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Ron Put

Supplements Thoughts

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I've been thinking about supplements. While I try to get most of my nutrients from foods (non-fortified), I also look at my daily pill assortment and think, "Wow! It's a lot of stuff!"

Here is what I take:

 

Curcumin (CurcuWIN 46x absorption): 2 caps

Lycopene: 15mg

Milk Thistle (30:1 extract): 2 cap

Glucosamine HCI: 1500mg

MSM: 1500mg

Vitamin B12: 1000mg

Vitamin D3: 2000

Vitamin K2 (MK-4)

Vitamin K2 (MK-7)

Alpha GPC: 150mg

Coenzyme Q-10: 200mg

Melatonin: 3mg

Resveratrol (Japanese Knotweed): 1450mg


I am thinking of stopping the vitamin K supplementation, since I seem to hit RDA every day now just from food.

I am also considering Biotin, since I seem to have trouble getting RDA according to Cronometer (but who knows how accurate it is, since for instance Almonds are not listed as containing any, but they do, as well as most nuts).

I am trying to decide on Calcium. I may follow Dean's example and add 250mg per day, since it's not easy to get RDA. BTW, baking soda seems to be especially rich in calcium, I wonder if it has any advantages over a pill?

Finally, I periodically go through a bottle of NMN, with maybe 2 month gaps between each bottle.

Anything wrong with the above?

Edited by Ron Put

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Ron, 

Dietary vitamin K (as listed in the USDA nutrition database and tracked in e.g. Cronometer) is not the same as vitamin K2. I would suggest continuing with the K2, especially MK7 unless you get K2-MK7 from natto, the only significant dietary source as far as I know. I'm dubious about the value of everything else on your list except curcumin, lycopene, B12, and D3, besides giving you very expensive pee. But I've become a supplement skeptic in the last few years, so take that as you will. 

Regarding the baking soda for calcium. As I understand it, not all calcium is created equal when it comes to bioavailability. I'd personally rather take less of a more bioavailable form (e. g. calcium citrate malate) given the evidence suggesting adverse cardiovascular effects associated with high dosage of standard calcium supplements. 

I'm not sure about your diet, but as a vegan I also supplement with iron, zinc, iodine, strontium (for bone health), and one fatty fish meal's worth of algae-derived DHA per week. 

--Dean 

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Thanks, Dean. Good point on the calcium. I will add it.

I do eat natto on periodically, when I buy a fresh batch. The stuff has a lot of protein though and I am already having trouble keeping mine low.

I eat 2-3 sheets of nori almost every day, good for iodine (100%+ of RDA), among other things.

I am a vegetarian (mostly vegan). For me, it seems easy to get enough iron, see the attached grab from Cronometer.


1190595795_ScreenShot2019-12-12at13_25_11.png.1a637917065346cf2d54c57fe2f98bdc.png


Strontium, hm? I never thought of it. It seems to be found in leafy vegetables, but perhaps not in sufficient amounts. Any drawbacks of taking it as a supplement?

I started taking glucosamine again recently, because of studies like this one: https://www.bmj.com/content/365/bmj.l1628

Similarly for melatonin: https://academic.oup.com/ehjcvp/article/2/4/258/2197075

And Q-10: http://www.clevelandheartlab.com/blog/horizons-coq10-what-are-the-heart-health-benefits/

I take MSM and milk thistle kind of as liver insurance, and MSM supposedly helps with skin elasticity. I may reconsider MSM, since it may increase methionine production. 

Edited by Ron Put

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Ron,

You and Dean have the micronutrients covered including D3, K2 and CoQ10.
Glucosamine is excellent as you’ve found - Vince Giuliano dedicated a glucosamine article on his blog covering its powerful in-vivo effects on decreasing all-cause mortality.

Lycopene is a carotenoid and is very beneficial, and I believe it’s valuable to get plenty of natural forms of vitamin A such as lutein, zeaxanthin, and beta-carotene (I consume carrots and spinach for this).

As far as polyphenols go, I would place a good green tea supplement at the top of the list.  One of the best is AOR Active Green Tea - I take this instead of drinking green tea since I want an effective dose and prefer to drink coffee.

Clinton

Edit:  I’ve recently been taking 250mg daily of Nicotinamide Riboside (instead of NMN).

 

Edited by Clinton

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Ron,

Regarding iron. I wouldn't put too much stock in meeting the RDA via vegan sources, since absorption varies so much by food type, food pairing and individual variation. Fortunately iron levels are easy to test. If your serum iron, haemoglobin and ferritin levels are within the normal range based on your diet alone, I wouldn't be inclined to supplement. 

Regarding glucosamine - that study seems like a pretty impressive result with respect to lowering cardiovascular disease. It is an anti-inflammatory, so it might make sense that it would be beneficial, at least in the general population. But I wonder if it would have the same benefits in people such as ourselves with very low baseline inflammation and low risk of CVD to start with due to our impeccable diet and lifestyle. I worry it might it be like another anti-inflammatory, aspirin, which seems beneficial for "normal" people at significant risk of CVD, but on balance not good for people with low risk of CVD due to (in aspirin's case) its potential to increase intestinal bleeding.

But the known side effects of glucosamine seem pretty mild, so it is a bit tempting. Glucosamine is commonly taken by people with osteoarthritis (OA). The authors of the head scratcher of a study linking OA to improved cognition and longevity (discussed here and here) claimed to have ruled out the effects of OA-related supplements/medications to explain their seemingly paradoxical finding. But who knows, maybe a lot of the OA sufferers were taking glucosamine and it was beneficial. 

Regarding melatonin, the review article you linked to I found less impressive, particular for those of us whose sleep patterns are already good. 

Regarding CoQ10, I'm not convinced of the benefits for those of us with low risk of CVD, already low levels of inflammation, already good cholesterol levels and blood pressure.

Regarding strontium, here is a discussion Michael and I had a few years back on the pros and cons. Michael doesn't (or didn't then) think the tenuous link between strontium and cardiovascular issues was worth worrying about. I'm not sure what he thinks now. In Europe, strontium is reserved as a treatment of osteoporosis in women patients at high risk of fracture without signs of cardiovascular disease. Here is a section from the full text of [1] on the pros and cons of strontium for bone health:

----------------------

Strontium ranelate


In the European Union, strontium ranelate is approved for
treatment of severe osteoporosis in women at high risk of
fracture who are not candidates for other osteoporosis therapies.[77] Strontium, which is absorbed onto the crystal surface
of bone, inhibits osteoclast activity and enhances osteoblast
activity, thereby decreasing bone resorption and increasing
bone formation, mass and strength.[77] Strontium ranelate
decreases risk of clinical vertebral fractures by 50% and all
osteoporotic fractures by 31%, but it has no effect on risk of
hip fracture.[78]


DRESS syndrome


Drug rash with eosinophilia and systemic symptoms (DRESS
syndrome) is a rare (1 per 49,959 patient-years) but life-threatening complication requiring permanent discontinuation of
strontium ranelate.[79] There have been eighty-six spontaneously reported postmarketing cases of DRESS and ten cases
of Stevens–Johnson syndrome and toxic epidermal necrolysis;
none were observed in the clinical trials.[80] Common DRESS
symptoms include skin rash, facial edema, enlarged lymph
nodes, fever, hypereosinophilia and multisystem (especially
hepatic) dysfunction.[79] DRESS typically occurs 2–6 weeks
after initiation and may persist after treatment discontinuation.[79] The mortality rate is about 8–10%.[79,81]


Venous thromboembolism and cardiovascular events


Strontium ranelate is associated with an increased risk of venous
thromboembolism (VTE) and myocardial infarction (MI). In a
pooled analysis of 7500 postmenopausal women treated with
strontium ranelate or placebo, incidence of VTE was 1.9%
versus 1.3% respectively (relative risk [RR] 1.5; 95% CI,
1.04–2.19), and incidence of MI was 1.7% versus 1.1% (RR
1.6, 95% CI, 1.07–2.38).[82] Strontium ranelate is contraindicated for persons with uncontrolled hypertension or a history of
or current VTE, ischemic heart disease, peripheral arterial disease or cerebrovascular disease; it should be reserved for patients
at high risk of fracture who are not candidates for other osteoporosis treatments.[77,82]

---------------

Here is a section from a very recent meta-analysis [2] of the effectiveness of various treatments to prevent osteoporotic fractures in men:

Strontium Ranelate and the Risk of Osteoporotic Fractures
Three studies (Ringe et al., 2010; Kaufman et al., 2013; Yan, 2014) reported strontium ranelate and the incidence of osteoporotic fractures. The overall effects of pooled analyses did not indicate any significant difference between groups concerning the risk of the vertebral fracture domain (RR, 0.79 [95% CI, 0.35–1.78]), nonvertebral fracture domain (RR, 0.52 [95% CI, 0.13–2.00]), or clinical fracture domain (RR, 0.71 [95% CI, 0.36–1.40]) (Figure S8).

Here is figure S8 from that meta-analysis:

Screenshot_20191212-183621_Word.jpg

As you can see, there is a definite trend towards reduced fracture risk from strontium in men. But as the authors indicate, the error bars are large and so even the pooled risk reduction is non-significant.

Given the above data, including identified risks and modest (at best) rewards (at least in men) and my general skepticism about supplements as of late, I think I may cut out my  strontium supplement out of an abundance of caution.

[Note to Saul: surprisingly, that same meta-analysis of osteoporosis treatment in men [2] also found that Forteo (aka teriparatide) was not associated with reduced fracture risk in men.]

Ron, thanks for prompting me to look at the most recent data on strontium.

As I said, glucosamine looks a bit tempting. Does anyone else here (besides Ron and Clinton) take it or have an opinion on it?

--Dean   

------------

[1] Expert Rev Clin Pharmacol. 2015;8(6):769-84. doi: 10.1586/17512433.2015.1099432. 

Epub 2015 Oct 20.

The safety and tolerability profile of therapies for the prevention and treatment
of osteoporosis in postmenopausal women.

Komm BS(1), Morgenstern D(1), A Yamamoto L(2), Jenkins SN(1).

Author information: 
(1)a Pfizer Inc , Collegeville , PA , USA.
(2)b Pfizer Japan Inc , Tokyo , Japan.

At a time when the prevalence of osteoporosis and related fractures is
increasing, initiation and continuation of pharmacologic therapies for prevention
and treatment of postmenopausal osteoporosis have declined. This decline has been
at least in part attributable to concerns about safety of these agents, such as
atypical fractures with bisphosphonates and breast cancer with estrogen/progestin
therapy, particularly when they are used long term by older women. However, in
many cases, absolute risk of serious adverse effects is small and should be
balanced against the larger potential for fracture reduction. Here, we review the
safety and tolerability of available therapies for postmenopausal osteoporosis.
Taking into consideration their relative efficacy, we also provide strategies for
optimization of the risk:benefit ratio.

DOI: 10.1586/17512433.2015.1099432 
PMID: 26482902  [Indexed for MEDLINE]
 

----------------

[2] Front Pharmacol. 2019 Aug 9;10:882. doi: 10.3389/fphar.2019.00882. eCollection

2019.

Does Routine Anti-Osteoporosis Medication Lower the Risk of Fractures in Male
Subjects? An Updated Systematic Review With Meta-Analysis of Clinical Trials.

Zeng LF(1)(2)(3), Pan BQ(4), Liang GH(1)(2), Luo MH(1), Cao Y(5), Guo D(1), Chen 
HY(1), Pan JK(1), Huang HT(3), Liu Q(6), Guan ZT(6), Han YH(3), Zhao D(3), Zhao
JL(3), Hou SR(3), Wu M(3), Lin JT(3), Li JH(3), Liang WX(1), Ou AH(1), Wang Q(1),
Yang WY(1), Liu J(1)(2)(3).

Author information: 
(1)The 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine
(Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
(2)Bone and Joint Research Team of Degeneration and Injury, Guangdong Provincial 
Academy of Chinese Medical Sciences, Guangzhou, China.
(3)The Second Clinical College of Guangzhou University of Chinese Medicine,
Guangzhou, China.
(4)Department of Traditional Chinese Medicine, Guangdong Women and Children
Hospital, Guangzhou, China.
(5)Department of Clinical Research/National Clinical Trials Institute, Sun
Yat-sen University Cancer Center, Guangzhou, China.
(6)World Federation of Chinese Medicine Societies, Beijing, China.

Background: Several epidemiological articles have reported the correlations
between anti-osteoporosis medication and the risks of fractures in male and
female subjects, but the specific efficacy of anti-osteoporosis medication for
male subjects remains largely unexplored. Objective: The aim of this study was to
evaluate the correlation between anti-osteoporosis medication and the risk of
fracture in relation to low bone mass [including outcomes of osteoporosis,
fracture, and bone mineral density (BMD) loss] in male subjects analyzed in
studies within the updated literature. Methods: Randomized controlled trials
(RCTs) that analyzed the effectiveness of a treating prescription for male
subjects with osteoporosis (or low BMD) and that focused on the outcomes of
fracture were included. Relevant studies from Embase, Web of Science, PubMed, and
Chinese database of CNKI were retrieved from inception to January 30th, 2019. Two
staff members carried out the eligibility assessment and data extraction. The
discrepancies were settled by consultation with another researcher. We calculated
the pooled relative risks (RRs) based on 95% confidence intervals (CIs). Results:
Twenty-seven documents (28 studies) with 5,678 subjects were identified. For the 
category of bisphosphonates, significant results were observed in pooled analyses
for decreased risk of the vertebral fracture domain (RR, 0.44 [95% CI,
0.31-0.62]), nonvertebral fracture domain (RR, 0.63 [95% CI, 0.46-0.87]), and
clinical fracture domain (RR, 0.59 [95% CI, 0.48-0.72]) compared with those of
controls. Participants with bisphosphonates had a 56% (95% CI = 38-69%) lower
risk of vertebral fractures, 37% (95% CI = 13-54%) lower risk of nonvertebral
fractures, and 41% (95% CI = 28-52%) lower risk of clinical fractures.
Furthermore, meta-analyses also demonstrated a decreased risk of the vertebral
fracture domain via treatment with risedronate (RR, 0.45 [95% CI, 0.28-0.72]) and
alendronate (RR, 0.41 [95% CI, 0.23-0.74]), but not with calcitriol, calcitonin, 
denosumab, ibandronate, monofluorophosphate, strontium ranelate, teriparatide, or
zoledronic acid, compared with that of controls.
Conclusions: This systematic
review confirms that bisphosphonates were connected with a decreased risk of
vertebral fractures, nonvertebral fractures, and clinical fractures for male
subjects with osteoporosis. Future research is needed to further elucidate the
role of nonbisphosphonates in treating fractures of osteoporosis subjects.

DOI: 10.3389/fphar.2019.00882 
PMCID: PMC6695469
PMID: 31447677 
 

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As I said, glucosamine looks a bit tempting. Does anyone else here (besides Ron and Clinton) take it or have an opinion on it?

I take glucosamine. But let's face it - as I said in a post about metformin: we simply do not know, period. There are so many interactions with other drugs, your diet, lifestyle, genes, individual physiology, age, gut microbiota and so forth, that it's almost impossible to make additive recommendations about an individual supplement such as glucosamine (as opposed to subtractive, such as "don't smoke" and "don't shoot yourself in the head"). The fact that glucosamine seems to work for people in aggregate is a statistically derived effect which may mean absolutely nothing by the time you are looking at a particular individual - and Dean is absolutely correct in pointing out that folks participating on these boards are a whole other kettle of fish compared the cohort from which that statistcal glucosamine effect was gleaned.

I am acutely aware that taking glucosamine, is a gamble on my part, as it is with pretty much all my interventions - and worse, a gamble the result of which I cannot ever know, it being a n-1 experiment without a corresponding control - it is essentially unknowable (at least at this stage of medical science, and I suspect probably for the next 100 years to come too). 

You asked about "opinions" - well, that's mine; it looks interesting, and I'm rolling the dice on it /shrug/, but don't ask me to "prove" anything, as that's impossible at this point in time and any speculation is going to be for entertainment purposes only. YMMV.

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Michael Rae takes 1500mg of glucosamine daily as well if you look at his daily supplement regimen.

 Tom, I agree with your comments on the epidemiological studies on glucosamine and trying extrapolating those effects to an individual; however those studies aren’t the only reason why I maintain consuming glucosamine.

Glucosamine seems to be a powerful up regulator of AMPK, and based on the 28% increased lifespan in rodents by ‘mimicking a low carb diet’, it seems to act like an actual CR mimetic in this regard (as opposed to other ‘CR mimetics’ that don’t appear to do much in healthy humans).

Finally, if you believe rapamycin and metformin combo seems to be a powerful anti-aging combo (which I believe but am not on at the moment), glucosamine is one of the closest (natural) mimetics to metformin, as EGCg (catechin of green tea) is to rapamycin (ref: ‘Towards Natural Mimetics of Metformin and Rapamycin’ Aliper, Jellen, Cortese and others.  Www.aging-us.com. Aging 2017 vol 9 No 11).

Clinton 

 

 

Edited by Clinton

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I fully understand the reasons why one could decide to take glucosamine - after all, I too take it. However, I'm not as optimistic as you are regarding how valid our justifications are. Sure glucosamine up-regulates AMPK, but that's classic biomechanistic reasoning, which is extremely poor grounds for any prescriptive actions - the only valid measure is long term health/longevity outcomes. The history of supplements and drugs is littered with promising sounding biomechanical justifications and poor outcomes.

AMPK is not like an on-off switch - there are at least 3 major pathways to upregulating AMPK, and they are not all equivalent. And merely upregulating AMPK does not tell you much about ultimate outcomes. Note, f.ex. that metformin is a famous AMPK upregulator, as is exercise. So people naturally thought that metformin and exercise would be additive. The opposite is true. Metformin - an AMPK upregulator - blunted the effect of the other AMPK upregulator, exercise. So how do you know that glucosamine, an AMPK upregulator is not working at cross purposes to exercise or any other element of your supplement, diet, exercise or lifestyle regimen - after all, metformin an AMPK regulator does that too!

For that matter, did you know that statins also upregulate AMPK? See this study of atorvastatin (which I take!):

https://www.ncbi.nlm.nih.gov/pubmed/17116771

Statins activate AMP-activated protein kinase in vitro and in vivo.

Abstract

BACKGROUND:

Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. AMP-activated protein kinase (AMPK) plays a central role in controlling energy and metabolism homeostasis in various organs. We therefore studied whether statins can activate AMPK, and if so, whether the activated AMPK regulates nitric oxide (NO) production and angiogenesis mediated by endothelial NO synthase, a substrate of AMPK in vascular endothelial cells.

METHODS AND RESULTS:

Western blotting of protein extracts from human umbilical vein endothelial cells treated with atorvastatin revealed increased phosphorylation of AMPK at Thr-172 in a time- and dose-dependent manner. The AMPK activity, assessed by SAMS assay, was also increased accordingly. The phosphorylation of acetyl-CoA carboxylase at Ser-79 and of endothelial NO synthase at Ser-1177, 2 putative downstream targets of AMPK, was inhibited by an adenovirus that expressed a dominant-negative mutant of AMPK (Ad-AMPK-DN) and compound C, an AMPK antagonist. The positive effects of atorvastatin, including NO production, cGMP accumulation, and in vitro angiogenesis in Matrigel, were all blocked by Ad-AMPK-DN. Mice given atorvastatin through gastric gavage showed increased AMPK, acetyl-CoA carboxylase, and endothelial NO synthase phosphorylation in mouse aorta and myocardium.

CONCLUSIONS:

Statins can rapidly activate AMPK via increased Thr-172 phosphorylation in vitro and in vivo. Such phosphorylation results in endothelial NO synthase activation, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system.

Now, statins famously are muscle-unfriendly - again, you'd think that since exercise upregulates AMPK, you'd have statins being additive to exercise, but no. And yet statins can certainly be very good for your vascular system through - as the study indicates - your endothelial cells.

The point being is that just because a given supplement does something that's considered "good" biomechanically, like "upregulates AMPK" doesn't mean much without seeing the full spectrum of interactions. Statins may still be an overall good for someone like me, who has uncontrollably high LDL cholesterol that is not amenable to diet/exercise interventions - but statins may be a big negative for someone who has naturally low LDL. Your individual physiology, your genetic/epigenetic profile, your dietary, exercise and other supplementary regimes all determine whether adding supplement "X" in a specific protocol will transpire to be a net positive.

Here is a fascinating talk given by a scientist who studied the effect of exercise - especially glucose transport - and zeroed in on AMPK, metformin, aicar ("exercise in a pill") - this was before the effect of metformin on exercise was illuminated, so it's an amazing experiment in time showing how our understanding has evolved:

 

If you want to jump straight to AMPK, you can start from minute 18:50.

 

 

Edited by TomBAvoider

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All good and informative points. Thanks.

As to Dean's comment about iron intake, my numbers are within the "normal" range, if on the low end:

Ferritin: 30 ng/mL (22-415)
HGB: 14.7 g.dL (14.0-18.0)
Iron: 127 ug/dL (35-168)

I guess absorption really matters, since according to Cronometer I am averaging 300% of dietary Iron RDA, yet my results are relatively low.

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Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank.
Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, Heianza Y, Qi L.
BMJ. 2019 May 14;365:l1628. doi: 10.1136/bmj.l1628.
PMID: 31088786
Abstract
OBJECTIVE:
To prospectively assess the association of habitual glucosamine use with risk of cardiovascular disease (CVD) events.
DESIGN:
Prospective cohort study.
SETTING:
UK Biobank.
PARTICIPANTS:
466 039 participants without CVD at baseline who completed a questionnaire on supplement use, which included glucosamine. These participants were enrolled from 2006 to 2010 and were followed up to 2016.
MAIN OUTCOME MEASURES:
Incident CVD events, including CVD death, coronary heart disease, and stroke.
RESULTS:
During a median follow-up of seven years, there were 10 204 incident CVD events, 3060 CVD deaths, 5745 coronary heart disease events, and 3263 stroke events. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, drug use, and other supplement use, glucosamine use was associated with a significantly lower risk of total CVD events (hazard ratio 0.85, 95% confidence interval 0.80 to 0.90), CVD death (0.78, 0.70 to 0.87), coronary heart disease (0.82, 0.76 to 0.88), and stroke (0.91, 0.83 to 1.00).
CONCLUSION:
Habitual use of glucosamine supplement to relieve osteoarthritis pain might also be related to lower risks of CVD events.

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But another large study showed an inverse association between osteoarthritis and CVD, and also lifespan and healthspan more generally.

So the apparent positive health benefits of glucosamine might actually just be because a significant fraction of osteoarthritics might be taking glucosamine.

"Correlation is not causation."

  -- Saul

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Hah! But it's also possible that OA sufferers are more likely to take glucosamine.... :)

Based on the discussion here and elsewhere, I've added a combined Calcium, Magnesium and Zinc supplement by Solimo (Amazon brand): https://www.amazon.com/gp/product/B079C799K4/ref=ppx_yo_dt_b_asin_title_o03_s00?ie=UTF8&psc=1

I take 1 caplet per day, which supplies:

Calcium: 333mg

Magnesium: 133mg

Zinc: 5mg

(The serving size is 3 caplets per day).

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