, LaBeaud AD, Ricci C, Karanja S, Drakesmith H, King CH, Zimmermann MB.
Front Immunol. 2020 Jul 13;11:1313. doi: 10.3389/fimmu.2020.01313. eCollection 2020.
PMID: 32754150 Free PMC article.
Background: Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. Methods: We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. Findings: In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk (p = 0.0071, p = 0.0339) and 18 mo (p = 0.0182, p = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk (p = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo (p = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria (p = 0.0484, p = 0.0439) and pneumococcus 19 at 18 mo (p = 0.0199, p = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG (p = 0.0415), seroconversion (p = 0.0531) and IgG avidity (p = 0.0425) at 11.5 mo. Interpretation: In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
Keywords: Kenya; anemia; infancy; iron; iron deficiency; seroconversion; vaccine response.

25-Hydroxyvitamin D status, vitamin D intake, and skin cancer risk: a systematic review and dose-response meta-analysis of prospective studies.
Mahamat-Saleh Y, Aune D, Schlesinger S.
Sci Rep. 2020 Aug 4;10(1):13151. doi: 10.1038/s41598-020-70078-y.
PMID: 32753685
Sun exposure is a major environmental risk factor for skin cancers and is also an important source of vitamin D. However, while experimental evidence suggests that vitamin D may have a protective effect on skin cancer risk, epidemiologic studies investigating the influence of 25-hydroxyvitamin D (25(OH)D) level and/or vitamin D intake on skin cancer risk are conflicting. A systematic review and dose-response meta-analyses of prospective studies was conducted to clarify these associations. Relevant studies were identified by searching the PubMed database up to 30th August 2019. Random effects dose-response meta-analyses were used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Overall, thirteen prospective studies were included. Circulating level of 25(OH)D was associated with higher risks of melanoma (SRR (95% CI) per 30 nmol = 1.42 (1.17-1.72)) and keratinocyte cancer (KC) (SRR (95% CI) per 30 nmol/L = 1.30 (1.13-1.49)). The SRR (95% CI) per 30 nmol/L increase in 25(OH) D level was 1.41 (1.19-1.67), and 1.57 (0.64-3.86), for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), respectively. However, while we found that vitamin D intake (from diet, supplemental and total) was not associated with risks of melanoma and SCC, vitamin D intake was associated with slightly increased BCC risk, albeit with no heterogeneity across skin cancer type. This meta-analysis suggests positive associations between circulating 25(OH)D level and risk of melanoma and KC, however, this finding is most likely confounded by sun exposure. We found no associations between vitamin D intake skin cancers, except positive associations with BCC risk.

Dietary zinc intake and incident chronic kidney disease.
Joo YS, Kim HW, Lee S, Nam KH, Yun HR, Jhee JH, Han SH, Yoo TH, Kang SW, Park JT.
Clin Nutr. 2020 Jul 15:S0261-5614(20)30352-6. doi: 10.1016/j.clnu.2020.07.005. Online ahead of print.
PMID: 32753349
Background & aims: Previous studies have shown that dietary zinc intake is closely related to cardiovascular complications and metabolic derangements. However, the effect of dietary zinc intake on renal function is not fully elucidated.
Methods: Data from the Korean Genome and Epidemiology Study were used. Dietary zinc intake was assessed by a Food Frequency Questionnaire and dietary zinc density was calculated as absolute zinc intake amount per daily energy intake (mg/1000 kcal day). The participants were categorized into quartiles according to dietary zinc density. The primary end point was incident chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2.
Results: A total of 7735 participants with normal renal function was included in the final analysis. The mean age was 52.0 ± 8.8 years, 47.5% were male, and mean eGFR was 92.1 ± 16.1 ml/min/1.73 m2. The mean daily zinc intake and zinc intake density were 8.6 ± 3.4 mg and 4.4 ± 0.9 mg/1000 kcal, respectively. During a median follow up of 11.5 (1.7-12.5) years and 70,617 person-years of observation, CKD developed in 1409 (18.2%) participants. Multivariable cox hazard analysis revealed that risk for CKD development was significantly higher in the quartile with a mean zinc intake density of 3.6 ± 0.2 mg/1000 kcal compared with the quartile with a mean zinc intake density of 5.6 ± 1.0 mg/1000 kcal (Hazard ratio; 1.36; 95% Confidence Interval 1.18-1.58; P < 0.001). This relationship remained significant even after adjustments for confounding factors.
Conclusion: Low dietary zinc intake may increase the risk of CKD development in individuals with normal renal function.
Keywords: Chronic kidney disease; Diet; Glomerular filtration rate; Kidney function; Zinc deficiency.

Is Caloric Restriction Associated with Better Healthy Aging Outcomes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Caristia S, Vito M, Sarro A, Leone A, Pecere A, Zibetti A, Filigheddu N, Zeppegno P, Prodam F, Faggiano F, Marzullo P.
Nutrients. 2020 Jul 30;12(8):E2290. doi: 10.3390/nu12082290.
PMID: 32751664 Review.
Background: Global dietary patterns have gradually shifted toward a 'western type' with progressive increases in rates of metabolic imbalance. Recently, animal and human studies have revealed positive effects of caloric restriction (CR) on many health domains, giving new knowledge for prevention of ill and health promotion; Methods: We conducted a systematic review (SR) of randomized controlled trials (RCTs) investigating the role of CR on health status in adults. A meta-analysis was performed on anthropometric, cardiovascular and metabolic outcomes; Results: A total of 29 articles were retrieved including data from eight RCTs. All included RCTs were at low risk for performance bias related to objective outcomes. Collectively, articles included 704 subjects. Among the 334 subjects subjected to CR, the compliance with the intervention appeared generally high. Meta-analyses proved benefit of CR on reduction of body weight, BMI, fat mass, total cholesterol, while a minor impact was shown for LDL, fasting glucose and insulin levels. No effect emerged for HDL and blood pressure after CR. Data were insufficient for other hormone variables in relation to meta-analysis of CR effects; Conclusion: CR is a nutritional pattern linked to improved cardiometabolic status. However, evidence is limited on the multidimensional aspects of health and requires more studies of high quality to identify the precise impact of CR on health status and longevity.
Keywords: caloric restriction; cardiovascular risk; healthy aging; hormones; longevity; predictors; psychological wellbeing; randomized controlled trials.

Fish Consumption and Coronary Heart Disease: A Meta-Analysis.
Zhang B, Xiong K, Cai J, Ma A.
Nutrients. 2020 Jul 29;12(8):E2278. doi: 10.3390/nu12082278.
PMID: 32751304 Review.
Epidemiological studies on the impact of fish consumption on coronary heart disease (CHD) incidence have shown inconsistent results. In addition, in terms of CHD mortality, although previous meta-analyses showed that fish consumption reduces the risk of CHD, six newly incorporated studies show that fish consumption has no impact on CHD. Therefore, the results still need to be verified. The purpose of this study is to quantitatively evaluate the impact of fish consumption on CHD incidence and mortality. Relevant studies were identified from PubMed, Web of Science, and Embase databases up to October 2019. The multivariate-adjusted relative risks (RRs) for the highest versus the lowest fish consumption categories and the 95% confidence intervals were computed with a random-effect model. A restricted cubic spline regression model was used to assess the dose-response relationship between fish consumption and CHD incidence and mortality. Forty prospective cohort studies were incorporated into research. Among them, 22 studies investigated the association between fish consumption and CHD incidence (28,261 cases and 918,783 participants), and the summary estimate showed that higher fish consumption was significantly associated with a lower CHD incidence [RR: 0.91, 95% CI: (0.84, 0.97); I2 = 47.4%]. Twenty-seven studies investigated the association between fish consumption and CHD mortality (10,568 events and 1,139,553 participants), and the summary estimate showed that higher fish intake was significantly associated with a lower CHD mortality [RR: 0.85, 95% CI: (0.77, 0.94); I2 = 51.3%]. The dose-response analysis showed that the CHD incidence and mortality were reduced by 4%, respectively, with a 20 g/day increment in fish consumption. This meta-analysis indicates that fish consumption is associated with a lower CHD incidence and mortality.
Keywords: coronary heart disease; fish; incidence; meta-analysis; mortality; systematic review.

The effect of maternal seafood consumption on perinatal outcomes: a systematic review and dose-response meta-analysis.
Zhao R, Gao Q, Wang S, Yang X, Hao L.
Crit Rev Food Sci Nutr. 2020 Aug 4:1-14. doi: 10.1080/10408398.2020.1802573. Online ahead of print.
PMID: 32748625
Observational studies have suggested inconsistent results between maternal seafood consumption and the risk of adverse birth outcomes. We aimed to explore the possible dose-response relationship between seafood consumption during pregnancy and perinatal outcomes. A systematic search was performed with the use of PubMed, Web of Science, Embase and Cochrane Library from inception to October 27, 2019. Random-effects model was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Dose-response meta-analysis was carried out by using generalized least-squares regression and restricted cubic splines. Twenty-one studies with a total of 571641 participants were included in the analyses. A 45 g/day increment in seafood consumption was associated with a reduced risk of low birth weight (LBW) (OR: 0.65, 95% CI: 0.47 to 0.90) and small for gestational age (SGA) (OR: 0.84, 95% CI: 0.71 to 0.98). Additionally, there was a non-linear dose-response relationship between maternal seafood consumption and the risk of preterm birth (PTB), with no further benefit observed when intake above 45 g/day. The results for subtypes of seafood showed a modest J-shaped association between fatty fish and PTB, and the lowest risk was observed with the consumption of 30 g/day. In conclusion, higher total seafood consumption during pregnancy was associated with a lower risk of adverse birth outcomes, but the consumption of fatty fish should not exceed 30 grams per day. These findings could provide substantial evidence for dietary recommendations regarding seafood intake for pregnant women. This review was registered in PROSPERO (CRD42020152912).
Keywords: Low birth weight; meta-analysis; preterm birth; seafood; small for gestational age.

New obesity guidelines shift focus to root causes rather than weight loss
Clinicians pushed to recognize any bias they may have against overweight patients
The Canadian Press · Posted: Aug 04, 2020

The effect of fasting and energy restricting diets on markers of glucose and insulin controls: a systematic review and meta-analysis of randomized controlled trials.
Fatahi S, Nazary-Vannani A, Sohouli MH, Mokhtari Z, Kord-Varkaneh H, Moodi V, Tan SC, Low TY, Zanghelini F, Shidfar F.
Crit Rev Food Sci Nutr. 2020 Aug 3:1-12. doi: 10.1080/10408398.2020.1798350. Online ahead of print.
PMID: 32744094
Inconsistencies exist with regard to influence of fasting and energy-restricting diets on markers of glucose and insulin controls. To address these controversial, this study was conducted to determine the impact of fasting diets on fasting blood sugars (FBSs), insulin, homeostatic model assessment insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) levels. A comprehensive systematic search was carried out in electronic databases, i.e., Scopus, PubMed, and Web of Science through June 2019 for RCTs that investigated the impact of fasting and energy-restricting diets on circulating FBS, insulin, HOMA-IR and HbA1c levels from. Weighted mean difference (WMD) with the 95% CI were used for estimating combined effect size. The subgroup analysis was applied to specify the source of heterogeneity among articles. Pooled results from 30 eligible articles with 35 arms demonstrated a significant decrease in FBS (WMD): -3.376 mg/dl, 95% CI: -5.159, -1.594, p < 0.001), insulin (WMD: -1.288 μU/ml, 95% CI: -2.385, -0.191, p = 0.021), HOMA-IR (WMD: -0.41 mg/dl, 95% CI: -0.71, -0.10, p = 0.01) levels following fasting or energy-restricting diets. Nevertheless, no significant changes were observed in serum HbA1c levels. The subgroup analyses showed that overweight or obese people with energy restricting diets and treatment duration >8 weeks had a greater reduction in FBS, insulin and HOMA-IR level compared with other subgroups. The evidence from available studies suggests that the fasting or energy-restricting diets leads to significant reductions in FBS, insulin and HOMA-IR level and has modest, but, non-significant effects on HbA1c levels.
Keywords: Energy restricting; fasting diets; glucose markers; insulin; insulin resistance.

Sleep, brain vascular health and ageing.
Mahalakshmi AM, Ray B, Tuladhar S, Bhat A, Bishir M, Bolla SR, Yang J, Essa MM, Chidambaram SB, Guillemin GJ, Sakharkar MK.
Geroscience. 2020 Aug 3. doi: 10.1007/s11357-020-00235-8. Online ahead of print.
PMID: 32748314 Review.
Sleep maintains the function of the entire body through homeostasis. Chronic sleep deprivation (CSD) is a prime health concern in the modern world. Previous reports have shown that CSD has profound negative effects on brain vasculature at both the cellular and molecular levels, and that this is a major cause of cognitive dysfunction and early vascular ageing. However, correlations among sleep deprivation (SD), brain vascular changes and ageing have barely been looked into. This review attempts to correlate the alterations in the levels of major neurotransmitters (acetylcholine, adrenaline, GABA and glutamate) and signalling molecules (Sirt1, PGC1α, FOXO, P66shc, PARP1) in SD and changes in brain vasculature, cognitive dysfunction and early ageing. It also aims to connect SD-induced loss in the number of dendritic spines and their effects on alterations in synaptic plasticity, cognitive disabilities and early vascular ageing based on data available in scientific literature. To the best of our knowledge, this is the first article providing a pathophysiological basis to link SD to brain vascular ageing.
Keywords: Cognition; Neurochemicals; Sleep deprivation; Synaptic plasticity; Vascular ageing.

Metabolic syndrome is associated with better quality of sleep in the oldest old: results from the "Mugello Study".
Laudisio A, Giovannini S, Finamore P, Navarini L, Margiotta DPE, Vannetti F, Macchi C, Coraci D, Imbimbo I, Molino-Lova R, Loreti C, Antonelli Incalzi R, Zuccalà G, Padua L; Mugello Study Working Group.
Diabetol Metab Syndr. 2020 May 24;12:46. doi: 10.1186/s13098-020-00554-y. eCollection 2020.
PMID: 32742311 Free PMC article.
Background and aims: Reduced sleep quality is common in advanced age. Poor sleep quality is associated with adverse outcomes, chiefly cardiovascular, in young and middle-aged subjects, possibly because of its association with metabolic syndrome (MetS). However, the correlates of sleep quality in oldest populations are unknown. We evaluated the association of sleep quality with MetS in a cohort of subjects aged 90+.
Methods and results: We analysed data of 343 subjects aged 90+ living in the Mugello area (Tuscany, Italy). Quality of sleep was assessed using the Pittsburgh Sleep Quality Assessment Index (PSQI). Good quality of sleep was defined by a PSQI score < 5. MetS was diagnosed according to the National Cholesterol Education Program's ATP-III criteria; 83 (24%) participants reported good quality of sleep. MetS was diagnosed in 110 (24%) participants. In linear and logistic models, MetS was inversely associated with PSQI score ((B = - 1.04; 95% CI - 2.06 to - .03; P = .044), with increased probability of good sleep quality (OR = 2.52; 95% CI 1.26-5.02; P = .009), and with a PSQI below the median (OR = 2.11; 95% CI 1.11-3.40, P = .022), after adjusting. None of the single components of MetS were associated with PSQI (all P values > .050). However, an increasing number of MetS components was associated with increasing probability of good quality of sleep (P for trend = .002), and of PSQI below the median (P for trend = .007). Generalized Additive Model analysis documented no smoothing function suggestive of nonlinear association between PSQI and MetS.
Conclusion: Our results confirm a high prevalence of poor sleep quality in oldest age; however, in these subjects, MetS seems to be associated with better sleep quality. Additional larger, dedicated studies are required to confirm our results, and, if so, to identify the subsystems involved and the potential therapeutic implications of such an association.
Keywords: Geriatric; Metabolic syndrome; Reverse epidemiology; Sleep quality.

Widowhood and mortality: a Danish nationwide register-based cohort study.
Blanner C, Mejldal A, Prina AM, Munk-Jørgensen P, Ersbøll AK, Andersen K.
Epidemiol Psychiatr Sci. 2020 Aug 3;29:e149. doi: 10.1017/S2045796020000591.
PMID: 32744212
Aims: Widowed people have increased mortality compared to married people of the same age. Although most widowed people are of older age, few studies include the oldest old. As life expectancy is increasing, knowledge of widowhood into older age is needed. This study aimed to examine mortality and widowhood in older age by comparing mortality in widowed and married people by sex, age, time since spousal loss and cause of death.
Methods: A Danish register-based matched cohort study of 10% of widowed persons ⩾65 years in the years 2000-2009. For each randomly drawn widowed person, five married persons were matched on sex and age. Mortality rate ratios (MRR) were calculated using Poisson regression, and stratified according to sex and 5-year age intervals. MRRs were furthermore calculated by time since spousal loss and by specific cause of death.
Results: The study included 82 130 persons contributing with 642 914.8 person-years. The overall MRR between widowed and married persons with up to 16 years of follow-up was 1.25 (95% CI 1.23-1.28). At age ⩾95 years for men, and ⩾90 years for women, no differences in mortality rates were seen between widowed and married persons. Mortality in widowed persons was increased for most specific causes of death, with the highest MRR from external causes (MRR 1.53 [1.35-1.74]) and endocrine diseases (MRR 1.51 [1.34-1.70]).
Conclusions: Widowhood was associated with increased mortality in older age for both men and women until age ⩾95 and ⩾90 years, respectively. Increased mortality was observed for almost all causes of death.
Keywords: Bereavement; elderly; geriatric psychiatry; survival analysis.

Improved metabolic function and cognitive performance in middle-aged adults following a single dose of wild blueberry.
Whyte AR, Rahman S, Bell L, Edirisinghe I, Krikorian R, Williams CM, Burton-Freeman B.
Eur J Nutr. 2020 Aug 3. doi: 10.1007/s00394-020-02336-8. Online ahead of print.
PMID: 32747995
Purpose: Research has demonstrated cognitive benefits following acute polyphenol-rich berry consumption in children and young adults. Berry intake also has been associated with metabolic benefits. No study has yet examined cognitive performance in middle-aged adults. We investigated the relationships among cognitive and metabolic outcomes in middle-aged adults following wild blueberry (WBB) consumption.
Methods: Thirty-five individuals aged 40-65 years participated in a randomized, double blind, cross-over study. Participants consumed a breakfast meal and 1-cup equivalent WBB drink or matched placebo beverage on two occasions. Participants completed cognitive tasks and had blood drawn before and at regular intervals for 8 h after each meal/treatment. Changes in episodic memory and executive function (EF) were assessed alongside plasma levels of glucose, insulin, and triglyceride.
Results: Analysis of the memory-related Auditory Verbal Learning Task (AVLT) word recognition measure revealed a decrease in performance over the test day after placebo intake, whereas performance after WBB was maintained. For the AVLT word rejection measure, participants identified more foils following WBB in comparison to placebo. Benefits were also observed for EF on the Go/No-Go task with fewer errors following WBB intake on cognitively demanding invalid No-Go trials in comparison to placebo. Furthermore, in comparison to placebo, response times were faster for the Go/No-Go task, specifically at 4 h and 8 h following WBB treatment. We also observed reduced post-meal glucose and insulin, but not triglyceride, concentrations in comparison to placebo over the first 2 h following ingestion. Though the addition of Age, BMI, glucose and insulin as covariates to the analysis reduced the significant effect of beverage for AVLT word rejection, metabolic outcomes did not interact with treatment to predict cognitive performance with the exception of one isolated trend.
Conclusions: This study indicated acute cognitive benefits of WBB intake in cognitively healthy middle-aged individuals, particularly in the context of demanding tasks and cognitive fatigue. WBB improved glucose and insulin responses to a meal. Further research is required to elucidate the underlying mechanism by which WBB improves cognitive function.
Keywords: Cognition; Executive function; Fruit; Glucose; Insulin; Polyphenols; Wild blueberry.

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Randomised clinical study: oral aspirin 325 mg daily vs placebo alters gut microbial composition and bacterial taxa associated with colorectal cancer risk.
Prizment AE, Staley C, Onyeaghala GC, Vivek S, Thyagarajan B, Straka RJ, Demmer RT, Knights D, Meyer KA, Shaukat A, Sadowsky MJ, Church TR.
Aliment Pharmacol Ther. 2020 Aug 8. doi: 10.1111/apt.16013. Online ahead of print.
PMID: 32770859
Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome.
Aims: To evaluate the effect of aspirin on the gut microbiome in a double-blinded, randomised placebo-controlled pilot trial.
Methods: Healthy volunteers aged 50-75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks. Serial measurements of gut microbial community composition and bacterial abundance were derived from 16S rRNA sequences. Linear discriminant analysis of effect size (LEfSe) was tested for between-arm differences in bacterial abundance. Mixed-effect regression with binomial distribution estimated the effect of aspirin use on changes in the relative abundance of individual bacterial taxa via an interaction term (treatment × time).
Results: Over the study period, there were differences in microbial composition in the aspirin vs placebo arm. After treatment, four taxa were differentially abundant across arms: Prevotella, Veillonella, Clostridium XlVa and Clostridium XVIII clusters. Of pre-specified bacteria associated with CRC (n = 😎 or aspirin intake (n = 4) in published studies, interactions were significant for four taxa, suggesting relative increases in Akkermansia, Prevotella and Ruminococcaceae and relative decreases in Parabacteroides, Bacteroides and Dorea in the aspirin vs placebo arm.
Conclusion: Compared to placebo, aspirin intake influenced several microbial taxa (Ruminococcaceae, Clostridium XlVa, Parabacteroides and Dorea) in a direction consistent with a priori hypothesis based on their association with CRC. This suggests that aspirin may influence CRC development through an effect on the gut microbiome. The findings need replication in a larger trial.

The Impact of Alcohol Intake on Atrial Fibrillation.
Voskoboinik A, Marcus GM.
Curr Cardiol Rep. 2020 Aug 8;22(10):111. doi: 10.1007/s11886-020-01369-z.
PMID: 32770492 Review.
Purpose of review: To evaluate (1) the impact of acute and habitual alcohol consumption on atrial fibrillation (AF) and atrial remodeling and (2) the role of alcohol reduction and/or abstinence in the primary and secondary prevention of AF.
Recent findings: Acute alcohol consumption appears to be a common AF trigger, with animal and human studies demonstrating changes in electrophysiological parameters, autonomic tone, and cellular properties expected to promote AF. Habitual consumption is associated with adverse atrial remodeling, higher risk of incident AF, and AF recurrence. Randomized data suggest that reduction in excessive alcohol consumption may reduce the risk of recurrent AF episodes and AF burden. Alcohol is an increasingly recognized risk factor for both new onset AF and discrete AF episodes. Excessive consumption should be avoided for primary and secondary prevention of AF.
Keywords: Alcohol; Atrial fibrillation; Binge drinking; Left atrium; Lifestyle; Remodeling.

Comparison of Postsurgical Scars Between Vegan and Omnivore Patients.
Fusano M, Fusano I, Galimberti MG, Bencini M, Bencini PL.
Dermatol Surg. 2020 Aug 3. doi: 10.1097/DSS.0000000000002553. Online ahead of print.
PMID: 32769530
Background: Postsurgical skin healing can result in different scars types, ranging from a fine line to pathologic scars, in relation to patients' intrinsic and extrinsic factors. Although the role of nutrition in influencing skin healing is known, no previous studies investigated if the vegan diet may affect postsurgical wounds.
Objective: The aim of this study was to compare surgical scars between omnivore and vegan patients.
Methods and materials: This is a prospective observational study. Twenty-one omnivore and 21 vegan patients who underwent surgical excision of a nonmelanoma skin cancer were enrolled. Postsurgical complications and scar quality were evaluated using the modified Scar Cosmesis Assessment and Rating (SCAR) scale.
Results: Vegans showed a significantly lower mean serum iron level (p < .001) and vitamin B12 (p < .001). Wound diastasis was more frequent in vegans (p = .008). After 6 months, vegan patients had a higher modified SCAR score than omnivores (p < .001), showing the worst scar spread (p < .001), more frequent atrophic scars (p < .001), and worse overall impression (p < .001).
Conclusion: This study suggests that a vegan diet may negatively influence the outcome of surgical scars.

Effects of high versus standard essential amino acid intakes on whole-body protein turnover and mixed muscle protein synthesis during energy deficit: A randomized, crossover study.
Gwin JA, Church DD, Hatch-McChesney A, Howard EE, Carrigan CT, Murphy NE, Wilson MA, Margolis LM, Carbone JW, Wolfe RR, Ferrando AA, Pasiakos SM.
Clin Nutr. 2020 Jul 22:S0261-5614(20)30384-8. doi: 10.1016/j.clnu.2020.07.019. Online ahead of print.
PMID: 32768315
Background & aims: Consuming 0.10-0.14 g essential amino acids (EAA)/kg/dose (0.25-0.30 g protein/kg/dose) maximally stimulates muscle protein synthesis (MPS) during energy balance. Whether consuming EAA beyond that amount enhances MPS and whole-body anabolism following energy deficit is unknown. The aims of this study were to determine the effects of standard and high EAA ingestion on mixed MPS and whole-body protein turnover following energy deficit.
Design: Nineteen males (mean ± SD; 23 ± 5 y; 25.4 ± 2.7 kg/m2) completed a randomized, double-blind crossover study consisting of two, 5-d energy deficits (-30 ± 4% of total energy requirements), separated by 14-d. Following each energy deficit, mixed MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET) were determined at rest and post-resistance exercise (RE) using primed, constant L-[2H5]-phenylalanine and L-[2H2]-tyrosine infusions. Beverages providing standard (0.1 g/kg, 7.87 ± 0.87 g) or high (0.3 g/kg, 23.5 ± 2.54 g) EAA were consumed post-RE. Circulating EAA were measured.
Results: Postabsorptive mixed MPS (%/h) at rest was not different (P = 0.67) between treatments. Independent of EAA, postprandial mixed MPS at rest (standard EAA, 0.055 ± 0.01; high EAA, 0.061 ± 0.02) and post-RE (standard EAA, 0.055 ± 0.01; high EAA, 0.065 ± 0.02) were greater than postabsorptive mixed MPS at rest (P = 0.02 and P = 0.01, respectively). Change in (Δ postabsorptive) whole-body (g/180 min) PS and PB was greater for high than standard EAA [mean treatment difference (95% CI), 3.4 (2.3, 4.4); P = 0.001 and -15.6 (-17.8, -13.5); P = 0.001, respectively]. NET was more positive for high than standard EAA [19.0 (17.3, 20.7); P = 0.001]. EAA concentrations were greater in high than standard EAA (P = 0.001).
Conclusions: These data demonstrate that high compared to standard EAA ingestion enhances whole-body protein status during underfeeding. However, the effects of consuming high and standard EAA on mixed MPS are the same during energy deficit.
Clinical trial registry: NCT03372928, https://clinicaltrials.gov.
Keywords: Energy deficit; Essential amino acids; Muscle protein synthesis; Protein; Whole-body protein turnover.

Inequalities in Life Expectancy and All-Cause Mortality in the United States by Levels of Happiness and Life Satisfaction: A Longitudinal Study.
Lee H, Singh GK.
Int J MCH AIDS. 2020;9(3):305-315. doi: 10.21106/ijma.392. Epub 2020 Jul 26.
PMID: 32765961 Free PMC article.
Background: Despite having one of the highest Gross Domestic Product (GDP) per capita levels, United States (US) ranks lower in subjective well-being, including happiness and life satisfaction, compared with European countries. Studies of the impact of happiness and life satisfaction on life expectancy and mortality in the US are limited or non-existent. Using a national longitudinal dataset, we examined the association between levels of happiness/life satisfaction and US life expectancy and all-cause mortality.
Methods: We analyzed the 2001 National Health Interview Survey (NHIS) prospectively linked to 2001-2014 mortality records in the National Death Index (NDI) (N=30,377). Cox proportional hazards regression was used to model survival time as a function of happiness, life satisfaction, and sociodemographic and behavioral covariates.
Results: Life expectancies at age 18 among adults with high levels of happiness and life satisfaction were, respectively, 7.5 and 8.9 years higher compared to those with low levels of happiness and life satisfaction. In Cox models with 14 years of mortality follow-up, all-cause mortality risk was 82% higher (hazard ratio

=1.82; 95% CI=1.59,2.08) in adults with little or no happiness, controlling for age, and 36% higher (HR=1.36; 95% CI=1.17,1.57) in adults with little/no happiness, controlling for sociodemographic, behavioral and health characteristics, when compared with adults reporting happiness all of the time. Mortality risk was 107% higher (HR=2.07; 95% CI=1.80,2.38) in adults who were very dissatisfied with their life, controlling for age, and 39% higher (HR=1.39; 95% CI=1.20,1.60) in adults who were very dissatisfied, controlling for all covariates, when compared with adults who were very satisfied.
Conclusions and global health implications: Adults with higher happiness and life satisfaction levels had significantly higher life expectancy and lower all-cause mortality risks than those with lower happiness and satisfaction levels. These findings underscore the significance of addressing subjective well-being in the population as a strategy for reducing all-cause mortality.
Keywords: Disparities; Happiness; Inequalities; Life expectancy; Life satisfaction; Longitudinal; Mortality; Social determinants.

Relationship Between Muscle-Strengthening Activity and Cause-Specific Mortality in a Large US Cohort.
Patel AV, Hodge JM, Rees-Punia E, Teras LR, Campbell PT, Gapstur SM.
Prev Chronic Dis. 2020 Aug 6;17:E78. doi: 10.5888/pcd17.190408.
PMID: 32762807
Introduction: Muscle-strengthening activity (MSA) has beneficial effects on hypertension, glucose homeostasis, and other health conditions; however, its association with mortality is not as well understood.
Methods: We analyzed data from the Cancer Prevention Study-II Nutrition Cohort (data collection 1982-2014), a prospective US cohort that consisted of 72,462 men and women who were free of major chronic diseases; 18,034 of the cohort died during 13 years of follow-up (2001-2014). We used Cox proportional hazards modeling, controlling for various potential confounding factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for MSA (none, >0 to <1 h/wk, 1 to <2 h/wk, and ≥2 h/wk) in relation to mortality risk, independent of and in combination with aerobic physical activity.
Results: The association between MSA and mortality appeared to be nonlinear (quadratic trend P value, <.001). After multivariable adjustment and comparison with no MSA, engaging in less than 2 hours per week of MSA was associated with lowered all-cause mortality (>0 to <1 h/wk: HR = 0.88, 95% CI, 0.82-0.94; 1 to <2 h/wk: HR = 0.90, 95% CI, 0.84-0.97), but engaging in 2 or more hours per week was not associated with reduced risk (HR = 1.01; 95% CI, 0.92-1.09). Associations were similar but not significant for cancer mortality. Engaging in >0 to <1 hr/wk of MSA was associated with a 19% lower risk (HR = 0.81; 95% CI, 0.71-0.92) of cardiovascular disease mortality, but more time spent in MSA was not associated with reduced risk (quadratic trend P value =.005). Associations did not vary by amount of moderate-to-vigorous aerobic physical activity.
Conclusion: Engaging in ≥2 hours per week of MSA was associated with lower all-cause mortality, independent of aerobic activity. Reasons for the lack of association with higher amounts of MSA are unclear. Our findings support recommending muscle-strengthening activities for overall health.

β-Hydroxybutyrate Suppresses Lipid Accumulation in Aged Liver through GPR109A-mediated Signaling.
Lee AK, Kim DH, Bang E, Choi YJ, Chung HY.
Aging Dis. 2020 Jul 23;11(4):777-790. doi: 10.14336/AD.2019.0926. eCollection 2020 Jul.
PMID: 32765945 Free PMC article.
Dietary interventions such as prolonged calorie restriction (CR) and intermittent fasting provide health benefits including a reduction in the inflammatory burden and regulation of energy metabolism. During CR, β-hydroxybutyrate (BHB) level is elevated in the serum. BHB is a ligand of GPR109A, which inhibits lipolysis and exerts anti-inflammatory effects on cells. During aging, comorbidities related to dyslipidemia are significantly associated with fatty liver. However, the underlying mechanisms of BHB in hepatic ER stress and dyslipidemia are unclear and remain to be elucidated. Here, we used aged rats that were administered with BHB and compared the modulatory effects of BHB through the GPR109A/AMPK pathway on the hepatic endoplasmic reticulum (ER) stress and lipid accumulation to CR rats. BHB caused suppression of hepatic ER stress and lipid accumulation through GPR109A/AMPK pathway in the aged rats. Aged rats of both treatment groups showed reduced cAMP level and PKA phosphorylation. Furthermore, AMPK-Ser173 phosphorylation via PKA was decreased, whereas AMPK-Thr172 phosphorylation was increased by BHB and CR. Further supporting evidence was provided in HepG2 cells that BHB inhibited ER stress and lipid accumulation induced by palmitate. These results suggest that BHB activates GPR109A and regulates the activation of AMPK. These findings were further confirmed by GPR109A-siRNA transfection in vitro. In addition, BHB treatment elevated the protein levels of AMPK leading to significant inhibition of hepatic steatosis, whereas AMPK-siRNA treatment abolished these effects. Taken together, these findings suggest that BHB could be a effective molecule that mimics CR in ameliorating age-related hepatic lipid accumulation via GPR109A signaling pathway.
Keywords: AMPK; ER stress; GPR109A; aged liver; lipid accumulation; β-hydroxybutyrate.

Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea
Seungjae Lee, MD1; Tark Kim, MD2; Eunjung Lee, MD1; et alCheolgu Lee, MD3; Hojung Kim, MD4; Heejeong Rhee, MD5; Se Yoon Park, MD1; Hyo-Ju Son, MD1; Shinae Yu, MD6; Jung Wan Park, MD6; Eun Ju Choo, MD2; Suyeon Park, MS7; Mark Loeb, MD8; Tae Hyong Kim, MD1
Author Affiliations Article Information
JAMA Intern Med. Published online August 6, 2020. doi:10.1001/jamainternmed.2020.3862
COVID-19 Resource Center
Key Points
Question  Are there viral load differences between asymptomatic and symptomatic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection?
Findings  In this cohort study that included 303 patients with SARS-CoV-2 infection isolated in a community treatment center in the Republic of Korea, 110 (36.3%) were asymptomatic at the time of isolation and 21 of these (19.1%) developed symptoms during isolation. The cycle threshold values of reverse transcription–polymerase chain reaction for SARS-CoV-2 in asymptomatic patients were similar to those in symptomatic patients.
Meaning  Many individuals with SARS-CoV-2 infection remained asymptomatic for a prolonged period, and viral load was similar to that in symptomatic patients; therefore, isolation of infected persons should be performed regardless of symptoms.
Importance  There is limited information about the clinical course and viral load in asymptomatic patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objective  To quantitatively describe SARS-CoV-2 molecular viral shedding in asymptomatic and symptomatic patients.
Design, Setting, and Participants  A retrospective evaluation was conducted for a cohort of 303 symptomatic and asymptomatic patients with SARS-CoV-2 infection between March 6 and March 26, 2020. Participants were isolated in a community treatment center in Cheonan, Republic of Korea.
Main Outcomes and Measures  Epidemiologic, demographic, and laboratory data were collected and analyzed. Attending health care personnel carefully identified patients’ symptoms during isolation. The decision to release an individual from isolation was based on the results of reverse transcription–polymerase chain reaction (RT-PCR) assay from upper respiratory tract specimens (nasopharynx and oropharynx swab) and lower respiratory tract specimens (sputum) for SARS-CoV-2. This testing was performed on days 8, 9, 15, and 16 of isolation. On days 10, 17, 18, and 19, RT-PCR assays from the upper or lower respiratory tract were performed at physician discretion. Cycle threshold (Ct) values in RT-PCR for SARS-CoV-2 detection were determined in both asymptomatic and symptomatic patients.
Results  Of the 303 patients with SARS-CoV-2 infection, the median (interquartile range) age was 25 (22-36) years, and 201 (66.3%) were women. Only 12 (3.9%) patients had comorbidities (10 had hypertension, 1 had cancer, and 1 had asthma). Among the 303 patients with SARS-CoV-2 infection, 193 (63.7%) were symptomatic at the time of isolation. Of the 110 (36.3%) asymptomatic patients, 21 (19.1%) developed symptoms during isolation. The median (interquartile range) interval of time from detection of SARS-CoV-2 to symptom onset in presymptomatic patients was 15 (13-20) days. The proportions of participants with a negative conversion at day 14 and day 21 from diagnosis were 33.7% and 75.2%, respectively, in asymptomatic patients and 29.6% and 69.9%, respectively, in symptomatic patients (including presymptomatic patients). The median (SE) time from diagnosis to the first negative conversion was 17 (1.07) days for asymptomatic patients and 19.5 (0.63) days for symptomatic (including presymptomatic) patients (P = .07). The Ct values for the envelope (env) gene from lower respiratory tract specimens showed that viral loads in asymptomatic patients from diagnosis to discharge tended to decrease more slowly in the time interaction trend than those in symptomatic (including presymptomatic) patients (β = −0.065 [SE, 0.023]; P = .005).
Conclusions and Relevance  In this cohort study of symptomatic and asymptomatic patients with SARS-CoV-2 infection who were isolated in a community treatment center in Cheonan, Republic of Korea, the Ct values in asymptomatic patients were similar to those in symptomatic patients. Isolation of asymptomatic patients may be necessary to control the spread of SARS-CoV-2.

Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span
Ke Zou1,2,3, View ORCID ProfileSilvia Rouskin4, Kevin Dervishi5, Mark A. McCormick6,7, Arjun Sasikumar8, Changhui Deng1, View ORCID ProfileZhibing Chen9, View ORCID ProfileMatt Kaeberlein10, View ORCID ProfileRachel B. Brem8, View ORCID ProfileMichael Polymenis11, View ORCID ProfileBrian K. Kennedy8,12,13,14, View ORCID ProfileJonathan S. Weissman4, View ORCID ProfileJiashun Zheng1,*, View ORCID ProfileQi Ouyang2,3,* and View ORCID ProfileHao Li1,*,†
Science Advances  05 Aug 2020:
Vol. 6, no. 32, eaba1306
DOI: 10.1126/sciadv.aba1306
Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR.

Low mercury, cadmium and lead concentrations in tuna products from the eastern Pacific.
Ormaza-González FI, Ponce-Villao GE, Pin-Hidalgo GM.
Heliyon. 2020 Jul 28;6(7):e04576. doi: 10.1016/j.heliyon.2020.e04576. eCollection 2020 Jul.
PMID: 32760843 Free PMC article.
Tuna species: Skipjack (Katsuwonus pelamis), yellowfin (Thunnus albacares) and bigeye (Thunnus obesus) are mainly processed into canned products (loins, solid pack, flakes) either in water or oil, and pre-cooked frozen loins. The National Institute of Fisheries of Ecuador (ISO/IEC 17025 certified), which is the official control laboratory, samples and analyses production batches of companies exporting to the European Union in order to ensure the quality control of Ecuadorean tuna product. From 2009 to 2016, 2572 samples have been analysed (by standard methods) for mercury, cadmium, and lead. The averages were 0.24 ± 0.14; 0.03 ± 0.03 and 0.05 ± 0.05 mg kg-1 (wet weight) respectively; which are well below the norms; i.e., total mercury: 1 mg kg-1; Lead: 0.3 mg kg-1 and Cadmium: 0.1 mg kg-1 according to the EU maximum limits. Over time mercury levels in the sample seemed to decrease but for cadmium and lead no clear pattern was observed. Additionally; samples of tuna can products taken at random from local vendor stores gave concentrations of: Mercury: 0.043 ± 0.004 mg kg-1; Cadmium: 0.012 ± 0.002 mg kg-1; Lead: below detection limit (0.01 mg kg-1). There were a few cases (15 out of 2572: 0.58%) of samples with readings near or just over-limit concentrations; of these, 12 corresponded to Cd, two to Pb and one to Hg. Some of them can be considered statistical outliers as well as cross contamination during analytical procedures. Raw tuna samples have given similar or lower concentrations. No significant statistical correlation was found between Hg, Cd and Pb values, this would suggest that the bioaccumulation of each metal is independent of each other. Literature reports that surface dissolved Hg, Cd, and Pb in the eastern Pacific are in the range of 2-18 ng kg-1. Assuming suggested bioaccumulation of 2-6 times, the end concentration in the tuna would be 0.012-0.042; 0.036-0.108 and 0.010-0.027 μg kg-1 of Hg, Cd, and Pb respectively, that would be one order (or more) below the safe consumption limit. Most, if not all the tuna processed in Ecuador is captured in the eastern Pacific and within its EEZ. Ecuadorian canned tuna complies with stringent standards for presence of these metals; therefore, it can be considered safe to be consumed from the point of view of these metal concentrations. However, further studies should assess metal concentrations exclusively from Ecuadorian tuna captured close to coastal and insular areas.
Keywords: Cadmium; Eastern Pacific; Ecuador; Environmental science; Food analysis; Food science; Lead; Mercury; Tuna.

Does high dietary protein intake contribute to the increased risk of developing prediabetes and type 2 diabetes?
Ancu O, Mickute M, Guess ND, Hurren NM, Burd NA, Mackenzie RWA.
Appl Physiol Nutr Metab. 2020 Aug 5. doi: 10.1139/apnm-2020-0396. Online ahead of print.
PMID: 32755490
Insulin resistance is a complex metabolic disorder implicated in the development of many chronic diseases. While it is generally accepted that body mass loss should be the primary approach for the management of insulin-resistance related disorders in overweight and obese individuals, there is no consensus among researchers regarding optimal protein intake during dietary restriction. Recently, it has been suggested that increased plasma branched-chain amino acid (BCAAs) concentrations are associated with the development of insulin resistance and T2D. The exact mechanism by which excessive amino acid availability may contribute to insulin resistance has not been fully investigated. However, it has been hypothesised that mammalian target of rapamycin complex 1 (mTORC1) hyperactivation in the presence of amino acid overload contributes to reduced insulin-stimulated glucose uptake due to insulin receptor substrate (IRS) degradation and reduced Akt-AS160 activity. In addition, the long-term effects of high-protein diets on insulin sensitivity during both weight stable and weight loss conditions require more research. This review focusses on the effects of high-protein diets on insulin sensitivity and discusses the potential mechanisms by which dietary amino acids can affect insulin signaling. Novelty bullet: ●Excess amino acids may over-activate mTOR, resulting in desensitisation of IRS-1 and reduced insulin-mediated glucose uptake.

Aspirin associated with a decreased incidence of uterine cancer: A retrospective population-based cohort study.
Li PC, Sung FC, Yang YC, Chen W, Wang JH, Lin SZ, Ding DC.
Medicine (Baltimore). 2020 Jul 31;99(31):e21446. doi: 10.1097/MD.0000000000021446.
PMID: 32756162
Aspirin (ASA) exerts an anti-tumor effect via the COX pathway. Clinical studies on the chemopreventive effects of ASA on uterine cancer (UC) remain inconsistent. We used population-based retrospective cohort study to evaluate the UC in ASA users in Taiwanese women. From insurance claims data, we identified 23,342 women received ASA treatment between 2000 and 2010 and a comparison group of same sample size randomly selected from the same database matched by the propensity score. The incidence of UC in the ASA cohort was 10% of that in the comparison group (0.28 vs 2.73 per 10,000 person-years). The Poisson regression analysis estimated adjusted incidence rate ratio (IRR) was 0.10 (95% confidence interval (CI) = 0.09-0.11) for ASA users relatives to comparisons after controlling for covariates. The UC incidence in ASA users decreased with age, from 0.61 per 10,000 person-years in the 20 to 39 years old (adjusted IRR = 0.21, 95% CI = 0.15-0.29) to 0.21 per 10,000 person-years in the 65 to 80 years old (adjusted IRR = 0.15, 95% CI = 0.12-0.16). The incidence was higher in longer term users. Hormone therapy of estradiol was associated with the increase of UC risk in both cohorts, but less in ASA users than comparisons (1.34 vs 4.75 per 10,000 person-years). This study suggests that ASA use was associated with a decreased risk of UC. Further prospective randomized clinical trials are warranted to confirm the association.

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Grain and dietary fiber intake and bladder cancer risk: a pooled analysis of prospective cohort studies.
Yu EYW, Wesselius A, Mehrkanoon S, Brinkman M, van den Brandt P, White E, Weiderpass E, Le Calvez-Kelm F, Gunter M, Huybrechts I, Liedberg F, Skeie G, Tjonneland A, Riboli E, Giles GG, Milne RL, Zeegers MP.
Am J Clin Nutr. 2020 Aug 10:nqaa215. doi: 10.1093/ajcn/nqaa215. Online ahead of print.
PMID: 32778880
Background: Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer.
Objectives: Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber.
Methods: We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose-response relations were examined using fractional polynomial regression models.
Results: We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose-response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism.
Conclusions: Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings.
Keywords: bladder cancer; cohort study; dietary fiber; dose-response analysis; grain.

Effect of aspirin on cancer incidence and mortality in older adults.
McNeil JJ, Gibbs P, Orchard SG, Lockery JE, Bernstein WB, Cao Y, Ford L, Haydon A, Kirpach B, Macrae F, McLean C, Millar J, Murray AM, Nelson MR, Polekhina G, Reid CM, Richmond E, Rodríguez LM, Shah RC, Tie J, Umar A, van Londen GJ, Ronaldson K, Wolfe R, Woods RL, Zalcberg J, Chan AT; ASPREE Investigator Group.
J Natl Cancer Inst. 2020 Aug 11:djaa114. doi: 10.1093/jnci/djaa114. Online ahead of print.
PMID: 32778876
Background: ASPirin in Reducing Events in the Elderly (ASPREE), a randomized double-blind placebo-controlled trial (RCT) of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast prior RCTs, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.
Methods: 19,114 Australian and U.S. community-dwelling participants aged 70+ years (U.S. minorities 65+ years) without cardiovascular disease, dementia or physical disability were randomized and followed for a median of 4.7 years. Fatal and non-fatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.
Results: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (HR = 1.04, 95% CI = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).
Conclusions: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and thus, suggest caution with its use in this age group.

Association Between Coffee Consumption and Functional Disability in the U.S. Older Adults.
Wang T, Wu Y, Wang W, Zhang D.
Br J Nutr. 2020 Aug 11:1-19. doi: 10.1017/S0007114520003153. Online ahead of print.
PMID: 32778181
The effect of coffee consumption on functional disability has been scarcely investigated. Thus, this study aimed to examine the association between coffee consumption and functional disability in older American adults. Participants (≥ 60 years old, N = 7,704) were from the National Health and Nutrition Examination Survey 2007-2016. Coffee consumption was assessed through two 24-h dietary recall interviews. Five domains of functional disability including lower-extremity mobility (LEM), general physical activity (GPA), leisure and social activities (LSA), activities of daily living (ADL), and instrumental activities of daily living (IADL) were self-reported. Aged and multivariate adjusted logistic regression models and restricted cubic splines analyses were used. Total coffee consumption was inversely associated with LEM, GPA, LSA, and IADL disability. Compared with non-drinkers of total coffee, those who consumed ≥2 cups/day total coffee had lower odds of reporting disability of LEM (OR:0.67, 95%CI: 0.50-0.91), GPA (OR:0.65, 95%CI: 0.47-0.88), LSA (OR:0.61, 95%CI: 0.45-0.83) and IADL (OR:0.59, 95%CI: 0.44-0.78). These relationships were confirmed by the dose-response analyses. Intake of ≥2 cups/day caffeinated coffee was also inversely linked to the disability of GPA (OR: 0.67, 95%CI: 0.48-0.92), LSA (OR: 0.66, 95%CI: 0.46-0.93) and IADL (OR: 0.57, 95%CI:0.43-0.75,). While the inverse association of 2+ cups/day decaffeinated coffee was only on LEM (OR:0.43, 95%CI:0.23-0.81) and LSA (OR:0.39, 95%CI:0.16-0.94) disability. The present study suggested that coffee consumption was inversely associated with functional disability in older American adults. Those associations of diverse coffee types differed across domains of functional disability. Further prospective studies are needed to confirm our findings.
Keywords: National Health and Nutrition Examination Survey; coffee consumption; cross-sectional study; functional disability

Insufficient maternal iodine intake is associated with subfecundity, reduced foetal growth, and adverse pregnancy outcomes in the Norwegian Mother, Father and Child Cohort Study.
Abel MH, Caspersen IH, Sengpiel V, Jacobsson B, Meltzer HM, Magnus P, Alexander J, Brantsæter AL.
BMC Med. 2020 Aug 11;18(1):211. doi: 10.1186/s12916-020-01676-w.
PMID: 32778101
Background: Severe iodine deficiency impacts fertility and reproductive outcomes. The potential effects of mild-to-moderate iodine deficiency are not well known. The aim of this study was to examine whether iodine intake was associated with subfecundity (i.e. > 12 months trying to get pregnant), foetal growth, and adverse pregnancy outcomes in a mild-to-moderately iodine-deficient population.
Methods: We used the Norwegian Mother, Father and Child Cohort Study (MoBa) and included 78,318 pregnancies with data on iodine intake and pregnancy outcomes. Iodine intake was calculated using an extensive food frequency questionnaire in mid-pregnancy. In addition, urinary iodine concentration was available in a subsample of 2795 pregnancies. Associations were modelled continuously by multivariable regression controlling for a range of confounding factors.
Results: The median iodine intake from food was 121 μg/day and the median urinary iodine was 69 μg/L, confirming mild-to-moderate iodine deficiency. In non-users of iodine supplements (n = 49,187), low iodine intake (< 100-150 μg/day) was associated with increased risk of preeclampsia (aOR = 1.14 (95% CI 1.08, 1.22) at 75 vs. 100 μg/day, p overall < 0.001), preterm delivery before gestational week 37 (aOR = 1.10 (1.04, 1.16) at 75 vs. 100 μg/day, p overall = 0.003), and reduced foetal growth (- 0.08 SD (- 0.10, - 0.06) difference in birth weight z-score at 75 vs. 150 μg/day, p overall < 0.001), but not with early preterm delivery or intrauterine death. In planned pregnancies (n = 56,416), having an iodine intake lower than ~ 100 μg/day was associated with increased prevalence of subfecundity (aOR = 1.05 (1.01, 1.09) at 75 μg/day vs. 100 μg/day, p overall = 0.005). Long-term iodine supplement use (initiated before pregnancy) was associated with increased foetal growth (+ 0.05 SD (0.03, 0.07) on birth weight z-score, p < 0.001) and reduced risk of preeclampsia (aOR 0.85 (0.74, 0.98), p = 0.022), but not with the other adverse pregnancy outcomes. Urinary iodine concentration was not associated with any of the dichotomous outcomes, but positively associated with foetal growth (n = 2795, p overall = 0.017).
Conclusions: This study shows that a low iodine intake was associated with restricted foetal growth and a higher prevalence of preeclampsia in these mild-to-moderately iodine-deficient women. Results also indicated increased risk of subfecundity and preterm delivery. Initiating iodine supplement use in pregnancy may be too late.
eywords: Foetal growth; Iodine intake; Iodine supplement; Mild-to-moderate iodine deficiency; Preeclampsia; Pregnancy cohort; Preterm delivery; Subfecundity; The Norwegian Mother, Father and Child Cohort Study (MoBa).

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Diabetes, Weight Change, and Pancreatic Cancer Risk.
Yuan C, Babic A, Khalaf N, Nowak JA, Brais LK, Rubinson DA, Ng K, Aguirre AJ, Pandharipande PV, Fuchs CS, Giovannucci EL, Stampfer MJ, Rosenthal MH, Sander C, Kraft P, Wolpin BM.
JAMA Oncol. 2020 Aug 13. doi: 10.1001/jamaoncol.2020.2948. Online ahead of print.
PMID: 32789511
Importance: Pancreatic cancer is the third-leading cause of cancer death in the United States; however, few high-risk groups have been identified to facilitate early diagnosis strategies.
Objective: To evaluate the association of diabetes duration and recent weight change with subsequent risk of pancreatic cancer in the general population.
Design, setting, and participants: This cohort study obtained data from female participants in the Nurses' Health Study and male participants in the Health Professionals Follow-Up Study, with repeated exposure assessments over 30 years. Incident cases of pancreatic cancer were identified from self-report or during follow-up of participant deaths. Deaths were ascertained through reports from the next of kin, the US Postal Service, or the National Death Index. Data collection was conducted from October 1, 2018, to December 31, 2018. Data analysis was performed from January 1, 2019, to June 30, 2019.
Exposures: Duration of physician-diagnosed diabetes and recent weight change.
Main outcome and measures: Hazard ratios (HRs) for subsequent development of pancreatic cancer.
Results: Of the 112 818 women (with a mean [SD] age of 59.4 [11.7] years) and 46 207 men (with a mean [SD] age of 64.7 [10.8] years) included in the analysis, 1116 incident cases of pancreatic cancers were identified. Compared with participants with no diabetes, those with recent-onset diabetes had an age-adjusted HR for pancreatic cancer of 2.97 (95% CI, 2.31-3.82) and those with long-standing diabetes had an age-adjusted HR of 2.16 (95% CI, 1.78-2.60). Compared with those with no weight loss, participants who reported a 1- to 4-lb weight loss had an age-adjusted HR for pancreatic cancer of 1.25 (95% CI, 1.03-1.52), those with a 5- to 8-lb weight loss had an age-adjusted HR of 1.33 (95% CI, 1.06-1.66), and those with more than an 8-lb weight loss had an age-adjusted HR of 1.92 (95% CI, 1.58-2.32). Participants with recent-onset diabetes accompanied by weight loss of 1 to 8 lb (91 incident cases per 100 000 person-years [95% CI, 55-151]; HR, 3.61 [95% CI, 2.14-6.10]) or more than 8 lb (164 incident cases per 100 000 person-years [95% CI, 114-238]; HR, 6.75 [95% CI, 4.55-10.00]) had a substantially increased risk for pancreatic cancer compared with those with neither exposure (16 incident cases per 100 000 person-years; 95% CI, 14-17). Incidence rates were even higher among participants with recent-onset diabetes and weight loss with a body mass index of less than 25 before weight loss (400 incident cases per 100 000 person-years) or whose weight loss was not intentional judging from increased physical activity or healthier dietary choices (334 incident cases per 100 000 person-years).
Conclusions and relevance: This study demonstrates that recent-onset diabetes accompanied by weight loss is associated with a substantially increased risk for developing pancreatic cancer. Older age, previous healthy weight, and no intentional weight loss further elevate this risk.

Dietary fish intake and the risk of multiple sclerosis: a systematic review and meta-analysis of observational studies.
Rezaeizadeh H, Mohammadpour Z, Bitarafan S, Harirchian MH, Ghadimi M, Homayon IA.
Nutr Neurosci. 2020 Aug 13:1-9. doi: 10.1080/1028415X.2020.1804096. Online ahead of print.
PMID: 32787642
Objectives: There is some inconclusive evidence for the role of fish consumption in susceptibility to multiple sclerosis (MS). The present study aimed to systematically review and determine the association between dietary fish intake and risk of MS. Methods: A systematic search with related keywords was carried out in PubMed-MEDLIN, Scopus-EMBASE, and OVID-MEDLINE from inception up to September 2019 to find observational studies that evaluated the association between dietary fish intake and the risk of MS. Random effect and subgroup analyses were performed to calculate pooled estimates at 95% CIs. Results: Six articles met the inclusion criteria for systematic review and meta-analysis. The results of this study indicated that the consumption of fish decreases the risk of MS [OR (95% CIs): 0.77 (0.64, 0.92); p-value = 0.004; I 2 = 54.7%] compared with controls. Discussion: Dietary intake of at least 0.5 servings of fish per week during adolescence and after might reduce the risk of MS; however, further studies are required to prove this preventive effect.
Keywords: Fish; fish oil; meta-analysis; multiple sclerosis; systematic review.

Energy Requirement Is Higher During Weight-Loss Maintenance in Adults Consuming a Low- Compared with High-Carbohydrate Diet.
Ebbeling CB, Bielak L, Lakin PR, Klein GL, Wong JMW, Luoto PK, Wong WW, Ludwig DS.
J Nutr. 2020 Aug 1;150(8):2009-2015. doi: 10.1093/jn/nxaa150.
PMID: 32470981 Free PMC article
Background: Longer-term feeding studies suggest that a low-carbohydrate diet increases energy expenditure, consistent with the carbohydrate-insulin model of obesity. However, the validity of methodology utilized in these studies, involving doubly labeled water (DLW), has been questioned.
Objective: The aim of this study was to determine whether dietary energy requirement for weight-loss maintenance is higher on a low- compared with high-carbohydrate diet.
Methods: The study reports secondary outcomes from a feeding study in which the primary outcome was total energy expenditure (TEE). After attaining a mean Run-in weight loss of 10.5%, 164 adults (BMI ≥25 kg/m2; 70.1% women) were randomly assigned to Low-Carbohydrate (percentage of total energy from carbohydrate, fat, protein: 20/60/20), Moderate-Carbohydrate (40/40/20), or High-Carbohydrate (60/20/20) Test diets for 20 wk. Calorie content was adjusted to maintain individual body weight within ± 2 kg of the postweight-loss value. In analyses by intention-to-treat (ITT, completers, n = 148) and per protocol (PP, completers also achieving weight-loss maintenance, n = 110), we compared the estimated energy requirement (EER) from 10 to 20 wk of the Test diets using ANCOVA.
Results: Mean EER was higher in the Low- versus High-Carbohydrate group in models of varying covariate structure involving ITT [ranging from 181 (95% CI: 8-353) to 246 (64-427) kcal/d; P ≤0.04] and PP [ranging from 245 (43-446) to 323 (122-525) kcal/d; P ≤0.02]. This difference remained significant in sensitivity analyses accounting for change in adiposity and possible nonadherence.
Conclusions: Energy requirement was higher on a low- versus high-carbohydrate diet during weight-loss maintenance in adults, commensurate with TEE. These data are consistent with the carbohydrate-insulin model and lend qualified support for the validity of the DLW method with diets varying in macronutrient composition. This trial was registered at clinicaltrials.gov as NCT02068885.
Keywords: carbohydrate-insulin model; dietary carbohydrate; dietary fat; energy expenditure; energy requirement; feeding study; metabolism; obesity.

Eat Your Carrots! β-Carotene and Cholesterol Homeostasis.
von Lintig J.
J Nutr. 2020 Aug 1;150(8):2003-2005. doi: 10.1093/jn/nxaa189.
PMID: 32747944 No abstract available.
β-Carotene Oxygenase 1 Activity Modulates Circulating Cholesterol Concentrations in Mice and Humans.
Amengual J, Coronel J, Marques C, Aradillas-García C, Morales JMV, Andrade FCD, Erdman JW, Teran-Garcia M.
J Nutr. 2020 Aug 1;150(8):2023-2030. doi: 10.1093/jn/nxaa143.
PMID: 32433733
Background: Plasma cholesterol is one of the strongest risk factors associated with the development of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction. Human studies suggest that elevated plasma β-carotene is associated with reductions in circulating cholesterol and the risk of myocardial infarction. The molecular mechanisms underlying these observations are unknown.
Objective: The objective of this study was to determine the impact of dietary β-carotene and the activity of β-carotene oxygenase 1 (BCO1), which is the enzyme responsible for the conversion of β-carotene to vitamin A, on circulating cholesterol concentration.
Methods: In our preclinical study, we compared the effects of a 10-d intervention with a diet containing 50 mg/kg of β-carotene on plasma cholesterol in 5-wk-old male and female C57 Black 6 wild-type and congenic BCO1-deficient mice. In our clinical study, we aimed to determine whether 5 common small nucleotide polymorphisms located in the BCO1 locus affected serum cholesterol concentrations in a population of young Mexican adults from the Universities of San Luis Potosí and Illinois: A Multidisciplinary Investigation on Genetics, Obesity, and Social-Environment (UP AMIGOS) cohort.
Results: Upon β-carotene feeding, Bco1-/- mice accumulated >20-fold greater plasma β-carotene and had ∼30 mg/dL increased circulating total cholesterol (P < 0.01) and non-HDL cholesterol (P < 0.01) than wild-type congenic mice. Our results in the UP AMIGOS cohort show that the rs6564851 allele of BCO1, which has been linked to BCO1 enzymatic activity, was associated with a reduction in 10 mg/dL total cholesterol concentrations (P = 0.009) when adjusted for vitamin A and carotenoid intakes. Non-HDL-cholesterol concentration was also reduced by 10 mg/dL when the data were adjusted for vitamin A and total carotenoid intakes (P = 0.002), or vitamin A and β-carotene intakes (P = 0.002).
Conclusions: Overall, our results in mice and young adults show that BCO1 activity impacts circulating cholesterol concentration, linking vitamin A formation with the risk of developing ASCVD.
Keywords: atherosclerosis; genetic variants; micronutrients; nutrition; retinoic acid.

A randomized crossover trial on the effect of plant-based compared with animal-based meat on trimethylamine-N-oxide and cardiovascular disease risk factors in generally healthy adults: Study With Appetizing Plantfood-Meat Eating Alternative Trial (SWAP-MEAT).
Crimarco A, Springfield S, Petlura C, Streaty T, Cunanan K, Lee J, Fielding-Singh P, Carter MM, Topf MA, Wastyk HC, Sonnenburg ED, Sonnenburg JL, Gardner CD.
Am J Clin Nutr. 2020 Aug 11:nqaa203. doi: 10.1093/ajcn/nqaa203. Online ahead of print.
PMID: 32780794
Background: Despite the rising popularity of plant-based alternative meats, there is limited evidence of the health effects of these products.
Objectives: We aimed to compare the effect of consuming plant-based alternative meat (Plant) as opposed to animal meat (Animal) on health factors. The primary outcome was fasting serum trimethylamine-N-oxide (TMAO). Secondary outcomes included fasting insulin-like growth factor 1, lipids, glucose, insulin, blood pressure, and weight.
Methods: SWAP-MEAT (The Study With Appetizing Plantfood-Meat Eating Alternatives Trial) was a single-site, randomized crossover trial with no washout period. Participants received Plant and Animal products, dietary counseling, lab assessments, microbiome assessments (16S), and anthropometric measurements. Participants were instructed to consume ≥2 servings/d of Plant compared with Animal for 8 wk each, while keeping all other foods and beverages as similar as possible between the 2 phases.
Results: The 36 participants who provided complete data for both crossover phases included 67% women, were 69% Caucasian, had a mean ± SD age 50 ± 14 y, and BMI 28 ± 5 kg/m2. Mean ± SD servings per day were not different by intervention sequence: 2.5 ± 0.6 compared with 2.6 ± 0.7 for Plant and Animal, respectively (P = 0.76). Mean ± SEM TMAO concentrations were significantly lower overall for Plant (2.7 ± 0.3) than for Animal (4.7 ± 0.9) (P = 0.012), but a significant order effect was observed (P = 0.023). TMAO concentrations were significantly lower for Plant among the n = 18 who received Plant second (2.9 ± 0.4 compared with 6.4 ± 1.5, Plant compared with Animal, P = 0.007), but not for the n = 18 who received Plant first (2.5 ± 0.4 compared with 3.0 ± 0.6, Plant compared with Animal, P = 0.23). Exploratory analyses of the microbiome failed to reveal possible responder compared with nonresponder factors. Mean ± SEM LDL-cholesterol concentrations (109.9 ± 4.5 compared with 120.7 ± 4.5 mg/dL, P = 0.002) and weight (78.7 ± 3.0 compared with 79.6 ± 3.0 kg, P < 0.001) were lower during the Plant phase.
Conclusions: Among generally healthy adults, contrasting Plant with Animal intake, while keeping all other dietary components similar, the Plant products improved several cardiovascular disease risk factors, including TMAO; there were no adverse effects on risk factors from the Plant products.
Keywords: cardiovascular disease risk factors; diet; meat; plant-based alternative meat; randomized controlled trial; trimethylamine-N-oxide.

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Associations of body composition with incident dementia in older adults: Cardiovascular Health Study-Cognition Study.
Cui C, Mackey RH, Shaaban CE, Kuller LH, Lopez OL, Sekikawa A.
Alzheimers Dement. 2020 Aug 17. doi: 10.1002/alz.12125. Online ahead of print.
PMID: 32803916
Introduction: A body of literature reported associations between late-life general adiposity measures (eg, body mass index) and dementia. Little is known about the association of late-life body composition with dementia risk.
Methods: We determined this association among cognitively normal participants from the Cardiovascular Health Study- Cognition Study. Body composition was assessed by dual-energy x-ray absorptiometry in 1994-1995. Dementia was ascertained at annual follow-up from 1998-1999 to 2013. Associations of body composition with incident dementia were assessed by the Fine-Gray model.
Result: Among 344 participants (mean age 78, 62.2% women), body composition was significantly different between men and women, despite similar body mass indexes (BMIs). Increased dementia risk was significantly associated with lower lean mass in men and marginally with low appendicular lean mass in women.
Discussion: Decreased lean mass was an indicator of increased dementia risk in older adults. Studies should test whether preventing lean mass loss in older adults reduces dementia risk.
Keywords: body composition; cohort study; dementia; older adults.

Low-density lipoprotein cholesterol and all-cause mortality: findings from the China health and retirement longitudinal study.
Zhou L, Wu Y, Yu S, Shen Y, Ke C.
BMJ Open. 2020 Aug 16;10(8):e036976. doi: 10.1136/bmjopen-2020-036976.
PMID: 32801200
Objectives: To investigate the relationship between low-density lipoprotein cholesterol (LDL-C) and all-cause mortality among middle-aged and elderly Chinese population.
Design: Prospective cohort study.
Setting: This study used data from the China Health and Retirement Longitudinal Study.
Participants: Middle-aged and elderly participants with complete data were enrolled for a 4-year follow-up of total mortality and plasma levels of LDL-C, including 4981 male respondents and 5529 female respondents.
Results: During a 4-year follow-up, there were 305 and 219 deaths in men and women, respectively. Compared with the first quintile (Q1) of LDL-C, the adjusted HRs (95% CIs) were 0.818 (0.531 to 1.260) for Q2, 0.782 (0.507 to 1.208) for Q3, 0.605 (0.381 to 0.962) for Q4 and 0.803 (0.506 to 1.274) for Q5 in men. The results from restricted cubic spine (RCS) showed that when the 20th percentile of LDL-C levels (84 mg/dL) was used as the reference, a lower LDL-C concentration (<84 mg/dL) was associated with a higher 4-year all-cause mortality risk. By contrast, both quintile analysis and RCS analysis did not show a statistically significant association in women.
Conclusions: Compared with moderately elevated LDL-C (eg, 117-137 mg/dL), a lower plasma level of LDL-C (eg, ≤84 mg/dL) was associated with an increased risk of 4-year all-cause mortality in middle-aged and elderly Chinese men. The results suggest the potential harmful effect of a quite low level of LDL-C on total mortality.
Keywords: epidemiology; preventive medicine; public health; risk management.

Association Between Bisphenol A Exposure and Risk of All-Cause and Cause-Specific Mortality in US Adults.
Bao W, Liu B, Rong S, Dai SY, Trasande L, Lehmler HJ.
JAMA Netw Open. 2020 Aug 3;3(8):e2011620. doi: 10.1001/jamanetworkopen.2020.11620.
PMID: 32804211
Importance: Bisphenol A (BPA) is a major public health concern because of its high-volume industrial production, ubiquitous exposure to humans, and potential toxic effects on multiple organs and systems in humans. However, prospective studies regarding the association of BPA exposure with long-term health outcomes are sparse.
Objective: To examine the association of BPA exposure with all-cause mortality and cause-specific mortality among adults in the United States.
Design, setting, and participants: This nationally representative cohort study included 3883 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2003-2008 and provided urine samples for BPA level measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2019.
Exposures: Urinary BPA levels were quantified using online solid-phase extraction coupled to high-performance liquid chromatography-isotope dilution tandem mass spectrometry.
Main outcomes and measures: Mortality from all causes, cardiovascular disease, and cancer.
Results: This cohort study included 3883 adults aged 20 years or older (weighted mean [SE] age, 43.6 [0.3] years; 2032 women [weighted, 51.4%]). During 36 514 person-years of follow-up (median, 9.6 years; maximum, 13.1 years), 344 deaths occurred, including 71 deaths from cardiovascular disease and 75 deaths from cancer. Participants with higher urinary BPA levels were at higher risk for death. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratio comparing the highest vs lowest tertile of urinary BPA levels was 1.49 (95% CI, 1.01-2.19) for all-cause mortality, 1.46 (95% CI, 0.67-3.15) for cardiovascular disease mortality, and 0.98 (95% CI, 0.40-2.39) for cancer mortality.
Conclusions and relevance: In this nationally representative cohort of US adults, higher BPA exposure was significantly associated with an increased risk of all-cause mortality. Further studies are needed to replicate these findings in other populations and determine the underlying mechanisms.

Effects of canola or olive oil on plasma lipids, lipoprotein-associated phospholipase A2 and inflammatory cytokines in patients referred for coronary angiography.
Khandouzi N, Zahedmehr A, Nasrollahzadeh J.
Lipids Health Dis. 2020 Aug 14;19(1):183. doi: 10.1186/s12944-020-01362-z.
PMID: 32795310
Background: The potential cardioprotective benefits of olive oil (OO) and canola oil (CO) consumption have been shown in some studies. The present study compared the effects of CO and OO on plasma lipids, some inflammatory cytokines, and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity in patients undergoing coronary angiography.
Methods: The current randomized, controlled, parallel-arm, clinical trial involved 48 patients (44 men and 4 women, aged 57.63 ± 6.34 years) with at least one classic cardiovascular risk factor (hypertension, dyslipidemia, or diabetes) who referred for coronary angiography. Patients were randomly divided into two groups and received 25 mL/day refined olive oil (n = 24) or canola oil (n = 24) for 6 weeks. Plasma lipids, some selected inflammatory markers, and Lp-PLA2 levels were measured at baseline and after the intervention.
Results: CO consumption produced a significant reduction in plasma Lp-PLA2 mass (- 0.97 ± 1.84 vs. 0.34 ± 1.57 ng/mL, p = 0.008 for CO and OO, respectively), whereas the mean changes in interleukine-6 concentration were significantly lower after OO consumption compared with CO (- 9.46 ± 9.46 vs. -0.90 ± 6.80 pg/mL, p = 0.008 for OO and CO, respectively). After 6 weeks of intervention, no significant changes were observed in plasma Lp-PLA2 activity, complement C3, C4, or lipid profiles in the two intervention groups.
Conclusions: Comparing the two vegetable oils in subjects with cardiovascular risk factors showed that the consumption of olive oil is more effective in reducing the level of inflammatory cytokine interleukine-6, whereas canola oil was more effective in lowering Lp-PLA2 levels; however, this finding should be interpreted with caution, because Lp-PLA2 activity did not change significantly.
Keywords: Canola oil; Inflammatory markers; Lipid profile; Lipoprotein-associated phospholipase A2; Olive oil.

Fruit and vegetable consumption and non-alcoholic fatty liver disease among Korean adults: a prospective cohort study.
Kim SA, Shin S.
J Epidemiol Community Health. 2020 Aug 13:jech-2020-214568. doi: 10.1136/jech-2020-214568. Online ahead of print.
PMID: 32796047
Background: Diet is an important risk factor contributing to the development of non-alcoholic fatty liver disease (NAFLD) and associated metabolic co-morbidities (obesity or metabolic syndrome). This study aimed to investigate the association between fruit and vegetable consumption and NAFLD risk according to sex among Korean adults.
Methods: We included 52 280 participants from the Health Examinees study cohort. The cumulative average intake of fruits and vegetables was estimated using a validated semi-quantitative food frequency questionnaire. Cox proportional hazards regression analysis was performed to estimate relative risk (RR) and 95% CI of NAFLD according to the quintiles of fruit and vegetable consumption.
Results: During 4.2 years of follow-up, 2130 cases of NAFLD were documented. In women, higher consumption of fruits (RR 0.77; 95% CI 0.62 to 0.96) and vegetables (RR 0.71; 95% CI 0.56 to 0.88) was associated with lower NAFLD risk (p for trend=0.0106 and 0.0071, respectively). Men showed a decreasing tendency of NAFLD risk according to vegetable consumption (p for trend =0.0374). Higher total intakes of fruits and vegetables were significantly associated with lower NAFLD risk in men (RR 0.75; 95% CI 0.62 to 0.92, p for trend =0.0047) and women (RR 0.74; 95% CI 0.59 to 0.93, p for trend =0.0021).
Conclusion: Fruit intake, vegetable intake, and total fruit and vegetable intake were associated with reduced NAFLD risk. Fruit and vegetable consumption can protect against NAFLD and associated metabolic co-morbidities.
Keywords: Cohort studies; diet; epidemiology; epidemiology of chronic diseases.

Selenium status in the body and cardiovascular disease: a systematic review and meta-analysis.
Kuria A, Tian H, Li M, Wang Y, Aaseth JO, Zang J, Cao Y.
Crit Rev Food Sci Nutr. 2020 Aug 17:1-10. doi: 10.1080/10408398.2020.1803200. Online ahead of print.
PMID: 32799545
Both experimental and observational studies have provided conflicting evidence on the associations of selenium with incidence and mortality of cardiovascular disease (CVD). The aim of this study was to evaluate the association between selenium status in the body and incidence and mortality of CVD by performing a systematic review and meta-analysis of observational studies and randomized controlled trials. Methods: A systematic search for articles in MEDLINE (Ovid), Embase, Web of Science (Thomson Reuters) and Cochrane library (Wiley) was conducted. Thirteen of the 1811 articles obtained from the databases met our inclusion criteria and were considered in the final analysis. The effect sizes were presented as weighted relative risk (RR) and 95% confidence intervals (CIs) using random-effects model. To detect dose-response relationships, we used meta-regression. Results: Overall, there was a reduced risk of CVD incidence (RR = 0.66; 95% CI: 0.40-1.09) and mortality (RR = 0.69; 95% CI: 0.57-0.84) in physiologically high selenium status compared to low selenium status in the body. There was a 15% (RR = 0.85, 95% CI: 0.76-0.94) decreased risk of CVD incidence per 10 µg increment in blood selenium concentration. In addition, a statistically significantly nonlinear dose-response relationship was found between CVD mortality and increased blood selenium concentration with the lowest risk at the 30-35 µg increment in blood selenium. Conclusions: Physiologically high selenium levels in the body are associated with decreased risk for CVD incidence and mortality, however, people should be cautious about the potential harmful effects from excessive intake of selenium.
Keywords: Cardiovascular disease; incidence; meta-analysis; mortality; selenium status.

Nervous system deletion of mammalian INDY in mice mimics dietary restriction-induced memory enhancement.
Wang PY, Sung CW, Tsai YH, Yeh SR, Lin WS, Fan SZ.
J Gerontol A Biol Sci Med Sci. 2020 Aug 18:glaa203. doi: 10.1093/gerona/glaa203. Online ahead of print.
PMID: 32808644
Reduced expression of the Indy (I'm Not Dead Yet) gene extends lifespan in C. elegans and D. melanogaster, and improves the metabolic heath of M. musculus through inducing a physiological status akin to dietary restriction (DR). Although the function of Indy in aging and hepatic metabolism has been extensively studied, its role in the mouse nervous system remains unclear. Here, we explore the effect of mammalian Indy (mIndy, SLC13A5) gene deletion on murine cognitive function. Similar to what is seen in DR animals, systemic deletion of the mIndy gene (mIndy KO) significantly improves memory performance and motor coordination of mice. Both DR and mIndy KO mice act normally in other behavioral tasks, including emotional, social, and food-seeking behaviors. Moreover, we find that tissue-specific deletion of mIndy in the nervous system is sufficient to improve memory performance, while liver-specific deletion has no effect on memory, and results in tests of motor coordination show no changes in either mutant. Mice with systemic or nervous system deletion of mIndy also exhibit increased hippocampal neurogenesis and dendritic spine formation in dentate granule cells; these changes are well-documented contributors to enhanced memory performance. Together, our studies demonstrate a critical role for brain-derived mIndy expression in the regulation of memory function in animals.
Keywords: Citrate; Dendritic spine; Hippocampus; Neurogenesis.

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Associations of Dietary Intake with Cardiovascular Disease, Blood Pressure, and Lipid Profile in the Korean Population: a Systematic Review and Meta-Analysis.
Kim J, Hoang T, Bu SY, Kim JM, Choi JH, Park E, Lee SM, Park E, Min JY, Lee IS, Youn SY.
J Lipid Atheroscler. 2020 Jan;9(1):205-229. doi: 10.12997/jla.2020.9.1.205. Epub 2020 Jan 16.
PMID: 32821732 Free PMC article.
Objective: Previous studies have separately reported the contributions of dietary factors to the risk of cardiovascular disease (CVD) and its markers, including blood pressure (BP) and lipid profile. This study systematically reviewed the current evidence on this issue in the Korean population.
Methods: Sixty-two studies from PubMed and Embase were included in this meta-analysis. We performed a random-effects model to analyze pooled odds ratios (ORs) and hazard ratios (HRs) and their 95% confidence intervals (CIs) for the consumption of 14 food items, three macro- and eight micro-nutrients, two dietary patterns, and three dietary indices.
Results: An analysis of pooled effect sizes from at least four individual study populations showed significant associations between coffee consumption and CVD (OR/HR, 0.71; 95% CI, 0.52-0.97) and elevated/high triglycerides (TG) (OR, 0.84; 95% CI, 0.78-0.90), sugar-sweetened beverage intake and elevated BP (OR/HR, 1.20; 95% CI, 1.09-1.33), and milk and dairy intake and elevated/high TG and low high-density lipoprotein cholesterol (HDL-C) (OR/HR, 0.82; 95% CI, 0.76-0.89 for both). Carbohydrate consumption and the low-carbohydrate-diet score were consistently related to an approximately 25% risk reduction for elevated TG and low HDL-C. A lower risk of elevated total cholesterol, but not low-density lipoprotein, was additionally observed for those with a higher low-carbohydrate-diet score. A healthy dietary pattern was only associated with a reduced risk of elevated TG in the Korea National Cancer Screenee Cohort (OR, 0.81; 95% CI, 0.67-0.98).
Conclusion: This study showed that milk and dairy and coffee had protective effects for CVD and its risk factors, such as BP and lipid profile, while sugar-sweetened beverages exerted harmful effects.
Keywords: Cardiovascular diseases; Dietary; Dyslipidemias; Hypertension; Koreans.

Body mass index and height in relation to brain tumor risk in a Japanese population.
Ogawa T, Sawada N, Iwasaki M, Budhathoki S, Yamaji T, Shimazu T, Narita Y, Tsugane S; Japan Public Health Center-based Prospective Study Group.
Ann Epidemiol. 2020 Aug 18:S1047-2797(20)30198-8. doi: 10.1016/j.annepidem.2020.06.001. Online ahead of print.
PMID: 32822852
Purpose: Although height and BMI are reported to be positively associated with several common cancers, evidence regarding their association with brain tumor risk remains sparse, particularly in Asian populations. In this study, we analyzed the association between height and BMI and brain tumor risk in a Japanese population using a large population-based prospective cohort study.
Method: A total of 102,925 subjects (48,213 men and 54,712women) enrolled in the Japan Public Health Center-based Prospective Study (JPHC Study) was followed from baseline, namely 1990 for cohort I and 1993 for cohort II, until 2012. Information on participants' dietary and lifestyle habits, including height and body weight, were collected through survey questionnaires administered at baseline. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for brain tumor incidence, with adjustment for potential confounding variables.
Results: During an average follow-up of 18.1 years, 157 (70 men and 87 women) cases of brain tumor were newly diagnosed. BMI showed a statistically insignificant positive association with the risk of brain tumor. In addition, statistically significant positive trends were seen for men and meningioma, with multivariable-adjusted HRs for a BMI of 27.5-<40 versus 18.5-<23 kg/m2 of 2.14 (95% CI= 0.99-4.59) (P=0.03) and 1.98 (95% CI= 0.84-4.67) (P=0.046), respectively. In contrast, height showed no clear association with brain tumor risk, overall or in subgroup analysis.
Conclusion: Compared to a BMI of 18-<23.5 kg/m2, higher BMI was associated with higher risk of brain tumor, particularly in men and with meningioma.

Ghrelin/GHS-R1a signaling plays different roles in anxiety-related behaviors after acute and chronic caloric restriction.
Zhang F, Xu F, Mi X, Dong L, Xiao Y, Jiang S, Li GD, Zhou Y.
Biochem Biophys Res Commun. 2020 Sep 3;529(4):1131-1136. doi: 10.1016/j.bbrc.2020.05.227. Epub 2020 Aug 4.
PMID: 32819576
The brain-gut hormone ghrelin and its receptor GHS-R1a, the growth hormone secretagogue receptor 1a, regulates diverse functions of central nervous system including stress response and mood. Both acute and chronic caloric restrictions (CR) were reported to increase endogenous ghrelin level meanwhile regulate anxiety-related behaviors; however, the causal relationship between CR-induced ghrelin elevation and anxiety are not fully established. Here, we introduced an acute (24 h) and a chronic (10wks) CR procedure to both GHS-R1a KO (Ghsr-/-) mice and WT (Ghsr+/+) littermates, and compared their anxiety-related behaviors. We found that acute CR induced anxiolytic and anti-despairing behaviors in Ghsr+/+ mice but not in Ghsr-/- mice. Ad-libitum refeeding abolished the effect of acute CR on anxiety-related behaviors. In contrast, chronic CR for 10wks facilitated despair-like behavior meanwhile inhibited anxiety-like behavior in Ghsr+/+ mice. GHS-R1a deficiency rescued despair-like behavior while did not affect anxiolytic response induced by chronic CR. In addition, we found elevated interleukin-6 (IL-6) in serum of Ghsr+/+ mice after chronic CR, but not in Ghsr-/- mice. Altogether, our findings indicated that acute CR and chronic CR have different impacts on anxiety-related behaviors, and the former is dependent on ghrelin/GHS-R1a signaling while the latter may not always be. In addition, our findings suggested that GHS-R1a-dependent elevation in serum IL-6 might contribute to increased despair-like behavior in chronic CR state.
Keywords: Anxiety; Calorie restriction; Despair; GHS-R1a; Ghrelin; Stress.

Impact of calculated plasma volume status on all-cause and cardiovascular mortality: 4-year nationwide community-based prospective cohort study.
Otaki Y, Watanabe T, Konta T, Watanabe M, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, Narita I, Kasahara M, Shibagaki Y, Iseki K, Moriyama T, Kondo M, Watanabe T.
PLoS One. 2020 Aug 20;15(8):e0237601. doi: 10.1371/journal.pone.0237601. eCollection 2020.
PMID: 32817643
Background: Plasma volume status (PVS), a marker of plasma volume expansion and contraction, is gaining attention in the field of cardiovascular disease because of its role in the prevention and of the management of heart failure. However, it remains undetermined whether an abnormal PVS is a risk for all-cause and cardiovascular mortality in the general population.
Methods and results: We used a nationwide database of 230,882 subjects (age 40-75 years) who participated in the annual "Specific Health Check and Guidance in Japan" check-up between 2008 and 2011. There were 586 cardiovascular deaths, 2,552 non-cardiovascular deaths, and 3,138 all-cause deaths during the follow-up period of four years. Abnormally high and low PVS were identified from the results of 80% of all subjects (high and low PVS ≥ 7 and < -13.3, respectively). Multivariate Cox proportional hazard regression analysis demonstrated that high PVS was an independent risk factor for all-cause, cardiovascular and non-cardiovascular deaths. Although low PVS was a positive risk factor for cardiovascular deaths as well, it was a negative risk factor for non-cardiovascular deaths. The addition of PVS to cardiovascular risk factors significantly improved the C-statistic, net reclassification, and integrated discrimination indexes.
Conclusions: This is the first prospective report to reveal the impact of PVS on all-cause and cardiovascular mortality. PVS could be an additional risk factor for all-cause and cardiovascular mortality in the general population.

Meat intake and cancer risk: prospective analyses in UK Biobank.
Knuppel A, Papier K, Fensom GK, Appleby PN, Schmidt JA, Tong TYN, Travis RC, Key TJ, Perez-Cornago A.
Int J Epidemiol. 2020 Aug 20:dyaa142. doi: 10.1093/ije/dyaa142. Online ahead of print.
PMID: 32814947
Background: Red and processed meat have been consistently associated with colorectal cancer risk, but evidence for other cancer sites and for poultry intake is limited. We therefore examined associations between total, red and processed meat and poultry intake and incidence for 20 common cancers.
Methods: We analyzed data from 474 996 participants (54% women) in UK Biobank. Participants were aged 37-73 years and cancer-free at baseline (2006-10). Multivariable-adjusted Cox proportional hazards models were used to determine associations between baseline meat intake and cancer incidence. Trends in risk across the baseline categories were calculated, assigning re-measured intakes from a subsample.
Results: During a mean follow-up of 6.9 years, 28 955 participants were diagnosed with malignant cancer. After correction for multiple testing, red and processed meat combined, and processed meat, were each positively associated with colorectal cancer risk [hazard ratio (HR) per 70 g/day higher intake of red and processed meat 1.32, 95% confidence interval 1.14-1.53; HR per 20 g/day higher intake of processed meat 1.18, 1.03-1.31] and red meat was associated with colon cancer risk (HR per 50 g/day higher intake of red meat 1.36, 1.13-1.64). Positive associations of red meat intake with colorectal and prostate cancer, processed meat intake with rectal cancer and poultry intake with cancers of the lymphatic and haematopoietic tissues did not survive multiple testing.
Conclusions: Higher intake of red and processed meat was specifically associated with a higher risk of colorectal cancer; there was little evidence that meat intake was associated with risk of other cancers.
Keywords: Cancer risk; meat; poultry; processed meat; prospective cohort study; red meat.

Association between the maternal protein nutrition status during pregnancy and the risk of preterm birth.
Xiong T, Wu Y, Huang L, Chen X, Zhang Y, Zhong C, Gao Q, Hong M, Hu X, Yang X, Yang N, Hao L.
Matern Child Nutr. 2020 Aug 20:e13043. doi: 10.1111/mcn.13043. Online ahead of print.
PMID: 32815668
We aimed to assess protein nutrition status during pregnancy by maternal plasma total protein (MTP) levels in urban pregnant women and to explore the association between the trimester-specific MTP levels and risk of preterm birth (PTB). A prospective design was conducted in 3,382 mother-newborn pairs with the second-trimester maternal MTP information and in 3,478 mother-newborn pairs with the third-trimester MTP information. Multiple Cox proportional hazard regression and multiple linear regression were used to analyse the associations between MTP levels and PTB risk as well as gestational duration, respectively. Nearly all the second-trimester MTP levels were within the clinical reference range, but more than 40% of the third-trimester MTP levels were less than the lower limit of normal. No significant association was found between the second-trimester MTP level and PTB risk. However, the adjusted hazard ratios (HRs) of PTB across increasing quartiles of the third-trimester MTP levels were 1.00 (reference), 0.59 (0.36, 0.95), 0.35 (0.20, 0.60), and 0.32 (0.19, 0.53) (p for trend < 0.001), respectively. Each standard deviations increment of the third-trimester MTP was associated with increase of 0.13 weeks in gestational duration. Moreover, stratified analyses showed that the effects of third-trimester MTP on PTB risk and gestational duration were stronger in pregnant women carrying female offspring than those carrying male offspring (p for interaction < 0.05). The third-trimester MTP level was inversely associated with PTB risk and was positively associated with gestational duration. Improving third-trimester MTP level may be helpful for preventing PTB.
Keywords: cohort study; gestational duration; plasma total protein; pregnant women; preterm birth.

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Associations of Number of Daily Eating Occasions with Type 2 Diabetes Risk in the Women's Health Initiative Dietary Modification Trial.
Neuhouser ML, Wertheim BC, Perrigue MM, Hingle M, Tinker LF, Shikany JM, Johnson KC, Waring ME, Seguin-Fowler RA, Vitolins MZ, Schnall E, Snetselaar L, Thomson C.
Curr Dev Nutr. 2020 Jul 21;4(8):nzaa126. doi: 10.1093/cdn/nzaa126. eCollection 2020 Aug.
PMID: 32832844 Free PMC article.
Background: Over 23 million Americans have type 2 diabetes (T2D). Eating habits such as breakfast consumption, time-restricted eating, and limiting daily eating occasions have been explored as behaviors for reducing T2D risk, but prior evidence is inconclusive.
Objectives: Our objectives were to examine associations between number of daily eating occasions and T2D risk in the Women's Health Initiative Dietary Modification Trial (WHI-DM) and whether associations vary by BMI, age, or race/ethnicity.
Methods: Participants were postmenopausal women in the WHI-DM who comprised a 4.6% subsample completing 24-h dietary recalls (24HRs) at years 3 and 6 as part of trial adherence activities (n = 2159). Numbers of eating occasions per day were obtained from the year 3 24HRs, and participants were grouped into approximate tertiles as 1-3 (n = 795), 4 (n = 713), and ≥5 (n = 651) daily eating occasions as the exposure. Incident diabetes was self-reported on semiannual questionnaires as the outcome.
Results: Approximately 15% (15.4%, n = 332) of the WHI-DM 24HR cohort reported incident diabetes at follow-up. Cox proportional hazards regression tested associations of eating occasions with T2D adjusted for neighborhood socioeconomic status, BMI, waist circumference, race/ethnicity, family history of T2D, recreational physical activity, Healthy Eating Index-2005, 24HR energy intake, and WHI-DM arm. Compared with women reporting 1-3 meals/d, those consuming 4 meals/d had a T2D HR = 1.38 (95% CI: 1.03, 1.84) without further increases in risk for ≥5 meals/d. In stratified analyses, associations for 4 meals/d compared with 1-3 meals/d were stronger in women with BMI <30.0 kg/m2 (HR = 1.55; 95% CI: 1.00, 2.39) and women aged ≥60 (HR = 1.61; 95% CI: 1.11, 2.33).
Conclusions: Four meals per day compared with 1-3 meals/d was associated with increased risk of T2D in postmenopausal women, but no dose-response effect was observed for additional eating occasions. Further studies are needed to understand eating occasions in relation to T2D risk.
Keywords: 24-hour recall; cohort; eating frequency; postmenopausal women; type 2 diabetes.

Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound.
Bazarbashi N, Kapadia SR, Nicholls SJ, Carlo J, Gad MM, Kaur M, Karrthik A, Sammour YM, Diab M, Ahuja KR, Tuzcu EM, Nissen SE, Puri R.
JACC Cardiovasc Imaging. 2020 Aug 16:S1936-878X(20)30606-9. doi: 10.1016/j.jcmg.2020.06.030. Online ahead of print.
PMID: 32828785
Objectives: This study sought to evaluate and assess the extent of serial coronary artery calcification in response to oral calcium supplementation.
Background: Oral calcium supplements are frequently used despite their cardiovascular safety remaining controversial. Their effects on serial coronary calcification are not well established.
Methods: In a post hoc patient-level analysis of 9 prospective randomized trials using serial coronary intravascular ultrasound, changes in serial percentage of atheroma volume (PAV) and calcium indices (CaI) were compared in matched segments of patients coronary artery disease who were receiving concomitant calcium supplements (n = 447) and in those who did not receive supplements (n = 4,700) during an 18- to 24-month trial period.
Results: Patients (mean age 58 ± 9 years; 73% were men; 43% received concomitant high-intensity statins) demonstrated overall annualized changes in PAV and CaI with a mean of -0.02 ± 1.9% (p = 0.44) and a median of 0.02 (interquartile range: 0.00 to 0.06) (p < 0.001) from baseline, respectively. Following propensity-weighted mixed modeling adjusting for treatment and a range of demographic, clinical, ultrasonic, and laboratory parameters (including but not limited to sex, race, baseline, and annualized change in PAV, baseline CaI, concomitant high-intensity statins, diabetes mellitus, renal function), there were no significant between-group differences in annualized changes in PAV (least-squares mean: 0.09; 95% confidence interval [CI]: -0.20 to 0.37 vs. 0.01; 95% CI: -0.27 to 0.29; p = 0.092) according to calcium supplement intake. Per a multivariable logistic regression model accounting for the range of covariates described, calcium supplementation independently associated with an increase in annualized CaI (odds ratio: 1.15; 95% CI: 1.05 to 1.26; p = 0.004).
Conclusions: Oral calcium supplementation may increase calcium deposition in the coronary vasculature independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation.
Keywords: IVUS; calcium supplements; coronary artery calcification.

Zinc in depression: From development to treatment: A comparative/ dose response meta-analysis of observational studies and randomized controlled trials.
Yosaee S, Clark CCT, Keshtkaran Z, Ashourpour M, Keshani P, Soltani S.
Gen Hosp Psychiatry. 2020 Aug 10:S0163-8343(20)30114-6. doi: 10.1016/j.genhosppsych.2020.08.001. Online ahead of print.
PMID: 32829928 Review.
Background: A previous meta-analysis suggested that zinc status may be linked to depression status. However, it remains unclear whether zinc status can predict the risk of depression development, or whether the monotherapy of zinc is superior to the combination of zinc supplementation and antidepressant medications in the treatment of depression. Therefore, this meta-analysis aimed to clarify the impact of zinc status and supplementation on depression development and status across all available evidence.
Methods: PubMed, EMBASE, Scopus, and ISI web of science were searched, up to 14 May 2020, for relevant publications. Pooled relative risks (RRs) with 95% confidence intervals (CI) in observational studies, and mean and standard deviation (SD) for the change in depression score in RCTs were calculated using a random-effects model.
Results: The meta-analysis of RCTs indicated that zinc supplementation significantly lowered depressive symptom scores of depressed patients [weighted mean difference (WMD = -4.15 point; 95% CI: -6.56, -1.75 point; P < 0.01)], and the improvement in depression status occurred only when zinc supplementation was prescribed as a monotherapy. The cohort studies showed that the highest level of zinc intake was associated with a 28% reduced risk of depression (RR: 0.66; 95% CI: 0.50, 0.82; I2 = 13.90). Dose-response analyses revealed a significant non-linear effect of baseline mood status on depression score.
Conclusion: Current evidence from observational studies and RCT's supports the potential benefits zinc to reduce the risk of, and alleviate, depression. However, further trials are needed to confirm the beneficial effect of zinc as a monotherapy versus adjunctive therapies.
Keywords: Depression; Meta-analysis; Monotherapy; Zinc.

Triglyceride glucose (TyG) index as a predictor of incident type 2 diabetes among non-obese adults: A 12-year longitudinal study of the Korean Genome and Epidemiology Study cohort.
Park B, Lee HS, Lee YJ.
Transl Res. 2020 Aug 19:S1931-5244(20)30201-2. doi: 10.1016/j.trsl.2020.08.003. Online ahead of print.
PMID: 32827706
The rate of undiagnosed type 2 diabetes tends to increase in lean Koreans, while the triglyceride glucose (TyG) index has been proposed as a surrogate marker of peripheral insulin resistance. We investigated the longitudinal relationship between TyG and incident type 2 diabetes among apparently healthy Korean adults. We assessed 4,285 lean adults without diabetes aged 40-69 years from the Korean Genome and Epidemiology Study. Participants were divided into four groups according to quartiles of TyG index, calculated as ln [fasting triglycerides (mg/dl) × fasting plasma glucose (mg/dl)/2]. We prospectively assessed the hazard ratios (HRs) with 95% CIs for incident type 2 diabetes, based on the American Diabetes Association criteria, using multivariate Cox proportional hazards regression models, over 12 years after the baseline survey. During the follow-up period, 631 (14.7%) participants had newly developed type 2 diabetes. The HRs of incident type 2 diabetes in each TyG index quartile were 1.00, 1.63 (95% CI, 1.18-2.24), 2.30 (95% CI, 1.68-3.14), and 3.67 (95% CI, 2.71-4.98), respectively, after adjusting for age, sex, body mass index, waist circumference, smoking status, alcohol intake, and physical activity. Higher TyG index precedes and significantly predicts type 2 diabetes among community-dwelling middle aged and elderly lean Koreans.
Keywords: Incident type 2 diabetes; Prospective cohort study; Triglyceride glucose index.

Reduction in saturated fat intake for cardiovascular disease.
Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS.
Cochrane Database Syst Rev. 2020 Aug 21;8:CD011737. doi: 10.1002/14651858.CD011737.pub3.
PMID: 32827219 Review.
Background: Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein.
Objectives: To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials.
Search methods: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019.
Selection criteria: Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available.
Data collection and analysis: Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment.
Main results: We included 15 randomised controlled trials (RCTs) (16 comparisons, 56,675 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.70 to 0.98, 12 trials, 53,758 participants of whom 8% had a cardiovascular event, I² = 67%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 53. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes.
Authors' conclusions: The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

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Adherence to the Recommended Intake of Calcium and Colorectal Cancer Risk in the HEXA Study.
Lee J, Shin A, Choi JY, Kang D, Lee JK.
Cancer Res Treat. 2020 Aug 25. doi: 10.4143/crt.2020.480. Online ahead of print.
PMID: 32854492
Purpose: Dietary calcium intake has been suggested to be protective against the development of colorectal cancer. The mean dietary calcium intake of Koreans is 490 mg/day, which is far below the recommended calcium intake of 700-800 mg/day. In this study, we explored the relationship between dietary calcium intake and colorectal cancer development in Koreans with relatively low calcium intake compared with individuals in Western countries.
Materials and methods: The Health Examinees Study, a large-scale genomic community-based prospective cohort study, was designed to identify the general characteristics of major chronic diseases in Koreans. A total of 119,501 participants aged 40-69 years recruited between 2004 and 2013 were included in this analysis. The calcium intake level was categorized using the Dietary Reference Intakes for Koreans (KDRIs). The Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and the corresponding 95% confidence intervals (CIs) for colorectal cancer risk, adjusting for potential confounders.
Results: In the multivariable-adjusted model, compared with the group that consumed less than the recommended amount of calcium, the group that consumed more than the recommended intake of calcium showed a significant reduction in the risk of colorectal cancer in women. (HR, 0.54; 95% CI, 0.31 to 0.95). Among men, however, no significant association was observed between dietary calcium intake and colorectal cancer risk (HR, 0.89; 95% CI, 0.54 to 1.45).
Conclusion: Korean women who adhere to the recommended intake of calcium showed a reduced risk of colorectal cancer.
Keywords: Calcium intake; Colorectal neoplasms; Korea; Recommended intake of calcium.

Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial.
Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, Du Y, Ma F, Wang X, Liu H, Huang G.
Eur J Nutr. 2020 Aug 28. doi: 10.1007/s00394-020-02373-3. Online ahead of print.
PMID: 32856190
Purpose: This study aimed to assess the effects of folic acid (FA) combined with a docosahexaenoic acid (DHA) intervention on the cognitive function and inflammatory cytokines in elderly subjects with mild cognitive impairment (MCI).
Methods: This randomized, double-blind, placebo-controlled trial recruited 240 individuals with MCI in Tianjin, China, and randomly allocated into 4 groups: FA + DHA (FA 800 μg/d + DHA 800 mg/d), FA (FA 800 μg/d), DHA (DHA 800 mg/d), and placebo. Cognitive function, serum folate and homocysteine (Hcy), plasma DHA and inflammatory cytokines levels were measured at baseline and 6 months.
Results: Daily oral FA, DHA and their combined use for 6 months significantly improved the full-scale intelligence quotient (FSIQ) and some subtests of Wechsler Adult Intelligence Scale compared to the placebo. The increases of FSIQ, arithmetic, picture completion scores in the FA group and picture completion, block design scores in the DHA group were significantly less than that in the FA combined DHA group (P < 0.05). Meanwhile, daily oral FA, DHA and their combined use for 6 months significantly decreased plasma inflammatory cytokines compared to the placebo. The changes of interleukin-1β levels in the FA group and interleukin-6 levels in the DHA group were significantly less than that in the FA + DHA group (P < 0.05).
Conclusions: Daily oral FA, DHA and their combined use for 6 months can significantly improve cognitive function and decrease plasma inflammatory cytokines in MCI individuals. The combination of FA and DHA was more beneficial than each individual nutrient on their own.
Keywords: Docosahexaenoic acid; Folic acid; Inflammatory cytokines; Liner mixed models; Mild cognitive impairment; Randomized double-blind; placebo-controlled trial.

Dairy consumption and risks of colorectal cancer incidence and mortality: a meta-analysis of prospective cohort studies.
Jin S, Kim Y, Je Y.
Cancer Epidemiol Biomarkers Prev. 2020 Aug 27:cebp.0127.2020. doi: 10.1158/1055-9965.EPI-20-0127. Online ahead of print.
PMID: 32855265
Background: Previous studies of dairy consumption and colorectal cancer incidence have shown inconsistent results, and there was no meta-analysis of dairy consumption with colorectal cancer mortality. Thus, we conducted a comprehensive analysis of prospective cohort studies to investigate these associations.
Methods: PubMed and Web of Science databases were searched for eligible studies published up to July 2019, and random effects model was used to estimate pooled RR.
Results: We identified 31 prospective cohort studies, which included 24,964 and 2,302 cases for colorectal cancer incidence and mortality, respectively. The pooled RR of colorectal cancer incidence for the highest versus lowest categories of total dairy consumption was 0.79 (95% confidence interval [CI], 0.74-0.85). For milk consumption, there was also a significant inverse association (RR: 0.81; 95% CI, 0.76-0.86). For cheese and fermented milk consumption, overall no association was found, but studies conducted in Europe showed a significant inverse association of cheese (RR: 0.87; 95% CI, 0.78-0.97) and fermented milk consumption (RR: 0.91; 95% CI, 0.85-0.98). For colorectal cancer mortality, we found 29% lower risk of death from colorectal cancer in subjects with high dairy consumption compared to those with low intakes of dairy products (RR: 0.71; 95% CI, 0.54-0.93), but each type of dairy consumption did not show a significant association.
Conclusions: High dairy consumption was associated with lower incidence and mortality of colorectal cancer.
Impact: Our findings suggest that high dairy consumption may be associated with lower colorectal cancer incidence and mortality, but further studies are warranted.

Lifestyle and risk of follicular lymphoma: a systematic review and meta-analysis of observational studies.
Odutola MK, Nnakelu E, Giles GG, van Leeuwen MT, Vajdic CM.
Cancer Causes Control. 2020 Aug 26. doi: 10.1007/s10552-020-01342-9. Online ahead of print.
PMID: 32851495 Review.
Purpose: To investigate the relationship between follicular lymphoma (FL) risk and common modifiable lifestyle factors, specifically smoking, alcohol, body mass index (BMI), and hair dye use.
Methods: We performed a systematic review and meta-analysis of observational studies published prior to 01 January 2020. We searched Ovid MEDLINE, Ovid EMBASE, and Web of Science and the reference lists of original studies and review articles. We used random-effects models to generate meta-estimates of relative risk (RR) with 95% confidence intervals (95% CI).
Results: Twenty-four cohort and ten case-control studies were eligible. Ten articles examined smoking, 11 alcohol, 13 BMI, and four hair dye use and risk of FL. The meta-estimate for current smoking was 1.11 (95% CI 0.92-1.35; I2 = 51%) and there was no significant dose-response per 5-year increase in duration (p-trend = 0.087). Current alcohol intake was inversely associated with FL risk (meta-RR 0.87, 95% CI 0.81-0.94; I2 = 0%) and there was a significant dose-response per 5 drinks/week increase in intake (p-trend = 0.008). There was no association with 5 kg/m2 increase in early adulthood BMI (meta-RR 1.05, 95% CI 0.91-1.20; I2 = 7%) or being overweight (meta-RR 0.99, 95% CI 0.92-1.07; I2 = 0%) or obese (meta-RR 1.08, 95% CI 0.99-1.17; I2 = 0%) as an adult. Hair dye use before 1980 was positively associated with FL risk (meta-RR 1.66, 95% CI 1.22-2.25; I2 = 55%) and no evidence of effect after 1980.
Conclusion: We found consistent evidence of an inverse association between current alcohol intake and FL risk, and a significant increased risk with hair dye use before 1980. The evidence for smoking is heterogeneous, but most studies did not support an association. Further research is required to understand the mechanisms underlying these associations and the potential for prevention strategies.
Keywords: Adiposity; Alcohol; Follicular lymphoma; Hair dye; Meta-analysis; Smoking.

Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension.
Onken B, Kalinava N, Driscoll M.
PLoS Genet. 2020 Aug 25;16(8):e1008982. doi: 10.1371/journal.pgen.1008982. Online ahead of print.
PMID: 32841230
High glucose diets are unhealthy, although the mechanisms by which ikelevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.

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Egg consumption and cardiovascular risk: a dose-response meta-analysis of prospective cohort studies.
Godos J, Micek A, Brzostek T, Toledo E, Iacoviello L, Astrup A, Franco OH, Galvano F, Martinez-Gonzalez MA, Grosso G.
Eur J Nutr. 2020 Aug 31. doi: 10.1007/s00394-020-02345-7. Online ahead of print.
PMID: 32865658
Purpose: Cardiovascular disease (CVD) is a leading cause of mortality globally and is strongly influenced by dietary risk factors. The aim was to assess the association between egg consumption and risk of CVD risk/mortality, including coronary heart disease (CHD), stroke, and heart failure.
Methods: MEDLINE, Embase, and Web of Science databases were searched through April 2020 for prospective studies. Two independent reviewers screened and extracted the data through standardized methods. Size effects were calculated as summary relative risks (SRRs) in a dose-response fashion through random-effects meta-analyses.
Results: Thirty-nine studies including nearly 2 million individuals and 85,053 CHD, 25,103 stroke, 7536 heart failure, and 147,124 CVD cases were included. The summary analysis including 17 datasets from 14 studies conducted on CVD (incidence and/or mortality) showed that intake of up to six eggs per week is inversely associated with CVD events, when compared to no consumption [for four eggs per week, SRR = 0.95 (95% CI: 0.90; 1.00)]; a decreased risk of CVD incidence was observed for consumption of up to one egg per day [SRR = 0.94 (95% CI: 0.89; 0.99)]. The summary analysis for CHD incidence/mortality including 24 datasets from 16 studies showed a decreased risk up to two eggs per week [(SRR = 0.96 (95% CI: 0.91; 1.00)]. No associations were retrieved with risk of stroke. The summary analysis for heart failure risk including six datasets from four studies showed that intake of one egg per day was associated with increased risk raising for higher intakes compared to no consumption [for 1 egg per day, SRR = 1.15 (95% CI:1.02; 1.30)]. After considering GRADE criteria for strength of the evidence, it was rated low for all outcomes but stroke, for which it was moderate (yet referring to no risk).
Conclusion: There is no conclusive evidence on the role of egg in CVD risk, despite the fact that higher quality studies are warranted to obtain stronger evidence for a possible protection of CVD associated with moderate weekly egg consumption compared to no intake; equally, future studies may strengthen the evidence for increased heart failure risk associated with high regular egg consumption.
Keywords: Cardiovascular disease; Dose–response; Egg; Meta-analysis; Prospective cohort; Stroke.

Periodontitis, Edentulism, and Risk of Mortality: A Systematic Review with Meta-analyses.
Romandini M, Baima G, Antonoglou G, Bueno J, Figuero E, Sanz M.
J Dent Res. 2020 Aug 31:22034520952401. doi: 10.1177/0022034520952401. Online ahead of print.
PMID: 32866427
Periodontitis has been independently associated with the chronic noncommunicable diseases that most frequently lead to death worldwide. The aim of the present systematic review was to study whether people with periodontitis/edentulism are at increased risk of all-cause and cause-specific mortality as compared with those without periodontitis/edentulism. Cohort studies were included that 1) evaluated periodontitis or edentulism as exposures in relation to all-cause or cause-specific mortality as an outcome and 2) reported effect estimates as hazard ratios, risk ratios, or odds ratios with 95% CIs or crude numbers. Two review authors independently searched for eligible studies, screened the titles and abstracts, did full-text analysis, extracted the data from the published reports, and performed the risk-of-bias assessment. In case of disagreement, a third review author was consulted. Study results were summarized through random effects meta-analyses. A total of 57 studies were included, involving 48 cohorts and 5.71 million participants. Periodontitis was associated with increased risk of all-cause mortality (risk ratio, 1.46 [95% CI, 1.15 to 1.85]) and mortality due to cardiovascular diseases (1.47 [1.14 to 1.90]), cancer (1.38 [1.24 to 1.53]), coronary heart disease (2.58 [2.20 to 3.03]), cerebrovascular diseases (3.11 [2.42 to 3.98]), but not pneumonia (0.98 [0.69 to 1.38]). Edentulism (all types) was associated with increased risk of all-cause mortality (1.66 [1.46 to 1.88]) and mortality due to cardiovascular diseases (2.03 [1.50 to 2.74]), cancer (1.55 [1.24 to 1.94]), pneumonia (1.72 [1.07 to 2.78]), coronary heart disease (2.98 [2.43 to 3.65]), and cerebrovascular diseases (3.18 [2.24 to 4.51]). Periodontitis and its ultimate sequela (edentulism) are associated with an increased risk of all-cause and cause-specific mortality (PROSPERO CRD42018100095).
Keywords: epidemiology; oral diseases; periodontal diseases; periomedicine; risk factors; systemic diseases.

Impaired function of the suprachiasmatic nucleus rescues the loss of body temperature homeostasis caused by time-restricted feeding.
Zhang Z, Zhai Q, Gu Y, Zhang T, Huang Z, Liu Z, Liu Y, Xu Y.
Sci Bull (Beijing). 2020 Aug 15;65(15):1268-1280. doi: 10.1016/j.scib.2020.03.025. Epub 2020 Mar 19.
PMID: 32864176
The suprachiasmatic nucleus (SCN) is the master circadian pacemaker that drives body temperature rhythm. Time-restricted feeding (TRF) has potential as a preventative or therapeutic approach against many diseases. The potential side effects of TRF remain unknown. Here we show that a 4-hour TRF stimulus in mice can severely impair body temperature homeostasis and can result in lethality. Nearly half of the mice died at 21 °C, and all mice died at 18 °C during 4-hour TRF. Moreover, this effect was modulated by the circadian clock and was associated with severe hypothermia due to loss of body temperature homeostasis, which is different from "torpor", an adaptive response under food deprivation. Disrupting the circadian clock by the SCN lesions or a non-invasive method (constant light) which disrupts circadian clock rescued lethality during TRF. Analysis of circadian gene expression in the dorsomedial hypothalamus (DMH) demonstrated that TRF reprograms rhythmic transcriptome in DMH and suppresses expression of genes, such as Ccr5 and Calcrl, which are involved in thermoregulation. We demonstrate a side effect of 4-hour TRF on the homeostasis of body temperature and a rescue function by impairing the SCN function. Altogether, our results suggested that constructing a circadian arrhythmicity may have a beneficial effect on the host response to an acute stress.
Keywords: Body temperature; Circadian Clock; Hypothermia; The dorsomedial hypothalamus; The suprachiasmatic nucleus; Time-restricted feeding.

Associations of soybean products intake with blood pressure changes and hypertension incidence: the China-PAR project.
Wei JL, Wang XY, Liu FC, Chen JC, Cao J, Li JX, Hu DS, Shen C, Lu FH, Zhao YX, Huang JF, Lu XF.
J Geriatr Cardiol. 2020 Jul 28;17(7):384-392. doi: 10.11909/j.issn.1671-5411.2020.07.005.
PMID: 32863820 Free PMC article.
Background: The relationships between dietary intake of soybean products and incident hypertension were still uncertain. This study aimed to illustrate the associations between intake of soybean products with risks of incident hypertension and longitudinal changes of blood pressure in a prospective cohort study.
Methods: We included 67, 499 general Chinese adults from the Project of Prediction for Atherosclerosis Cardiovascular Disease Risk in China (China-PAR). Information about soybean products consumption was collected by standardized questionnaires, and study participants were categorized into the ideal (≥ 125 g/day) or non-ideal (< 125 g/day) group. Hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) for incident hypertension were calculated using Cox proportional hazard models. Among participants with repeated measures of blood pressure, generalized linear models were used to examine the relationships between soybean products consumption and blood pressure changes.
Results: During a median follow-up of 7.4 years, compared with participants who consumed < 125 g of soybean products per day, multivariable adjusted HR for those in the ideal group was 0.73 (0.67-0.80). This inverse association remained robust across most subgroups while significant interactions were tested between soybean products intake and age, sex, urbanization and geographic region (P values for interaction < 0.05). The mean systolic and diastolic blood pressure levels were 1.05 (0.71-1.39) mmHg and 0.44 (0.22-0.66) mmHg lower among participants in the ideal group than those in the non-ideal group.
Conclusions: Our study showed that intake of soybean products might reduce the long-term blood pressure levels and hypertension incidence among Chinese population, which has important public health implications for primary prevention of hypertension.
Keywords: Blood pressure changes; Chinese population; Cohort study; Hypertension; Soybean products.

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenesis in subcutaneous adipose tissue.
Aquilano K, Sciarretta F, Turchi R, Li BH, Rosina M, Ceci V, Guidobaldi G, Arena S, D'Ambrosio C, Audano M, Salvatori I, Colella B, Faraonio R, Panebianco C, Pazienza V, Caruso D, Mitro N, Di Bartolomeo S, Scaloni A, Li JY, Lettieri-Barbato D.
Redox Biol. 2020 Jul 9;36:101633. doi: 10.1016/j.redox.2020.101633. Online ahead of print.
PMID: 32863211
Low-protein/high-carbohydrate (LPHC) diet has been suggested to promote metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1-and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.
Keywords: Metabolism; Mitochondria; Serca; Systems physiology; Ucp1.

Taurine Improves Lipid Metabolism and Increases Resistance to Oxidative Stress.
Wang Z, Ohata Y, Watanabe Y, Yuan Y, Yoshii Y, Kondo Y, Nishizono S, Chiba T.
J Nutr Sci Vitaminol (Tokyo). 2020;66(4):347-356. doi: 10.3177/jnsv.66.347.
PMID: 32863308
Calorie restriction (CR) by 30-40% decreases morbidity of age-related diseases and prolongs the lifespan of various laboratory animal species. Taurine (2-aminoethanesulfonic acid) is an important nutrient for lipid metabolism as it conjugates bile acids. Here, we investigated how taurine supplementation induces effects similar to the CR beneficial effects. Sprague Dawley rats were fed a diet containing different taurine concentrations (0, 0.5, 1.0, 3.0, 5.0%) to analyze the effects on growth, blood, and hepatic parameters. Rats fed a 5% taurine-supplemented diet showed a significant decrease in visceral fat weight, compared with control rats. Moreover, there were significant decreases in the serum total cholesterol, hepatic cholesterol and triglyceride concentrations in the taurine-supplemented groups compared with the control group in a dose-dependent manner. These results were associated with decreased mRNA expression of fatty acid synthase, and increased mRNA expression of carnitine palmitoyltransferase 1α. C57BL/6 mice were fed a 5.0% taurine-supplemented diet, and their response to 3-nitropropionic acid-induced oxidative stress was analyzed. The rate of weight loss due to oxidative stress decreased and the survival rate significantly increased in the taurine-supplemented groups compared with the control group. Finally, cells were treated with 100 μM taurine and their resistance to UV-induced oxidative stress was analyzed. We found that the p53-Chk1 pathway was less activated in taurine-treated cells compared with control cells. Furthermore, damage to cells evaluated by oxidative stress indicators revealed a reduction in oxidative damage with taurine treatment. These findings suggest that taurine partially acts as a CR mimetic.
Keywords: 3-nitropropionic acid; UV; calorie restriction; lipid metabolism; oxidative stress; taurine.

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Unexpected Association of Desacyl-Ghrelin with Physical Activity and Chronic Food Restriction: A Translational Study on Anorexia Nervosa.
Duriez P, Robichon L, Dardennes R, Lavoisy G, Grouselle D, Epelbaum J, Ramoz N, Gorwood P, Tolle V, Viltart O.
J Clin Med. 2020 Aug 28;9(9):E2782. doi: 10.3390/jcm9092782.
PMID: 32872151
Anorexia nervosa (AN) is a severe metabopsychiatric disorder characterised by caloric intake restriction and often excessive physical exercise. Our aim is to assess in female AN patients and in a rodent model, the co-evolution of physical activity and potential dysregulation of acyl-(AG) and desacyl-(DAG) ghrelin plasma concentrations during denutrition and weight recovery. AN inpatients were evaluated at inclusion (T0, n = 29), half-(T1) and total (T2) weight recovery, and one month after discharge (T3, n = 13). C57/Bl6 mice with access to a running wheel, were fed ad libitum or submitted to short-(15 days) or long-(50 days) term quantitative food restriction, followed by refeeding (20 days). In AN patients, AG and DAG rapidly decreased during weight recovery (T0 to T2), AG increased significantly one-month post discharge (T3), but only DAG plasma concentrations at T3 correlated negatively with BMI and positively with physical activity. In mice, AG and DAG both increased during short- and long-term food restriction. After 20 days of ad libitum feeding, DAG was associated to persistence of exercise alteration. The positive association of DAG with physical activity during caloric restriction and after weight recovery questions its role in the adaptation mechanisms to energy deprivation that need to be considered in recovery process in AN.
Keywords: acyl-ghrelin; animal models; chronic food restriction; desacyl-ghrelin; physical activity; restrictive anorexia nervosa; weight recovery.

Metabolically healthy overweight/obesity are associated with increased risk of cardiovascular disease in adults, even in the absence of metabolic risk factors: A systematic review and meta-analysis of prospective cohort studies.
Opio J, Croker E, Odongo GS, Attia J, Wynne K, McEvoy M.
Obes Rev. 2020 Sep 1. doi: 10.1111/obr.13127. Online ahead of print.
PMID: 32869512 Review.
This review examined the risk of cardiovascular disease in adults with metabolically healthy overweight/obesity. A systematic review and meta-analysis using data from Medline, EMBASE, SCOPUS and Cochrane Library searched from inception up to 31st October 2019. We included prospective cohort studies of adults who are metabolically healthy or unhealthy. Outcomes were fatal and nonfatal cardiovascular events, all-cause mortality. Pooled relative risk was calculated for each outcome in populations with metabolically healthy overweight and metabolically healthy obesity using metabolically healthy normal weight as reference. A random-effects model was used for meta-analysis, and risk of bias assessment tool for nonrandomized studies assessed risk of bias within each study. Twenty-three prospective cohort studies with 4,492,723 participants were included. Cardiovascular disease risk was increased in metabolically healthy groups with overweight (RR = 1.34, CI: 1.23-1.46, n = 20, I2 = 90.3%) and obesity (RR = 1.58, CI: 1.34-1.85, n = 21, I2 = 92.2) compared with a reference group with metabolically healthy normal weight. Cardiovascular disease risk was similar irrespective of the number of risk factors used to define metabolically healthy and the risk remained in the group with no metabolic risk factors. Cardiovascular disease risk is increased in populations with overweight and obesity classified as metabolically healthy even when there were no metabolic risk factors.
Keywords: cardiovascular disease; metabolic health; obesity; overweight.

Replacement of Red and Processed Meat With Other Food Sources of Protein and the Risk of Type 2 Diabetes in European Populations: The EPIC-InterAct Study.
Ibsen DB, Steur M, Imamura F, Overvad K, Schulze MB, Bendinelli B, Guevara M, Agudo A, Amiano P, Aune D, Barricarte A, Ericson U, Fagherazzi G, Franks PW, Freisling H, Quiros JR, Grioni S, Heath AK, Huybrechts I, Katze V, Laouali N, Mancini F, Masala G, Olsen A, Papier K, Ramne S, Rolandsson O, Sacerdote C, Sánchez MJ, Santiuste C, Simeon V, Spijkerman AMW, Srour B, Tjønneland A, Tong TYN, Tumino R, van der Schouw YT, Weiderpass E, Wittenbecher C, Sharp SJ, Riboli E, Forouhi NG, Wareham NJ.
Diabetes Care. 2020 Aug 31:dc201038. doi: 10.2337/dc20-1038. Online ahead of print.
PMID: 32868270
Objective: There is sparse evidence for the association of suitable food substitutions for red and processed meat on the risk of type 2 diabetes. We modeled the association between replacing red and processed meat with other protein sources and the risk of type 2 diabetes and estimated its population impact.
Research design and methods: The European Prospective Investigation into Cancer (EPIC)-InterAct case cohort included 11,741 individuals with type 2 diabetes and a subcohort of 15,450 participants in eight countries. We modeled the replacement of self-reported red and processed meat with poultry, fish, eggs, legumes, cheese, cereals, yogurt, milk, and nuts. Country-specific hazard ratios (HRs) for incident type 2 diabetes were estimated by Prentice-weighted Cox regression and pooled using random-effects meta-analysis.
Results: There was a lower hazard for type 2 diabetes for the modeled replacement of red and processed meat `(50 g/day) with cheese (HR 0.90, 95% CI 0.83-0.97) (30 g/day), yogurt (0.90, 0.86-0.95) (70 g/day), nuts (0.90, 0.84-0.96) (10 g/day), or cereals (0.92, 0.88-0.96) (30 g/day) but not for replacements with poultry, fish, eggs, legumes, or milk. If a causal association is assumed, replacing red and processed meat with cheese, yogurt, or nuts could prevent 8.8%, 8.3%, or 7.5%, respectively, of new cases of type 2 diabetes.
Conclusions: Replacement of red and processed meat with cheese, yogurt, nuts, or cereals was associated with a lower rate of type 2 diabetes. Substituting red and processed meat by other protein sources may contribute to the prevention of incident type 2 diabetes in European populations.

Dietary vitamin A, C, and E intake and subsequent fracture risk at various sites: A meta-analysis of prospective cohort studies.
Zhou P, Shao R, Wang H, Miao J, Wang X.
Medicine (Baltimore). 2020 Aug 28;99(35):e20841. doi: 10.1097/MD.0000000000020841.
PMID: 32871858
Background: This study aimed to provide reliable estimates for dietary antioxidant vitamin (vitamins A, C, and E) intake and their effect on fracture risk at various sites.
Methods: The PubMed, EMBASE, and Cochrane Library databases were searched to identify prospective cohort studies published throughout October 2019. The pooled relative risk (RR) with its 95% confidence interval (CI) was calculated using a random-effects model.
Results: In total, 13 prospective cohort studies involving 384,464 individuals were selected for this meta-analysis. The summary RR indicated that increased antioxidant vitamin intake was associated with a reduced fracture risk (RR: 0.92; 95% CI: 0.86-0.98; P = .015). When stratified by the vitamin types, increased vitamin E intake was found to be associated with a reduced fracture risk (RR: 0.66; 95% CI: 0.46-0.95; P = .025), whereas increased vitamin A and C intake did not affect this risk. Increased antioxidant vitamin intake was associated with a reduced fracture risk, irrespective of fracture sites (HR: 0.90; 95% CI: 0.86-0.94; P < .001); however, it did not affect hip fracture risk. Furthermore, increased antioxidant vitamin intake was associated with a reduced fracture risk in men (RR: 0.81; 95% CI: 0.68-0.96; P = .017) and combined men and women (RR: 0.83; 95%CI: 0.73-0.93; P = .002); however, it did not affect fracture risk in women.
Conclusion: Fracture risk at any site is significantly reduced with increased antioxidant vitamin intake, especially vitamin E intake and in men.

Intermittent Fasting Enhanced the Cognitive Function in Older Adults with Mild Cognitive Impairment by Inducing Biochemical and Metabolic changes: A 3-Year Progressive Study.
Ooi TC, Meramat A, Rajab NF, Shahar S, Ismail IS, Azam AA, Sharif R.
Nutrients. 2020 Aug 30;12(9):E2644. doi: 10.3390/nu12092644.
PMID: 32872655
Intermittent fasting (IF) refers to various dietary regimens that cycle between a period of non-fasting and a period of total fasting. This study aimed to determine the effects of IF on cognitive function among elderly individuals who practice IF who have mild cognitive impairment (MCI). A total of 99 elderly subjects with MCI of Malay ethnicity without any terminal illness were recruited from a larger cohort study, LRGS TUA. The subjects were divided into three groups, comprising those who were regularly practicing IF (r-IF), irregularly practicing IF (i-IF), and non-fasters (n-IF). Upon 36 months of follow-up, more MCI subjects in the r-IF group reverted to successful aging with no cognitive impairment and diseases (24.3%) compared to those in i-IF (14.2%) and n-IF groups (3.7%). The r-IF group's subjects exhibited significant increment in superoxide dismutase (SOD) activity and reduction in body weight, levels of insulin, fasting blood glucose, malondialdehyde (MDA), C-reactive protein (CRP), and DNA damage. Moreover, metabolomics analysis showed that IF may modulate cognitive function via various metabolite pathways, including the synthesis and degradation of ketone bodies, butanoate metabolism, pyruvate metabolism, and glycolysis and gluconeogenesis pathways. Overall, the MCI-afflicted older adults who practiced IF regularly had better cognitive scores and reverted to better cognitive function at 36 months follow-up.
Keywords: DNA damage; inflammation; intermittent fasting; metabolomics; mild cognitive impairment; older adults; oxidative stress.

Beneficial effect on serum cholesterol levels, but not glycaemic regulation, after replacing SFA with PUFA for three days: a randomised crossover trial.
Gaundal L, Myhrstad MCW, Leder L, Byfuglien MG, Gjøvaag T, Rud I, Retterstøl K, Holven KB, Ulven SM, Telle-Hansen VH.
Br J Nutr. 2020 Sep 2:1-29. doi: 10.1017/S0007114520003402. Online ahead of print.
PMID: 32873354
Replacing intake of saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) reduces serum cholesterol levels and cardiovascular disease risk. The effect on glycaemic regulation is however, less clear. The main objective of the present study was to investigate the short-term effect of replacing dietary SFA with PUFA on glycaemic regulation.Seventeen healthy, normal-weight participants completed a 25-day double blind, randomised, and controlled, two-period crossover study. Participants were allocated to either interventions with PUFA products or SFA products (control) in a random order for three consecutive days, separated by a 1.5-week washout period between the intervention periods. Glucose, insulin and triglycerides were measured before and after an oral glucose tolerance test. In addition, fasting total cholesterol, non-esterified fatty acids and plasma total fatty acid profile were measured before and after the three-day interventions. Fasting and postprandial glucose, insulin, and triglyceride levels and fasting levels of non-esterified fatty acids and plasma fatty acids profile did not differ between the groups. However, replacing dietary SFA with PUFA significantly reduced total cholesterol levels with 8 % after three days (P = 0.002). Replacing dietary SFA with PUFA for only three days have beneficial cardio-metabolic effects by reducing cholesterol levels in healthy individuals.
Keywords: RCT; cholesterol; fatty acids; glycaemic regulation; healthy subjects.

The impact of a vegan diet on pregnancy outcomes.
Avnon T, Paz Dubinsky E, Lavie I, Ben-Mayor Bashi T, Anbar R, Yogev Y.
J Perinatol. 2020 Sep 1. doi: 10.1038/s41372-020-00804-x. Online ahead of print.
PMID: 32873905
Objective: To determine the effect of a maternal vegan diet on pregnancy outcome.
Study design: This is a prospective observational study. Women with a singleton pregnancy who maintained the same diet prior to, and throughout current pregnancy were enrolled. Stratification was performed according to diet type: vegans, lacto-ovo-vegetarians, fish-eaters, and omnivores.
Results: Overall, 273 women were enrolled, of them, 112 omnivores, 37 fish-eaters, 64 lacto-ovo-vegetarians, and 60 vegans. The vegan diet was significantly associated with an increased risk of small-for-gestational-age newborns compared only to an omnivore diet (RR = 5.9, 95% CI, 1.2-21.8). The incidence of preterm birth was similar in all groups. Vegans had lower birthweight compared to lacto-ovo-vegetarians (3015 ± 420 g vs. 3285 ± 482 g, P = 0.004), and to omnivores (3328 ± 495 g, P < 0.001), but not to fish-eaters. Vegans also had a lower mean gestational weight gain compared only to omnivores (11.6 ± 4.2 kg vs. 14.3 ± 4.6 kg, P = 0.001).
Conclusion: The vegan diet is associated with an increased risk for small-for-gestational-age newborns and lower birthweight.

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