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Changes in Diet Quality from Mid- to Late Life Are Associated with Cognitive Impairment in the Singapore Chinese Health Study.
Tong EH, Lai JS, Whitton C, Neelakantan N, Zhou Y, Chen C, van Dam RM, Feng L, Pan A, Chong MF, Koh WP.
J Nutr. 2021 May 28:nxab179. doi: 10.1093/jn/nxab179. Online ahead of print.
PMID: 34049404
Abstract
Background: Although higher diet quality at mid-life has been associated with better cognitive function in late adulthood, it is unclear whether dietary improvement after mid-life may reduce the risk of cognitive impairment.
Objectives: We examined associations between changes in diet quality and risk of cognitive impairment in the Singapore Chinese Health Study cohort.
Methods: We used data from 14,683 Chinese men and women who were recruited at ages 45 to 74 y from 1993 to 1998 and re-interviewed after 20 y at ages 61 to 96 y during follow-up 3 (2014-2016). Diet quality was measured using the Dietary Approaches to Stop Hypertension (DASH) scores at baseline and follow-up 3 interviews. Cognitive impairment was defined using scores from the Singapore-modified Mini-Mental State Examination at the follow-up 3 interview. Multivariable logistic regression models were used to estimate ORs and 95% CIs for the associations between change in DASH scores and cognitive impairment.
Results: Higher quintiles in DASH scores at baseline and follow-up 3 interviews were associated with lower odds of cognitive impairment in a dose-dependent manner (both: P-trend < 0.001). Compared with participants with consistently low DASH scores, the OR (95% CI) of cognitive impairment was lowest, at 0.64 (0.51, 0.79), in those with consistently high DASH scores. Those with small (OR: 0.80, 95% CI: 0.65, 0.98) or moderate-large (OR: 0.72, 95% CI: 0.59, 0.86) increases in DASH scores were associated with significantly lower odds of cognitive impairment than those with consistently low DASH scores. Associations were consistent across subgroups by sex, BMI (kg/m2; <23 or ≥23), and age (<60 y, ≥60 y) at baseline.
Conclusions: Although maintaining high diet quality confers the lowest risk, improving diet quality from mid- to late life was still associated with a lower risk of cognitive impairment in late adulthood.
Keywords: Chinese; DASH; cognitive impairment; diet quality; mid-life.

Tourism experiences and the lower risk of mortality in the Chinese elderly: a national cohort study.
Du M, Tao L, Liu M, Liu J.
BMC Public Health. 2021 May 27;21(1):996. doi: 10.1186/s12889-021-11099-8.
PMID: 34044805
Abstract
Background: Cohort studies about the effects of tourism experiences on the risk of death among Chinese older adults are still lacking. We aimed to examine the association between tourism experiences and mortality in Chinese aged 65 or above.
Methods: We included 9520 participants aged 65 years or above from the Chinese Longitudinal Healthy Longevity Survey at baseline in 23 provinces in 2011. They were followed up in 2014 and 2018. Cox proportional hazards models were used to assess the association between tourism experiences and the risk of death.
Results: Among 9520 participants, 7.85% had at least one tourism experience outside of their local city/county during the past 2 years. During 35,994.26 person-years of follow-up, in total 4635 deaths were observed. The crude rate of death was greater in participants who had no tourism experience than in older travelers (incidence rate: 13.70 versus 5.24 per 100 person-years). Elderly travelers had a significantly lower risk for all-cause mortality (crude hazard ratio: 0.38, 95% CI: 0.33-0.44) compared with non-travelers. After adjustment for all covariates, the risk of all-cause mortality was 27% lower among those with at least one tourism experience than among non-travelers (adjusted hazard ratio: 0.73, 95% CI: 0.62-0.85). Subgroup analysis showed that the associations between tourism and the decreased risk of mortality were stable.
Conclusions: Tourism decreases the risk of mortality in the Chinese elderly. Tourism should be considered as a modifiable lifestyle factor and an effective way to reduce mortality and promote longevity and healthy aging.
Keywords: Chinese; Cohort; Mortality; Older; Tourism.

Aging as a consequence of selection to reduce the environmental risk of dying.
Omholt SW, Kirkwood TBL.
Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):e2102088118. doi: 10.1073/pnas.2102088118.
PMID: 34031251 Free article.
Abstract
Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual's lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild.
Keywords: aging; evolution; life-history modeling; mortality risk; senescence.

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Associations between sleep disturbances, diabetes and mortality in the UK Biobank cohort: A prospective population-based study.
von Schantz M, Ong JC, Knutson KL.
J Sleep Res. 2021 Jun 8:e13392. doi: 10.1111/jsr.13392. Online ahead of print.
PMID: 34101927
Abstract
Non-communicable diseases, including diabetes, are partly responsible for the deceleration of improvements of life expectancy in many countries. Diabetes is also associated with sleep disturbances. Our aim was to determine whether sleep disturbances, particularly in people with diabetes, were associated with increased mortality risk. Data from the UK Biobank were analysed (n = 487,728, mean follow-up time = 8.9 years). The primary exposure was sleep disturbances, assessed through the question: Do you have trouble falling asleep at night or do you wake up in the middle of the night? The primary outcome was mortality. We also dichotomized sleep disturbances into "never/sometimes" versus "usually" (frequently), and combined with the presence/absence of diabetes: 24.2% of participants reported "never/rarely" experiencing sleep disturbances, 47.8% "sometimes" and 28.0% "usually". In age- and sex-adjusted models, frequent sleep disturbances were associated with an increased risk of all-cause mortality (hazard ratio {HR}, 1.31; 95% confidence interval [CI], 1.26-1.37), which remained significant in the fully adjusted model (HR 1.13, 95% CI 1.09-1.18). The presence of both diabetes and frequent sleep disturbances was associated with greater risk of all-cause mortality than either condition alone. In the fully adjusted model, the hazard ratio for all-cause mortality was 1.11 (95% CI, 1.07-1.15) for frequent sleep disturbances alone, 1.67 (95% CI, 1.57-1.76) for diabetes alone and 1.87 for both (95% CI, 1.75-2.01). Frequent sleep disturbances (experienced by more than one quarter of the sample) were associated with increased risk of all-cause mortality. Mortality risk was highest in those with both diabetes and frequent sleep disturbances. Complaints of difficulty falling or staying asleep merit attention by physicians.
Keywords: cohort study; diabetes mellitus; insomnia; non-communicable disease; sleep disorders.

Impact of dietary carbohydrate type and protein-carbohydrate interaction on metabolic health.
Wali JA, Milner AJ, Luk AWS, Pulpitel TJ, Dodgson T, Facey HJW, Wahl D, Kebede MA, Senior AM, Sullivan MA, Brandon AE, Yau B, Lockwood GP, Koay YC, Ribeiro R, Solon-Biet SM, Bell-Anderson KS, O'Sullivan JF, Macia L, Forbes JM, Cooney GJ, Cogger VC, Holmes A, Raubenheimer D, Le Couteur DG, Simpson SJ.
Nat Metab. 2021 Jun 8. doi: 10.1038/s42255-021-00393-9. Online ahead of print.
PMID: 34099926
Abstract
Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.

Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials.
Zijlstra LE, Jukema JW, Westendorp RGJ, Du Puy RS, Poortvliet RKE, Kearney PM, O'Keeffe L, Dekkers OM, Blum MR, Rodondi N, Collet TH, Quinn TJ, Sattar N, Stott DJ, Trompet S, den Elzen WPJ, Gussekloo J, Mooijaart SP.
Front Endocrinol (Lausanne). 2021 May 20;12:674841. doi: 10.3389/fendo.2021.674841. eCollection 2021.
PMID: 34093444 Free PMC article.
Abstract
Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).
Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.
Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.
Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.
Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.
Keywords: cardiovascular disease; levothyroxine; older adults; randomised controlled trial; subclinical hypothyroidism.

Intermittent administration of a fasting-mimicking diet reduces intestinal inflammation and promotes repair to ameliorate inflammatory bowel disease in mice.
Song S, Bai M, Ling Z, Lin Y, Wang S, Chen Y.
J Nutr Biochem. 2021 Jun 1:108785. doi: 10.1016/j.jnutbio.2021.108785. Online ahead of print.
PMID: 34087411
Abstract
Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4+ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4+ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium.
Keywords: Dietary intervention; Inflammatory bowel disease; Intestine; Nutrition; Regeneration.

Who wants to live forever? Age cohort differences in attitudes toward life extension.
Barnett MD, Helphrey JH.
J Aging Stud. 2021 Jun;57:100931. doi: 10.1016/j.jaging.2021.100931. Epub 2021 Apr 12.
PMID: 34083000
Abstract
Introduction: Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension.
Methods: This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever.
Results: Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults.
Discussion: If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.
Keywords: Aging attitudes; Immortality; Technology.

Urinary polycyclic aromatic hydrocarbon metabolites and mortality in the United States: A prospective analysis.
Patel AP, Mehta SS, White AJ, Niehoff NM, Arroyave WD, Wang A, Lunn RM.
PLoS One. 2021 Jun 4;16(6):e0252719. doi: 10.1371/journal.pone.0252719. eCollection 2021.
PMID: 34086784
Abstract
Background: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous organic compounds associated with chronic disease in epidemiologic studies, though the contribution of PAH exposure on fatal outcomes in the U.S. is largely unknown.
Objectives: We investigated urinary hydroxylated PAH metabolites (OH-PAHs) with all-cause and cause-specific mortality in a representative sample of the U.S. population.
Methods: Study participants were ≥20 years old from the National Health and Nutrition Examination Survey 2001-2014. Concentrations (nmol/L) of eight OH-PAHs from four parent PAHs (naphthalene, fluorene, phenanthrene, pyrene) were measured in spot urine samples at examination. We identified all-cause, cancer-specific, and cardiovascular-specific deaths through 2015 using the National Death Index. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ΣOH-PAHs and mortality endpoints. We assessed potential heterogeneity by age, gender, smoking status, poverty, and race/ethnicity. Additionally, we examined the overall mixture effect using quantile g-computation.
Results: In 9,739 eligible participants, there were 934 all-cause deaths, 159 cancer-specific deaths, and 108 cardiovascular-specific deaths (median 6.75 years follow-up). A log10 increase in ΣOH-PAHs was associated with higher all-cause mortality (HRadj = 1.39 [95%CI: 1.21, 1.61]), and possibly cancer-specific mortality (HRadj = 1.15 [95%CI: 0.79, 1.69]), and cardiovascular-specific mortality (HRadj = 1.49 [95%CI: 0.94, 2.33]). We observed substantial effect modification by age, smoking status, gender, and race/ethnicity across mortality endpoints. Risk of cardiovascular mortality was higher for non-Hispanic blacks and those in poverty, indicating potential disparities. Quantile g-computation joint associations for a simultaneous quartile increase in OH-PAHs were HRadj = 1.15 [95%CI: 1.02, 1.31], HRadj = 1.41 [95%CI: 1.05, 1.90], and HRadj = 0.98 [95%CI: 0.66, 1.47] for all-cause, cancer-specific, and cardiovascular-specific mortalities, respectively.
Discussion: Our results support a role for total PAH exposure in all-cause and cause-specific mortality in the U.S. population.

Edited by AlPater

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Analysis of Repeated Measurements of Serum Carotenoid Levels and All-Cause and Cause-Specific Mortality in Japan.
Fujii R, Tsuboi Y, Maeda K, Ishihara Y, Suzuki K.
JAMA Netw Open. 2021 Jun 1;4(6):e2113369. doi: 10.1001/jamanetworkopen.2021.13369.
PMID: 34115126
Abstract
Importance: The associations of levels of diverse serum carotenoids ascertained via repeated measurements with all-cause, cancer, and cardiovascular disease (CVD) mortality risk have not been considered in previous prospective studies.
Objective: To investigate the association between repeated measurement of serum carotenoid levels and all-cause and cause-specific mortality risk.
Design, setting, and participants: This cohort study's baseline data were collected using information from physical examinations from 1990 to 1999. Eligible participants were followed up until December 2017, with a median (interquartile range) follow-up period of 22.3 (15.5-25.3) years. Included individuals were age 40 years or older at the baseline data collection, were residents of the study site in the town of Yakumo, Hokkaido, Japan, and participated in a physical examination at least once from 1990 to 1999. Among eligible participants, after excluding 332 individuals, 3116 individuals were included in the analysis. Data analysis was conducted in April 2020.
Exposures: Repeated measurements of 6 serum carotenoid levels and 4 associated indices.
Main outcomes and measures: All-cause, cancer, and CVD mortality, categorized by International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, were recorded. A time-dependent Cox regression model was performed to examine associations between time-varying serum carotenoid levels and mortality.
Results: Among 3116 individuals who received physical examinations, the mean (SD) age was 54.7 (10.6) years and 1883 (60.4%) were women. During the follow-up period, 762 deaths from all causes, 253 deaths from cancer, and 210 deaths from CVD were ascertained. In a time-dependent Cox regression analysis, for every 25% higher serum levels of total carotenoids, risks were statistically significantly lower for all-cause mortality (hazard ratio {HR}, 0.85; 95% CI, 0.82-0.87; P < .001), cancer mortality (HR, 0.82; 95% CI, 0.78-0.87; P < .001), and CVD mortality (HR, 0.86; 95% CI, 0.81-0.91; P < .001). Using only baseline measures, for every 25% higher serum levels of total carotenoids, risks were also statistically significantly lower for all-cause mortality (HR, 0.92; 95% CI, 0.89-0.95; P < .001), cancer mortality (HR, 0.87; 95% CI, 0.83-0.93; P < .001), and CVD mortality (HR, 0.93; 95% CI, 0.88-0.99; P = .03) but with larger HRs than those associated with repeated measurements.
Conclusions and relevance: This study found that higher levels of serum carotenoids in analysis using repeated measurements were associated with significantly lower all-cause and cause-specific mortality over a follow-up period of 25 years.

Fasting Ketonuria and the Risk of Incident Nonalcoholic Fatty Liver Disease With and Without Liver Fibrosis in Nondiabetic Adults.
Kim Y, Chang Y, Kwon MJ, Hong YS, Kim MK, Sohn W, Cho YK, Shin H, Wild SH, Byrne CD, Ryu S.
Am J Gastroenterol. 2021 Jun 11. doi: 10.14309/ajg.0000000000001344. Online ahead of print.
PMID: 34114568
Abstract
Introduction: Dietary carbohydrate restriction or ketogenic diets are known to be beneficial in preventing liver fat accumulation. However, the effect of ketonemia on the risk of nonalcoholic fatty liver disease (NAFLD) in nondiabetic population is largely unknown. We investigated the association between fasting ketonuria and the risk of incident NAFLD in healthy adults.
Methods: A cohort of 153,076 nondiabetic Koreans with no hepatic steatosis and low probability of fibrosis at baseline was followed for a median of 4.1 years. The outcome was incident hepatic steatosis with or without liver fibrosis, and it was assessed by liver ultrasound and noninvasive fibrosis indices, including fibrosis-4 and the NAFLD fibrosis score (NFS). Parametric proportional hazard models were used to estimate hazard ratios (HRs) for outcome according to ketonuria status.
Results: Within 677,702.1 person-years of follow-up, 31,079 subjects developed hepatic steatosis. Compared with no ketonuria (reference), fasting ketonuria was significantly associated with a decreased risk of incident hepatic steatosis, with multivariable-adjusted HRs (95% confidence interval) of 0.81 (0.78-0.84). The corresponding HRs for incident hepatic steatosis with intermediate-to-high NFS were 0.79 (0.69-0.90). Similar associations were observed replacing NFS with fibrosis-4. In addition, the presence of persistent ketonuria at both baseline and subsequent visit was associated with the greatest decrease in the adjusted HR for incident NAFLD.
Discussion: Ketonuria was associated with a reduced risk of developing incident hepatic steatosis with and without intermediate-to-high probability of advanced fibrosis in a large cohort of nondiabetic healthy individuals. The role of hyperketonemia in the prevention of NAFLD requires further exploration.

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, Jang C, Kasza I, Nikodemova M, Wakai MH, Tomasiewicz JL, Yang SE, Miller BR, Pak HH, Brinkman JA, Rojas JM, Quinn WJ 3rd, Cheng EP, Konon EN, Haider LR, Finke M, Sonsalla M, Alexander CM, Rabinowitz JD, Baur JA, Malecki KC, Lamming DW.
Cell Metab. 2021 May 4;33(5):905-922.e6. doi: 10.1016/j.cmet.2021.03.025. Epub 2021 Apr 21.
PMID: 33887198
Abstract
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Keywords: FGF21; GCN2; body mass index; branched-chain amino acids; diabetes; insulin resistance; isoleucine; mTORC1; obesity; valine.

Are people with metabolically healthy obesity really healthy? A prospective cohort study of 381,363 UK Biobank participants.
Zhou Z, Macpherson J, Gray SR, Gill JMR, Welsh P, Celis-Morales C, Sattar N, Pell JP, Ho FK.
Diabetologia. 2021 Jun 10. doi: 10.1007/s00125-021-05484-6. Online ahead of print.
PMID: 34109441
Abstract
Aims/hypothesis: People with obesity and a normal metabolic profile are sometimes referred to as having 'metabolically healthy obesity' (MHO). However, whether this group of individuals are actually 'healthy' is uncertain. This study aims to examine the associations of MHO with a wide range of obesity-related outcomes.
Methods: This is a population-based prospective cohort study of 381,363 UK Biobank participants with a median follow-up of 11.2 years. MHO was defined as having a BMI ≥ 30 kg/m2 and at least four of the six metabolically healthy criteria. Outcomes included incident diabetes and incident and fatal atherosclerotic CVD (ASCVD), heart failure (HF) and respiratory diseases.
Results: Compared with people who were not obese at baseline, those with MHO had higher incident HF (HR 1.60; 95% CI 1.45, 1.75) and respiratory disease (HR 1.20; 95% CI 1.16, 1.25) rates, but not higher ASCVD. The associations of MHO were generally weaker for fatal outcomes and only significant for all-cause (HR 1.12; 95% CI 1.04, 1.21) and HF mortality rates (HR 1.44; 95% CI 1.09, 1.89). However, when compared with people who were metabolically healthy without obesity, participants with MHO had higher rates of incident diabetes (HR 4.32; 95% CI 3.83, 4.89), ASCVD (HR 1.18; 95% CI 1.10, 1.27), HF (HR 1.76; 95% CI 1.61, 1.92), respiratory diseases (HR 1.28; 95% CI 1.24, 1.33) and all-cause mortality (HR 1.22; 95% CI 1.14, 1.31). The results with a 5 year landmark analysis were similar.
Conclusions/interpretation: Weight management should be recommended to all people with obesity, irrespective of their metabolic status, to lower risk of diabetes, ASCVD, HF and respiratory diseases. The term 'MHO' should be avoided as it is misleading and different strategies for risk stratification should be explored.
Keywords: Cardiovascular disease; Metabolically healthy obesity; Obesity.

Regulation of the one carbon folate cycle as a shared metabolic signature of longevity.
Annibal A, Tharyan RG, Schonewolff MF, Tam H, Latza C, Auler MMK, Antebi A.
Nat Commun. 2021 Jun 9;12(1):3486. doi: 10.1038/s41467-021-23856-9.
PMID: 34108489
Abstract
The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are pervasively regulated in common. We observed similar changes in long-lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.

Edited by AlPater

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Cold Spells and Cause-Specific Mortality in 47 Japanese Prefectures: A Systematic Evaluation.
Ma C, Yang J, Nakayama SF, Iwai-Shimada M, Jung CR, Sun XL, Honda Y.
Environ Health Perspect. 2021 Jun;129(6):67001. doi: 10.1289/EHP7109. Epub 2021 Jun 15.
PMID: 34128690
Abstract
Background: Many studies have investigated the devastating health effects of heat waves, but less is known about health risks related to cold spells, despite evidence that extreme cold may contribute to a larger proportion of deaths.
Objectives: We aimed to systematically investigate the association between cold spells and mortality in Japan.
Methods: Daily data for weather conditions and 12 common causes of death during the 1972-2015 cold seasons (November-March) were obtained from 47 Japanese prefectures. Cold spells were defined as ≥2 consecutive days with daily mean temperatures ≤5th percentile for the cold season in each prefecture. Quasi-Poisson regression was combined with a distributed lag model to estimate prefecture-specific associations, and pooled associations at the national level were obtained through random-effects meta-analysis. The potential influence of cold spell characteristics (intensity, duration, and timing in season) on associations between cold spells and mortality was examined using a similar two-stage approach. Temporal trends were investigated using a meta-regression model.
Results: A total of 18,139,498 deaths were recorded during study period. Mortality was significantly higher during cold spell days vs. other days for all selected causes of death. Mortality due to age-related physical debilitation was more strongly associated with cold spells than with other causes of death. Associations between cold spells and mortality from all causes and several more specific outcomes were stronger for longer and more intense cold spells and for cold spells earlier in the cold season. However, although all outcomes were positively associated with cold spell duration, findings for cold spell intensity and seasonal timing were heterogeneous across the outcomes. Associations between cold spells and mortality due to cerebrovascular disease, cerebral infarction, and age-related physical debility decreased in magnitude over time, whereas temporal trends were relatively flat for all-cause mortality and other outcomes.
Discussion: Our findings may have implications for establishing tailored public health strategies to prevent avoidable cold spell-related health consequences. 

Muscle-strengthening activities and risk of cardiovascular disease, type 2 diabetes, cancer and mortality: A review of prospective cohort studies.
Giovannucci EL, Rezende LFM, Lee DH.
J Intern Med. 2021 Jun 13. doi: 10.1111/joim.13344. Online ahead of print.
PMID: 34120373 Review.
Abstract
The benefits of aerobic moderate-to-vigorous physical activity (MVPA) on major non-communicable diseases (NCDs) are well established. However, much less is known whether muscle-strengthening activities (i.e., resistance/weight/strength training) confer similar benefits. Herein, we conducted a narrative literature review and summarized the existing evidence from large prospective cohort studies on muscle strengthening activities and risk of major chronic diseases and mortality in adults generally free of major NCDs at baseline. Current epidemiologic evidence suggests that engagement in muscle-strengthening activities over 1-2 sessions (or approximately 60-150 min) per week was associated with reduced risk of cardiovascular disease (7 studies; approximately 20-25% reduction), type 2 diabetes (4 studies; approximately 30% reduction), cancer mortality (4 studies; approximately 15-20% reduction) as well as all-cause mortality (6 studies; approximately 20-25% reduction). For diabetes, the risk appears to lower further with even higher levels of muscle-strengthening activities, but some studies for cardiovascular and overall mortality suggest a reversal whereby higher levels have less benefit (≥2.5 hours/week), or are even harmful, relative to lower levels of activity. The likely mechanisms contributing to a benefit include improvement in body composition, lipid profile, insulin resistance and inflammation. The evidence supports engaging in 1-2 sessions per week, preferably performed complementary to the recommended levels of aerobic MVPA, up to 2.5 total per week. Although data are limited, caution is suggested for training exceeding 2.5 hours per week. Further studies are required to better understand the influence of frequency, duration, and intensity of muscle-strengthening activities on major NCDs and mortality in diverse populations.
Keywords: cancer; cardiovascular disease; diabetes; mortality; muscle-strengthening; resistance training; strength training; weight training.

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Effect of carbohydrate-restricted dietary interventions on LDL particle size and number in adults in the context of weight loss or weight maintenance: a systematic review and meta-analysis.
Falkenhain K, Roach LA, McCreary S, McArthur E, Weiss EJ, Francois ME, Little JP.
Am J Clin Nutr. 2021 Jun 22:nqab212. doi: 10.1093/ajcn/nqab212. Online ahead of print.
PMID: 34159352
Abstract
Background: LDL particle size and number (LDL-P) are emerging lipid risk factors. Nonsystematic reviews have suggested that diets lower in carbohydrates and higher in fats may result in increased LDL particle size when compared with higher-carbohydrate diets.
Objectives: This study aimed to systematically review available evidence and conduct meta-analyses of studies addressing the association of carbohydrate restriction with LDL particle size and LDL-P.
Methods: We searched 6 electronic databases on 4 January, 2021 for randomized trials of any length that reported on dietary carbohydrate restriction (intervention) compared with higher carbohydrate intake (control). We calculated standardized mean differences (SMDs) in LDL particle size and LDL-P between the intervention and control groups of eligible studies, and pooled effect sizes using random-effects models. We performed prespecified subgroup analyses and examined the effect of potential explanatory factors. Internal validity and publication bias were assessed using Cochrane's risk-of-bias tool and funnel plots, respectively. Studies that could not be meta-analyzed were summarized qualitatively.
Results: This review summarizes findings from 38 randomized trials including a total of 1785 participants. Carbohydrate-restricted dietary interventions were associated with an increase in LDL peak particle size (SMD = 0.50; 95% CI: 0.15, 0.86; P < 0.01) and a reduction in LDL-P (SMD = -0.24; 95% CI: -0.43, -0.06; P = 0.02). The effect of carbohydrate-restricted dietary interventions on LDL peak particle size appeared to be partially explained by differences in weight loss between intervention groups and exploratory analysis revealed a shift from small dense to larger LDL subclasses. No statistically significant association was found between carbohydrate-restricted dietary interventions and mean LDL particle size (SMD = 0.20; 95% CI: -0.29, 0.69; P = 0.37).
Conclusions: The available evidence indicates that dietary interventions restricted in carbohydrates increase LDL peak particle size and decrease the numbers of total and small LDL particles.
Keywords: LDL particle; low-carbohydrate; meta-analysis; obesity; overweight; systematic review; weight loss.

https://en.wikipedia.org/wiki/Water_chlorination#Drawbacks
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Association of Blood Trihalomethane Concentrations with Risk of All-Cause and Cause-Specific Mortality in U.S. Adults: A Prospective Cohort Study.
Sun Y, Chen C, Mustieles V, Wang L, Zhang Y, Wang YX, Messerlian C.
Environ Sci Technol. 2021 Jun 21. doi: 10.1021/acs.est.1c00862. Online ahead of print.
PMID: 34152769
Abstract
Water chlorination can lead to the formation of disinfection byproducts, including trihalomethanes (THMs). However, few epidemiologic studies have explored associations between THM exposure and mortality. This study included 6720 adults aged ≥40 years from the National Health and Nutrition Examination Survey 1999-2012 who had blood THM concentrations quantified. A higher risk of all-cause mortality was found across increasing quartile concentrations of blood chloroform (TCM) and total THMs (TTHMs; sum of all four THMs) (both p for trend = 0.02). Adults in the highest quartile of TCM and TTHM concentrations had hazard ratios (HRs) of 1.35 (95% confidence intervals: 1.05-1.74) and 1.37 (1.05-1.79), respectively, for all-cause mortality, compared with adults in the lowest quartile. When cause-specific mortality was evaluated, a positive relationship was found between blood bromodichloromethane (BDCM), dibromochloromethane (DBCM), bromoform (TBM), total brominated THMs (Br-THMs; sum of BDCM, DBCM, and TBM), and TTHM concentrations and risk of cancer death and between blood TCM and TTHMs and risk of other cause (noncancer/nonheart disease) mortality. Our findings suggest that higher exposure to Br-THMs was associated with increased cancer mortality risk, whereas TCM was associated with a greater risk of noncancer/nonheart disease mortality.
Keywords: NHANES; adults; cancer; mortality; trihalomethanes.

FGF21 prevents low protein diet-induced renal inflammation in aged mice.
Fang H, Ghosh S, Sims L, Stone KP, Hill CM, Spires DR, Ilatovskaya DV, Morrison CD, Gettys T, Stadler K.
Am J Physiol Renal Physiol. 2021 Jun 21. doi: 10.1152/ajprenal.00107.2021. Online ahead of print.
PMID: 34151592
Abstract
Low protein diets extend lifespan through a comprehensive improvement in metabolic health across multiple tissues and organs. Many of these metabolic responses to protein restriction are secondary to transcriptional activation and release of FGF21 from the liver. However, the effects of a low protein (LP) diet on the kidney in the context of aging has not been examined. Therefore, the goal of the current study was to investigate the impact of chronic consumption of a LP diet on the kidney in aging mice lacking FGF21. Wild type (WT, C57BL/6J) and FGF21 KO mice were fed a normal protein (NP, 20% casein) or a LP (5% casein) diet ad libitum from 3 to19 months of age. The LP diet led to a decrease in kidney weight and urinary albumin/creatinine ratio in both WT and FGF21 KO mice. Although the LP diet produced only mild fibrosis and infiltration of leukocytes in WT kidneys, the effects were significantly exacerbated by the absence of FGF21. Accordingly, transcriptomic analysis showed that inflammation-related pathways were significantly enriched and upregulated in response to LP diet in FGF21 KO but not WT mice. Collectively, these data demonstrate that the LP diet negatively affected the kidney during aging, but in the absence of FGF21, the LP diet-induced renal damage and inflammation were significantly worse, indicating a protective role of FGF21 in the kidney.
Keywords: FGF21; aging; inflammation; kidney; low protein diet.

Dietary glycemic index, glycemic load and mortality: Japan Public Health Center-based prospective study.
Huang HL, Abe SK, Sawada N, Takachi R, Ishihara J, Iwasaki M, Yamaji T, Iso H, Mizoue T, Noda M, Hashizume M, Inoue M, Tsugane S; JPHC Study Group.
Eur J Nutr. 2021 Jun 22. doi: 10.1007/s00394-021-02621-0. Online ahead of print.
PMID: 34159430
Abstract
Purpose: Long-term associations of dietary glycemic index (GI) and glycemic load (GL) with mortality outcomes remain unclear.
Methods: The present analysis included 72,783 participants of the Japan Public Health Center-based Prospective Study. Participants who responded to the 5-year follow-up questionnaire in 1995-1999 were followed-up until December 2015. We estimated the risk of total and cause-specific mortality associated with GI and GL using Cox proportional hazards regression models.
Results: During 1,244,553 person years of follow-up, 7535 men and 4913 women died. GI was positively associated with all-cause mortality. As compared with the lowest quartile, the multivariable HR for those who had the highest quartile of GI was 1.14 (95% CI 1.08-1.20). The HRs for death comparing the highest with the lowest quartile were 1.28 (95% CI 1.14-1.42) for circulatory system diseases, 1.33 (95% CI 1.14-1.55) for heart disease, 1.32 (95% CI 1.11-1.57) for cerebrovascular disease, and 1.45 (95% CI 1.18-1.78) for respiratory diseases. GI was not associated with mortality risks of cancer and digestive diseases. GL showed a null association with all-cause mortality (highest vs lowest quartile; HR 1.04; 95% CI 0.96-1.12). However, among those who had the highest quartile of GL, the HRs for death from circulatory system diseases was 1.24 (95% CI 1.05-1.46), cerebrovascular disease was 1.34 (95% CI 1.03-1.74), and respiratory diseases was 1.35 (95% CI 1.00-1.82), as compared with the lowest quartile.
Conclusion: In this large prospective cohort study, dietary GI and GL were associated with mortality risks.
Keywords: Glycemic index; Glycemic load; Japan; Mortality; Prospective cohort.

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Amino acid metabolism and signalling pathways: potential targets in the control of infection and immunity.
Tomé D.
Eur J Clin Nutr. 2021 Jun 23:1-9. doi: 10.1038/s41430-021-00943-0. Online ahead of print.
PMID: 34163018 Free PMC article. Review.
Abstract
Defences to pathogens such as SarCoV2 in mammals involves interactions between immune functions and metabolic pathways to eradicate infection while preventing hyperinflammation. Amino acid metabolic pathways represent with other antimicrobial agent potential targets for therapeutic strategies. iNOS-mediated production of NO from Arg is involved in the innate inflammatory response to pathogens and NO overproduction can induce hyperinflammation. The two Arg-catabolising enzymes Arg1 and IDO1 reduce the hyperinflammation by an immunosuppressive effect via either Arg starvation (for Arg1) or via the immunoregulatory activity of the Arg-derived metabolites Kyn (for IDO1). In response to amino acid abundance mTOR activates the host protein translation and Coronaviruses use this machinery for their own protein synthesis and replication. In contrast GCN2, the sensor of amino acid starvation, activates pathways that restrict inflammation and viral replication. Gln depletion alters the immune response that become more suppressive, by favouring a regulatory T phenotype rather than a Th1 phenotype. Proliferating activated immune cells are highly dependent on Ser, activation and differentiation of T cells need enough Ser and dietary Ser restriction can inhibit their proliferation. Cys is strictly required for T-cell proliferation because they cannot convert Met to Cys. Restricting Met inhibits both viral RNA cap methylation and replication, and the proliferation of infected cells with an increased requirement for Met. Phe catabolism produces antimicrobial metabolites resulting in the inhibition of microbial growth and an immunosuppressive activity towards T lymphocytes.

Associations of dietary polyunsaturated fatty acids with dyslipidemia among the U.S. adults: the findings from NHANES 2009-2016.
Zhou J, Cai L, Ni S, Zhong Z, Yang M, Yu H, Zhao Y, Xun P, Bai J.
Br J Nutr. 2021 Jun 21:1-28. doi: 10.1017/S0007114521002300. Online ahead of print.
PMID: 34165051
Abstract
Dyslipidemia, a significant risk factor of cardiovascular disease, is threatening human health worldwide with a high economic burden. Polyunsaturated fatty acids (PUFAs) are crucial long-chain fatty acids for triglyceride synthesis and removal, potentially decreasing dyslipidemia risk. We examined dyslipidemia prevalence among 15,244 adults aged ≥20 years from NHANES 2009-2016. The dyslipidemia was defined as total cholesterol ≥240 mg/dL, or high-density lipoprotein cholesterol <40 mg/dL/50 mg/dL for males/females respectively, or low-density lipoprotein cholesterol ≥160 mg/dL, or triglyceride ≥200 mg/dL, or taking lipid-modifying medications. We measured the daily PUFA intake using a 24-h dietary recall. Demographics, social-economics, and lifestyle factors were collected using questionnaires/interviews. Additionally, we measured selenium and mercury levels in the whole blood. Logistic regression models were used to examine the association between PUFAs and dyslipidemia. The unweighted and weighted dyslipidemia prevalences were 72.4% and 71.0%, respectively. When grouped into tertiles, PUFA intake above 19.524 g/day was associated with an independent 19% decrease in dyslipidemia risk [O.R.=0.81(95%C.I.: 0.71-0.94)] compared with the lowest tertile (PUFA intake ≤12.349 g/day). A threshold inverse association was further determined by the restricted cubic spline analysis. When PUFA intake was increased to its turning point, i.e., 19 g/day, the lower nadir risk for dyslipidemia was obtained [O.R.=0.72(95% C.I.: 0.56-0.89)]. When the exposure was the sum of α-linolenic acid and octadecatetraenoic acid, the inverse linear association remained. Dietary PUFA intake is a beneficial factor for dyslipidemia among American adults, independent of many potential confounders, including mercury and selenium. Future prospective studies are warranted.
Keywords: Dyslipidemia; NHANES; polyunsaturated fatty acids (PUFAs); threshold association.

Menarche characteristics in association with total and cause-specific mortality: a prospective cohort study of Mexican teachers.
Lozano-Esparza S, Jansen E, Hernandez-Avila JE, Muñoz SZ, Stern D, Lajous M.
Ann Epidemiol. 2021 Jun 21:S1047-2797(21)00155-1. doi: 10.1016/j.annepidem.2021.06.007. Online ahead of print.
PMID: 34166807
Abstract
Purpose: We evaluated the relation between age at menarche and time to menstrual regularity with all-cause and cause specific mortality in a cohort of Mexican women.
Methods: We followed 113,540 women from the Mexican Teachers' Cohort. After a mean follow-up time of 9.2 years, 1,355 deaths were identified. We estimated hazard ratios from Cox regression models for total mortality and a competitive risk model for cause-specific mortality adjusting for year of birth and childhood factors.
Results: Women with extreme age of menarche were at increased risk of all-cause mortality [HR (95%CI): <11yr 1.50 (1.20, 1.87); 14yr 1.19 (0.97, 1.43)] relative to those with menarche at 13 years. Extreme ages had higher risk of mortality for diabetes [HR: <11yr 1.66 (0.90, 3.05); 14yr 1.47 (0.90, 2.40)], breast cancer [HR: <11yr 1.34(0.56, 3.20)], and other cancer [HR:<11yr 1.65 (1.10, 2.48)] compared to menarche at 13 years. Women who took three or more years to achieve menstrual regularity had a higher risk of all-cause mortality compared to those who took less [HR: 1.27 (1.01, 1.58)].
Conclusion: Extreme ages at menarche and longer time to reach menstrual regularity were associated with an increased rate of all-cause and cause-specific mortality.
Keywords: Cancer; Diabetes; Hispanic; Menarche; Mexico; Mortality.

Association between frequency of snacking and all-cause mortality among community-dwelling young-old adults: An age-specific prospective cohort study.
Kobayashi T, Zhao W, Ukawa S, Wakai K, Tsushita K, Kawamura T, Ando M, Tamakoshi A.
Geriatr Gerontol Int. 2021 Jun 25. doi: 10.1111/ggi.14209. Online ahead of print.
PMID: 34173313
Abstract
Aim: We aimed to clarify whether snacking habits decrease the risk of all-cause mortality in an older Japanese population.
Methods: The study participants were 64- or 65-year-old community-dwelling residents recruited each survey year from 1996 through 2005. Data on the frequency of snacking and other lifestyle factors were obtained during the baseline survey using self-administered questionnaires, and the participants were followed up annually until the end of 2017. In total, 2943 participants (1484 men and 1459 women) were eligible. All-cause mortality was compared among participants grouped by frequency of snacking (no snacking, one to four times/week, or every day).
Results: The number of deaths recorded over the study period of 43 204 person-years was 357 (24.1%) for men and 173 (11.9%) for women. The mean ± standard deviations for the follow-up period were 14.2 ± 4.9 years in men and 15.2 ± 4.5 years in women. Cox proportional hazard regression analyses showed that after adjusting for potential confounding factors, the hazard ratios for women were 0.64 (95% confidence interval [CI], 0.43-0.94) in the group that had a habit of snacking one to four times/week, and 0.93 (95% CI 0.63-1.36) in the group that had a habit of snacking every day compared with those in the no snacking group. These associations were not observed among men.
Conclusions: A moderate frequency of snacking slightly decreases the risk of all-cause mortality among women. Our findings might be useful for improving the nutrition statuses in older female adults.
Keywords: eating behavior; epidemiology; mortality; older adults snacking.

Comparative efficacy and safety of acetaminophen, topical and oral non-steroidal anti-inflammatory drugs for knee osteoarthritis: evidence from a network meta-analysis of randomized controlled trials and real-world data.
Zeng C, Doherty M, Persson MSM, Yang Z, Sarmanova A, Zhang Y, Wei J, Kaur J, Li X, Lei G, Zhang W.
Osteoarthritis Cartilage. 2021 Jun 23:S1063-4584(21)00810-4. doi: 10.1016/j.joca.2021.06.004. Online ahead of print.
PMID: 34174454 Review.
Abstract
Objective: Current global guidelines regarding the first-line analgesics (acetaminophen, topical or oral non-steroidal anti-inflammatory drugs [NSAIDs]) for knee osteoarthritis remain controversial and their comparative risk-benefit profiles have yet to be adequately assessed.
Design: Pubmed, Embase, Cochrane Library, and Web of Science were searched from database inception to March 2021 for randomized controlled trials (RCTs) comparing acetaminophen, topical NSAIDs and oral NSAIDs directly or indirectly in knee osteoarthritis. Bayesian network meta-analyses were conducted. A propensity-score matched cohort study was also conducted among patients with knee osteoarthritis in The Health Improvement Network database.
Results: 122 RCTs (47,113 participants) were networked. Topical NSAIDs were superior to acetaminophen (standardized mean difference [SMD]=-0.29, 95% credible interval [CrI]: -0.52 to -0.06) and not statistically different from oral NSAIDs (SMD=0.03, 95% CrI: -0.16 to 0.22) for function. It had lower risk of gastrointestinal adverse effects (AEs) than acetaminophen (relative risk [RR]=0.52, 95%CrI: 0.35 to 0.76) and oral NSAIDs (RR=0.46, 95%CrI: 0.34 to 0.61) in RCTs. In real-world data, topical NSAIDs showed lower risks of all-cause mortality (hazard ratio


=0.59, 95% confidence interval [CI]: 0.52 to 0.68), cardiovascular diseases (HR=0.73, 95%CI: 0.63 to 0.85) and gastrointestinal bleeding (HR=0.53, 95%CI: 0.41 to 0.69) than acetaminophen during the one-year follow-up (n=22,158 participants/group). A better safety profile was also observed for topical than oral NSAIDs (n=14,218 participants/group).
Conclusions: Topical NSAIDs are more effective than acetaminophen but not oral NSAIDs for function improvement in people with knee osteoarthritis. Topical NSAIDs are safer than acetaminophen or oral NSAIDs in trials and real-world data.
Keywords: Acetaminophen; Cohort; Meta-analysis; NSAIDs; Oral; Osteoarthritis; Topical.

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Dietary protein intake, kidney function, and survival in a nationally representative cohort.
Narasaki Y, Okuda Y, Moore LW, You AS, Tantisattamo E, Inrig JK, Miyagi T, Nakata T, Kovesdy CP, Nguyen DV, Kalantar-Zadeh K, Rhee CM.
Am J Clin Nutr. 2021 Jul 1;114(1):303-313. doi: 10.1093/ajcn/nqab011.
PMID: Abstract
Background: High-protein diets (e.g., Paleo, Atkins, South Beach, ketogenic) have gained popularity as a means to promote weight loss and avoid excess carbohydrate consumption. Yet in chronic kidney disease (CKD) patients, evidence suggests low dietary protein intake (DPI) leads to attenuation of kidney function decline, although concerns remain for risk of protein-energy wasting.
Objectives: To examine associations of DPI with mortality in a nationally representative cohort of US adults, stratified by kidney function.
Methods: We examined the association between daily DPI scaled to actual body weight (ABW), ascertained by 24-h dietary recall, with all-cause mortality among 27,604 continuous NHANES adult participants (1999-2010), stratified according to impaired versus normal kidney function (estimated glomerular filtration rates <60 compared with ≥60 ml/min/1.72 m2, respectively), using multivariable Cox models. We also examined the relation between high biological value (HBV) protein consumption with mortality.
Results: In participants with impaired kidney function, a high DPI of ≥1.4 g/kg ABW/day was associated with higher mortality, while lower DPI levels were not associated with mortality (reference, 0.6 to <1.0 g/kg ABW/day): the adjusted HRs (aHRs) were 1.09 (95% CI: 0.90, 1.32), 1.03 (95% CI: 0.82, 1.29), and 1.37 (95% CI: 1.02, 1.85) for DPI <0.6, 1.0 to <1.4, and ≥1.4 g/kg ABW/day, respectively. Yet in participants with normal kidney function, a low DPI of <0.6 g/kg ABW/day was associated with higher mortality, whereas higher DPI levels were not associated with death: the aHRs were 1.18 (95% CI: 1.04, 1.34), 0.92 (95% CI: 0.81, 1.04), and 0.99 (95% CI: 0.85, 1.16) for DPI <0.6, 1.0 to <1.4, and ≥1.4 g/kg ABW/day, respectively. The highest 2 tertiles of HBV consumption were associated with higher mortality in participants with impaired kidney function.
Conclusions: Among participants with impaired kidney function, a higher DPI and greater HBV consumption were associated with higher mortality, whereas a lower DPI was associated with higher mortality in those with normal kidney function. Further studies are needed to elucidate the specific pathways between higher DPI and mortality in CKD.
Keywords: chronic kidney disease; dietary protein; kidney function; mortality; survival, NHANES.


Meat consumption and risk of incident dementia: cohort study of 493,888 UK Biobank participants.
Zhang H, Greenwood DC, Risch HA, Bunce D, Hardie LJ, Cade JE.
Am J Clin Nutr. 2021 Jul 1;114(1):175-184. doi: 10.1093/ajcn/nqab028.
PMID: 33748832 Free PMC article.
Abstract
Background: Worldwide, the prevalence of dementia is increasing and diet as a modifiable factor could play a role. Meat consumption has been cross-sectionally associated with dementia risk, but specific amounts and types related to risk of incident dementia remain poorly understood.
Objective: We aimed to investigate associations between meat consumption and risk of incident dementia in the UK Biobank cohort.
Methods: Meat consumption was estimated using a short dietary questionnaire at recruitment and repeated 24-h dietary assessments. Incident all-cause dementia comprising Alzheimer disease (AD) and vascular dementia (VD) was identified by electronic linkages to hospital and mortality records. HRs for each meat type in relation to each dementia outcome were estimated in Cox proportional hazard models. Interactions between meat consumption and the apolipoprotein E (APOE) ε4 allele were additionally explored.
Results: Among 493,888 participants included, 2896 incident cases of all-cause dementia, 1006 cases of AD, and 490 cases of VD were identified, with mean ± SD follow-up of 8 ± 1.1 y. Each additional 25 g/day intake of processed meat was associated with increased risks of incident all-cause dementia (HR: 1.44; 95% CI: 1.24, 1.67; P-trend < 0.001) and AD (HR: 1.52; 95% CI: 1.18, 1.96; P-trend = 0.001). In contrast, a 50-g/d increment in unprocessed red meat intake was associated with reduced risks of all-cause dementia (HR: 0.81; 95% CI: 0.69, 0.95; P-trend = 0.011) and AD (HR: 0.70; 95% CI: 0.53, 0.92; P-trend = 0.009). The linear trend was not significant for unprocessed poultry and total meat. Regarding incident VD, there were no statistically significant linear trends identified, although for processed meat, higher consumption categories were associated with increased risks. The APOE ε4 allele increased dementia risk by 3 to 6 times but did not modify the associations with diet significantly.
Conclusion: These findings highlight processed-meat consumption as a potential risk factor for incident dementia, independent of the APOE ε4 allele.
Keywords: Alzheimer disease; UK Biobank; dementia; meat consumption; processed meat; vascular dementia.

Tea consumption and long-term risk of type 2 diabetes and diabetic complications: a cohort study of 0.5 million Chinese adults.
Nie J, Yu C, Guo Y, Pei P, Chen L, Pang Y, Du H, Yang L, Chen Y, Yan S, Chen J, Chen Z, Lv J, Li L.
Am J Clin Nutr. 2021 Jul 1;114(1):194-202. doi: 10.1093/ajcn/nqab006.
PMID: 33709113 Free PMC article.
Abstract
Background: Evidence from epidemiological studies remains inconsistent or limited about the associations of tea consumption with incident diabetes and risk of diabetic complications and death among patients with diabetes.
Objectives: We aimed to investigate the associations of tea consumption with long-term risk of developing type 2 diabetes (T2D) and risks of diabetic complications and death among patients with diabetes.
Methods: This study included 482,425 diabetes-free participants and 30,300 patients with diabetes aged 30-79 y at study enrollment from the China Kadoorie Biobank. Tea consumption information was collected at baseline by interviewer-administered questionnaires. Incidences of diabetes, diabetic complications, and death were identified by linkages to the National Health Insurance system, disease registries, and death registries. Cox proportional hazard regression models were used to estimate HRs and 95% CIs.
Results: The mean ± SD age of participants free of diabetes was 51.2 ± 10.5 y and 41% were male. The mean ± SD age of patients with diabetes was 58.2 ± 9.6 y and 39% were male. Of all daily tea consumers, 85.8% preferred green tea. In the diabetes-free population, 17,434 participants developed incident T2D during 11.1 y of follow-up. Compared with participants who never consumed tea in the past year, the HR (95% CI) of T2D for daily consumers was 0.92 (0.88, 0.97). In patients with diabetes, we identified 6572 deaths, 12,677 diabetic macrovascular cases, and 2441 diabetic microvascular cases during follow-up. Compared with patients who never consumed tea in the past year, the HRs (95% CIs) of all-cause mortality and risk of microvascular complications for daily consumers were 0.90 (0.83, 0.97) and 0.88 (0.78, 1.00), respectively. Tea consumption was not associated with risk of macrovascular complications among patients with diabetes. With regard to tea consumed, the inverse associations between daily tea consumption and risks of T2D and all-cause mortality in patients with diabetes were only observed among daily green tea drinkers.
Conclusions: In Chinese adults, daily green tea consumption was associated with a lower risk of incident T2D and a lower risk of all-cause mortality in patients with diabetes, but the associations for other types of tea were less clear. In addition, daily tea consumption was associated with a lower risk of diabetic microvascular complications, but not macrovascular complications.
Keywords: China Kadoorie Biobank; death; diabetic complications; prospective cohort study; tea consumption; type 2 diabetes.

Nighttime ambulatory pulse pressure predicts cardiovascular and all-cause mortality among middle-aged participants in the 21-year follow-up.
Lempiäinen PA, Ylitalo A, Huikuri H, Kesäniemi YA, Ukkola OH.
J Clin Hypertens (Greenwich). 2021 Jul 3. doi: 10.1111/jch.14317. Online ahead of print.
PMID: 34216537
Abstract
Office pulse pressure (PP) is a predictor for cardiovascular (CV) events and mortality. Our aim was to evaluate ambulatory PP as a long-term risk factor in a random cohort of middle-aged participants. The Opera study took place in years 1991-1993, with a 24-h ambulatory blood pressure measurement (ABPM) performed to 900 participants. The end-points were non-fatal and fatal CV events, and deaths of all-causes. Follow-up period, until the first event or until the end of the year 2014, was 21.1 years (mean). Of 900 participants, 22.6% died (29.6% of men/15.6% of women, p<.001). A CV event was experienced by 208 participants (23.1%), 68.3% of them were male (p<.001). High nighttime ambulatory PP predicted independently CV mortality (hazard ratio {HR} 2.60; 95% confidence interval [CI 95%] 1.08-6.31, p=.034) and all-cause mortality in the whole population (HR 1.72; Cl 95% 1.06-2.78, p=.028). In males, both 24-h PP and nighttime PP associated with CV mortality and all-cause mortality (24-h PP HR for CV mortality 2.98; CI 95% 1.11-8.04, p=.031 and all-cause mortality HR 2.40; CI 95% 1.32-4.37, p=.004). Accordingly, nighttime PP; HR for CV mortality 3.13; CI 95% 1.14-8.56, p=.026, and for all-cause mortality HR 2.26; CI 95% 1.29-3.96, p=.004. Cox regression analyses were adjusted by sex, CV risk factors, and appropriate ambulatory mean systolic BP. In our study, high ambulatory nighttime PP was detected as a long-term risk factor for CV and all-cause mortality in middle-aged individuals.
Keywords: all-cause mortality; ambulatory pulse pressure; cardiovascular mortality; follow-up; nighttime pulse pressure.

Trajectory patterns of blood pressure change up to six years and the risk of dementia: a nationwide cohort study.
Cheng G, He S, He Q, Xie X, Tang C, Xie Q, Wu X, Jiang N, Li C, Min X, Yan Y.
Aging (Albany NY). 2021 Jul 1;13. doi: 10.18632/aging.203228. Online ahead of print.
PMID: 34198262
Abstract
The present study aimed to investigate the associations between the trajectory of blood pressure (BP) change and the risk of subsequent dementia and to explore the differences in age, gender, and hypertension subgroups. We included 10,660 participants aged ≥ 60 years from 1998 to 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. Latent growth mixture models were used to estimate BP trajectories. Cox-proportional hazard models were used to analyze the effects of BP trajectories on the risk of dementia. According to the results, stabilized systolic BP (SBP) was found to be associated with a higher risk of dementia compared with normal SBP [adjusted hazard ratio (aHR): 1.62; 95% confidence interval (CI): 1.27-2.07] and elevated SBP (aHR: 2.22; 95% CI: 1.51-3.28) in and only in the subgroups of the oldest-old, women, and subjects without hypertension at baseline. Similarly, stabilized pulse pressure (PP) was associated with a higher risk of dementia compared with normal PP (aHR: 1.52; 95% CI: 1.24-1.88) and elevated PP (aHR: 2.12; 95% CI: 1.48-3.04) in and only in the subgroups of the oldest-old, women, and subjects with hypertension at baseline. These findings suggest that stabilized SBP and PP have predictive significance for the occurrence of dementia in late life, and the factors of age, gender, and late-life hypertension should be considered when estimating the risk of BP decline on dementia.
Keywords: blood pressure; dementia; late-life; pulse pressure; trajectory.

Prognostic power of conventional echocardiography in individuals without history of cardiovascular diseases: A systematic review and meta-analysis.
Fernandes LP, Barreto ATF, Neto MG, Câmara EJN, Durães AR, Roever L, Aras-Júnior R.
Clinics (Sao Paulo). 2021 Jun 28;76:e2754. doi: 10.6061/clinics/2021/e2754. eCollection 2021.
PMID: 34190849
Abstract
Echocardiographic abnormalities are associated with a higher incidence of adverse cardiovascular outcomes. This systematic review and meta-analysis aimed to evaluate whether echocardiographic abnormalities are predictors of cardiovascular events in individuals without previous cardiovascular diseases. The PubMed, Scopus, and SciELO databases were searched for longitudinal studies investigating the association between echocardiographic abnormalities and cardiovascular events among individuals without known cardiovascular diseases. Two independent reviewers analyzed data on the number of participants, age and sex, echocardiographic alterations, follow-up time, and cardiovascular outcomes. The meta-analysis estimated the risk ratio (RR) and 95% confidence interval (CI). Heterogeneity was assessed using I2 test. Twenty-two longitudinal studies met the eligibility criteria, comprising a total of 55,603 patients. Left ventricular hypertrophy (LVH) was associated with non-fatal cardiovascular events (RR 2.16; 95% CI 1.22-3.84), death from cardiovascular disease (RR 2.58; 95% CI 1.83- 3.64), and all-cause mortality (RR 2.02; 95% CI 1.34-3.04). Left ventricular diastolic dysfunction (LVDD) and left atrial dilation (LA) were associated with fatal and non-fatal cardiovascular events (RR 2.01; 95% CI 1.32-3.07) and (RR 1.78; 95% CI 1.16-2.73), respectively. Aortic root dilation was associated with non-fatal cardiovascular events (RR 1.25; 95% CI 1.09-1.43). In conclusion, LVH, LVDD, dilations of the LA, and of the aortic root were associated with an increased risk of adverse events in individuals without previous cardiovascular diseases. This study suggests that simple data obtained on conventional echocardiography can be an important predictor of cardiovascular outcomes in a low-risk population.

Epidemiology of dementia onset captured in Canadian primary care electronic medical records.
Pham ANQ, Voaklander D, Wagg A, Drummond N.
Fam Pract. 2021 Jun 28:cmab056. doi: 10.1093/fampra/cmab056. Online ahead of print.
PMID: 34180503
Abstract
Background: Dementia is an increasing concern in many countries, especially in those experiencing rapid growth in the proportion of older adults in their population.
Objective: This study aims to describe trends and demographic characteristics of incident dementia cases in community-dwelling older adults managed by primary care physicians.
Methods: We used electronic medical records from the Canadian Primary Care Sentinel Surveillance Network database to conduct a retrospective analysis to determine the number of, and trends for, incident diagnoses of dementia. Age-standardized annual incidence rates were calculated. Participants in our cohort are Canadian community dwelling seniors aged 65+ years who were not diagnosed with dementia before baseline with at least six years of record at their primary care clinics.
Results: The cohort consisted of 39 067 patients of whom 57% were females; the mean (SD) follow-up was 8.4 (1.5) years. During follow-up, 4935 patients were diagnosed with dementia. The risk for dementia diagnosis increased with increasing age but decreased in the last four years among people aged 80 and older at baseline (P < 0.001). People with dementia were more likely to be females (P = 0.001) and urban residents (P < 0.001), they are less likely to be classified into the least deprived group (P = 0.012).
Conclusions: The incidence of dementia diagnosis increased with age except in the oldest old in both sexes. This may be attributed to the effect of mortality competing risk. Future research on the association between risk factors and dementia should consider studying dementia among the oldest old separately to minimize bias.
Keywords: Aging; dementia; electronic health record; epidemiology; geriatric; primary care.

Prospective Analysis of Fruit and Vegetable Variety on Health Outcomes in Community-Dwelling Chinese Older Adults.
Yeung SSY, Zhu ZLY, Chan RSM, Kwok T, Woo J.
J Nutr Health Aging. 2021;25(6):735-741. doi: 10.1007/s12603-021-1605-7.
PMID: 34179926
Abstract
Objectives: Evidence on the topic regarding fruit and vegetable (FV) variety and health outcomes among older adults is limited. This study explored the prospective association of fruit variety, vegetable variety and combined FV variety with the risk of sarcopenia, frailty, all-cause and cause-specific mortality in community-dwelling Chinese older adults.
Design: Prospective cohort study.
Setting: Community.
Participants: Community-dwelling Chinese older adults aged ≥65 years in Hong Kong.
Measurements: Fruit variety, vegetable variety and combined FV variety at baseline were assessed using a validated food frequency questionnaire and the variety scores were stratified into tertiles. Sarcopenia (Asian Working Group for Sarcopenia 2019), frailty (Cardiovascular Health Study) and all-cause and cause-specific mortality (retrieved from an official database) were assessed at 14-year follow-up. Adjusted binary logistic regression or Cox proportional hazards model were performed to examine the association of fruit variety, vegetable variety and combined FV variety with each health outcome. Data are presented as hazard ratios (HRs) and 95% confidence intervals (CIs).
Results: Baseline dietary data of 3992 participants (median age: 72 years (interquartile range: 68-76), 49.9% women) was available. There were 436 and 371 participants who were newly identified as having sarcopenia and frailty respectively, and 1654 all-cause mortality, 367 cardiovascular diseases (CVD) mortality and 534 cancer mortality over 14-year. Tertiles of fruit variety, vegetable variety and combined FV variety were not associated with sarcopenia, frailty, CVD mortality and cancer mortality. Participants in the highest tertile of fruit variety (HR 0.81, 95% CI 0.70-0.95, p-trend 0.010), vegetable variety (HR 0.77, 95% CI 0.67-0.89, p-trend <0.001) and combined FV variety (HR 0.77, 95% CI 0.67-0.89. p-trend <0.001) showed lower risk of all-cause mortality compared with participants in the lowest tertile.
Conclusion: Among community-dwelling Chinese older adults, FV variety was not associated with sarcopenia, frailty, CVD mortality and cancer mortality over 14-year. Higher fruit variety, vegetable variety and combined FV variety were associated with a lower risk of all-cause mortality. Promoting a wide FV variety might be recommended to benefit the health and longevity of this population.
Keywords: Aged; fruit; mortality; variety; vegetables.

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Renal markers and risks of all cause and cardiovascular mortality from the Taichung community based cohort study.
Lin CC, Chen TY, Li CI, Liu CS, Lin CH, Wang MC, Yang SY, Li TC.
Sci Rep. 2021 Jul 8;11(1):14143. doi: 10.1038/s41598-021-93627-5.
PMID: 34239018
Abstract
This study aimed to explore the associations between renal-related and arterial stiffness biomarkers with all-cause and expanded cardiovascular disease (CVD) mortality in a general Taiwanese population. This prospective community-based cohort study included 4883 subjects aged ≥ 20 years who were followed up until December 31, 2016. Renal-related biomarkers consisted of blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Arterial stiffness biomarker consisted of brachial-ankle pulse wave velocity (baPWV). The death status of the subjects was ascertained by matching information from death records with the identification number and date of birth of the subjects. Cox proportional hazard models with restricted cubic splines estimated the hazard ratios and 95% confidence intervals for all-cause mortality and expanded CVD mortality. During a mean 8.3 years of follow up, 456 deaths were recorded, 146 of which were due to expanded CVD mortality. The multivariable-adjusted hazard ratios of all-cause mortality was 1.53 (95% CI 1.21-1.94) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 1.57 (1.15-2.14) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 1.55 (1.25-1.92) for UACR (≥ 30 mg/g vs. < 30 mg/g), and 1.75 (1.14-2.67) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). The expanded CVD mortality was 1.89 (95% CI 1.30-2.73) for BUN (≥ 20 mg/dL vs. < 20 mg/dL), 2.28 (1.13-4.57) for eGFR (< 90 mL/min/1.73 m2 vs. ≥ 90 mL/min/1.73 m2), 2.13 (1.52-2.99) for UACR (≥ 25 mg/g vs. < 25 mg/g), and 15.73 (2.14-115.61) for baPWV (≥ 1400 cm/s vs. < 1400 cm/s). High levels of BUN, UACR, and baPWV and low levels of eGFR showed high risks with all-cause and expanded CVD mortality. Our study provides insights into screening tests to target populations at high risk of premature death due to CVD.

The energy allocation trade-offs underlying life history traits in hypometabolic strepsirhines and other primates.
Simmen B, Morino L, Blanc S, Garcia C.
Sci Rep. 2021 Jul 9;11(1):14196. doi: 10.1038/s41598-021-93764-x.
PMID: 34244546
Abstract
Life history, brain size and energy expenditure scale with body mass in mammals but there is little conclusive evidence for a correlated evolution between life history and energy expenditure (either basal/resting or daily) independent of body mass. We addressed this question by examining the relationship between primate free-living daily energy expenditure (DEE) measured by doubly labeled water method (n = 18 species), life history variables (maximum lifespan, gestation and lactation duration, interbirth interval, litter mass, age at first reproduction), resting metabolic rate (RMR) and brain size. We also analyzed whether the hypometabolic primates of Madagascar (lemurs) make distinct energy allocation tradeoffs compared to other primates (monkeys and apes) with different life history traits and ecological constraints. None of the life-history traits correlated with DEE after controlling for body mass and phylogeny. In contrast, a regression model showed that DEE increased with increasing RMR and decreasing reproductive output (i.e., litter mass/interbirth interval) independent of body mass. Despite their low RMR and smaller brains, lemurs had an average DEE remarkably similar to that of haplorhines. The data suggest that lemurs have evolved energy strategies that maximize energy investment to survive in the unusually harsh and unpredictable environments of Madagascar at the expense of reproduction.

Investigating the association of testosterone with survival in men and women using a Mendelian randomization study in the UK Biobank.
Schooling CM, Zhao JV.
Sci Rep. 2021 Jul 7;11(1):14039. doi: 10.1038/s41598-021-93360-z.
PMID: 34234209
Abstract
Life expectancy in the developed West is currently stagnated and remains shorter in men than women. Well-established evolutionary biology theory suggests lifespan trades-off against reproductive success, possibly sex-specifically. We examined whether a key driver of reproductive success, testosterone, affected survival using a Mendelian randomization longevity study in the UK Biobank to obtain unbiased estimates, along with control exposures. We applied published genetic instruments for testosterone to obtain inverse variance weighted estimates of associations with survival to (i.e., age at) recruitment, in 167,020 men and 194,174 women. We similarly obtained estimates for a positive control (smoking initiation), and a negative control (absorbate), a marker of vitamin C metabolism. Testosterone was associated with poorer survival (0.10 years younger at recruitment per effect size of testosterone, 95% confidence interval (CI) 0.004 to 0.20). As expected, smoking initiation was also associated with poorer survival (0.37 years younger, 95% CI 0.25 to 0.50), but not absorbate (0.01 years younger, 95% CI - 0.09 to 0.11). Several aspects of a healthy lifestyle (low animal fat diet) and several widely used medications (statins, metformin, dexamethasone and possibly aspirin) may modulate testosterone. Explicitly designing interventions sex-specifically based on these insights might help address stagnating life expectancy and sexual disparities.

Prognostic value of Neutrophil-to-lymphocyte ratio in COVID-19 patients: A systematic review and meta-analysis.
Ulloque-Badaracco JR, Salas-Tello WI, Al-Kassab-Córdova A, Alarcón-Braga EA, Benites-Zapata VA, Maguiña JL, Hernandez AV.
Int J Clin Pract. 2021 Jul 6:e14596. doi: 10.1111/ijcp.14596. Online ahead of print.
PMID: 34228867
Abstract
Background: Neutrophil-to-lymphocyte ratio (NLR) is an accessible and widely used biomarker. NLR may be used as an early marker of poor prognosis in patients with COVID-19.
Objective: To evaluate the prognostic value of the NLR in patients diagnosed with COVID-19.
Methods: We conducted a systematic review and meta-analysis. Observational studies that reported the association between baseline NLR values (i.e. at hospital admission) and severity or all-cause mortality in COVID-19 patients were included. The quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS). Random effects models and inverse variance method were used for meta-analyses. The effects were expressed as odds ratios (OR) and their 95% confidence intervals (CI). Small study effects were assessed with the Egger's test.
Results: We analyzed sixty-one studies (n=15522 patients), 58 cohorts and three case-control. An increase of one unit of NLR was associated with a higher odds of severity (OR 6.22; 95%CI 4.93 to 7.84; p<0.001) and higher odds of all-cause mortality (OR 12.6; 95%CI 6.88 to 23.06; p<0.001). In our sensitivity analysis, we found that 41 studies with low risk of bias and moderate heterogeneity (I2 =53% and 58%) maintained strong association between NLR values and both outcomes (severity: OR 5.36; 95% CI 4.45 to 6.45; p<0.001; mortality: OR 10.42 95%CI 7.73 to 14.06; p=0.005).
Conclusions: Higher values of NLR were associated with severity and all-cause mortality in hospitalized COVID-19 patients.
Keywords: COVID-19; Mortality; NLR; Prognosis; Severity.

Nut, corn, and popcorn consumption and the incidence of diverticular disease.
Strate LL, Liu YL, Syngal S, Aldoori WH, Giovannucci EL.
JAMA. 2008 Aug 27;300(8):907-14. doi: 10.1001/jama.300.8.907.
PMID: 18728264 Free PMC article.
Abstract
Context: Patients with diverticular disease are frequently advised to avoid eating nuts, corn, popcorn, and seeds to reduce the risk of complications. However, there is little evidence to support this recommendation.
Objective: To determine whether nut, corn, or popcorn consumption is associated with diverticulitis and diverticular bleeding.
Design and setting: The Health Professionals Follow-up Study is a cohort of US men followed up prospectively from 1986 to 2004 via self-administered questionnaires about medical (biennial) and dietary (every 4 years) information. Men reporting newly diagnosed diverticulosis or diverticulitis were mailed supplemental questionnaires.
Participants: The study included 47,228 men aged 40 to 75 years who at baseline were free of diverticulosis or its complications, cancer, and inflammatory bowel disease and returned a food-frequency questionnaire.
Main outcome measures: Incident diverticulitis and diverticular bleeding.
Results: During 18 years of follow-up, there were 801 incident cases of diverticulitis and 383 incident cases of diverticular bleeding. We found inverse associations between nut and popcorn consumption and the risk of diverticulitis. The multivariate hazard ratios for men with the highest intake of each food (at least twice per week) compared with men with the lowest intake (less than once per month) were 0.80 (95% confidence interval, 0.63-1.01; P for trend = .04) for nuts and 0.72 (95% confidence interval, 0.56-0.92; P for trend = .007) for popcorn. No associations were seen between corn consumption and diverticulitis or between nut, corn, or popcorn consumption and diverticular bleeding or uncomplicated diverticulosis.
Conclusions: In this large, prospective study of men without known diverticular disease, nut, corn, and popcorn consumption did not increase the risk of diverticulosis or diverticular complications. The recommendation to avoid these foods to prevent diverticular complications should be reconsidered.

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The regulation of healthspan and lifespan by dietary amino acids.
Babygirija R, Lamming DW.
Transl Med Aging. 2021;5:17-30. doi: 10.1016/j.tma.2021.05.001. Epub 2021 May 24.
PMID: 34263088 Free PMC article.
Abstract
As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.
Keywords: aging; amino acids; branched-chain amino acids; methionine; protein restriction.

Association of dietary zinc intake with coronary artery calcium progression: the Multi-Ethnic Study of Atherosclerosis (MESA).
Gao JW, Zhang SL, Hao QY, Huang FF, Liu ZY, Zhang HF, Yan L, Wang JF, Liu PM.
Eur J Nutr. 2021 Aug;60(5):2759-2767. doi: 10.1007/s00394-020-02452-5. Epub 2021 Jan 4.
PMID: 33394121
Abstract
Purpose: Zinc is considered protective against atherosclerosis; however, the association between dietary zinc intake and cardiovascular disease remains debated. We investigated whether dietary zinc intake was associated with coronary artery calcium (CAC) progression in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods: This analysis included 5186 participants aged 61.9 ± 10.2 years (48.8% men; 41.3% white, 25.0% black, 21.6% Hispanic, and 12.1% Chinese American) from the MESA. Dietary zinc intake was assessed by a self-administered, 120-item food frequency questionnaire at baseline (2000-2002). Baseline and follow-up CAC were measured by computed tomography. CAC progression was defined as CAC > 0 at follow-up for participants with CAC = 0 at baseline; and an annualized change of 10 or percent change of ≥ 10% for those with 0 < CAC < 100 or CAC ≥ 100 at baseline, respectively.
Results: Dietary zinc intake was 8.4 ± 4.5 mg/day and 2537 (48.9%) of the included participants had CAC at baseline. Over a median follow-up of 3.4 years (25th-75th percentiles = 2.0-9.1 years), 2704 (52.1%) participants had CAC progression. In the fully adjusted model, higher dietary zinc was associated with a lower risk of CAC progression in both men (hazard ratio {HR}) 0.697, 95% confidence interval [CI] 0.553-0.878; p = 0.002) and women (HR 0.675; 95% CI 0.496-0.919; p = 0.012, both comparing extreme groups). Furthermore, such an inverse association was attributable to dietary zinc intake from non-red meat (p < 0.05), rather than red meat sources (p > 0.05).
Conclusions: In this multiethnic population free of clinically apparent cardiovascular disease, higher dietary zinc intake from non-red meat sources was independently associated with a lower risk of CAC progression.
Keywords: Cardiovascular disease; Coronary artery calcium progression; Dietary zinc intake; Risk factors.

Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice.
Mulvey L, Wilkie SE, Griffiths K, Sinclair A, McGuinness D, Watson DG, Selman C.
Mol Cell Endocrinol. 2021 Jul 8:111376. doi: 10.1016/j.mce.2021.111376. Online ahead of print.
PMID: 34246728 Review.
Abstract
The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved by CR only in TejJ114, while strains TejJ89 and TejJ114 were relatively hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue from strains TejJ89 and TejJ114 mice under AL and 40% CR. gWAT from TejJ89 showed a significant reduction in several long chain unsaturated fatty acids following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR, with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under CR observed in these mice.
Keywords: Dietary restriction; Genetic heterogeneity; Metabolomics; White adipose tissue; brown adipose tissue.

Single-oocyte transcriptome analysis reveals aging-associated effects influenced by life stage and calorie restriction.
Mishina T, Tabata N, Hayashi T, Yoshimura M, Umeda M, Mori M, Ikawa Y, Hamada H, Nikaido I, Kitajima TS.
Aging Cell. 2021 Jul 10:e13428. doi: 10.1111/acel.13428. Online ahead of print.
PMID: 34245092
Abstract
Chromosome segregation errors in oocytes lead to the production of aneuploid eggs, which are the leading cause of pregnancy loss and of several congenital diseases such as Down syndrome. The frequency of chromosome segregation errors in oocytes increases with maternal age, especially at a late stage of reproductive life. How aging at various life stages affects oocytes differently remains poorly understood. In this study, we describe aging-associated changes in the transcriptome profile of mouse oocytes throughout reproductive life. Our single-oocyte comprehensive RNA sequencing using RamDA-seq revealed that oocytes undergo transcriptome changes at a late reproductive stage, whereas their surrounding cumulus cells exhibit transcriptome changes at an earlier stage. Calorie restriction, a paradigm that reportedly prevents aging-associated egg aneuploidy, promotes a transcriptome shift in oocytes with the up-regulation of genes involved in chromosome segregation. This shift is accompanied by the improved maintenance of chromosomal cohesin, the loss of which is a hallmark of oocyte aging and causes chromosome segregation errors. These findings have implications for understanding how oocytes undergo aging-associated functional decline throughout their reproductive life in a context-dependent manner.

Keywords: aging; chromosome segregation; cohesin; oocyte; transcriptome.

Triiodothyronine (T3) enhances lifespan and protects against oxidative stress via activation of Klotho in Caenorhabditis elegans.
Mohanty SK, Suchiang K.
Biogerontology. 2021 Aug;22(4):397-413. doi: 10.1007/s10522-021-09923-0. Epub 2021 Apr 13.
PMID: 33851304
Abstract
Age predisposes individuals to significant diseases, and the biological processes contributing to aging are currently under intense investigation. Klotho is an anti-aging protein with multifaceted roles and is an essential component of the endocrine fibroblast growth factor. In Caenorhabditis elegans (C. elegans), there are two prospective orthologs of α-Klotho, C50F7.10, and E02H9.5, identified. The two orthologs' products are homologous to the highly conserved KL1 domain of human and mouse Klotho protein. Considering the endocrine system's major involvement in an organism's homeostasis and that thyroid disorders increase with advancing age, the molecular mechanisms underlying its impact on different endocrine components during the aging process remain poorly characterized. In this study, we sought to determine the regulatory role of Triiodothyronine (T3) on homologs genes of klotho and its impact on different parameters of aging in the C. elegans model organism. We showed that T3 could increase the mRNA expressions of the klotho homologous genes in C. elegans. Moreover, T3 could also extend a worm lifespan and modulate oxidative stress resistance and aging biomarkers significantly and positively. Further investigations employing different mutant and transgenic strains reveal that these observed effects are mediated through the EGL-17/EGL-15 pathway via Klotho activation along with the involvement of transcription factor DAF-16. In conclusion, these findings have revealed an unexpected link between T3 and Klotho and how this link can modulate the aging process in C. elegans via activation of klotho. This study will help understand the crosstalk and regulations of different endocrine components and their consequences on the aging process in multiple species.
Keywords: Aging; DAF-16; EGL-15; Klotho; Oxidative stress; Triiodothyronine.

Relationship of higher-level functional capacity with long-term mortality in Japanese older people: NIPPON DATA90.
Nagata H, Miura K, Tanaka S, Kadota A, Hayakawa T, Kondo K, Fujiyoshi A, Takashima N, Kita Y, Okayama A, Okamura T, Ueshima H.
J Epidemiol. 2021 Jul 10. doi: 10.2188/jea.JE20210077. Online ahead of print.
PMID: 34248110
Abstract
Background: Basic and instrumental activities of daily living (BADL, IADL) are known predictors of mortality. However, the relationship between higher-level functional capacity (HLFC) and mortality and related sex differences have rarely been investigated.
Methods: A prospective population-based cohort study was conducted in 1,824 older residents (≥65 years) with independent BADL from 300 randomly selected areas in Japan from 1995, and the participants were followed up until 2010. Using the Cox proportional hazards model, the relationship between HLFC and mortality risk was investigated with adjustment for possible confounders. HLFC was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Baseline data were collected using a questionnaire or by home-visit interviews.
esults: During an average 12.2-year follow-up, all-cause death was observed in 836 (45.8%) participants. Impaired HLFC was significantly associated with mortality (hazard ratio {HR}) 1.37; 95% confidence interval [CI], 1.13-1.65). Lower social role was significantly associated with higher mortality risk in men (HR 1.38; 95% CI, 1.13-1.68). Lower IADL and intellectual activity were significantly associated with higher mortality risk in women (HR 1.50; 95% CI, 1.15-1.95; HR 1.46; 95% CI, 1.19-1.79). The relationship between HLFC and mortality risk showed a similar tendency among cardiovascular diseases, stroke, cancer, and pneumonia.
onclusion: Impaired HLFC was associated with a high risk of all-cause mortality among community-dwelling older people with independent BADL. In particular, social role in men and IADL and intellectual activity in women were associated with long-term mortality risk.
Keywords: disease-specific; higher-level functional capacity; mortality; older people; sex difference.

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Serum albumin and risks of hospitalization and death: Findings from the Atherosclerosis Risk in Communities study.
Shannon CM, Ballew SH, Daya N, Zhou L, Chang AR, Sang Y, Coresh J, Selvin E, Grams ME.
J Am Geriatr Soc. 2021 Jul 23. doi: 10.1111/jgs.17313. Online ahead of print.
PMID: 34298583
Abstract
Objectives: To determine whether lower serum albumin in community-dwelling, older adults is associated with increased risk of hospitalization and death independent of pre-existing disease.
Design: Prospective cohort study of participants in the fifth visit of the Atherosclerosis Risk in Communities (ARIC) study. Baseline data were collected from 2011 to 2013. Follow-up was available to December 31, 2017. Replication was performed in Geisinger, a health system in rural Pennsylvania.
Setting: For ARIC, four US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and suburbs of Minneapolis, Minnesota.
Participants: A total of 4947 community-dwelling men and women aged 66 to 90 years.
Exposure: Serum albumin.
Main outcomes: Incident all-cause hospitalization and death.
Results: Among the 4947 participants, mean age was 75.5 years (SD: 5.12) and mean baseline serum albumin concentration was 4.05 g/dL (SD: 0.30). Over a median follow-up period of 4.42 years (interquartile interval: 4.16-5.05), 553 participants (11.2%) died and 2457 participants (49.7%) were hospitalized at least once. The total number of hospitalizations was 5725. In analyses adjusted for demographics and numerous clinical characteristics, including tobacco use, obesity, frailty, cardiovascular disease, kidney disease, diabetes C-reactive protein (CRP), cognitive status, alcohol use, medication use, respiratory disease, and systolic blood pressure, 1 g/dL lower baseline serum albumin concentration was associated with higher risk of both hospitalization (incidence rate ratio [IRR]: 1.58; 95% confidence interval [CI]: 1.36-1.82; p < 0.001) and death (hazard ratio {HR}: 1.67; 95% CI: 1.24-2.24; p < 0.001). Associations were weaker with older age but not different by frailty status or level of high-sensitivity CRP. Associations between serum albumin, hospitalizations, and death were also similar in a real-world cohort of primary care patients.
Conclusions: Lower baseline serum albumin was significantly associated with increased risk of both all-cause hospitalization and death, independent of pre-existing disease. Older adults with low serum albumin should be considered a high-risk population and targeted for interventions to reduce the risk of adverse outcomes.
Keywords: bromocresol purple; death; frailty; hospitalization; serum albumin.

Meta-regression of randomized control trials with antithrombotics: weak correlation between net clinical benefit and all cause-mortality.
Kilo R, Laporte S, Arab R, Mainbourg S, Provencher S, Grenet G, Bertoletti L, Villeneuve L, Cucherat M, Lega JC; META-EMBOL Group.
Sci Rep. 2021 Jul 19;11(1):14728. doi: 10.1038/s41598-021-94160-1.
PMID: 34282198
Abstract
This study aimed to explore the validity of the use of the net clinical benefit (NCB), i.e. the sum of major bleeding and thrombotic events, as a potential surrogate for all-cause mortality in clinical trials assessing antithrombotics. Published randomized controlled trials testing anticoagulants in the prevention or treatment of venous thromboembolism (VTE) and non-valvular atrial fibrillation (NVAF) were systematically reviewed. The validity of NCB as a surrogate endpoint was estimated by calculating the strength of correlation of determination (R2) and its 95% confidence interval (CI) between the relative risks of NCB and all-cause mortality. Amongst the 125 trials retrieved, the highest R2trial values were estimated for NVAF (R2trial = 0.41, 95% CI [0.03; 0.48]), and acute VTE (R2trial = 0.30, 95% CI [0.04; 0.84]). Conversely, the NCB did not correlate with all-cause mortality in prevention studies with medical (R2trial = 0.12, 95% CI [0.00; 0.36]), surgical (R2trial = 0.05, 95% CI [0.00; 0.23]), and cancer patients (R2trial = 0.006, 95% CI [0.00; 1.00]). A weak correlation between NCB and all cause-mortality was found in NVAF and acute VTE, whereas no correlation was observed in clinical situations where the mortality rate was low. Consequently, NCB should not be considered a surrogate outcome for all cause-mortality in anticoagulation trials.

Active and receptive arts participation and their association with mortality among adults in the United States: a longitudinal cohort study.
Story KM, Yang Z, Bravata DM.
Public Health. 2021 Jul 15;196:211-216. doi: 10.1016/j.puhe.2021.05.034. Online ahead of print.
PMID: 34274695
Abstract
Objectives: The aim of the study was to explore associations between active and receptive arts participation and all-cause mortality among adults in the United States population.
Study design: This was a prospective cohort study.
Methods: Data were derived from the Health and Retirement Study. Separate Cox proportional hazards models were constructed for two cohorts (2012 and 2014) to examine associations between arts participation and mortality.
Results: Independent of sociodemographic and health factors, participants aged ≥65 years had a higher mortality risk if they did not engage in music listening, hazard ratio (HR) 1.39 (95% confidence interval [CI]: 1.12-1.71); singing/playing an instrument, HR 1.49 (95% CI: 1.07-2.0); or doing arts and crafts, HR 1.39 (95% CI: 1.00-1.92). For participants aged <65 years, there was a higher mortality risk if they did not listen to music, HR 1.79 (95% CI: 1.07-3.01). Older participants from the 2014 cohort had a higher mortality risk if they did not engage in active arts, HR 1.73 (95% CI: 1.08-2.77).
Conclusions: Engagement in the arts was associated with lower risk of mortality even after risk adjustment, especially for adults aged ≥65 years. Greater access and integration of arts in everyday life is recommended.
Keywords: Adults; Arts participation; Mortality; Music listening.

Effects of lycopene intake on HDL-cholesterol and triglyceride levels: A systematic review with meta-analysis.
Inoue T, Yoshida K, Sasaki E, Aizawa K, Kamioka H.
J Food Sci. 2021 Jul 15. doi: 10.1111/1750-3841.15833. Online ahead of print.
PMID: 34268742 Review.
Abstract
Lycopene is a lipophilic unsaturated carotenoid and has a very strong singlet oxygen-quenching ability. Increased serum or plasma lycopene levels have been reported to be associated with a lower risk of metabolic syndrome. We aimed to investigate the effects of lycopene intake on blood HDL-cholesterol (HCL-c) and triglyceride (TG) levels, which are metabolic syndrome biomarkers, by systematic review and meta-analyses of human interventional trials. We searched 15 databases and included studies that assessed the effects of oral lycopene intake on blood HDL-c and TG levels of participants ≥18 years of age. Three reviewers independently selected applicable studies, then assessed study qualities. Data were pooled as standardized mean difference (SMD) and analyzed by random-effects model. Heterogeneity was assessed by I2 statistics. Meta-analysis including 12 trial arms (n = 781) revealed a significantly increased HDL-c level in the lycopene group compared with that in the control group (SMD = 0.33 [95% CI: 0.12, 0.54], p = 0.002) and moderate heterogeneity (I2 = 45%). Most subgroup meta-analyses (restricted to study design, test food type, intake period, and participants' characteristics) showed similar results for HDL-c level. On the other hand, meta-analysis including 11 studies (n = 854) revealed no significant difference in TG level between the lycopene and control groups. Most studies which met eligibility criteria had moderate risk of bias. Funnel plots for HDL-c and TG suggested an absence of publication bias. In conclusion, this systematic review and meta-analyses suggested that lycopene intake significantly improved blood HDL-c levels but not TG levels.

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Causal relationship from coffee consumption to diseases and mortality: a review of observational and Mendelian randomization studies including cardiometabolic diseases, cancer, gallstones and other diseases.
Nordestgaard AT.
Eur J Nutr. 2021 Jul 28. doi: 10.1007/s00394-021-02650-9. Online ahead of print.
PMID: 34319429 Review.
Abstract
Purpose: High coffee consumption is associated with low risk of mortality and morbidity, but the causality remains unclear. This review aims to discuss findings from observational studies on coffee consumption in context of Mendelian randomization studies.
Methods: The PubMed database was searched for all Mendelian randomization studies on coffee consumption and corresponding observational studies.
Results: High coffee consumption is associated with low risk of all-cause and cardiovascular mortality in observational studies (HRs of 0.85-0.90 vs. no/low consumers), with no support of causality in Mendelian randomization studies. Moderate/high consumption is associated with low risk of cardiometabolic diseases, including ischemic heart disease (HRs of 0.85-0.90 vs. no/low consumption), stroke (HRs of approximately 0.80 vs. no/low consumption), type 2 diabetes (HRs of approximately 0.70 vs. no/low consumption) and obesity in observational studies, but not in Mendelian randomization studies. High consumption is associated with low risk of endometrial cancer and melanoma and high risk of lung cancer in observational studies, but with high risk of colorectal cancer in Mendelian randomization studies. In observational and Mendelian randomization studies, high coffee consumption is associated with low risk of gallstones (HRs of 0.55-0.70 for high vs. no/low self-reported and 0.81 (0.69-0.96) for highest vs. lowest genetic consumption).
Conclusion: High coffee consumption is associated with low risk of mortality, cardiometabolic diseases, some cancers and gallstones in observational studies, with no evidence to support causality from Mendelian randomization studies for most diseases except gallstones.
Keywords: Cardiovascular disease; Diabetes; Epidemiology; Genetics; Mendelian randomization.

No Associations Between Regular Use of Proton Pump Inhibitors and Risk of All-Cause and Cause-Specific Mortality: A Population-Based Cohort of 0.44 Million Participants.
He Q, Xia B, Meng W, Fan D, Kuo ZC, Huang J, Qin X, Zou H, He Y, Zhang C, Fang S, Pan Y, Yang M, Yuan J.
Am J Gastroenterol. 2021 Jul 27. doi: 10.14309/ajg.0000000000001377. Online ahead of print.
PMID: 34313608
Abstract
Introduction: The association between proton pump inhibitors' (PPIs) use and mortality remains unclear.
Methods: This was a prospective analysis of 440,840 UK residents and 13,154 deaths. We evaluated the associations with multivariate Cox regression.
Results: After adjusting for confounders, such as over health status and longstanding diseases, the regular use of PPIs was not associated with an increased risk of all-cause mortality and mortality due to neoplasms, circulatory system diseases, respiratory system diseases, digestive system diseases, external causes, and other causes.
Discussion: Regular use of PPIs was not associated with an increased risk of all-cause and cause-specific mortality.

Interaction between cognitive leisure activity and long-chain polyunsaturated fatty acid intake on global cognitive decline in a Japanese longitudinal cohort study: National Institute for Longevity Sciences-Longitudinal Study of Aging.
Horikawa C, Otsuka R, Nishita Y, Tange C, Kato Y, Tanaka T, Rogi T, Shibata H, Ando F, Shimokata H.
BMC Geriatr. 2021 Jul 27;21(1):443. doi: 10.1186/s12877-021-02359-8.
PMID: 34315440
Abstract
Background: There is a growing interest in the significance of adopting a variety of lifestyle habits for maintaining cognitive function among older adults. A lifestyle that is easy to modify, simple, and less burdensome for older people is ideal. We investigated the longitudinal association between global cognitive decline and cognitive leisure activities (CLAs) combined with long-chain polyunsaturated fatty acids (LCPUFAs) intake.
Methods: The National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) enrolled community-dwelling middle-aged and older men and women who were randomly selected from Obu-City and Higashiura Town, Aichi, Japan. Baseline data (2006-2008), including CLAs and dietary intake, were obtained from 517 participants (aged 60-84 years) with normal cognition. Global cognitive decline, defined as the Mini-Mental State Examination (MMSE) score ≤ 27, was assessed at baseline and four years later. Interaction between CLAs and LCPUFAs on cognitive decline was investigated using a multiple logistic analysis with adjustment for confounders. CLA engagement and LCPUFA intake were divided into high and low groups according to the frequency at which each participant engaged in the activity and the median intake level according to sex, respectively.
Results: A significant interaction was detected for the combination of CLA engagement and LCPUFA intake. Logistic regression coefficients revealed significant interactions when participants engaged in more than five CLA varieties. One of the CLAs, art appreciation, produced a significant main effect against cognitive decline and a significant interaction in combination with LCPUFA intake. The major LCPUFAs-docosahexaenoic acid and arachidonic acid-also exhibited a significant interaction. The combination of high LCPUFA intake and high art appreciation frequency yielded a lower adjusted odds ratio for cognitive decline than the combination of low LCPUFA and low art appreciation [0.25 (95 % confidence intervals, 0.11-0.56)].
Conclusions: Preserving cognitive function might be associated with a combination of varied and high-frequency engagement in CLAs combined with high LCPUFA intake.
Keywords: NILS-LSA; cognitive leisure activities; long-chain polyunsaturated fatty acids.

Herb-induced liver injury: Systematic review and meta-analysis.
Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J.
World J Clin Cases. 2021 Jul 16;9(20):5490-5513. doi: 10.12998/wjcc.v9.i20.5490.
PMID: 34307603 Free PMC article.
Abstract
Background: The use of herbal supplements and alternative medicines has been increasing in the last decades. Despite popular belief that the consumption of natural products is harmless, herbs might cause injury to various organs, particularly to the liver, which is responsible for their metabolism in the form of herb-induced liver injury (HILI).
Aim: To identify herbal products associated with HILI and describe the type of lesion associated with each product.
Methods: Studies were retrieved using Medical Subject Headings Descriptors combined with Boolean operators. Searches were run on the electronic databases Scopus, Web of Science, MEDLINE, BIREME, LILACS, Cochrane Library for Systematic Reviews, SciELO, Embase, and Opengray.eu. Languages were restricted to English, Spanish, and Portuguese. There was no date of publication restrictions. The reference lists of the studies retrieved were searched manually. To access causality, the Maria and Victorino System of Causality Assessment in Drug Induced Liver Injury was used. Simple descriptive analysis were used to summarize the results.
Results: The search strategy retrieved 5918 references. In the final analysis, 446 references were included, with a total of 936 cases reported. We found 79 types of herbs or herbal compounds related to HILI. He-Shou-Wu, Green tea extract, Herbalife, kava kava, Greater celandine, multiple herbs, germander, hydroxycut, skullcap, kratom, Gynura segetum, garcinia cambogia, ma huang, chaparral, senna, and aloe vera were the most common supplements with HILI reported. Most of these patients had complete clinical recovery (82.8%). However, liver transplantation was necessary for 6.6% of these cases. Also, chronic liver disease and death were observed in 1.5% and 10.4% of the cases, respectively.
Conclusion: HILI is normally associated with a good prognosis, once the implied product is withdrawn. Nevertheless, it is paramount to raise awareness in the medical and non-medical community of the risks of the indiscriminate use of herbal products.
Keywords: Dietary supplements; Drug induced liver injury; Herb-induced liver injury; Herbal

Associations between elevated kidney and liver biomarker ratios, metabolic syndrome and all-cause and coronary heart disease (CHD) mortality: analysis of the U.S. National Health and Nutrition Examination Survey (NHANES).
Oye-Somefun A, Kuk JL, Ardern CI.
BMC Cardiovasc Disord. 2021 Jul 26;21(1):352. doi: 10.1186/s12872-021-02160-w.
PMID: 34311708
Abstract
Background: We examined the relationship between ratios of select biomarkers of kidney and liver function on all-cause and coronary heart disease (CHD) mortality, both in isolation, and in combination with metabolic syndrome (MetS), among adults (20 + years, n = 10,604).
Methods: Data was derived from the U.S. National Health and Nutrition Examination Survey (1999-2016) including public-use linked mortality follow-up files through December 31, 2015.
Results: Select biomarker ratios of kidney (UACR or albuminuria and BUN-CR) and liver (AST-ALT and GGT-ALP) function in isolation and in combination with MetS were associated with all-cause and CHD mortality. Compared to individuals with neither elevated biomarker ratios nor MetS (HR = 1.00, referent), increased risk of all-cause mortality was observed in the following groups: MetS with elevated UACR (HR, 95% CI = 2.57, 1.99-3.33), MetS with elevated AST-ALT (HR = 2.22, 1.61-3.07), elevated UACR without MetS (HR = 2.12, 1.65-2.72), and elevated AST-ALT without MetS (HR = 1.71, 1.35-2.18); no other biomarker ratios were associated with all-cause mortality. For cause-specific deaths, elevated risk of CHD mortality was associated with MetS with elevated UACR (HR = 1.67, 1.05-2.67), MetS with elevated AST-ALT (HR = 2.80, 1.62-4.86), and elevated BUN-CR without MetS (HR = 2.12, 1.12-4.04); no other biomarker ratios were associated with CHD mortality.
Conclusion: Future longitudinal studies are necessary to examine the utility of these biomarker ratios in risk stratification for chronic disease management.
Keywords: Biomarkers; Kidney function; Metabolic syndrome; Mortality; NHANES; Obesity.

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Food sources of dietary fibre and risk of total knee replacement related to severe osteoarthritis, the Singapore Chinese Health Study.
Leung YY, Jin A, Tan KB, Ang LW, Yuan JM, Koh WP.
RMD Open. 2021 Jul;7(2):e001602. doi: 10.1136/rmdopen-2021-001602.
PMID: 34330847
https://rmdopen.bmj.com/content/rmdopen/7/2/e001602.full.pdf
Abstract
Objectives: We aimed to evaluate the association between fibre intake and its food sources, and the risk of total knee replacement (TKR) due to severe knee osteoarthritis (KOA).
Methods: We used data from the Singapore Chinese Health Study, a prospective cohort study that recruited 63 257 participants aged 45-74 years from 1993 to 1998. At baseline, we assessed diet using a validated 165-item semiquantitative food frequency questionnaire, together with body mass index (BMI) and lifestyle factors. Incident TKR cases were identified via record linkage with nationwide hospital discharge database through 2017.
Results: There were 2816 cases of incident TKR due to severe KOA. The total fibre intake at baseline was not associated with the risk of TKR after adjustment for confounders. Among the food sources of fibre, higher intake of legumes was associated with a lower risk of TKR in a dose-dependent manner; compared with those having the lowest quartile intake, HR (95% CI) was 0.86 (0.76, 0.96) for those having the highest quartile intake (p for trend=0.004). This association was consistent after including BMI in the model and homogeneous across BMI categories. The consumption of other fibre sources, namely grain products, nuts and seeds, soy food, fruits and vegetables, was not associated with the risk of TKR.
Conclusion: Intake of legumes, but not total fibre, was associated with a reduced risk of TKR. Further research is needed to replicate our findings and to evaluate possible biological mechanisms that could explain the effect of dietary legumes on pathogenesis or progression of KOA.
Keywords: epidemiology; knee; osteoarthritis.

Trends in Mortality From COVID-19 and Other Leading Causes of Death Among Latino vs White Individuals in Los Angeles County, 2011-2020.
Simon P, Ho A, Shah MD, Shetgiri R.
JAMA. 2021 Jul 19. doi: 10.1001/jama.2021.11945. Online ahead of print.
PMID: 34279553 No abstract available.
https://jamanetwork.com/journals/jama/fullarticle/2782334
Latino individuals in the US have experienced lower rates of mortality than non-Latino White individuals despite higher rates of poverty, often referred to as the “Latino mortality paradox.”1,2 This paradox may be attributable to behavioral and social factors, including strong family ties and support networks, rather than to a healthy migrant effect or to immigrants returning to their native countries near the end of life.2
Los Angeles County has the largest Latino population of any local jurisdiction in the US, comprising 49% of the county’s 10 million residents in 2019 vs 28% for non-Latino White individuals. We assessed trends in mortality before and during the COVID-19 pandemic in the Latino population relative to the non-Latino White population in the county.
Methods
...
Results
Of 465 389 deaths included in the analysis, 37.5% occurred among Latino individuals, 62.5% among White individuals, 51.9% among males, and 48.1% among females. From 2011 through 2019, annual AAMRs were lower in the Latino population than in the White population (516.0 deaths vs 630.3 per 100 000 in 2019; AAMR ratio, 0.82; 95% CI, 0.80-0.83), but in 2020 the AAMR increased to 741.7 deaths per 100 000 in the Latino population vs 699.0 deaths per 100 000 in the White population (AAMR ratio, 1.06; 95% CI, 1.04-1.08; Figure).
Among Latino individuals, COVID-19 was the leading cause of death in 2020, with an associated AAMR of 160.1 deaths per 100 000, compared with 51.7 deaths per 100 000 among White individuals (AAMR ratio, 3.10; 95% CI, 2.93-3.27). From 2019 to 2020, AAMRs increased among Latino individuals for heart disease (AAMR ratio, 1.19; 95% CI, 1.15-1.23) and for diabetes (AAMR ratio, 1.22; 95% CI, 1.14-1.30) without accompanying statistically significant increases among White individuals (Table).
Discussion
The longstanding mortality advantage in the Latino population relative to the White population in Los Angeles County was reversed in 2020. Deaths from COVID-19 accounted for most of this reversal. Latino individuals also experienced an increase in heart disease and diabetes AAMRs from 2019 to 2020 that was not observed among White individuals.
The findings may reflect increased risks of SARS-CoV-2 infection among Latino individuals associated with crowded living conditions and low-wage employment in unsafe work settings, as well as increased risks of disease progression associated with a higher prevalence of comorbidities.4 The increases in mortality from heart disease and diabetes among Latino individuals may in part reflect reduced access to medical services, including preventive services.5
 

Association of dietary sulfur amino acid intake with mortality from diabetes and other causes.
Dong Z, Gao X, Chinchilli VM, Sinha R, Muscat J, Winkels R, Richie JP Jr.
Eur J Nutr. 2021 Jul 29. doi: 10.1007/s00394-021-02641-w. Online ahead of print.
PMID: 34327571
Abstract
Purpose: Sulfur amino acid (SAA) consumption in Western countries is far greater than recommended levels. In preclinical studies, reduced SAA intake enhanced longevity and reduced risk for numerous chronic diseases. The current objective was to examine for associations between the intake of total SAA, including methionine (Met) and cysteine (Cys), and all-cause and disease-specific mortality US adults.
Methods: This prospective analysis included 15,083 US adult participants (mean age = 46.7 years) from the Third National Examination and Nutritional Health Survey (NHANES III, 1988-1994) with available mortality status (National Death Registry, 1988-2011). Dietary SAA intake was obtained from 24-h recall data. Associations between quintile (Q) of SAA intake (expressed as absolute intake or protein density) and mortality were assessed using Cox proportional hazard models and expressed as hazard ratio (HR).
Results: During follow-up (mean = 16.9 years), 4636 deaths occurred. After multivariable adjustment (including demographics and traditional risk factors, such as fat and other micronutrients intake), diabetes-caused mortality rates were nearly threefold higher in the highest compared to lowest SAA intake quintiles [HRQ5-Q1 total SAA, 2.68 (1.46-4.90); HRQ5-Q1 methionine, 2.45 (1.37-4.38); HRQ5-Q1 cysteine, 2.91 (1.57-5.37)] (P < 0.01)]. Higher total SAA protein density was also associated with diabetes-caused mortality [HRQ5-Q1 1.75 (1.31-2.35)]. Associations between SAA intake and all-cause mortality, and mortality caused by other major diseases were not detected.
Conclusion: Results suggest that high-SAA diets are associated with increased risk for diabetes mortality and that lowering intake towards to Recommended Dietary Allowance levels could lead to reductions in lifetime risk.
Keywords: Cysteine; Diabetes; Methionine; Sulfur amino acid restriction; Sulfur amino acids.

Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians.
Sato Y, Atarashi K, Plichta DR, Arai Y, Sasajima S, Kearney SM, Suda W, Takeshita K, Sasaki T, Okamoto S, Skelly AN, Okamura Y, Vlamakis H, Li Y, Tanoue T, Takei H, Nittono H, Narushima S, Irie J, Itoh H, Moriya K, Sugiura Y, Suematsu M, Moritoki N, Shibata S, Littman DR, Fischbach MA, Uwamino Y, Inoue T, Honda A, Hattori M, Murai T, Xavier RJ, Hirose N, Honda K.
Nature. 2021 Jul 29. doi: 10.1038/s41586-021-03832-5. Online ahead of print.
PMID: 34325466
Abstract
Centenarians display decreased susceptibility to ageing-associated illness, chronic inflammation, and infectious disease1-3. Here we show that centenarians have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids (BAs), including iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallo-lithocholic acid (LCA). Among these BAs, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian's faecal microbiota, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. IsoalloLCA exerted potent antimicrobial effects against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to the maintenance of intestinal homeostasis.

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Fasting may help ward off infections, study in mice suggests
Date: August 5, 2021
Source: PLOS
Summary:
Fasting before and during exposure to Salmonella enterica bacteria protects mice from developing a full-blown infection, in part due to changes in the animals' gut microbiomes, according to new research.
https://www.sciencedaily.com/releases/2021/08/210805140612.htm
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Fasting increases microbiome-based colonization resistance and reduces host inflammatory responses during an enteric bacterial infection.
Graef FA, Celiberto LS, Allaire JM, Kuan MTY, Bosman ES, Crowley SM, Yang H, Chan JH, Stahl M, Yu H, Quin C, Gibson DL, Verdu EF, Jacobson K, Vallance BA.
PLoS Pathog. 2021 Aug 5;17(8):e1009719. doi: 10.1371/journal.ppat.1009719. eCollection 2021 Aug.
PMID: 34352037 Free PMC article.
Abstract
Reducing food intake is a common host response to infection, yet it remains unclear whether fasting is detrimental or beneficial to an infected host. Despite the gastrointestinal tract being the primary site of nutrient uptake and a common route for infection, studies have yet to examine how fasting alters the host's response to an enteric infection. To test this, mice were fasted before and during oral infection with the invasive bacterium Salmonella enterica serovar Typhimurium. Fasting dramatically interrupted infection and subsequent gastroenteritis by suppressing Salmonella's SPI-1 virulence program, preventing invasion of the gut epithelium. Virulence suppression depended on the gut microbiota, as Salmonella's invasion of the epithelium proceeded in fasting gnotobiotic mice. Despite Salmonella's restored virulence within the intestines of gnotobiotic mice, fasting downregulated pro-inflammatory signaling, greatly reducing intestinal pathology. Our study highlights how food intake controls the complex relationship between host, pathogen and gut microbiota during an enteric infection.

Carrots vs. Russet Potato
https://www.soupersage.com/compare-nutrition/carrots-vs-russet-potato
[Al: It looks like they used data for peeled russet potatoes, since the usda data for baked or raw potatoes shows better nutrition.]
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Frequency of Boiled Potato Consumption and All-Cause and Cardiovascular Disease Mortality in the Prospective Population-Based HUNT Study.
Moholdt T, Nilsen TIL.
Front Nutr. 2021 Jul 19;8:681365. doi: 10.3389/fnut.2021.681365. eCollection 2021.
PMID: 34350204 Free PMC article.
Abstract
Few studies have assessed the association between potato consumption and mortality, especially cardiovascular disease (CVD) mortality. Our objective was to investigate the association between consumption of boiled potatoes and all-cause and CVD mortality in a Norwegian population. We used data from the population based HUNT3 study in Norway, with data on boiled potato consumption frequency in 2006-2008 from 49,926 males and females aged 20 years or above. All-cause and CVD mortality were identified during 10 years follow-up through the national Cause of Death Registry, which is virtually complete. We used Cox regression to estimate hazard ratio (HR) with a 95% confidence interval (CI) for death controlling for potential confounders, and conducted additional analyses stratified by sex, body mass index (BMI) ±25 kg/m2, and age ±65 years. There were 4,084 deaths and 1,284 of these were due to CVD. Frequency of boiled potato consumption was not associated with all-cause mortality, nor with CVD mortality. Compared to those individuals who consumed boiled potatoes less than once weekly, those who reported to consume boiled potatoes 1-3 times per week had an adjusted HR (95% CI) of 1.12 (0.89, 1.41) for all-cause mortality and 1.20 (0.78, 1.86) for CVD mortality. Individuals who consumed boiled potatoes 4-6 times per week had HRs of 0.97 (0.78, 1.21) and 1.03 (0.68, 1.55), for all-cause and CVD mortality, respectively, whereas those who consumed boiled potatoes more than once daily had HRs of 1.04 (0.83, 1.29) and 1.09 (0.73, 1.63) for all-cause and CVD mortality, respectively. There was no evidence of differential associations for males vs. females, nor between people with BMI ± 25 kg/m2. The associations between frequency of boiled potato consumption and all-cause mortality showed different patterns between those younger vs. older than 65 years, with a tendency of increased risk only in the oldest age group. In conclusion, frequency of consumption of boiled potatoes was not associated with all-cause or CVD mortality in the HUNT population in Norway.
Keywords: diet; heart disease; nutrients; survival; vegetables.

Association between dietary omega-3 fatty acid intake and depression in postmenopausal women.
Chae M, Park K.
Nutr Res Pract. 2021 Aug;15(4):468-478. doi: 10.4162/nrp.2021.15.4.468. Epub 2021 Mar 8.
PMID: 34349880 Free PMC article.
Abstract
Background/objectives: This study aimed to analyze the association between dietary omega-3 fatty acid intake and depression in postmenopausal women using data from the Korea National Health and Nutrition Examination Survey (KNHANES) VI.
Subjects/methods: The KNHANES is a cross-sectional nationwide health and nutrition survey. Dietary data, including omega-3 fatty acids, were assessed using the 24-h recall method. Depression was evaluated using a survey questionnaire. The association between dietary omega-3 fatty acids and depression was evaluated using multivariate logistic regression analysis. Depression, according to the dietary omega-3 fatty acid intake, was expressed as the odds ratio (OR) with a 95% confidence interval (CI). A total of 4,150 postmenopausal women were included in the analysis.
Results: In the fully-adjusted model, the group with the highest dietary omega-3 fatty acid intake significantly showed lower prevalence of depression than the group with the lowest intake (OR, 0.52; 95% CI, 0.33-0.83); a significant linear trend was detected (P for trend = 0.04). According to the dose-response analysis using cubic restricted spline regression, this association was linear and monotonic (P for non-linearity = 0.32).
Conclusions: In this study, the dietary omega-3 fatty acid intake in postmenopausal women was inversely proportional to depression in a dose-response manner. Large cohort studies are needed to verify the causality between omega-3 fatty acids and depression in Korean postmenopausal women.
Keywords: Korea; Omega-3 fatty acids; depression; menopause; women.

Terminal decline in objective and self-reported measures of motor function before death: 10 year follow-up of Whitehall II cohort study.
Landré B, Fayosse A, Ben Hassen C, Machado-Fragua MD, Dumurgier J, Kivimaki M, Sabia S, Singh-Manoux A.
BMJ. 2021 Aug 4;374:n1743. doi: 10.1136/bmj.n1743.
PMID: 34348957
Abstract
Objectives: To examine multiple objective and self-reported measures of motor function for their associations with mortality.
Design: Prospective cohort study.
Setting: UK based Whitehall II cohort study, which recruited participants aged 35-55 years in 1985-88; motor function component was added at the 2007-09 wave.
Participants: 6194 participants with motor function measures in 2007-09 (mean age 65.6, SD 5.9), 2012-13, and 2015-16.
Main outcome measures: All cause mortality between 2007 and 2019 in relation to objective measures (walking speed, grip strength, and timed chair rises) and self-reported measures (physical component summary score of the SF-36 and limitations in basic and instrumental activities of daily living (ADL)) of motor function.
Results: One sex specific standard deviation poorer motor function in 2007-09 (cases/total, 610/5645) was associated with an increased mortality risk of 22% (95% confidence interval 12% to 33%) for walking speed, 15% (6% to 25%) for grip strength, 14% (7% to 23%) for timed chair rises, and 17% (8% to 26%) for physical component summary score over a mean 10.6 year follow-up. Having basic/instrumental ADL limitations was associated with a 30% (7% to 58%) increased mortality risk. These associations were progressively stronger when measures were drawn from 2012-13 (mean follow-up 6.8 years) and 2015-16 (mean follow-up 3.7 years). Analysis of trajectories showed poorer motor function in decedents (n=484) than survivors (n=6194) up to 10 years before death for timed chair rises (standardised difference 0.35, 95% confidence interval 0.12 to 0.59; equivalent to a 1.2 (men) and 1.3 (women) second difference), nine years for walking speed (0.21, 0.05 to 0.36; 5.5 (men) and 5.3 (women) cm/s difference), six years for grip strength (0.10, 0.01 to 0.20; 0.9 (men) and 0.6 (women) kg difference), seven years for physical component summary score (0.15, 0.05 to 0.25; 1.2 (men) and 1.6 (women) score difference), and four years for basic/instrumental ADL limitations (prevalence difference 2%, 0% to 4%). These differences increased in the period leading to death for timed chair rises, physical component summary score, and ADL limitations.
Conclusion: Motor function in early old age has a robust association with mortality, with evidence of terminal decline emerging early in measures of overall motor function (timed chair rises and physical component summary score) and late in basic/instrumental ADL limitations.

Fine Particulate Matter and Dementia Incidence in the Adult Changes in Thought Study.
Shaffer RM, Blanco MN, Li G, Adar SD, Carone M, Szpiro AA, Kaufman JD, Larson TV, Larson EB, Crane PK, Sheppard L.
Environ Health Perspect. 2021 Aug;129(8):87001. doi: 10.1289/EHP9018. Epub 2021 Aug 4.
PMID: 34347531
Abstract
Background: Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States.
Objectives: We evaluated the association between time-varying, 10-y average fine particulate matter (
PM2.5) exposure and hazard of all-cause dementia. An additional goal was to understand how to adequately control for age and calendar-time-related confounding through choice of the time axis and covariate adjustment.
Methods: Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based 
PM2.5 exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-y average 
PM2.5 exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time. Alternative models used calendar time as the time axis.
Results: We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y average PM2.5 was 10.1 (±2.9)μg/m3. Each 1-μg/m3 increase in the moving average of 10-y PM2.5 was associated with a 16% greater hazard of all-cause dementia [1.16 (95% confidence interval: 1.03, 1.31)]. Results using calendar time as the time axis were similar.
Discussion: In this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to PM2.5 was associated with increased hazard of all-cause dementia. We found that optimal control of age and time confounding could be achieved through use of either age or calendar time as the time axis in our study. Our results strengthen evidence on the neurodegenerative effects of 
PM2.5. 

Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies.
Kim MS, Kim WJ, Khera AV, Kim JY, Yon DK, Lee SW, Shin JI, Won HH.
Eur Heart J. 2021 Aug 1:ehab454. doi: 10.1093/eurheartj/ehab454. Online ahead of print.
PMID: 34333589
Abstract
Aims: The aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality.
Methods and results : Observational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality.
Conclusion : High adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships.
Keywords: Cardiovascular disease; Coronary heart disease; Mendelian randomization study; Meta-analysis; Stroke; Umbrella review.

Edited by AlPater

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Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study.
Lankester J, Zanetti D, Ingelsson E, Assimes TL.
PLoS One. 2021 Aug 11;16(8):e0255801. doi: 10.1371/journal.pone.0255801. eCollection 2021.
PMID: 34379647
Abstract
Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

Revisiting the association of sedentary behavior and physical activity with all-cause mortality using a compositional approach: the Women's Health Study.
Migueles JH, Lee IM, Sanchez CC, Ortega FB, Buring JE, Shiroma EJ.
Int J Behav Nutr Phys Act. 2021 Aug 10;18(1):104. doi: 10.1186/s12966-021-01173-0.
PMID: 34376213
Abstract
Background: While physical activity has consistently been associated with decreased mortality rates, it remains unknown if there is a single "ideal" combination of time in physical activities of different intensities and sedentary behavior (SB) associated with the lowest rate. This study examined the associations of combinations of time in moderate-to-vigorous intensity (MVPA), higher-light intensity (HLPA), lower-light intensity activities (LLPA), and SB with mortality rates in older women.
Methods: This prospective cohort study included 16,676 older women from throughout the United States enrolled in the Women's Health Study. Women wore accelerometers on their hip from 2011 to 2015 and were followed through 2017 (mean (SD) of 4.3 (1.1) years). Deaths were confirmed with medical records, death certificates, or the National Death Index. Compositional Cox regression models were used.
Results: The mean (SD) age was 72 (5.7) years at accelerometer wear; 503 women died. Compared to the least active women (mean, 3 min/day MVPA, 27 min/day HLPA, 162 min/day LLPA, and 701 min/day SB): compositional models showed an inverse L-shaped dose-response association of MVPA replacing other behaviors with mortality rates mortality rates (P = .02); SB relative to LLPA, HLPA, and MVPA was directly associated with mortality rates in a curvilinear dose-response manner (P < .001); replacing 10 min of SB for MVPA (HR (95% CI) = .86 (.73-.98)) or for HLPA (HR (95% CI.94 (.88-1.00)) associated with 14 and 6% lower mortality rates, respectively; a 47% risk reduction (HR [95% CI] = .53 [.42-.64]) was observed among women meeting physical activity guidelines (mean, 36 min/day MVPA, 79 min/day HLPA, 227 min/day LLPA and 549 min/day SB); and similar mortality rate reductions of 43% (HR (95% CI) = .57 (.41-.73)) were observed with increases in HLPA and LLPA without increasing MVPA, e.g., reallocating SB to 90 min/day of HLPA plus 120 min/day of LLPA.
Conclusions: There was no "ideal" combination of physical activities of different intensities and SB associated with the lowest mortality rates. Of particular relevance to older women, replacing SB with light intensity activity was associated with lower mortality rates, and "mixing and matching" times in different intensities yielded equivalent mortality risk reductions.

Familial factors, diet, and risk of cardiovascular disease: a cohort analysis of the UK Biobank.
Zhang H, Zeng Y, Yang H, Hu Y, Hu Y, Chen W, Ying Z, Sun Y, Qu Y, Li Q, Valdimarsdóttir UA, Song H.
Am J Clin Nutr. 2021 Aug 10:nqab261. doi: 10.1093/ajcn/nqab261. Online ahead of print.
PMID: 34375391
Abstract
Background: Both diet and familial factors have a major role in the development of cardiovascular disease (CVD). However, it remains unclear whether familial predisposition to CVD modifies the association between dietary factors and CVD.
Objectives: The aim was to assess whether the association between diet and CVD varies with familial predisposition to CVD.
Methods: In this prospective cohort of the UK Biobank, 462,155 CVD-free participants were included in 2006-2010 and followed for CVD incidence until 2020. Food intake was measured using a short food-frequency questionnaire. Familial predisposition was measured by self-reported family history of CVD and by polygenic risk score (PRS) for CVD based on summary statistics of independent genome-wide association studies.
Results: During a median follow-up of 11.2 y, 46,164 incident CVD cases were identified. A moderately higher risk of CVD was associated with more frequent processed-meat consumption, with an adjusted HR of 1.07 (95% CI: 1.03, 1.11; highest vs. lowest level). Conversely, intakes of fish, cheese, vegetables, and fruit were each associated with reduced CVD risk [HR (95% CI): 0.92 (0.89, 0.96), 0.90 (0.86, 0.94), 0.98 (0.95, 1.00), and 0.93 (0.89, 0.96), respectively]. Stratification analyses by family history of CVD and by PRS for CVD revealed an inverse association between CVD and intakes of fish and cheese, for both subgroups with and without a familial predisposition to CVD. Notably, while the association between processed-meat intake and CVD was restricted to individuals with a familial predisposition to CVD [e.g., HR: 1.11 (1.05, 1.16) and 1.03 (0.97, 1.10) for with and without a family history, respectively, P-interaction < 0.001], the risk reduction of CVD associated with vegetable and fruit intake was only noted among participants without a CVD familial predisposition [e.g., HR for fruit consumption: 1.00 (0.97, 1.03) and 0.91 (0.87, 0.95), respectively, P < 0.001].
Conclusions: Familial factors modify the association between diet and CVD, underscoring the need for personalized dietary guidelines for CVD prevention.
Keywords: cardiovascular disease; family history of cardiovascular disease; food intake; modification effect; polygenic risk score; risk factor.

Time-restricted feeding prevents metabolic diseases through the regulation of galanin/GALR1 expression in the hypothalamus of mice.
Sun J, She Y, Fang P, Gu X, Zhang Z.
Eat Weight Disord. 2021 Aug 9. doi: 10.1007/s40519-021-01280-8. Online ahead of print.
PMID: 34370270
Abstract
Purpose: Time-restricted feeding (TRF) reverses obesity and insulin resistance, yet the central mechanisms underlying its beneficial effects are not fully understood. Recent studies suggest a critical role of hypothalamic galanin and its receptors in the regulation of energy balance. It is yet unclear whether TRF could regulate the expression of galanin and its receptors in the hypothalamus of mice fed a high-fat diet.
Methods: To test this effect, we subjected mice to either ad lib or TRF of a high-fat diet for 8 h per day. After 4 weeks, galanin and many neuropeptides associated with the function of metabolism were examined.
Results: The present findings showed that mice under TRF consume equivalent calories from a high-fat diet as those with ad lib access, yet are protected against obesity and have improved glucose metabolism. Plasma galanin, orexin A, irisin and adropin levels were significantly reversed by TRF regimen. Besides, TRF regimen reversed the progression of metabolic disorders in mice by increasing GLUT4 and PGC-1α expression in skeletal muscles. Moreover, the levels of galanin and GALR1 expression were severely diminished in the hypothalamus of the TRF mice, whereas GALR2 was highly expressed.
Conclusions: TRF diminished galanin and GALR1 expression, and increased GALR2 expression in the hypothalamus of mice fed a high-fat diet. The current studies provide additional evidence that TRF is effective in improving HFD-induced hyperglycemia and insulin resistance in mice, and this effect could be associated with TRF-induced changes of the galanin systems in the hypothalamus.

Association between body mass index, its change and cognitive impairment among Chinese older adults: a community-based, 9-year prospective cohort study.
Wu S, Lv X, Shen J, Chen H, Ma Y, Jin X, Yang J, Cao Y, Zong G, Wang H, Yuan C.
Eur J Epidemiol. 2021 Aug 9. doi: 10.1007/s10654-021-00792-y. Online ahead of print.
PMID: 34370136
Abstract
To examine the association of baseline body mass index (BMI) and BMI change with cognitive impairment among older adults in China. The study included data from the Chinese Longitudinal Healthy Longevity Study, a national community-based prospective cohort study from 2002 to 2018. Baseline BMI and BMI change were available for 12,027 adults aged older than 65 years. Cognitive impairment was defined as Chinese version of the Mini Mental State Examination score lower than 18. Multivariable Cox proportional hazard model was used. Among 12,027 participants (mean age was 81.23 years old and 47.48% were male), the proportion of underweight, normal, overweight and obese at baseline was 33.87%, 51.39%, 11.39% and 3.34%, respectively. During an average of 5.9 years' follow-up, 3086 participants (4.35 per 100 person-years) with incident cognitive impairment were identified. Compared with normal weight group, adjusted hazard ratio (AHR) for cognitive impairment was 0.86 (95% CI 0.75-0.99) among overweight group, whereas corresponding AHR was 1.02 (95% CI 0.94-1.10) in underweight and 1.01 (95% CI 0.80-1.28) in obese participants. Large weight loss (< -10%) was significantly associated with an increased risk of cognitive impairment (AHR, 1.42, 95% CI 1.29-1.56), compared to stable weight status group (-5% ~ 5%). In the restricted cubic spline models, BMI change showed a reverse J-shaped association with cognitive impairment. BMI-defined overweight, but not obesity, was associated with a lower risk of cognitive impairment among elderly Chinese adults, while large weight loss was associated with an increased risk. These findings are consistent with weight loss in the prodromal phase of dementia.
Keywords: BMI; BMI change; Chinese; Cognitive impairment; Cohort; Older adults.

Associations of plasma metal concentrations with the risks of all-cause and cardiovascular disease mortality in Chinese adults.
Shi L, Yuan Y, Xiao Y, Long P, Li W, Yu Y, Liu Y, Liu K, Wang H, Zhou L, Yang H, Li X, He M, Wu T.
Environ Int. 2021 Aug 5;157:106808. doi: 10.1016/j.envint.2021.106808. Online ahead of print.
PMID: 34365319
Abstract
Background: Exposure to metals/metalloids from both the natural environment and anthropogenic sources have a complex influence on human health. However, relatively few studies have explored the relations of exposure to multiple metals/metalloids with mortality. Therefore, this prospective study aims to examine the relations of multiple metal/metalloids exposures with all-cause and cardiovascular disease (CVD) mortality.
Methods: A total of 6155 participants within the Dongfeng-Tongji (DF-TJ) cohort were involved in this analysis, which were followed for mortality until December 31, 2018. We applied inductively coupled plasma mass spectrometry (ICP-MS) to measure baseline plasma concentrations of 23 metals. We utilized Cox regression models to calculate the hazard ratios (HRs) for all-cause and CVD mortality associated with metal concentrations. We proposed plasma metal score to assess the simultaneous exposure to multiple metals through summing each metal concentration weighted by the regression coefficients with all-cause mortality.
Results: During the follow-up (mean duration, 9.8 years), we ascertained 876 deaths, including 416 deaths of CVD (157 deaths of coronary heart disease and 259 deaths of stroke). In the multiple-metals model, after adjusting for potential confounders, plasma copper, molybdenum, and vanadium were positively associated with all-cause mortality, whereas manganese, selenium, and thallium were negatively associated with the risk of all-cause mortality, with adjusted HRs (95% Confidence Interval, CI) of the fourth quartiles were 1.73 (1.42-2.11, P-trend < 0.001) for copper, 1.33 (1.09-1.63, P-trend = 0.005) for molybdenum, 1.43 (1.16-1.77, P-trend < 0.001) for vanadium, 0.74 (0.58-0.94, P-trend = 0.005) for manganese, 0.68 (0.56-0.83, P-trend < 0.001) for selenium, and 0.74 (0.59-0.92, P-trend = 0.002) for thallium, respectively. Positive associations were observed between plasma copper, molybdenum, vanadium concentrations and CVD mortality, whereas negative associations were found for plasma selenium and thallium concentrations with CVD mortality in the multiple-metals model. Compared with the first quartiles, the HRs of fourth quartiles were 1.94 (1.45-2.58, P-trend < 0.001) for copper, 1.72 (1.26-2.35, P-trend < 0.001) for molybdenum, 1.81 (1.32-2.47, P-trend < 0.001) for vanadium, 0.67 (0.50-0.89, P-trend = 0.003) for selenium, and 0.58 (0.41-0.81, P-trend < 0.001) for thallium, respectively. The plasma metal score was significantly associated with higher risks of all-cause and CVD death in dose-response fashions. When compared with the first quartiles of plasma metal score, the HRs of fourth quartiles were 2.16 (1.76-2.64; P-trend < 0.001) for all-cause mortality and 3.00 (2.24-4.02; P-trend < 0.001) for CVD mortality.
Conclusions: The study indicated that several plasma metals/metalloids were key determinants and predictors of all-cause and CVD death in the Chinese population. Our findings highlighted the importance to comprehensively assess and monitor multiple metals/metalloids exposures.
Keywords: All-cause mortality; CVD mortality; Manganese; Molybdenum; Plasma metal score; Prospective study.

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Biomarker-Calibrated Macronutrient Intake and Chronic Disease Risk among Postmenopausal Women.
Prentice RL, Pettinger M, Neuhouser ML, Raftery D, Zheng C, Gowda GAN, Huang Y, Tinker LF, Howard BV, Manson JE, Wallace R, Mossavar-Rahmani Y, Johnson KC, Lampe JW.
J Nutr. 2021 Aug 7;151(8):2330-2341. doi: 10.1093/jn/nxab091.
PMID: 33880504
Abstract
Background: Knowledge about macronutrient intake and chronic disease risk has been limited by the absence of objective macronutrient measures. Recently, we proposed novel biomarkers for protein, protein density, carbohydrate, and carbohydrate density, using established biomarkers and serum and urine metabolomics profiles in a human feeding study.
Objectives: We aimed to use these biomarkers to develop calibration equations for macronutrient variables using dietary self-reports and personal characteristics and to study the association between biomarker-calibrated intake estimates and cardiovascular disease, cancer, and diabetes risk in Women's Health Initiative (WHI) cohorts.
Methods: Prospective disease association analyses are based on WHI cohorts of postmenopausal US women aged 50-79 y when enrolled at 40 US clinical centers (n = 81,954). We used biomarker intake values in a WHI nutritional biomarker study (n = 436) to develop calibration equations for each macronutrient variable, leading to calibrated macronutrient intake estimates throughout WHI cohorts. We then examined the association of these intakes with chronic disease incidence over a 20-y (median) follow-up period using HR regression methods.
Results: In analyses that included doubly labeled water-calibrated total energy, HRs for cardiovascular diseases and cancers were mostly unrelated to calibrated protein density. However, many were inversely related to carbohydrate density, with HRs (95% CIs) for a 20% increment in carbohydrate density of 0.81 (0.69, 0.95) and 0.83 (0.74, 0.93), respectively, for primary outcomes of coronary heart disease and breast cancer, as well as 0.74 (0.60, 0.91) and 0.87 (0.81, 0.93) for secondary outcomes of heart failure and total invasive cancer. Corresponding HRs (95% CIs) for type 2 diabetes incidence in relation to protein density and carbohydrate density were 1.17 (1.09, 1.75) and 0.73 (0.66, 0.80), respectively.
Conclusions: At specific energy intake, a diet high in carbohydrate density is associated with substantially reduced risk of major chronic diseases in a population of US postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.
Keywords: biomarker; cancer; cardiovascular disease; diabetes; diet; macronutrient; measurement error; metabolomics.

Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F.
J Nutr. 2021 Aug 7;151(8):2153-2160. doi: 10.1093/jn/nxab119.
PMID: 33978188 Free PMC article.
Abstract
Background: Supplementation of citicoline (CDP-choline), a naturally occurring mononucleotide, has shown beneficial effects on memory function and behavior in populations with a wide range of impairments. However, few studies have investigated its effect in healthy older populations.
Objective: The objective of this study was to investigate the effects of citicoline (Cognizin®), on memory in healthy elderly populations with age-associated memory impairment (AAMI).
Methods: A total of 100 healthy men and women aged between 50 and 85 y with AAMI participated in this randomized, double-blind, placebo-controlled trial. Participants were randomized to receive placebo (n = 51) or citicoline (n = 49; 500 mg/d) for 12 wk. Memory function was assessed at baseline and end of the intervention (12 wk) using computerized tests (Cambridge Brain Sciences, Ontario, Canada). Safety measurements included adverse events query, body weight, blood pressure, and hematology and metabolic panel. Intent-to-treat analysis was conducted using ANCOVA for the primary and secondary outcome variables with Bonferroni correction for multiple comparisons.
Results: A total of 99 out of 100 participants completed the study in its entirety. After the 12-wk intervention, participants supplemented with citicoline showed significantly greater improvements in secondary outcomes of episodic memory (assessed by the Paired Associate test), compared with those on placebo (mean: 0.15 vs. 0.06, respectively, P = 0.0025). Composite memory (secondary outcome), calculated using the scores of 4 memory tests, also significantly improved to a greater extent following citicoline supplementation (mean: 3.78) compared with placebo (mean: 0.72, P = 0.0052).
Conclusions: Dietary supplementation of citicoline for 12 wk improved overall memory performance, especially episodic memory, in healthy older males and females with AAMI. The findings suggest that regular consumption of citicoline may be safe and potentially beneficial against memory loss due to aging.
Keywords: 5′-cytidine diphosphate choline; aging; brain; citicoline; memory loss.

Dietary Acid Load and Mortality from All Causes, Cardiovascular Disease, and Cancer: results from the Golestan Cohort Study.
Hejazi E, Emamat H, Sharafkhah M, Saidpour A, Poustchi H, Sepanlou SG, Sotoudeh M, Dawsey SM, Boffetta P, Abnet CC, Kamangar F, Etemadi A, Pourshams A, Fazeltabar-Malekshah A, Brennan P, Malekzadeh R, Hekmatdoost A.
Br J Nutr. 2021 Aug 16:1-20. doi: 10.1017/S0007114521003135. Online ahead of print.
PMID: 34392847
Abstract
Given the limited studies, and controversial results on association between dietary acid load and mortality from cardiovascular disease (CVD) and cancers, we aimed to investigate this association in a large population cohort study in Middle-East, with a wide range of dietary acid load.The study was conducted on the platform of the Golestan Cohort Study (GCS), which enrolled 50,045 participants in 2004-2008. Dietary intake was assessed using a validated food frequency questionnaire (FFQ). Dietary potential renal acid load (PRAL) score was calculated from nutrient intake. Death and its causes were identified, and confirmed by two or three physicians. Cox proportional hazards regression was used to estimate HRs and 95% CIs for total and cause specific mortalities. Then, the associations were modeled using restricted cubic splines.PRAL range was -57.36 to +53.81 mEq/d for men and -76.70 to +49.08 for women. During 555,142 person-years of follow-up, we documented 6830 deaths, including 3070 cardiovascular deaths, 1502 cancer deaths and 2258 deaths from other causes. For overall deaths, in final model after adjustment for confounders, participants in the first and 5th quintiles of PRAL had a higher risk of mortality compared to the second quintile of PRAL (HR: 1.08; 95% CI:1.01-1.16 and HR: 1.07; 95% CI: 1.01-1.15, respectively); P for trend <0.05). Participants in the first and 5th quintiles of PRAL had a 12% higher risk of CVD mortality compared to the Q2 of PRAL (HR: 1.12; 95% CI: 1.01-1.25 and HR: 1.12; 95% CI: 1.01-1.26, respectively; P for trend <0.05). We found that all-cause and CVD mortality rates were higher in the lowest and highest PRAL values, in an approximately U-shaped relation (P-values for the overall association and the non-linear association of energy-adjusted PRAL with total mortality were <0.001 and <0.001, and with CVD mortality were 0.008 and 0.003, respectively).Our results highlight unfavorable associations of high acidity and alkalinity of diet with the increased total and CVD mortality risk. It may be important to consider a balanced acid-base diet as a protective strategy to prevent premature death, especially from CVD.
Keywords: GCS; Mortality; cancer; cardiovascular; cohort.

Estimating Under-recognized COVID-19 Deaths, United States, March 2020-May 2021 using an Excess Mortality Modelling Approach.
Iuliano AD, Chang HH, Patel NN, Threlkel R, Kniss K, Reich J, Steele M, Hall AJ, Fry AM, Reed C.
Lancet Reg Health Am. 2021 Jul 13:100019. doi: 10.1016/j.lana.2021.100019. Online ahead of print.
PMID: 34386789 Free PMC article.
Abstract
Background: In the United States, Coronavirus Disease 2019 (COVID-19) deaths are captured through the National Notifiable Disease Surveillance System and death certificates reported to the National Vital Statistics System (NVSS). However, not all COVID-19 deaths are recognized and reported because of limitations in testing, exacerbation of chronic health conditions that are listed as the cause of death, or delays in reporting. Estimating deaths may provide a more comprehensive understanding of total COVID-19-attributable deaths.
Methods: We estimated COVID-19 unrecognized attributable deaths, from March 2020-April 2021, using all-cause deaths reported to NVSS by week and six age groups (0-17, 18-49, 50-64, 65-74, 75-84, and ≥85 years) for 50 states, New York City, and the District of Columbia using a linear time series regression model. Reported COVID-19 deaths were subtracted from all-cause deaths before applying the model. Weekly expected deaths, assuming no SARS-CoV-2 circulation and predicted all-cause deaths using SARS-CoV-2 weekly percent positive as a covariate were modelled by age group and including state as a random intercept. COVID-19-attributable unrecognized deaths were calculated for each state and age group by subtracting the expected all-cause deaths from the predicted deaths.
Findings: We estimated that 766,611 deaths attributable to COVID-19 occurred in the United States from March 8, 2020-May 29, 2021. Of these, 184,477 (24%) deaths were not documented on death certificates. Eighty-two percent of unrecognized deaths were among persons aged ≥65 years; the proportion of unrecognized deaths were 0•24-0•31 times lower among those 0-17 years relative to all other age groups. More COVID-19-attributable deaths were not captured during the early months of the pandemic (March-May 2020) and during increases in SARS-CoV-2 activity (July 2020, November 2020-February 2021).
Discussion: Estimating COVID-19-attributable unrecognized deaths provides a better understanding of the COVID-19 mortality burden and may better quantify the severity of the COVID-19 pandemic.
Keywords: COVID-19; Excess mortality; Mortality; SARS-CoV-2; Unrecognized deaths.

METABOLISM CHANGES WITH AGE, JUST NOT WHEN YOU MIGHT THINK
Researchers have precisely measured life’s metabolic highs and lows, from birth to old age, and the findings might surprise you.
https://today.duke.edu/2021/08/metabolism-changes-age-just-not-when-you-might-think
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Daily energy expenditure through the human life course.
Pontzer H, Yamada Y, Sagayama H, Ainslie PN, Andersen LF, Anderson LJ, Arab L, Baddou I, Bedu-Addo K, Blaak EE, Blanc S, Bonomi AG, Bouten CVC, Bovet P, Buchowski MS, Butte NF, Camps SG, Close GL, Cooper JA, Cooper R, Das SK, Dugas LR, Ekelund U, Entringer S, Forrester T, Fudge BW, Goris AH, Gurven M, Hambly C, El Hamdouchi A, Hoos MB, Hu S, Joonas N, Joosen AM, Katzmarzyk P, Kempen KP, Kimura M, Kraus WE, Kushner RF, Lambert EV, Leonard WR, Lessan N, Martin C, Medin AC, Meijer EP, Morehen JC, Morton JP, Neuhouser ML, Nicklas TA, Ojiambo RM, Pietiläinen KH, Pitsiladis YP, Plange-Rhule J, Plasqui G, Prentice RL, Rabinovich RA, Racette SB, Raichlen DA, Ravussin E, Reynolds RM, Roberts SB, Schuit AJ, Sjödin AM, Stice E, Urlacher SS, Valenti G, Van Etten LM, Van Mil EA, Wells JCK, Wilson G, Wood BM, Yanovski J, Yoshida T, Zhang X, Murphy-Alford AJ, Loechl C, Luke AH, Rood J, Schoeller DA, Westerterp KR, Wong WW, Speakman JR; IAEA DLW Database Consortium.
Science. 2021 Aug 13;373(6556):808-812. doi: 10.1126/science.abe5017.
PMID: 34385400
Abstract
Total daily energy expenditure ("total expenditure") reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass-adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.

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"Calories in, calories out" and macronutrient intake: the hope, hype, and science of calories.
Howell S, Kones R.
Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E608-E612. doi: 10.1152/ajpendo.00156.2017. Epub 2017 Aug 1.
PMID: 28765272 Free article.
Abstract
One of the central tenets in obesity prevention and management is caloric restriction. This perspective presents salient features of how calories and energy balance matter, also called the "calories in, calories out" paradigm. Determinants of energy balance and relationships to dietary macronutrient content are reviewed. The rationale and features of the carbohydrate-insulin hypothesis postulate that carbohydrate restriction confers a metabolic advantage. According to this model, a large amount of fat intake is enabled without weight gain. Evidence concerning this possibility is detailed. The relationship and application of the laws of thermodynamics are then clarified with current primary research. Strong data indicate that energy balance is not materially changed during isocaloric substitution of dietary fats for carbohydrates. Results from a number of sources refute both the theory and effectiveness of the carbohydrate-insulin hypothesis. Instead, risk for obesity is primarily determined by total calorie intake.
Keywords: CHO-insulin hypothesis; NuSI; calories in, calories out; energy expenditure; laws of thermodynamics; low-carbohydrate diet; metabolic adaptation; metabolic advantage; obesity; thermic effect of food.

Dietary fats high in linoleic acids impair anti-tumor T cell responses by inducing E-FABP-mediated mitochondrial dysfunction.
Jin R, Hao J, Yi Y, Yin D, Hua Y, Li X, Bao H, Han X, Egilmez NK, Sauter ER, Li B.
Cancer Res. 2021 Aug 16:canres.CAN-21-0757-A.2021. doi: 10.1158/0008-5472.CAN-21-0757. Online ahead of print.
PMID: 34400394
Abstract
The most recent American Dietary Guidelines (2020-2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear. Here we demonstrated that high fat diets (HFD) rich either in OA or LA induced a similar degree of murine obesity, but the LA-rich HFD specifically promoted mammary tumor growth. LA impaired anti-tumor T cell responses by promoting naïve T cell apoptosis and inhibiting TNFα production. While exogenous OA and LA were taken up by T cells with similar efficacy, only LA induced significant mitochondrial ROS production and lipid peroxidation. Importantly, naïve T cells predominantly expressed epidermal fatty acid binding protein (E-FABP), which is central in facilitating LA mitochondrial transport and cardiolipin incorporation. Genetic depletion of E-FABP rescued LA-impaired T cell responses and suppressed LA-rich HFD-associated mammary tumor growth. Collectively, these data suggest that dietary oils high in LA promote mammary tumors by inducing E-FABP-mediated T cell dysfunction.

Visual Impairment, Eye Diseases, and Dementia Risk: A Systematic Review and Meta-Analysis.
Kuźma E, Littlejohns TJ, Khawaja AP, Llewellyn DJ, Ukoumunne OC, Thiem U.
J Alzheimers Dis. 2021 Aug 13. doi: 10.3233/JAD-210250. Online ahead of print.
PMID: 34397414
Abstract
Background: Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies.
Objective: To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes.
Methods: We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies.
Results: Thirty studies met our eligibility criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR] = 1.38, 95%confidence interval [CI]: 1.19-1.59, I2 = 28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio {HR} = 1.17, 95%CI 1.00-1.38, I2 = 0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR = 1.34, 95%CI 1.11-1.61, I2 = 63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR = 0.97, 95%CI 0.90-1.04, I2 = 51.5%) or age-related macular degeneration (7,800,692 participants, > 2,559 cases, HR = 1.15, 95%CI 0.88-1.50, I2 = 91.0%) and risk of dementia, respectively.
Conclusion: As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation.
Keywords: Alzheimer’s disease; dementia; eye diseases; prospective studies; vision disorders.

Edited by AlanPater

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Steps per Day and All-Cause Mortality in Middle-aged Adults in the Coronary Artery Risk Development in Young Adults Study.
Paluch AE, Gabriel KP, Fulton JE, Lewis CE, Schreiner PJ, Sternfeld B, Sidney S, Siddique J, Whitaker KM, Carnethon MR.
JAMA Netw Open. 2021 Sep 1;4(9):e2124516. doi: 10.1001/jamanetworkopen.2021.24516.
PMID: 34477847 Free PMC article.
Abstract
Importance: Steps per day is a meaningful metric for physical activity promotion in clinical and population settings. To guide promotion strategies of step goals, it is important to understand the association of steps with clinical end points, including mortality.
Objective: To estimate the association of steps per day with premature (age 41-65 years) all-cause mortality among Black and White men and women.
Design, setting, and participants: This prospective cohort study was part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were aged 38 to 50 years and wore an accelerometer from 2005 to 2006. Participants were followed for a mean (SD) of 10.8 (0.9) years. Data were analyzed in 2020 and 2021.
Exposure: Daily steps volume, classified as low (<7000 steps/d), moderate (7000-9999 steps/d), and high (≥10 000 steps/d) and stepping intensity, classified as peak 30-minute stepping rate and time spent at 100 steps/min or more.
Main outcomes and measures: All-cause mortality.
Results: A total of 2110 participants from the CARDIA study were included, with a mean (SD) age of 45.2 (3.6) years, 1205 (57.1%) women, 888 (42.1%) Black participants, and a median (interquartile range [IQR]) of 9146 (7307-11 162) steps/d. During 22 845 person years of follow-up, 72 participants (3.4%) died. Using multivariable adjusted Cox proportional hazards models, compared with participants in the low step group, there was significantly lower risk of mortality in the moderate (hazard ratio {HR}, 0.28 [95% CI, 0.15-0.54]; risk difference [RD], 53 [95% CI, 27-78] events per 1000 people) and high (HR, 0.45 [95% CI, 0.25-0.81]; RD, 41 [95% CI, 15-68] events per 1000 people) step groups. Compared with the low step group, moderate/high step rate was associated with reduced risk of mortality in Black participants (HR, 0.30 [95% CI, 0.14-0.63]) and in White participants (HR, 0.37 [95% CI, 0.17-0.81]). Similarly, compared with the low step group, moderate/high step rate was associated with reduce risk of mortality in women (HR, 0.28 [95% CI, 0.12-0.63]) and men (HR, 0.42 [95% CI, 0.20-0.88]). There was no significant association between peak 30-minute intensity (lowest vs highest tertile: HR, 0.98 [95% CI, 0.54-1.77]) or time at 100 steps/min or more (lowest vs highest tertile: HR, 1.38 [95% CI, 0.73-2.61]) with risk of mortality.
Conclusions and relevance: This cohort study found that among Black and White men and women in middle adulthood, participants who took approximately 7000 steps/d or more experienced lower mortality rates compared with participants taking fewer than 7000 steps/d. There was no association of step intensity with mortality.

Effects of Diet on Sleep: A Narrative Review.
Binks H, E Vincent G, Gupta C, Irwin C, Khalesi S.
Nutrients. 2020 Mar 27;12(4):936. doi: 10.3390/nu12040936.
PMID: 32230944 Free PMC article. Review.
Abstract
Many processes are involved in sleep regulation, including the ingestion of nutrients, suggesting a link between diet and sleep. Aside from studies investigating the effects of tryptophan, previous research on sleep and diet has primarily focused on the effects of sleep deprivation or sleep restriction on diet. Furthermore, previous reviews have included subjects with clinically diagnosed sleep-related disorders. The current narrative review aimed to clarify findings on sleep-promoting foods and outline the effects of diet on sleep in otherwise healthy adults. A search was undertaken in August 2019 from the Cochrane, MEDLINE (PubMed), and CINAHL databases using the population, intervention, control, outcome (PICO) method. Eligible studies were classified based on emerging themes and reviewed using narrative synthesis. Four themes emerged: tryptophan consumption and tryptophan depletion, dietary supplements, food items, and macronutrients. High carbohydrate diets, and foods containing tryptophan, melatonin, and phytonutrients (e.g., cherries), were linked to improved sleep outcomes. The authors posit that these effects may be due in part to dietary influences on serotonin and melatonin activity.
Keywords: adults; dietary supplements; food; nutrients; sleep duration; sleep quality.

Supplementation with oil rich in eicosapentaenoic acid, but not in docosahexaenoic acid, improves global cognitive function in healthy, young adults: results from randomized controlled trials.
Patan MJ, Kennedy DO, Husberg C, Hustvedt SO, Calder PC, Khan J, Forster J, Jackson PA.
Am J Clin Nutr. 2021 Jun 10;114(3):914-24. doi: 10.1093/ajcn/nqab174. Online ahead of print.
PMID: 34113957 Free PMC article.
Abstract
Background: Evidence regarding the effects of the omega-3 (ɷ-3) PUFAs (n-3 PUFAs) DHA and EPA on cognition is lacking.
Objectives: We investigated whether supplementation with oils rich in EPA or DHA improves cognition, prefrontal cortex (PFC) hemoglobin (Hb) oxygenation, and memory consolidation.
Methods: Healthy adults (n = 310; age range: 25-49 y) completed a 26-wk randomized controlled trial in which they consumed either 900 mg DHA/d and 270 mg EPA/d (DHA-rich oil), 360 mg DHA/d and 900 mg EPA/d (EPA-rich oil), or 3000 mg/d refined olive oil (placebo). Cognitive performance and memory consolidation were assessed via computerized cognitive test battery. PFC Hb oxygenation was measured using near infrared spectroscopy (NIRS).
Results: Both global accuracy and speed improved with EPA-rich oil compared with placebo and DHA-rich oil [EPA vs. placebo accuracy: estimated marginal mean (EMM) = 0.17 (95% CI: 0.09, 0.24) vs. EMM = 0.03 (95% CI = -0.04, 0.11); P = 0.044; EPA vs. placebo speed: EMM = -0.15 (95% CI: -0.22, -0.07) vs. EMM = 0.03 (95% CI: -0.05, 0.10); P = 0.003]. Accuracy of memory was improved with EPA compared with DHA [EMM = 0.66 (95% CI: 0.26, 1.06) vs. EMM = -0.08 (95% CI: -0.49, 0.33); P = 0.034]. Both EPA- and DHA-rich oils showed trends towards reduced PFC oxygenated Hb (oxy-Hb) compared with placebo [placebo: EMM = 27.36 µM (95% CI: 25.73, 28.98); DHA: EMM = 24.62 µM (95% CI: 22.75, 26.48); P = 0.060; EPA: EMM = 24.97 µM (95% CI: 23.35, 26.59); P = 0.082].
Conclusions: EPA supplementation improved global cognitive function and was superior to the oil enriched with DHA. Interpreted within a neural efficiency framework, reduced PFC oxygenated Hb suggests that n-3 PUFAs may be associated with increased efficiency.These trials were registered in the clinical trials registry (https://clinicaltrials.gov/) as NCT03158545, NCT03592251, NCT02763514.
Keywords: cognition; docosahexaenoic acid; eicosapentaenoic acid; memory; n-3 polyunsaturated fatty acids; self-micro-emulsifying.

Habitual use of fish oil supplements, genetic predisposition, and risk of fractures: a large population-based study.
Mei Z, et al.
Am J Clin Nutr. 2021.
PMID: 34038933
Abstract
Background: Epidemiologic studies have suggested an inverse association between circulating concentrations of long-chain ω-3 PUFAs and fracture risk. However, whether supplementation of long-chain ω-3 PUFA (i.e. fish oil) is associated with fracture risk, and whether the association is modified by genetic predisposition to fracture risk remain unclear.
Objectives: To evaluate the associations of habitual fish oil supplement use with fracture risk, and to explore the potential effect modification by genetic predisposition.
Methods: This study included 492,713 participants from the UK Biobank who completed a questionnaire on habitual fish oil supplement use between 2006 and 2010. HRs and 95% CIs for fractures were estimated from multivariable Cox proportional hazards models. A weighted fracture-genetic risk score (GRS) was derived from 14 validated single nucleotide polymorphisms.
Results: During a median follow-up of 8.1 y, 12,070 incident fractures occurred among participants free of fracture at baseline (n = 441,756). Compared with nonuse, habitual use of fish oil supplements was associated with a lower risk of total fractures (HR = 0.93; 95% CI: 0.89, 0.97), hip fractures (HR = 0.83; 95% CI: 0.75, 0.92), and vertebrae fractures (HR = 0.85; 95% CI: 0.72, 0.99). The inverse association for total fractures was more pronounced among participants having a higher fracture-GRS than among those with a lower fracture-GRS (P-interaction <0.001). Among participants with a history of fracture at baseline (n = 50,957), fish oil use was associated with a lower risk of total recurrent fractures (HR = 0.88; 95% CI: 0.82, 0.96) and vertebrae recurrent fractures (HR = 0.64; 95% CI: 0.46, 0.88) but not with hip fracture recurrence.
Conclusions: Our findings suggest that habitual fish oil supplement use is associated with lower risks of both incident and recurrent fractures. The inverse associations of fish oil use with total fractures appeared to be more pronounced among individuals at higher genetic risk of fractures than those with lower genetic risk.
Keywords: UK Biobank; fish oil supplements; fracture; genetic predisposition; prospective study.

Edited by AlanPater

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