Grade changes. Every letter that moved, and why.

Su et al. (Front Med, 2024; PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 39071082) pooled six trials in sarcopenia Age-related loss of muscle mass and strength.: handgrip 1.26 kg higher, muscle mass unchanged. Hernandez-Martinez et al. (Medicine, 2026; PMID 42700006) pooled seven trials of strength training with supplements: no significant handgrip gain where HMB was added to training. With Gu et al. (2025; PMID 39999663) positive, the pooled analyses disagree, which is C under the written definition. Every other use on the record is already C or D, so the headline is C.

Skin moisture and elasticity are measured skin markers, not an established stand-in for a clinical outcome, so under the B definition they qualify for nothing above C; the pooled analysis behind the B (Zhou et al., Nutrients, 2021; PMID 34578794) and the trial in it (Tominaga et al., Acta Biochim Pol, 2012; PMID 22428137) measured those markers. It is the same rule that returned MitoQ's flow-mediated dilation to C in October 2026. Every other use on the record is already C or D, so the headline is C.

An outside audit of October 2026 read the trials in full. The larger trials were null on their registered primary outcomes: Dharsono et al. (2019; PMID 30198828) on global severity, Fuller et al. (2017; PMID 28606567) on confirmed infections, and Mah et al. (2020; PMID 30380356) on the number and duration of episodes. The positive results are per-protocol or secondary, and the pooled analysis (Zhong et al., 2021; PMID 33900466) reports high heterogeneity How much the results of the pooled trials differ from each other. High heterogeneity makes a combined estimate less reliable.. Grade B needs at least one well-designed trial showing a meaningful effect; C covers small trials and mixed results.

Earlier today the B was scoped to pharmaceutical-grade chondroitin sulfate at 800 mg a day, the preparation tested by Reginster et al. (Ann Rheum Dis, 2017; PMID 28533290) and pooled by Honvo et al. (Adv Ther, 2019; PMID 30879253). A check found it is a registered medicine in several European countries and is not sold in the United States. A letter readers cannot act on is not published, so the record now carries the letter for chondroitin as generally sold, whose large independent trials, including GAIT (Clegg et al., N Engl J Med, 2006; PMID 16495392), were null or mixed: C.

The B leaned on an observational Research that watches what people already do rather than assigning a treatment. It can show that two things travel together, not that one causes the other. mortality meta-analysis A study that pools the numbers from several trials into one combined estimate. (Cappuccio et al., Sleep, 2010; PMID 20469800), and EBL never grades on observational data. Without it, the graded evidence is sleep extension trials on surrogate markers A lab value or measurement used in place of the outcome that matters, such as LDL cholesterol standing in for heart attacks. Moving a surrogate does not always move the outcome.. A PubMed search found them mixed: Zhu et al. (Eur J Cardiovasc Nurs, 2022; PMID 34279625) found no overall change in blood pressure, glucose or insulin resistance, and Beals et al. (Diabetes Care, 2026; PMID 41564347) found no change in clamp-measured insulin sensitivity. Tasali et al. (JAMA Intern Med, 2022; PMID 35129580) found lower energy intake in one trial. Mixed or unreplicated results are the written C definition. The descriptions of Gonzales 2022 and Hartescu 2022 were also corrected.

The B rested on one meta-analysis described as consistent. A PubMed search for every randomized trial and pooled analysis of whole-body vibration on bone density found the two largest independent trials null: Slatkovska et al. (Ann Intern Med, 2011; PMID 22084333), 202 postmenopausal women for 12 months with blinded assessors, and Kiel et al. (J Bone Miner Res, 2015; PMID 25581217), 174 adults with a mean age of 82 for 24 months against a placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received. platform. Five meta-analyses disagree site by site. Mixed results with failed large trials meet the written C definition. EBL is paid a commission on a vibration plate listed under this therapy; this change was made through the logged review that payment requires, and it lowers the letter.

The October upgrade to A counted Kayumov et al. (Psychosom Med, 2001; PMID 11211063) as the replication The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. of Sletten et al. (PLoS Med, 2018; PMID 29912983). The Kayumov trial enrolled 22 people, and the rule this log publishes requires more than 30 participants before a trial can move a grade. Without it the use rests on one qualifying trial of 116 people, supported by smaller trials that agree (Dahlitz et al., 1991; PMID 1674014; Mundey et al., 2005; PMID 16295212) and a two-trial pooled estimate (Buscemi et al., 2005; PMID 16423108). That is the written B definition. The use returns to B and the headline follows. Applied the published grade rules under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

Antibody lowering replicates across meta-analyses (Huwiler et al., Thyroid, 2024; PMID 38243784) and the CATALYST trial (Larsen et al., Eur Thyroid J, 2024; PMID 38215286), but thyroid peroxidase antibodies are not an established stand-in for a clinical outcome, and quality of life, CATALYST's primary outcome, improved equally on placebo. The editor, who had signed the B in October, returned it to C the next day on the strict reading of the B definition (Arnold Sandlow, D.C.).

The use rests on one randomized trial of 63 people (Hadanny et al., Aging, 2020; PMID 32589613), and a search found no independent replication. The C definition covers a single positive trial nobody has independently repeated. Applied the written grade definition in October 2026.

The heart failure use rests on one trial, WAON-CHF (Tei et al., Circ J, 2016; PMID 27001189), whose primary endpoint The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight. was null. The vascular use rests on a small marker trial (Masuda et al., 2004; PMID 15090706) against a null crossover A trial design in which each participant receives both the treatment and the comparison, one after the other, and serves as their own control. (Hussain et al., 2022; PMID 34954348); a coronary disease trial was also null on vascular measures (Debray et al., 2023; PMID 37650138). A single unrepeated trial is C, and an oxidative-stress marker is not an established stand-in. Applied the written grade definition: the B definition admits a biomarker A measurable sign in the body, such as a blood test value, used to track a condition or the effect of a treatment. only when it is an established stand-in for a clinical outcome, such as HbA1c A blood test that reflects average blood sugar over the previous two to three months., LDL Low-density lipoprotein cholesterol, the cholesterol fraction most closely tied to plaque in the arteries., blood pressure or bone density, the strict reading the editor confirmed in October 2026.

Homocysteine An amino acid in the blood that rises when vitamin B12, folate or B6 are low. lowering by betaine replicates (Olthof et al., J Nutr, 2003; PMID 14652361; Ashtary-Larky et al., 2022; PMID 33764214), but homocysteine is not an established stand-in for a clinical outcome. Applied the written grade definition: the B definition admits a biomarker only when it is an established stand-in for a clinical outcome, such as HbA1c, LDL, blood pressure or bone density, the strict reading the editor confirmed in October 2026.

Positive trials (Knapen et al., Thromb Haemost, 2015; PMID 25694037; Vossen et al., JAMA Cardiol, 2026; PMID 42268593) stand beside null ones (Witham et al., J Am Soc Nephrol, 2020; PMID 32817311; Fulton et al., J Nutr Health Aging, 2016; PMID 26892582; Bartstra et al., 2021; PMID 33068157), and arterial stiffness and coronary calcium are not established stand-ins for a clinical outcome. Applied the written grade definition: the B definition admits a biomarker only when it is an established stand-in for a clinical outcome, such as HbA1c, LDL, blood pressure or bone density, the strict reading the editor confirmed in October 2026.

Three randomized trials agree on the markers (Moludi et al., Nutr Metab (Lond), 2022; PMID 35870947; Maleki et al., Diabetol Metab Syndr, 2020; PMID 32015761; Li et al., iScience, 2025; PMID 40546935), but adhesion molecules, hs-CRP High-sensitivity C-reactive protein, a blood marker of low-grade inflammation., TNF-alpha and vascular function are not established stand-ins for a clinical outcome. Applied the written grade definition: the B definition admits a biomarker only when it is an established stand-in for a clinical outcome, such as HbA1c, LDL, blood pressure or bone density, the strict reading the editor confirmed in October 2026.

Earlier in October the use was raised to B on Rossman et al. (Hypertension, 2018; PMID 29661838) and Kirkman et al. (Am J Physiol Renal Physiol, 2023; PMID 37560769). On review the editor returned it to C. The B definition admits a biomarker only when it is an established stand-in for a clinical outcome; flow-mediated dilation predicts events in cohorts (Ras et al., Int J Cardiol, 2013; PMID 23041097) but no trial has shown that raising it prevents one. The second trial is an 18-patient pilot whose groups started apart. Editor decision, October 2026 (Arnold Sandlow, D.C.).

The protocol carried one A for both the training and the weekly dose in its name. The editor split it in October 2026. Measured VO2max The most oxygen the body can use during all-out exercise, a standard measure of aerobic fitness. after low-to-moderate intensity training keeps A: Gormley et al. (Med Sci Sports Exerc, 2008; PMID 18580415), the DREW trial (Church et al., JAMA, 2007; PMID 17507344) and a 50-trial pooling (Nuuttila et al., 2026; PMID 41543030). The 150-minute weekly dose is C on its own row: only DREW's 136-minute arm comes near it, no other group has repeated it, and DREW found a steady dose response with no threshold (Arnold Sandlow, D.C.).

Rossman et al. (Hypertension, 2018; PMID 29661838) and Kirkman et al. (Am J Physiol Renal Physiol, 2023; PMID 37560769), independent groups at 20 mg/day, both found flow-mediated dilation improved against placebo. The use was held at C because the populations differed and the marker is not a clinical outcome. The editor decided that a replicated randomized effect on a measured physiological marker carries B, and that the B definition does not require the replicating trials to share a population. The letter is capped at B because no trial measured a cardiovascular event. Editor decision, October 2026 (Arnold Sandlow, D.C.).

The headline sat on the harm finding (Gliemann et al., J Physiol, 2013; PMID 23878368) while the record's best use, metabolic markers in obese men (Timmers et al., Cell Metab, 2011; PMID 22055504, against null replications), is C. The headline now shows C labeled with that use, and the harm finding stays D on Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale. on its own row, listed directly beneath. No evidence changed. Headline policy adopted by the editor in October 2026 (Arnold Sandlow, D.C.): the headline letter is the record's best graded use, labeled with that use, and every other use, including any harm finding, is listed beneath it.

The headline showed C on longevity while the record's best use, seizure frequency in children with drug-resistant epilepsy (Neal et al., Lancet Neurol, 2008; PMID 18456557; Lambrechts et al., Acta Neurol Scand, 2017; PMID 27027847; Cochrane, PMID 32588435), is B. The headline now shows B labeled with that use, and longevity and cardiometabolic markers keep C on their own row (Patikorn et al., BMC Med, 2023; PMID 37231411). No evidence changed. Headline policy adopted by the editor in October 2026 (Arnold Sandlow, D.C.): the headline letter is the record's best graded use, labeled with that use, and every other use, including any harm finding, is listed beneath it.

The hormone-response use was graded C on Corpas et al. (J Clin Endocrinol Metab, 1992; PMID 1379256), which randomized only the order of two active doses in 10 men, and Vittone et al. (Metabolism, 1997; PMID 9005976), which was uncontrolled. The site's written definition of a randomized controlled trial People are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. is people randomly assigned to treatment or placebo; neither study had a placebo arm, so sermorelin has not been tested in a randomized trial on any outcome. The use moves to D on Route 1 No human randomized trial has been run, so the record rests on animal or mechanistic evidence only. One of the two routes to the lowest letter on EBL's scale. and the headline follows. Applied the written grade definition at the editor's request of October 2026 to settle the calls the definitions decide (Arnold Sandlow, D.C.).

The perioperative use was held at B because the Montreal Cognitive Assessment is administered rather than recorded by an instrument. The written A definition also accepts a validated outcome scale scored by a clinician blinded to treatment, and two double-blind Neither the participants nor the people assessing them know who received the real treatment until the trial ends. trials from independent groups found less postoperative cognitive dysfunction with active stimulation: Zhou et al. (Aging Clin Exp Res, 2022; PMID 35809206) and Ma et al. (J Geriatr Oncol, 2026; PMID 42456197), with Li et al. (Neuromodulation, 2026; PMID 42104979) agreeing. The use moves to A, with the limits (one country, about 100 patients per trial, one retrospective registration) stated beside the letter. Applied the written grade definition at the editor's request of October 2026 to settle the calls the definitions decide (Arnold Sandlow, D.C.).

The delayed sleep phase use was held at B by judgment while its own note said the endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. qualifies for A. Under the written A definition, sleep onset measured by polysomnography or actigraphy is function recorded by an instrument, and two independent groups found it earlier on melatonin than on placebo in double-blind trials: Kayumov et al. (Psychosom Med, 2001; PMID 11211063) and Sletten et al. (PLoS Med, 2018; PMID 29912983). The use moves to A with a replication block naming both trials and their limits, and the headline follows the best use. Applied the written grade definition at the editor's request of October 2026 to settle the calls the definitions decide (Arnold Sandlow, D.C.).

The record graded a whole modality on one cognition meta-analysis with no population, device or dose, and named an autonomic endpoint with no autonomic citation. It now carries four uses. Postoperative cognitive dysfunction in older surgical patients: three double-blind sham-controlled trials from three centers agree (Zhou et al., 2022; PMID 35809206; Li et al., 2026; PMID 42104979; Ma et al., 2026; PMID 42456197), with less postoperative delirium in a fourth (Shi et al., 2026; PMID 41835922); a validated cognitive test replicated across independent groups meets the written B definition, and the headline follows the best use, C to B. Cognitive test performance in mixed samples stays C on the heterogeneous pools (Liu et al., 2026; PMID 42339645; Ridgewell et al., 2021; PMID 34043386). Mild cognitive impairment is C on one trial (Wang et al., 2022; PMID 36150665). Heart rate variability in healthy adults is D on Route 2, tested and no benefit shown in pooled sham-controlled trials (Souza et al., 2026; PMID 41506123; Soltani et al., 2023; PMID 37119426). Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The title read Grade C for the hormone response while the headline letter was D, and the hormone row called two studies from the same National Institute on Aging group independent. Under the site's convention the headline follows the best use, so it is C; every health outcome stays D on Route 1 on its own row. The hormone row now says Corpas 1992 (PMID 1379256) randomized dose order only, with no placebo, and Vittone 1997 (PMID 9005976) was uncontrolled. The cognition row and ref called Friedman 2013 (PMID 23689947) a second positive trial; it is a spectroscopy substudy of Baker 2012 (PMID 22869065). Veldhuis 2004 (PMID 15579798), GHRH(1-44), is added as context beside the other different-molecule trials. DEXA lean and fat mass are retyped as a surrogate. The editor may prefer the headline held at D for health outcomes, as the record formerly had it. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record rested on Timmers et al. (Cell Metab, 2011; PMID 22055504) alone and described sirtuin activation, NAD+ Nicotinamide adenine dinucleotide, a molecule cells use in energy metabolism. Its level falls with age in some tissues. amplification, a personality's protocol and ongoing longevity trials, none with a trial behind them. The independent attempts to reproduce the Timmers result were null on clamp-measured insulin sensitivity (Poulsen et al., Diabetes, 2013; PMID 23193181; Yoshino et al., Cell Metab, 2012; PMID 23102619; de Ligt et al., Mol Metab, 2018; PMID 29706321), and pooled trials find no effect on cardiovascular risk factors (Sahebkar et al., 2015; PMID 25885871): mixed, C, the headline unchanged. Gliemann et al. (J Physiol, 2013; PMID 23878368), where 250 mg/day blunted the fitness, blood pressure and lipid gains from exercise training in older men, is a D Route 2 row with the harm badge. The Timmers trial's co-author employed by the formulation's maker is stated beside the letter. The dose line now states the trial doses. The headline moves C to D under the convention that a harm finding, where one exists, leads the record; the editor may prefer the headline on the best use. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record cited one Cochrane review (Jin et al., 2016; PMID 27045603) without saying the trials used different preparations, that no trial measured survival, or that the review rated quality unsatisfying; the use row and form note now say so, and the tumor response figure with its interval crossing 1 is not leaned on. The cardiometabolic use a reader meets in marketing was untouched: the Cochrane review of cardiovascular risk factors (Klupp et al., 2015; PMID 25686270) and the largest placebo-controlled trial (Klupp et al., Sci Rep, 2016; PMID 27511742) are null, D Route 2 on their own row. A case report of acute liver injury (Guedikian et al., 2023; PMID 37885515) is added to the cautions as a signal. The evidence type is corrected to pooled randomized trials. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record's C rested on two meta-analyses it described as showing modest benefit; both are null on their pooled outcomes (Sahebkar, 2017; PMID 25897620, lipids; Ostadmohammadi et al., 2019; PMID 30848564, glucose), so those uses are D Route 2 rows. The only positive pooled quercetin-alone evidence is blood pressure: systolic about 2 to 3 mmHg lower at 500 mg/day or more in two meta-analyses (Serban et al., 2016; PMID 27405810; Huang et al., 2020; PMID 31940027) with the 2023 umbrella review finding very high heterogeneity and diastolic pressure unchanged (Arabi et al., PMID 37654199), mixed, C, and the headline now attaches to it. The best-use line led with senolytic A compound intended to clear senescent cells: older cells that have stopped dividing but remain in tissue. use in combination with dasatinib or fisetin and the dose line described a quercetin plus fisetin schedule with no trial behind it; quercetin alone as a senolytic is untested on any outcome, D Route 1 with an absence record, and the one quercetin-alone marker study (Mury et al., 2025; PMID 40375481) is cited as such. The phytosome form note's Mayo Clinic claim and 20-fold figure, unsupported, are removed. The headline letter stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record already named the two null trials in its ref but graded nothing on them. They now carry their own rows: collagen markers in hypertension with raised galectin-3 (Lau et al., JACC Basic Transl Sci, 2021; PMID 33532663) and knee osteoarthritis symptoms (Andrews et al., Contemp Clin Trials Commun, 2020; PMID 31872160), each tested once without benefit, D on Route 2. The prostate use stays D Route 1 on its own row: the 78 percent without PSA progression (Keizman et al., 2021; PMID 34959847) is an uncontrolled figure, now said so, and the 18-month extension (Keizman et al., 2023; PMID 37630724) reports only the 39 men who responded at six months. The developer's review (Eliaz et al., Nutrients, 2019; PMID 31683865) and the combination cell work (Jiang et al., Integr Cancer Ther, 2013; PMID 22532035) are labeled as background and mechanism. The observational flag is removed from a record whose studies are single-arm interventional. Headline D unchanged. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The grade basis called Martens 2026 (PMID 42478598) the first randomized trial of NR alone against clinical outcomes; Dollerup 2018 (PMID 29992272), Orr et al. (2024; PMID 37994989), NICE (McDermott et al., Nat Commun, 2024; PMID 38871717) and Wu et al. (2025; PMID 41357333) came first and are now cited. The one positive, six-minute walk in peripheral artery disease at a one-sided 0.10 level, is a C row, unreplicated; blood NAD+ is a C row under the blood-level rule applied to NMN today; clamp insulin sensitivity in obese men (one null) and cognition in mild cognitive impairment (two independent nulls) are D Route 2 rows. Dolopikou 2020 (PMID 30725213) is relabeled: VO2max unchanged. The NR plus pterostilbene trial (PMID 29184669) is labeled as funded by the combination's seller with its employees as authors, and the NR supplier's funding or product supply across most trials is stated. Ratajczak 2016 (PMID 27725675) is labeled cell and mouse work. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The headline C rested on one meta-analysis in schizophrenia while the best-use line listed glutathione, antioxidant, liver, mucolytic and insulin-sensitivity claims none of the cited trials tested, and the ref said cognition was not an outcome when Yolland et al. (2020; PMID 31826654) measured it. Schizophrenia is now a row: Berk 2008 (PMID 18436195) and Yolland positive after 24 weeks, Zhang et al. (2024; PMID 37712506) null across 8 trials, Neill et al. (2022; PMID 35857752) and Conus et al. (2018; PMID 29462456) null on symptoms, mixed, C. COPD exacerbations, NAC's best-studied use and absent from the record, are a row: PANTHEON (Zheng et al., Lancet Respir Med, 2014; PMID 24621680) and HIACE (Tse et al., Chest, 2013; PMID 23348146) positive at 600 mg twice daily, BRONCUS (Decramer et al., Lancet, 2005; PMID 15866309) and Zhou et al. (Nat Commun, 2024; PMID 39349461) null, mixed, C. The condition-page PCOS row (Rizk et al., 2005; PMID 15705376) is given its own row at C as a single cited trial. The endpoint type is corrected to clinician-rated, the dose line to the trial doses. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record cited two positive sleep trials and said tart cherry raises endogenous melatonin; Howatson et al. (2012; PMID 22038497) attribute the rise to melatonin in the juice and Chung et al. (2022; PMID 36011907) found no change. Added: the two larger null trials (Tucker et al., 2024; PMID 39683518, 500 mg powder; Hillman et al., 2026; PMID 35790450, juice or capsules for 30 days) and the two small older positives (Losso et al., 2018; PMID 28901958; Pigeon et al., 2010; PMID 20438325). The dose line listed an extract dose no positive sleep trial used; it now states what was studied. Exercise recovery, claimed without a citation or a letter, now has its own row: pooled analyses positive on measured strength (Hill et al., 2021; PMID 33440334; Daab et al., 2026; PMID 41945263) against independent nulls (Lamb et al., 2019; PMID 31337122; Abbott et al., 2020; PMID 31188696; Morehen et al., 2021; PMID 32672095), mixed, C. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

One C covered COPD symptoms, fatty liver and sleep as if one finding, and the record omitted the only hard-endpoint trial. Each indication now has its own row at C as a single unreplicated small trial (Zheng et al., 2021; PMID 33985501; Tao et al., 2022; PMID 35734974; Gao et al., 2026; PMID 40826930), with the sleep trial's funding by a device company, which took part in analysis and writing, stated beside the letter. HYBRID II (Tamura et al., EClinicalMedicine, 2023; PMID 36969346) missed its primary neurological outcome and is D on Route 2 for that use, with its favorable secondary outcomes and early stop stated. Ohsawa 2007 (PMID 17486089) is relabeled as cell culture and rat work. The endpoint type is corrected: the COPD and sleep scores are self-reported or actigraphic, only liver fat is a surrogate. Shi 2023 (PMID 37970554) and Ono 2017 (PMID 28669654) are added as context. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The best-use line described a mechanism and named no endpoint; the C now attaches to brachial flow-mediated dilation in older adults (Rossman et al., 2018; PMID 29661838; Kirkman et al., 2023; PMID 37560769), with the manufacturer's contract and capsule supply stated beside the letter. Added as tested nulls at the record's own 20 mg dose: physical function in healthy older adults (Murray et al., J Physiol, 2026; PMID 41733122) and endurance performance (Gonzalo-Skok et al., 2024; PMID 38981985; Shill et al., 2016; PMID 27501153; Broome et al., 2022; PMID 35623315 and PMID 35201920), each D on Route 2. Added as context: no slowing of Parkinson's disease over a year (Snow et al., 2010; PMID 20568096) and a single 80 mg dose that lowered VO2max (Hughes et al., 2023; PMID 38061764). Broome 2022 is relabeled as an exercise-training trial, and Gane 2010 (PMID 20492507) as a different dose and population. The headline stays C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record's endpoint, memory and cognitive measures, rested on Telch et al. (2014; PMID 25018057), whose primary question was retention of fear extinction; memory was secondary. The closest test of the stated endpoint, Rodriguez et al. (Radiology, 2016; PMID 27351678), one oral dose in 26 healthy adults with 7 percent better retrieval, was not cited; it is from the same laboratory, so the two do not replicate each other. The one trial measuring cognition over months, 195 mg/day in bipolar disorder (Alda et al., 2017; PMID 27284082), was null and is added. The name says low-dose, but the trials used about 260 mg once; the daily few-milligram use consumer products supply has no randomized trial and now carries its own D Route 1 row with an absence record. The headline stays C on the single-dose row. The serotonin syndrome and G6PD cautions were already on the record. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

One B row covered sleep onset in primary sleep disorders on two pooled analyses. Read against the literature it was three claims. Ordinary adult insomnia: the pooled gain is a few minutes (Buscemi et al., 2005; PMID 16423108; Ferracioli-Oda et al., 2013; PMID 23691095) and the adult-only analysis is null (Choi et al., Sleep Med Rev, 2022; PMID 36179487), mixed evidence, C. Delayed sleep phase disorder: sleep onset earlier by polysomnography or actigraphy in four independent trials (Kayumov et al., 2001; PMID 11211063; Dahlitz et al., 1991; PMID 1674014; Mundey et al., 2005; PMID 16295212; Sletten et al., 2018; PMID 29912983) and a pooled 38.8 minutes, B, with A left to the editor because the only large trial paired melatonin with behavioral scheduling. Jet lag: nine of ten trials positive on self-rated symptoms in the Cochrane review (Herxheimer and Petrie, 2002; PMID 12076414) against the largest trial null (Spitzer et al., 1999; PMID 10484950), B at the self-report ceiling. The headline stays B on the two B uses. Brzezinski 2005 (PMID 15649737) is relabeled as 17 small studies mostly in healthy people. The antioxidant claim, with no randomized clinical evidence, is removed from the best-use line. Added to safety: 5 mg impaired glucose tolerance in MTNR1B risk-allele carriers (Qian et al., 2026; PMID 42346809) and the Cochrane case reports in epilepsy and on warfarin. The timed-release claim is now cited (Maruani et al., 2023; PMID 37434463) and limited to what the review found. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The use held B on COLONPREV alone (Castells et al., Lancet, 2025; PMID 40158525), with its second citation the same trial's baseline report (PMID 22356323), and the review of October owed a replication search. The search found none: CONFIRM (Dominitz et al., Am J Gastroenterol, 2017; PMID 29016565) has published only its design, and SCREESCO (Westerberg et al., Nat Med, 2026; PMID 41721101) compares each test with usual care and reports incidence, not mortality. A single trial nobody has repeated is C. The gFOBT A and the FIT-specific D Route 1 are unchanged. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The headline moved B to C in October because joint pain and skin were bundled and the evidence across them was mixed. Graded by use, as the decision sheet proposed: activity-related joint pain in athletes and active adults rests on three randomized placebo-controlled trials that agree (Clark et al., 2008; PMID 18416885; Zdzieblik et al., 2017; PMID 28177710; Kviatkovsky et al., 2023; PMID 37551682), replicated randomized evidence on self-reported pain, B at the self-report ceiling; skin rests on pooled analyses whose benefit disappears in independent and high-quality trials (Myung and Park, 2025; PMID 40324552; Pu et al., 2023; PMID 37432180), mixed, C. The headline follows the best use to B. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The headline C bundled a replicated instrument-measured skin result with a mixed self-reported knee result. Graded by use: skin hydration, elasticity and wrinkle depth rest on four randomized trials (PMIDs 25834304, 34203487, 38009035, 41422283) and a 7-trial meta-analysis (Amin et al., 2025; PMID 40911749), replicated randomized evidence on surrogates, B, with every trial manufacturer-run and the funding stated beside the letter under the September rule; knee symptoms rest on a trend (Tashiro et al., 2012; PMID 23226979), a null primary (Kalman et al., 2008; PMID 18208600) and a self-rating (Sugiyama et al., 2024; PMID 38234616), mixed, C. The headline follows the best use to B. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The headline C bundled three populations whose evidence points three ways. The written rule grades by use: in diagnosed sarcopenia, Gu et al. (Maturitas, 2025; PMID 39999663) pool five randomized trials with higher muscle mass index and handgrip strength, replicated randomized evidence on an instrument-measured outcome, B; in adults over 50 without sarcopenia the poolings disagree (Li et al., 2025; PMID 40248035; Wang et al., 2026; PMID 41934514) and the largest factorial trial was null (Osuka et al., 2021; PMID 34081113), C; in resistance-trained young men the one trial found no effect (Tritto et al., 2019; PMID 30859862), D Route 2. The headline follows the best use to B. The sarcopenia row is held at B rather than A by a stated judgment about the width of the pooled confidence intervals The range the true effect probably falls in. A wide interval means the estimate is uncertain., which the editor may overrule. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The headline was held at D Route 1 because the record was framed on mortality, which no trial has tested, while its uses carried B (blood pressure above two drinks a day; Xin et al., Hypertension, 2001; PMID 11711507; Roerecke et al., Lancet Public Health, 2017; PMID 29253389) and C (AF recurrence; Voskoboinik et al., N Engl J Med, 2020; PMID 31893513). The site's headline letter is the best graded use on every other record, and a D on the index beside a B inside the record read as 'tested or untested' for a thing with replicated randomized evidence. The headline now follows the best use; the absence of mortality trials is stated in the reading and carries no letter. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

Three pooled analyses of randomized trials agree that selenium lowers thyroid peroxidase antibodies: Wichman et al. (Thyroid, 2016; PMID 27702392), Huwiler et al. (Thyroid, 2024; PMID 38243784; 35 studies, moderate certainty) and Zhang et al. (Medicine, 2025; PMID 40898469). Replicated randomized evidence on a surrogate is B; the antibody titer, with no shown link to symptoms or thyroid function, is what keeps it from A, and the record states that no pooled analysis shows a clinical change. The headline, previously C on mixed cancer and cardiovascular trials, follows the best use to B; those trials keep their own rows and letters. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record held B on Hadanny et al. (Aging, 2020; PMID 32589613), one randomized trial, with Hachmo et al. (Aging, 2020; PMID 33206062), an uncontrolled study from the same center, beside it, and had sat in the replication baseline since September as a known contradiction of Rule 03. A search in October found no independent randomized trial. A single positive trial nobody has repeated is C. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

Same evidence as the Zone 2 protocol: Gormley et al. (Med Sci Sports Exerc, 2008; PMID 18580415) replicated by the DREW trial (Church et al., JAMA, 2007; PMID 17507344) and pooled in Nuuttila et al. (Scand J Med Sci Sports, 2026; PMID 41543030). Replicated instrument-measured VO2max is A. The record keeps its statement that higher intensities produce larger gains. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The record rested on Gormley et al. (Med Sci Sports Exerc, 2008; PMID 18580415) alone. The replication search found Church et al. (JAMA, 2007; PMID 17507344), the DREW trial, 464 sedentary women trained at 50 percent of peak VO2 for 6 months with a dose arm of 136 minutes a week, and Nuuttila et al. (Scand J Med Sci Sports, 2026; PMID 41543030), 50 pooled low-intensity trials. Replicated instrument-measured VO2max is A under the rule applied to VO2max training in October, and a B beside an A for the same evidence would have graded one fact two ways. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).

The use was built at C in October and the editor corrected it the same night: the Cochrane pooling (Avenell et al., 2014; PMID 24729336) is high-quality evidence of a hip-fracture reduction (RR 0.84) across nine randomized trials, and Chapuy et al. (N Engl J Med, 1992; PMID 1331788) is a 3,270-patient trial on the same endpoint, so the combination has replicated randomized evidence on a hard outcome, which is B. The null community trials (Jackson et al., N Engl J Med, 2006; PMID 16481635; Grant et al., Lancet, 2005; PMID 15885294) keep the scope to institutionalized or deficient older adults and keep it from A. The record's headline follows its best use to B. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The protocol held B on one trial, Q-SYMBIO (Mortensen et al., JACC Heart Fail, 2014; PMID 25282031; 420 patients, ubiquinone 100 mg three times daily), with the not-replicated flag set, and was named for ubiquinol, a form no cited trial gave. The pooled analysis (Xu et al., BMC Cardiovasc Disord, 2024; PMID 39462324) rests on the same trial for mortality. Under the single-trial rule that is C, and the name now states the form and dose studied, CoQ10 (ubiquinone) 300 mg/day. The CoQ10 supplement record's heart-failure use is held at B pending a replication search. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

Weight loss rested on one phase 2 trial, Jastreboff et al. (N Engl J Med, 2023; PMID 37366315; 338 adults), with the not-replicated flag accurately set, and the first phase 3, Bajaj et al. (Lancet, 2026; PMID 42250575), reports glycemic and anthropometric endpoints in a different population. The written rule says a single positive trial nobody has repeated is C, and the compound is not approved anywhere. Moved to C; it returns to B when a second peer-reviewed obesity trial reports. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The record was held at B while its own ref said the written rule allowed A. The rule names measured VO2max as a qualifying endpoint, and the gain from structured aerobic training is replicated by independent groups: Gormley et al. (Med Sci Sports Exerc, 2008; PMID 18580415), Church et al. (JAMA, 2007; PMID 17507344, the DREW trial) and Helgerud et al. (Med Sci Sports Exerc, 2007; PMID 17414804), with three pooled analyses in agreement (An et al., 2024, PMID 38878596; Nuuttila et al., 2026, PMID 41543030; Mattioni Maturana et al., 2026, PMID 42730846). The earlier hold rested on the view that a fitness measure is not a health outcome; the rule makes no such distinction and was written so that an instrument-recorded function could reach A without a mortality trial. The grade reading states that the trials tested structured aerobic training at either intensity, with intervals giving the larger gain for the same work, so the A is not read as a claim about Zone 2 alone. The mortality association (Kodama et al., JAMA, 2009; PMID 19454641) stays observational context. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The record held D Route 1 while linking Yau et al. (J Alzheimers Dis, 2024; PMID 39544014), a randomized double-blind placebo-controlled pilot in 19 adults aged 60 or over with mild cognitive impairment, 25 mg three times a week for a year, in which Rey Auditory Verbal Learning Test performance improved and plasma neurofilament light chain stayed stable against placebo. Under the written rule a single positive randomized trial is C, and holding D while citing the trial read as hedging. The C is scoped to that population and endpoint; the pilot size, the unstated funder and the absence of a second trial are the reasons it is not more. Cheah et al. (Antioxid Redox Signal, 2017; PMID 27488221), the human uptake study, and the observational papers by Cheah 2016 (PMID 27444382), Wu 2022 (PMID 36139790) and Wu 2021 (PMID 34673145) remain context. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.), closing the review opened October.

The hair row held a single D Route 1 while disclosing Amini et al. (Life (Basel), 2025; PMID 40141845), a randomized saline-controlled trial in 20 men whose plant-extract exosome formulation raised hair count against saline. Under the written rule a single positive randomized trial is C, but a C on a row named for exosome therapy would read as a C for the human stem-cell-derived products clinics sell, which no randomized trial has tested. The row is therefore split: the plant-derived formulation tested is C on one trial, and human stem-cell-derived exosomes for hair stay D Route 1 with their own absence check. The review hold on the hair row is closed. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The C rested on the view that the human evidence was pilot-scale. It is not: Wei et al. (Sci Transl Med, 2017; PMID 28202779) randomized 100 adults to three cycles, Micarelli et al. (Cell Rep Med, 2025; PMID 39970875) randomized 102 in crossover to six, and Mohammadzadeh et al. (Diabetol Metab Syndr, 2025; PMID 40287774) pooled 11 randomized trials, agreeing on lower blood pressure, HbA1c and IGF-1 and on no effect elsewhere. Replicated randomized evidence on validated surrogates is B under the written rule. The letter is scoped: against a Mediterranean diet, Mishra et al. (NPJ Metab Health Dis, 2023; PMID 40604264) found no between-group difference, and against continuous energy restriction Sadeghian et al. (Obes Surg, 2021; PMID 33420673) found no weight difference, so the B is for the comparison with an unrestricted diet only. Every positive trial used the maker's kit with the equity-holding inventor as coauthor; under the replication funding rule of September those trials count and are disclosed beside the letter. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.).

Both type 2 diabetes uses rested on one trial, Moludi et al. (Nutr Metab (Lond), 2022; PMID 35870947; 120 adults), null on fasting glucose and positive on endothelial and inflammatory markers. The search found independent trials on both. Endothelial and inflammatory markers: Maleki et al. (Diabetol Metab Syndr, 2020; PMID 32015761; 50 adults) and Li et al. (iScience, 2025; PMID 40546935; 165 adults, Chongqing, blood pressure, vasodilation and pulse wave velocity) replicate the direction, so a replicated surrogate reaches B. Glycemic control: Maleki et al. (Amino Acids, 2020; PMID 32472292) and Esmaeili et al. (Can J Diabetes, 2021; PMID 32861603), the same Tabriz group at the same 3 g/day dose without a diet, found fasting glucose and HOMA-IR fall, and pooled analyses (Tzang et al., 2024; PMID 38755142; Nie et al., 2026; PMID 41275513) find small reductions; one null and two positive trials is mixed, C. The headline follows the best use. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.) of a use-specific literature search, every trial re-fetched from PubMed before the letter rose; the search is recorded on the record.

The record graded SAM-e D on Route 2 for depression as monotherapy or add-on together, on two null pooled analyses (Galizia et al., Cochrane, 2016; PMID 27727432; Peng et al., Gen Hosp Psychiatry, 2024; PMID 38199136). The largest and most recent pooled analysis, Limveeraprajak et al. (Prog Neuropsychopharmacol Biol Psychiatry, 2024; PMID 38423354; 23 trials, 2,183 patients), finds SAM-e alone superior to placebo (SMD -0.58) and SAM-e as an add-on not. Two questions with two answers were under one letter. Monotherapy, with positive and null pooled analyses side by side and the best modern trials null (Mischoulon et al., 2014; PMID 24500245; Sarris et al., 2020; PMID 31712971), is mixed evidence, C. Add-on use, with one early positive trial (Papakostas et al., 2010; PMID 20595412; 73 patients) and the two larger later trials null (Targum et al., 2018; PMID 30368163; Sarris et al., 2018; PMID 30115553), stays D on Route 2. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.) of a use-specific literature search, every trial re-fetched from PubMed before the letter rose; the search is recorded on the record.

The blood NAD use held a C on one dose-ranging trial, Yi et al. (GeroScience, 2023; PMID 36482258; 80 adults). Three further randomized placebo-controlled trials report the same result: Pencina et al. (J Clin Endocrinol Metab, 2023; PMID 36740954; 30 adults, 28 days), Morifuji et al. (GeroScience, 2024; PMID 38789831; 60 older adults, 12 weeks) and Katayoshi et al. (Sci Rep, 2023; PMID 36797393; 36 adults, 12 weeks). A replicated surrogate reaches B under the written rule. Every one of the four was run or funded by a company that sells NMN, so the funding and investigator line prints beside the letter under the rules of September and October. The pooled metabolic endpoints across NMN trials (Yang et al., Nutrients, 2026; PMID 42514320) show no clear clinical benefit, which the record states. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.) of a use-specific literature search, every trial re-fetched from PubMed before the letter rose; the search is recorded on the record.

The B rested on the medical-ward subgroup of Chen et al. (Mol Neurobiol, 2016; PMID 26189834), a meta-analysis whose pooled primary was not significant (P=0.08). The subgroup's positive trial is Al-Aama et al. (Int J Geriatr Psychiatry, 2011; PMID 20845391; 145 patients, 0.5 mg). Two later medical-ward trials, neither cited, are null: Jaiswal et al. (Am J Med, 2018; PMID 29729237; 3 mg, delirium numerically more frequent on melatonin) and RESTORE (Al Alawi et al., BMJ Open, 2026; PMID 41592826; 5 or 8 mg, stopped for futility). One positive and two null trials on the same ward is mixed evidence, which is C. The endpoint type is corrected to clinician_rated, since delirium by the Confusion Assessment Method is a clinician-scored scale. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.) of a use-specific literature search; the search is recorded on the record.

The magnesium glycinate elemental protocol held a B on a meta-analysis of oral magnesium salts generally (Zhang et al., Hypertension 2016; PMID 27402922), which the record itself said did not test glycinate. EBL grades magnesium by the salt on the label. The only glycinate trial with a blood pressure outcome gave it with vitamin D (Cheung et al., Nutrition 2022; PMID 35576873). Untested for this salt: D on Route 1. This is not a finding that magnesium does not work. Editor adjudication, October 2026.

The magnesium glycinate 300 to 400 mg protocol held a B on a review of trials that used other magnesium salts (Morais et al., Nutrition 2017; PMID 28526383). EBL grades magnesium by the salt on the label. No randomized trial of magnesium glycinate alone has measured insulin resistance, and a 2024 clamp trial of oral magnesium was null (Drenthen et al., Diabetologia 2024; PMID 37922013). Untested for this salt: D on Route 1. This is not a finding that magnesium does not work. Editor adjudication, October 2026.

Pterostilbene held a C on its single trial (Riche et al., Evid Based Complement Alternat Med 2014; PMID 25057276), whose pre-specified primary outcome was lipids. LDL cholesterol rose by 17.1 mg/dL; blood pressure fell only as a secondary outcome. The trial was funded by the company that makes the pterostilbene tested. Tested on its primary question and adverse: D on Route 2. Editor adjudication, October 2026.

EEG neurofeedback held a C on a network meta-analysis of digital interventions whose neurofeedback signal rests on unblinded ratings (Mei et al., Front Psychiatry 2026; PMID 42358407). The largest double-blind sham-controlled trial was null at every time point (Neurofeedback Collaborative Group, J Am Acad Child Adolesc Psychiatry 2021; PMID 32853703), and meta-analyses limited to probably blinded ratings found no effect (Cortese et al., J Am Acad Child Adolesc Psychiatry 2016; PMID 27238063; Westwood et al., JAMA Psychiatry 2025; PMID 39661381). Tested, no benefit: D on Route 2. Editor adjudication, October 2026.

The general 2 to 4 g/day omega-3 protocol held a B on pooled analyses mostly at 1 g/day or less and on REDUCE-IT, which tested purified EPA. At this dose of mixed EPA and DHA the large trials were null: STRENGTH (Nicholls et al., JAMA 2020; PMID 33190147) and OMEMI (Kalstad et al., Circulation 2021; PMID 33191772). C. Editor adjudication, October 2026.

The melatonin 0.5 to 1 mg protocol held a B on a meta-analysis that pooled all doses and found larger effects at higher doses (Ferracioli-Oda et al., PLoS One 2013; PMID 23691095), which does not test a low-dose protocol. Direct low-dose trials are small and population-specific (Zhdanova et al., J Clin Endocrinol Metab 2001; PMID 11600532; Sletten et al., PLoS Med 2018; PMID 29912983), and a jet lag trial with 0.5 mg arms was null (Spitzer et al., Am J Psychiatry 1999; PMID 10484950). C. Editor adjudication, October 2026.

Collagen held one B across joint and skin uses. Joint pain rests on small self-reported trials in athletes (Clark et al., Curr Med Res Opin 2008; PMID 18416885; Zdzieblik et al., Appl Physiol Nutr Metab 2017; PMID 28177710). For skin, Myung et al. (Am J Med 2025; PMID 40324552) found no effect in trials without industry funding and in high-quality trials. Mixed across the named uses: C. Editor adjudication, October 2026.

Citicoline held a B on a 2005 Cochrane review of 14 short, heterogeneous trials (Fioravanti and Yanagi, Cochrane Database Syst Rev 2005; PMID 15846601). The only 12-month double-blind trial was null (Cohen et al., Cerebrovasc Dis 2003; PMID 12865605), and the European Food Safety Authority found a memory benefit not established (EFSA J 2024; PMID 38966137). Mixed: C. The Cochrane authors are now named correctly as Fioravanti and Yanagi. Editor adjudication, October 2026.

Beetroot held a B on one positive trial in hypertensive adults (Kapil et al., Hypertension 2015; PMID 25421976) and an early meta-analysis of mostly acute trials. The largest trial (Sundqvist et al., Am J Clin Nutr 2020; PMID 32091599; 231 adults) was null on 24-hour blood pressure, and pooled analyses find the effect only on clinic readings (Ashor et al., J Hypertens 2017; PMID 28319596; Gronroos et al., Nutr Metab Cardiovasc Dis 2024; PMID 39069465). Mixed: C. Editor adjudication, October 2026.

The Bacopa 600 mg+ protocol held a B on meta-analyses whose trials mostly used 300 to 450 mg/day (Kongkeaw et al., J Ethnopharmacol 2014; PMID 24252493; Pase et al., J Altern Complement Med 2012; PMID 22747190). The only chronic trial at 600 mg/day (Peth-Nui et al., Evid Based Complement Alternat Med 2012; PMID 23320031) used a 5 percent saponin extract, and a recent trial was null (Lopresti et al., Clin Drug Investig 2025; PMID 41091332). At the named dose this is C. Editor adjudication, October 2026.

ALCAR held a B on two meta-analyses and one neuropathy trial. The largest Alzheimer's trial (Thal et al., Neurology 1996; PMID 8797468) was null, the Cochrane review of dementia (Hudson and Tabet, Cochrane Database Syst Rev 2003; PMID 12804452) found no benefit on objective cognition, and the Cochrane review of diabetic neuropathy (Rolim et al., Cochrane Database Syst Rev 2019; PMID 31201734) found very low certainty and no benefit at 1,500 mg/day or less. A 409-patient trial (Hershman et al., J Clin Oncol 2013; PMID 23733756) found it worsened chemotherapy neuropathy. Mixed: C. Editor adjudication, October 2026.

Bromelain held a C on a trial of a three-ingredient enzyme product (Henrotin et al., RMD Open 2025; PMID 40803821) sponsored by the product's maker. The bromelain-alone search found two placebo-controlled trials on the graded uses and both were null: Brien et al. (QJM 2006; PMID 17121765) in knee osteoarthritis and Ley et al. (Chin J Integr Med 2016; PMID 27412590) on inflammation markers. Tested alone, no benefit: D on Route 2. Editor adjudication, October 2026.

Vitamin D3 held a B headline on fracture reduction in deficient or older adults. The trial it rested on, Chapuy et al. (N Engl J Med 1992; PMID 1331788), gave vitamin D3 with calcium. For vitamin D alone, the Cochrane review (Avenell et al., Cochrane Database Syst Rev 2014; PMID 24729336) and a 69-trial meta-analysis (Masse et al., BMJ 2026; PMID 42161415) found no fracture benefit: D on Route 2. Falls moved to C: a later meta-analysis was null (Ling et al., Clin Nutr 2021; PMID 34656949) and high doses increased falls (Sanders et al., JAMA 2010; PMID 20460620). Respiratory infection moved to C: the same group's update is no longer significant (Jolliffe et al., Lancet Diabetes Endocrinol 2025; PMID 39993397). The headline follows to C. Editor adjudication, October 2026.

The general red and near-infrared light page held one B across pain, wound healing, skin aging and cognition, on one skin trial (Wunsch et al., Photomed Laser Surg 2014; PMID 24286286) and a mechanism review. Searched use by use in October 2026, those uses rest on small, mixed or self-reported trials, which is C. Oral mucositis prevention keeps its A on its own page. Editor adjudication, October 2026.

The D3 2,000 to 4,000 IU plus MK-7 100 mcg protocol held a B on one MK-7-alone trial at 180 mcg (Knapen et al., Osteoporos Int 2013; PMID 23525894) measuring bone density, a surrogate. No trial has tested the combination at these doses. The largest combination trial, AVADEC (Diederichsen et al., Circulation 2022; PMID 35465686; 720 mcg MK-7 plus 1,000 IU D3), missed its primary endpoint, and vitamin D alone did not prevent fractures in VITAL (LeBoff et al., N Engl J Med 2022; PMID 35939577) or D-Health (Waterhouse et al., Lancet Diabetes Endocrinol 2023; PMID 37011645). C, with the name's doses flagged as untested. Editor adjudication, October 2026.

The TM record held a B on one trial, Schneider et al. (Circ Cardiovasc Qual Outcomes 2012; PMID 23149426), 201 adults with coronary heart disease. No independent trial has repeated it. The Cochrane review (Rees et al., Cochrane Database Syst Rev 2024; PMID 38358047) extracts the same trial as null, and a later trial from the same group (Norris et al., Front Med 2025; PMID 40177279) missed its primary endpoint. A single positive trial nobody has repeated is C. Editor adjudication, October 2026.

The L-theanine 200 mg sleep protocol held a B on Hidese et al. (Nutrients 2019; PMID 31623400), a 30-person crossover trial of stress in which sleep quality was a secondary, self-reported outcome, funded by the company that makes the L-theanine tested. The review it cited as confirmation (Gerolymos et al., Mol Psychiatry 2026; PMID 42410082) does not pool sleep outcomes. The sleep meta-analysis (Bulman et al., Sleep Med Rev 2025; PMID 40056718) is positive on self-report only and pools combination products. One small unreplicated trial is C. Editor adjudication, October 2026.

Time-restricted eating held a B on the claim that its trials isolate a timing effect independent of calories. One of the two trials cited, Wilkinson et al. (Cell Metab 2020; PMID 31813824), is single-arm with no control group. The other, Sutton et al. (Cell Metab 2018; PMID 29754952), is a crossover in 8 men. The larger randomized trials that matched calories found no added effect of the eating window: Liu et al. (N Engl J Med 2022; PMID 35443107; 139 adults, 12 months) and Lin et al. (Ann Intern Med 2023; PMID 37364268; 90 adults, 12 months). One small positive trial without replication is C, and the isocaloric-timing claim is withdrawn. Editor adjudication, October 2026.

The DHA 1 to 2 g/day protocol held a B on one trial, MIDAS (Yurko-Mauro et al., Alzheimers Dement 2010; PMID 20434961), which gave 900 mg/day, improved one memory test of several and was led by an employee of the company that made the DHA tested. The larger and longer trials are null: EPOCH (Danthiir et al., Am J Clin Nutr 2018; PMID 29722833) at 1,720 mg/day for 18 months, MAPT (Andrieu et al., Lancet Neurol 2017; PMID 28359749) over 3 years, and the DHA-specific meta-analysis (Balachandar et al., Eur J Clin Pharmacol 2020; PMID 32060571). A Cochrane review of cardiovascular prevention that the record cited for cognition has been removed. Tested, no benefit: D on Route 2. Editor adjudication, October 2026.

Luteolin held a C on Di Stadio et al. (Curr Neuropharmacol, 2022; PMID 35450527), a randomized trial of a fixed palmitoylethanolamide plus luteolin combination with olfactory training. The trial does not isolate luteolin, and under the published scale a combination product grades the combination, not its parts. A PubMed search in October 2026 for randomized trials naming luteolin returned 14 records, all combination or mixture products; the only luteolin-alone arm is a pseudo-randomized botanical crossover in Gulf War illness (Hodgin et al., Int J Environ Res Public Health, 2021; PMID 33802381), a different claim. With no randomized trial of luteolin alone on any graded outcome the letter is D on Route 1, untested. Moved October 2026 by editor adjudication; the absence check and the search are recorded on the record.

The R-ALA protocol held a B on the same bibliography as the supplement record: Ansar et al. (Saudi Med J, 2011; PMID 21666939), one 8-week glycemic trial of 57 adults; SYDNEY 2 (Ziegler et al., Diabetes Care, 2006; PMID 17065669); NATHAN 1 (Ziegler et al., Diabetes Care, 2011; PMID 21775755), null on its primary; and Han et al. (Eur J Endocrinol, 2012; PMID 22837391), a mostly intravenous pool. None used R-alpha-lipoic acid or fasted dosing. One positive glycemic trial without replication is C. Moved October 2026 by editor adjudication; the name's R-form and fasted claims stay on the review roster.

Alpha-lipoic acid held a B on SYDNEY 2 (Ziegler et al., Diabetes Care, 2006; PMID 17065669), a 5-week oral trial in 181 adults, with replication claimed from Han et al. (Eur J Endocrinol, 2012; PMID 22837391), a meta-analysis of mostly intravenous trials its own authors rate as poor. The 4-year oral trial, NATHAN 1 (Ziegler et al., Diabetes Care, 2011; PMID 21775755; 460 adults, 600 mg/day), missed its primary composite endpoint and recorded more serious adverse events on treatment. The glycemic claim rests on Ansar et al. (Saudi Med J, 2011; PMID 21666939), one 8-week trial of 57 adults. One positive short oral trial, one null long oral trial and an intravenous pool do not meet the B definition of an independently replicated randomized result; the letter is C. Moved October 2026 by editor adjudication; the search is recorded on the record.

The soy-derived phosphatidylserine protocol held a C on the strength of Cenacchi et al. (Aging (Milano), 1993; PMID 8323999), a trial of bovine-cortex phosphatidylserine, a different product. The two randomized trials of the soy form in the population it is sold to, Jorissen et al. (Nutr Neurosci, 2001; PMID 11842880; 120 adults, 300 or 600 mg/day, 12 weeks) and Kato-Kataoka et al. (J Clin Biochem Nutr, 2010; PMID 21103034; 78 adults, 100 or 300 mg/day, 6 months), found no between-group difference from placebo. Under the published scale a product tested in its own form and population without benefit is Grade D on Route 2. The letter moved in October 2026 after an editor adjudication of a machine second check and five independent reviews; the search behind the move is recorded on the protocol.

The record carried a C on two prostate cancer studies that measured PSA doubling time in 13 and 59 men (Guess et al., Prostate Cancer Prostatic Dis 2003; Keizman et al., Nutrients 2021). Neither had a control group. A PubMed search in October 2026 for randomized controlled trials of modified citrus pectin returned none, for any outcome. Under EBL's rule a C needs human randomized evidence, so the letter moves to D on Route 1: untested, which is different from tested and failed. The record's notes also carried a stale sentence arguing for a B on galectin-3 reduction; it is gone. Five independent reviews of the second citation check reached the same reading.

Incident type 2 diabetes rests on one trial, the SURMOUNT-1 three-year analysis (Jastreboff et al., N Engl J Med, 2025; PMID 39536238), and the cardiovascular trial is a non-inferiority comparison with dulaglutide (Nicholls et al., N Engl J Med, 2025; PMID 41406444). Under Rule 03 a single positive trial without independent replication is C, the rule applied to retatrutide in October. Closes the review opened October. Applied by the written grade definitions, October 2026.

The B rested on a Cochrane review that rates its five small placebo-controlled trials very low quality, with withdrawals tied to the outcome and evidence of publication bias (Stewart et al., Cochrane Database Syst Rev, 2016; PMID 27021597). The written definition of B requires at least one well-designed trial supported by others; small trials of very low quality are C. Walking distance gains are unchanged as findings. Applied by the written grade definitions, October 2026.

Four randomized trials agree that oral NMN raises blood NAD (Yi et al., GeroScience, 2023; PMID 36482258; Pencina et al., J Clin Endocrinol Metab, 2023; PMID 36740954; Morifuji et al., GeroScience, 2024; PMID 38789831; Katayoshi et al., Sci Rep, 2023; PMID 36797393). The editor settled the open question of what counts as a qualifying biomarker in October 2026 and added it to the B definition: a biomarker qualifies only when it is an established stand-in for a clinical outcome, and a blood level of the supplement or of what the body makes from it shows absorption and qualifies for nothing above C. Blood NAD is that kind of level, so the use and the headline move to C, the same reasoning that holds nicotinamide riboside at C. This supersedes the correction of earlier the same day that confirmed the B. Editor decision, Arnold Sandlow, D.C., October 2026.

The use-level A rested on one pooled review and did not cite the largest trial. PLACIDE (Allen et al., Lancet, 2013; PMID 23932219), 2,981 older inpatients, found no significant reduction in C. difficile diarrhea. The 2025 Cochrane update (Esmaeilinezhad et al.; PMID 40931979) still finds fewer cases overall, about one prevented for every 65 people treated, and rates that evidence low certainty. The positive trials tested different products, so the benefit does not attach to probiotics as a class. The record's headline grade was already C and does not change.

Grade A requires the effect a record reports to replicate across independent research groups. CoQ10's A reported fewer deaths and major cardiovascular events, and that result rests on one trial, Q-SYMBIO (Mortensen et al., Journal of the American College of Cardiology: Heart Failure, 2014; PMID 25282031). Cochrane (Al Saadi et al., 2021; PMID 35608922) could pool only that study for mortality. An independent 1993 trial from Naples (Morisco et al.; PMID 8241697) reported fewer heart-failure hospitalizations, which keeps the use above C. The record now names what would raise it back to A: an independent trial on current heart-failure therapy with mortality or major events as its primary endpoint. The change was prompted by an outside review of the site.

Resistance training was carried as THREE separate top-level records: blood pressure and lipids at Grade B, glycemic control at Grade B, and progressive overload for strength at Grade A. One intervention, three endpoints, three letters, and the glycemic record's entire evidence base was a single paper the blood-pressure record already cited. With the records split that way, nothing checked the letters against each other: gate_g13 compares a headline against the uses beneath it, and three separate top-level records slipped past that check entirely. They are now one record graded by use, the shape already used for creatine, omega-3 and CoQ10. The surviving record's headline is A, matching the site convention that a headline is no better than its best use, and the A is scoped on the record to muscle size and strength. Blood pressure with lipids, and glycemic control, remain at B as separate uses because every endpoint behind them is a surrogate. No letter changed its meaning in this consolidation: the A, and both Bs, rest on exactly the citations they rested on before.

Two uses on the consumer wearables record carried letters: sleep staging agreement against polysomnography at Grade C (de Zambotti 2019, PMID 28323455) and VO2max estimate agreement against a metabolic cart at Grade D (Caserman 2024, PMID 39083800). Both letters have been withdrawn. A letter on this site means published human randomized evidence, and an agreement study cannot be randomized: it compares one instrument against a reference standard in the same people at the same time. The record's own grade note already said consumer wearables are measurement instruments rather than interventions, so the letters contradicted the record that carried them. The findings are unchanged and remain on the record: the Oura ring agrees reasonably with polysomnography on total sleep time and poorly on staging, and the Apple Watch underestimated VO2max against the reference standard in 19 adults. What changed is that they are now stated as findings rather than graded as efficacy. Separately, 27 citations across the site were amended to name their first author, and one misattribution was corrected: PMID 33071237 was cited as Petr et al. and is Kulkarni et al.

The NMN supplement record moved to Grade C. The dosing protocol built on the same two trials stayed at B, and its own description said so out loud: one strong randomized trial, replication still needed. Yoshino 2021 (PMID 33888596) carries the insulin-sensitivity result and Yi 2023 (PMID 36482258) measured blood NAD in a different population, so neither repeats the other. Both records now read C.

This record entered the Longevity Rx list in August at Grade B on STOP-NIDDM (PMID 12086760) alone, and carried the not-replicated flag from the day it was written. Rule 03 places a single unrepeated randomized trial at Grade C. The letter is corrected. The evidence is unchanged: acarbose delayed conversion from impaired glucose tolerance to type 2 diabetes in one multicenter trial, there is no randomized human trial of acarbose on mortality or healthspan, and the mouse lifespan result that puts it on longevity lists moves no letter here.

In September this record moved from A to B, on the finding that its two citations are the China Coronary Secondary Prevention Study and that study's own elderly hypertensive subgroup, rather than two trials. The B did not follow from that finding. Rule 03 states that a single positive trial without independent replication is a Grade C, however large or well conducted it is, and CCSPS is one trial. Its size, roughly 4,870 adults after myocardial infarction, and its hard endpoints An outcome that matters directly to a person and is counted without judgment, such as death, heart attack, stroke or fracture. are why the trial is worth citing; neither is a substitute for a second independent group reporting the same thing. The letter is corrected to C. Nothing about the trial's result has changed, and the record still names it in full.

The cognitive protocol carried a Grade A resting on Prokopidis 2023 (PMID 35984306). Rereading the meta-analysis against the letter: the pooled memory effect is SMD 0.29 (95 percent CI 0.04 to 0.53) with I-squared of 66 percent, concentrated in adults aged 66 to 76 (SMD 0.88) and absent in adults aged 11 to 31 (SMD 0.03, -0.14 to 0.20). A signal that reverses to nothing across half the age range is mixed trial data. Regraded C. This was found while splitting the creatine supplement record by use, which had carried one letter across muscle strength, cognition and brain energy reserve. Creatine's Grade A is scoped to measured strength, where it rests on instrument-recorded one-repetition maximum in two mixed-sex meta-analyses, and is unchanged. The bone density use is newly graded D by Route 2 on two 2-year randomized trials that found no effect.

Curcumin now carries two graded uses instead of one headline letter. Systemic inflammatory markers stay at C: only one cited trial isolates curcumin, the other tests a curcuminoid-piperine combination, and every endpoint is a surrogate. Knee osteoarthritis pain and function is newly graded C on two head-to-head randomized trials against ibuprofen (PMID 24672232, PMID 19678780) and an 11-trial meta-analysis in which curcuminoids beat placebo (PMID 29622343). It is C rather than B for three reasons the meta-analysis states about itself: study quality was low overall, most trials enrolled under 100 participants, and the pooled arm mixes formulations. The trials used 1,500 to 2,000 mg/day of unenhanced curcuminoid extract, not the enhanced-bioavailability form at a lower dose that is commonly sold.

Probiotics is not one intervention. Prevention of antibiotic-associated Clostridioides difficile diarrhea holds Grade A on pooled randomized evidence. Inflammatory markers in type 2 diabetes is C on surrogate endpoints. The headline letter is now C, the grade of the general-purpose use, so that an A earned on one narrow clinical endpoint is not read as a verdict on the category.

The headline Grade B sat above per-use grades of C, C and D. A headline letter may not exceed the best use it rests on, so the headline is now C. The longevity, healthspan and mortality use remains D: no cited trial measures it.

The Grade B rested on two citations and both tested GlyNAC, glycine combined with N-acetylcysteine, so neither isolated glycine. The record's own reference field said so and the grade did not follow. The only placebo-controlled human study of glycine alone bearing on sleep is Bannai 2012 (PMID 22529837), which gave 3 g before bed to healthy volunteers under experimental sleep restriction and found reduced next-day fatigue and improved psychomotor vigilance. Small, unreplicated, not a population with insomnia, and PubMed assigns it no trial publication type. The widely quoted Yamadera 2007 glycine sleep study appeared in a journal PubMed does not index, so it carries no identifier and is not used. Regraded C.

The Grade B rested on four citations, none of which was a chronic randomized trial of nicotinamide riboside alone against a meaningful endpoint: a pharmacokinetic study, a cell-biology paper, an acute exercise crossover, and a repeat-dose trial of nicotinamide riboside combined with pterostilbene, which cannot isolate a single ingredient. A phase-II randomized placebo-controlled trial in older adults with amnestic mild cognitive impairment (Martens et al., Alzheimers Dement, 2026) has since reported that 12 weeks of nicotinamide riboside doubled blood NAD+ and produced no improvement in cognitive function, total cerebral blood flow, or blood pressure. Raising the marker is established. Benefit from raising it is not.