Additions. New records and new evidence.

Breathing steam for a cold or sinus symptoms now has a record. A Cochrane review of six trials could not show a benefit in the common cold (Singh et al., Cochrane Database Syst Rev, 2017; 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. 28849871), and advice to use steam did not reduce sinus disability in 871 adults (Little et al., CMAJ, 2016; PMID 27431306). Burn centers report scalds from it every year, mostly in children (Baartmans et al., Br J Gen Pract, 2012; PMID 22781995). Grade 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..

Steam rooms, steam baths and Turkish hammams now have a record. No randomized trial has compared regular steam room use with no steam on a health outcome: a trial in allergic rhinitis gave both groups steam and varied only the herbs (Tungsukruthai et al., J Integr Med, 2018; PMID 29397091), and a hammam trial in endometriosis pain combined steam with massage (Rodriguez-Ruiz et al., Medicina, 2024; PMID 39459464). Grade 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..

The traditional Finnish sauna now has its own record, separate from infrared saunas. Sauna added after exercise lowered systolic blood pressure by 8 mmHg more than exercise alone in 47 adults over 8 weeks (Lee et al., Am J Physiol Regul Integr Comp Physiol, 2022; PMID 35785965), and sauna alone changed neither vascular function nor blood pressure in 41 adults with coronary disease (Debray et al., J Appl Physiol, 2023; PMID 37650138): Grade C. The Kuopio cohort findings on mortality, dementia and stroke (Laukkanen et al., JAMA Intern Med, 2015; PMID 25705824) are shown on the record as 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. and carry no letter.

Regular blood donation is widely repeated as a way to lower heart attack risk by lowering iron stores. It now has a graded record. The one randomized trial on hard outcomes removed blood every 6 months in 1,277 veterans with peripheral artery disease and did not significantly reduce death (hazard ratio How often an event happened in the treated group compared with the control group over the same period. A ratio of 0.80 means 20 percent fewer events. 0.85) or death, heart attack and stroke (hazard ratio 0.88) (Zacharski et al., JAMA, 2007; PMID 17299195): Grade D on Route 2. In healthy donors, donors deferred essentially at random by a false-positive screening test had the same coronary heart disease rate as donors who kept giving (Germain et al., Transfusion, 2013; PMID 23320537), and a systematic review A review that searches for every study on a question using a method set in advance, then assesses them together. of 44 studies found the question unresolved, with positive studies likely reflecting the healthy donor effect (Quee et al., Transfus Med Rev, 2022; PMID 35606245). One small randomized trial in metabolic syndrome found lower systolic blood pressure; it has not been repeated.

The plant-based diet page carried a Grade B with no record behind it and no citation. It now has a graded record. A meta-analysis A study that pools the numbers from several trials into one combined estimate. of 30 randomized trials found vegetarian and vegan diets lowered LDL Low-density lipoprotein cholesterol, the cholesterol fraction most closely tied to plaque in the arteries. cholesterol by 0.30 mmol/L against omnivorous diets (Koch et al., Eur Heart J, 2023; PMID 37226630), and a meta-analysis of 7 trials found HbA1c A blood test that reflects average blood sugar over the previous two to three months. 0.40 percentage points lower in type 2 diabetes (Guest et al., Adv Nutr, 2024; PMID 39415400): both Grade B, on established surrogates. Heart attacks, strokes and mortality are Grade D: no randomized trial has tested the diet on its own against them, and the Cochrane review found none of its trials reported a cardiovascular event (Rees et al., Cochrane Database Syst Rev, 2021; PMID 33629376). Against other healthy diets, the LDL difference was small or absent.

AREDS (Age-Related Eye Disease Study Research Group, Arch Ophthalmol, 2001; PMID 11594942) found zinc 80 mg with copper, combined with antioxidants, slowed progression to advanced macular degeneration in 3,640 adults with signs of the disease; zinc alone reached significance only in the higher-risk group. One trial, not independently repeated against placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received., is C. The record's top letter does not change.

VITAL-DEP (Okereke et al., JAMA, 2020; PMID 32749491) randomized 18,353 adults aged 50 and over to 2,000 IU a day or placebo for a median 5.3 years, with depression as a primary endpoint The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight., and found no difference in depression or mood scores. One large null trial on the endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. it was built for is Route 2, as on other single-trial rows, so this use enters at D. The record's top letter does not change.

A post hoc analysis of 777 adults aged 70 and older in the DO-HEALTH trial (Bischoff-Ferrari et al., Nat Aging, 2025; PMID 39900648) found 1 g/day of omega-3 slowed three of four DNA methylation clocks by about 3 to 4 months over 3 years. A methylation clock is not an established stand-in for a clinical outcome and the finding has not been repeated, so the row enters at C. The record's top letter does not change.

Meta-analyses of randomized trials, 28 trials (Whitehead et al., Am J Clin Nutr, 2014; PMID 25411276), 58 trials (Ho et al., Br J Nutr, 2016; PMID 27724985) and 13 trials in adults with raised cholesterol (Yu et al., Nutrients, 2022; PMID 35631184), find 3 g/day or more of oat beta-glucan lowers LDL cholesterol, and a randomized trial found the effect depends on molecular weight (Wolever et al., Am J Clin Nutr, 2010; PMID 20660224). LDL is a surrogate, so B is the ceiling. The high-cholesterol condition page previously listed oats under a soluble-fiber row whose evidence was psyllium only; oats now have their own row.

NOPARK (Brakedal et al., JAMA, 2026; PMID 42848371), a phase 3 randomized trial of 410 people with early Parkinson disease, found that those on nicotinamide riboside 1,000 mg/day for 52 weeks did worse than placebo on the primary rating score and on non-motor symptoms. This use enters at D with the TESTED, HARM FOUND badge. The record's top letter does not change.

Two large randomized trials of the standardized extract, GEM (DeKosky et al., JAMA, 2008; PMID 19017911) in 3,069 adults aged 75 and over and GuidAge (Vellas et al., Lancet Neurol, 2012; PMID 22959217) in 2,854 adults with memory complaints, did not prevent dementia or Alzheimer's disease. Prevention now has its own row at D, tested and no benefit. The rows on symptoms in people who already have dementia, and the record's top letter, do not change.

HOPE-2 (Lonn et al., N Engl J Med, 2006; PMID 16531613) and NORVIT (Bønaa et al., N Engl J Med, 2006; PMID 16531614) lowered homocysteine An amino acid in the blood that rises when vitamin B12, folate or B6 are low. without lowering heart attacks or cardiovascular deaths, and a Cochrane review of 15 trials (Martí-Carvajal et al., Cochrane Database Syst Rev, 2017; PMID 28816346) found no effect on heart attacks or deaths. This use enters at D, tested and no benefit. The separate first-stroke row and the record's top letter do not change.

The record graded cancer prevention only. HOPE (Yusuf et al., N Engl J Med, 2000; PMID 10639540), the Physicians' Health Study II (Sesso et al., JAMA, 2008; PMID 18997197) and the Women's Health Study (Lee et al., JAMA, 2005; PMID 15998891), three large randomized trials, did not lower major cardiovascular events, so heart protection now has its own row at D, tested and no benefit. The record's top letter does not change.

The completeness check found two endpoints the record did not grade. All-cause mortality: D-Health (Neale et al., Lancet Diabetes Endocrinol, 2022; PMID 35026158), 21,315 older Australians, found no reduction, and a pooled analysis of 52 trials (Zhang et al., BMJ, 2019; PMID 31405892) agrees, so this use enters at D, tested and no benefit. Progression from prediabetes to diabetes: D2d (Pittas et al., N Engl J Med, 2019; PMID 31173679), 2,423 adults, was not significant, while a three-trial pooled analysis by the same group (Pittas et al., Ann Intern Med, 2023; PMID 36745886), which includes a prescription vitamin D analog, was positive. Results that disagree are C under the written definition. The record's top letter does not change.

New device record. Randomized trials against dim light or an inactive device replicate a benefit on clinician-rated depression scales in winter seasonal depression and in non-seasonal major depression (Lam et al., JAMA Psychiatry 2016; PMID 26580307. Menegaz de Almeida et al., JAMA Psychiatry 2025; PMID 39356500). Held at B rather than A because blinding is hard with a visible light and is not confirmed trial by trial, and one placebo-controlled trial found a benefit only on strict remission criteria (Eastman et al., Arch Gen Psychiatry 1998; PMID 9783558). The record carries the hypomania caution for bipolar disorder (Tuunainen et al., Cochrane 2004; PMID 15106233) and does not cover prevention, timing, colored light or sunlight after waking. Decided by Arnold Sandlow, D.C.

A new graded protocol covers structured exercise programs after treatment for early-stage cancer, graded on disease-free and overall survival. CHALLENGE (Courneya et al., N Engl J Med, 2025; PMID 40450658) randomized 889 people after colon cancer chemotherapy and found 5-year disease-free survival of 80.3 against 73.9 percent. A 2026 meta-analysis of 21 randomized trials (Tzang et al., Br J Sports Med; PMID 42744658) found the same direction across cancer types. Graded B rather than A because the pooled trials are mostly in breast cancer and in colon cancer the result rests on one trial. CHALLENGE was also added to the landmark trials library.

Taverniti et al. (Microorganisms, 2026; PMID 42354894) randomized 140 healthy adults to Lacticaseibacillus rhamnosus CRL 1505 at 1 billion CFU a day or placebo for 12 weeks. Fewer people on the probiotic had three or more respiratory infections by week 16, while the one-or-more and two-or-more thresholds of the same primary endpoint were not significant. A single positive trial nobody has independently repeated is C under the written definition, and the authors include the strain's owner and licensee. The use is graded for this strain only; the headline stays C. Applied the written grade definition at the editor's request of October 2026 (Arnold Sandlow, D.C.).

The ward row disclosed four intensive-care poolings that split two null and two positive, and the question put to the editor was whether to add an intensive-care use. The trials point in opposite directions by unit, so one combined row would misstate both. General intensive care: the two largest trials are null, Pro-MEDIC (Wibrow et al., Intensive Care Med, 2022; PMID 35220473; 847 patients) and DEMEL (Mekontso Dessap et al., Intensive Care Med, 2025; PMID 40608082; 355 ventilated patients), as is the lowest-bias pooling (Lakbar et al., Intensive Care Med, 2025; PMID 41051561); D on Route 2. Cardiac surgery: small trials and a pooling are positive (Javaherforoosh Zadeh et al., Iran J Med Sci, 2021; PMID 33753956; Han et al., Front Cardiovasc Med, 2022; PMID 35665270) against the largest single trial, Healthy Heart-Mind (Ford et al., J Am Geriatr Soc, 2020; PMID 31595489; 210 patients), which found no difference; C. The ward row's review is closed. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The fracture row graded vitamin D3 alone (D Route 2) while citing Chapuy et al. (N Engl J Med, 1992; PMID 1331788), a trial of vitamin D3 with calcium. The combination is a different intervention with its own evidence: positive in 3,270 institutionalized women (Chapuy 1992) and in the Cochrane pooling (Avenell et al., 2014; PMID 24729336; hip fracture RR 0.84, benefit concentrated in institutions), null in the Women's Health Initiative (Jackson et al., N Engl J Med, 2006; PMID 16481635) and RECORD (Grant et al., Lancet, 2005; PMID 15885294) outside institutions. Mixed by population: C, scoped to institutionalized or deficient older adults. Added because a reader asking about D3 with calcium was being answered with the D3-alone result. Decided October 2026 by editor adjudication (Arnold Sandlow, D.C.).

The ref described Saadati 2024 (PMID 39770949) as a trial of carnosine 'on musculoskeletal and metabolic measures' without saying it was null on all of them, and the best-use line named musculoskeletal measures as the use. That use is now D Route 2, with O'Toole 2026 (PMID 42308284) beside it. The glycemic evidence that is the only basis for a C is now cited: Houjeghani 2018 (PMID 29420997), Hariharan 2024 (PMID 38172006), Peng 2020 (PMID 31987255). The nulls from the same parent trial on vascular, lipid, organ and inflammatory outcomes (PMIDs 38004228, 39599686) are stated, the population (prediabetes and type 2 diabetes, never healthy adults) is stated, and the pooled analyses that mix beta-alanine (PMIDs 34333586, 40999397) are labeled. Headline C held pending editor confirmation.

The record leaned on an observational global analysis and said only that no randomized trial exists. The randomized evidence it was missing is now cited: Xin 2001 (PMID 11711507) and Roerecke 2017 (PMID 29253389) pooled 15 and 36 trials and found blood pressure falls with reduced drinking, but only in people drinking more than two drinks a day; that is a new use at B. Voskoboinik 2020 (PMID 31893513), abstinence and AF recurrence, is a new use at C. Gardiner 2025 (PMID 39631226) is described as what it is, acute alcohol-before-sleep studies showing REM disruption, not a trial of reducing intake. The GBD 'zero is safest' conclusion is kept as context only. Headline D Route 1 held pending editor confirmation.

Sardeli et al. (Nutrients, 2018; PMID 29596307) pooled six randomized trials in older adults with obesity who were restricting calories. Adding resistance training three times a week prevented 93.5 percent of the lean mass lost with restriction alone, while fat and total weight loss did not differ significantly. The record now cites it beside CALERIE-2. It addresses the muscle cost of restriction rather than the aging endpoint, so the C stays.

Harmsen et al. (Cell Metab, 2026; PMID 41418772) ran a randomized 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. in 13 adults with type 2 diabetes: 4.5 days of daylight through office windows kept glucose in the normal range for longer than constant artificial light, and shifted metabolism toward fat burning. Two large UK Biobank analyses add observational context: brighter days and darker nights went with lower mortality across 88,905 people wearing light sensors (Windred et al., PNAS, 2024; PMID 39405349), and each daily hour outdoors in daylight went with fewer insomnia symptoms and better mood (Burns et al., J Affect Disord, 2021; PMID 34488088). The trial is small and short and measures glucose, not disease, so daylight carries no grade.

Kane et al. (bioRxiv preprint, 2024; PMID 38979132), in a version revised in 2026, gave NMN to mice from middle age for life. Frailty accumulated more slowly in both sexes, but median lifespan rose 8.5 percent in females only, and the female control mice were short-lived, so the result may reflect correcting poor baseline health. It is a mouse study and not peer reviewed. No human trial has tested NMN against lifespan, healthspan or mortality, so that use stays D.

Hawkinson et al. (Nat Metab, 2026; PMID 42265388) found oral glucosamine worsened cognition in Alzheimer's mouse models, and in health records glucosamine use went with faster disease progression and shorter survival. A preprint by Nakashima et al. (medRxiv, 2026; PMID 42619916) found the same progression estimate for multivitamin and calcium plus vitamin D records and no mortality excess, which points to the record marking the patient. Both are cited on the record as context. The C for knee osteoarthritis is unchanged.

Liao et al. (J Prev Alzheimers Dis, 2026; PMID 42000571) reported faster cognitive decline among older adults in the ADNI cohort who took omega-3 supplements, and Dyall and Plourde (J Prev Alzheimers Dis, 2026; PMID 42612546) replied that confounding and method limits may explain it. Supplement type and dose were not recorded, so this is not a test of the DHA dose the protocol names. Both are now cited on the DHA cognition protocol, whose B was already under review for resting on a single trial. The letter does not move on observational data.

Hua et al. (BMJ Open, 2026; PMID 41571412) followed 5,065 US adults for six years and found slightly faster cognitive decline among vitamin D supplement users, confined to those whose blood level was already normal at baseline. An observational association cannot show the supplement caused it. It is now cited on the record as context beside the existing D grades for already-replete adults, where randomized trials found no benefit. No letter moves.

The 2023 animal work behind the taurine longevity claim argued that taurine falls with age. Fernandez et al. (Science, 2025; PMID 40472098), from the National Institute on Aging, measured it in three human cohorts, in monkeys and in mice, both in the same individuals over time and across age groups, and found it rose or held steady. The aging use was already D on Route 1, because no human trial has tested taurine against an aging outcome, and it stays D. The record now cites the failed 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. alongside the original claim.

Mattioni Maturana et al. (Sports Med, 2026; PMID 42730846) pooled 69 randomized trials with 2,387 participants. Interval training raised VO2max The most oxygen the body can use during all-out exercise, a standard measure of aerobic fitness. more than moderate continuous training, and about 80 percent of its maximal effect arrived at roughly 11 minutes per session including recovery, against about 52 minutes for continuous moderate training. Effects on blood pressure, lipids, glucose and body composition were comparable. This is a second, independent meta-analysis of randomized trials on the endpoint the B rests on, and it is now part of the open review of the record's not-replicated flag. The letter stays B pending that review.

STAREE (Zoungas et al., N Engl J Med, 2026; PMID 42670961) randomized 9,971 adults aged 70 and over without cardiovascular disease, diabetes or dementia to atorvastatin 40 mg or placebo for a median 5.9 years. Major cardiovascular events fell about 30 percent (hazard ratio 0.70, 95% CI 0.61 to 0.82). Disability-free survival, the trial's second primary endpoint, did not change (hazard ratio 0.94, 95% CI 0.84 to 1.05). The library now carries both halves side by side, because together they show a hard endpoint An outcome that matters directly to a person and is counted without judgment, such as death, heart attack, stroke or fracture. moving while the healthspan endpoint did not. No grade changes.

EBL joined Holy Hydrogen's affiliate program and now earns a commission when a reader buys the Lourdes Hydrofix through the link on the hydrogen water page. Holy Hydrogen is the US seller the manufacturer links to, and it was already where that link went, unpaid. The generator carries no grade. The therapy it sits under, Molecular Hydrogen Water, keeps its C, now locked: it changes only through a logged review that names the evidence. The disclosure page now lists three commercial relationships instead of two.

SAM-e (S-adenosyl-L-methionine) enters the database at Grade D on Route 2: tested, no benefit demonstrated. Galizia et al. (Cochrane Database of Systematic Reviews, 2016; PMID 27727432) pooled 8 randomized trials in 934 adults and found no strong evidence of a difference from placebo as monotherapy. Peng et al. (General Hospital Psychiatry, 2024; PMID 38199136) pooled 14 trials in 1,522 subjects and found no significant difference from placebo as monotherapy or as an adjunct A treatment tested on top of standard prescribed therapy rather than in place of it.. Rutjes et al. (Cochrane Database of Systematic Reviews, 2009; PMID 19821403) found a pain difference of about 0.4 cm on a 10 cm scale in knee or hip osteoarthritis, with a confidence interval The range the true effect probably falls in. A wide interval means the estimate is uncertain. crossing zero. In the three-arm trial of Mischoulon et al. (Journal of Clinical Psychiatry, 2014; PMID 24500245), neither SAM-e nor escitalopram beat placebo.

New device record, graded for one use. Two large sham-controlled trials, Gollwitzer et al. (J Bone Joint Surg Am 2015; PMID 25948515) and Gerdesmeyer et al. (Am J Sports Med 2008; PMID 18832341), found less heel pain at 12 weeks, and two meta-analyses of sham-controlled trials, Aqil et al. (Clin Orthop Relat Res 2013; PMID 23813184) and Sun et al. (Medicine 2017; PMID 28403111), agree. An independent trial, Buchbinder et al. (JAMA 2002; PMID 12234230), found no benefit and is cited on the record. Self-reported pain caps the letter at B. Shoulder, elbow, sexual function and regeneration uses are not covered.

New device record under the Grade A rule as revised in September 2026, which counts a clinician-assigned outcome grade scored blind to treatment. Low-level light applied inside the mouth during head and neck radiotherapy or stem cell transplant cut severe mucositis in sham-controlled trials from independent groups in Brazil, India and the United States (Antunes et al., Radiother Oncol 2013; PMID 24044799. Gautam et al., Radiother Oncol 2012; PMID 22884841. Hu et al., Support Care Cancer 2026; PMID 42360517), and the MASCC/ISOO guideline recommends it for prevention (Zadik et al., Support Care Cancer 2019; PMID 31286228). Not covered: treating sores already present, children, where trials found no benefit (Andriakopoulou et al., In Vivo 2024; PMID 38688628), and any US FDA clearance, since none exists for this use.

New device record, and the first letter set under the Grade A rule as revised in September 2026, which now counts a validated outcome scale scored by a clinician blinded to treatment. On the Hamilton and Montgomery-Asberg scales, sham-controlled trials in treatment-resistant depression replicate across more than 100 randomized trials (Mutz et al., BMJ 2019; PMID 30917990), including an NIH trial with an active sham A fake version of a procedure or device used as the comparison, so participants cannot tell which one they received. (George et al., Arch Gen Psychiatry 2010; PMID 20439832). The record keeps what the letter does not cover: no trial shows fewer suicide attempts or hospitalizations, about one extra remission per 8 to 12 people treated, an effect that fades after the course ends, and a Veterans Affairs trial with no difference from sham (Yesavage et al., JAMA Psychiatry 2018; PMID 29955803).

New device record, graded for one narrow claim: early quadriceps strength and mobility after total knee replacement, compared with usual care. Strength measured on a dynamometer and timed mobility tests improved in randomized trials from independent groups in the United States, Japan and Greece (Stevens-Lapsley et al., Phys Ther 2012; PMID 22095207. Klika et al., J Knee Surg 2022; PMID 32610358), and a meta-analysis of nine trials still found a strength benefit at 12 months (Peng et al., Front Med 2021; PMID 34926522). The letter does not say stimulation beats a progressive strengthening program: in the largest trial, 200 patients, it added nothing when combined with one (Petterson et al., Arthritis Rheum 2009; PMID 19177542).

Same gap again. The record carries no letter: a test measures aerobic capacity and does not raise it, and the training that raises it is graded on its own records. It cites the methods literature on what makes a test maximal, and the validation work on the estimates consumer wearables report. Cited: Midgley et al. (Sports Med, 2007; PMID 18027991); Schaun (Sports Med Open, 2017; PMID 29218470); Carrier et al. (Sensors (Basel), 2025; PMID 39797066).

Same gap as DEXA: a published page with no record. The record carries no letter. It describes the instrument only, and says plainly that grip strength as a prognostic marker belongs with the biomarkers A measurable sign in the body, such as a blood test value, used to track a condition or the effect of a treatment. and that isometric handgrip training is a separate graded therapy, so a reading from this device says nothing about whether squeezing a handgrip treats anything. Cited: Roberts et al. (Age Ageing, 2011; PMID 21624928); Dos Santos et al. (Hand Ther, 2026; PMID 40626051).

The DEXA page has been published for months with no record behind it, which left its safety and medication text written by hand in the page's own HTML and invisible to every check that reads the data. The record carries no letter, by design: DEXA measures body composition and bone density and treats nothing, and the A to D scale grades treatment efficacy. It cites two measurement-accuracy studies rather than outcome trials. Cited: Schubert et al. (Clin Physiol Funct Imaging, 2019; PMID 30325573); Nickerson et al. (Int J Sport Nutr Exerc Metab, 2017; PMID 28787184).

New measurement entry, ungraded by design. PNOE agreed strongly with a laboratory metabolic cart on a cycle ergometer (Tsekouras et al., Front Sports Act Living 2019; PMID 33344948) and moderately with another portable system during walking (Kwok et al., J Funct Morphol Kinesiol 2025; PMID 40407443). Accuracy varies widely between metabolic systems (Van Hooren et al., Scand J Med Sci Sports 2024; PMID 37697640).

New measurement entry, ungraded by design because an analyzer is an instrument, not an intervention. The InBody 770 agreed well with a four-compartment model and with DXA for tracking, with a known systematic offset against DXA: Brewer et al. (Clin Physiol Funct Imaging 2021; PMID 33752260) and Potter et al. (BMJ Nutr Prev Health 2022; PMID 36619314).

New device record. Randomized trials by independent groups, including two with placebo insoles, and a 2026 meta-analysis of seven trials (Lin et al., Disabil Rehabil 2026; PMID 40844962) found less low back pain and disability with custom-made foot orthotics. Every outcome is self-reported, which caps the letter at B, and the effect is short term: seen at 4 to 6 weeks and gone from the largest trial (Cambron et al., Arch Phys Med Rehabil 2017; PMID 28465224) by 12. The two placebo-insole trials are Castro-Méndez et al. (Prosthet Orthot Int 2013; PMID 23327838) and Castro-Méndez et al. (Int J Environ Res Public Health 2021; PMID 34201981). Custom orthotics are fitted from a practitioner-taken impression; off-the-shelf insoles are not what this letter covers.

New record for the two-ingredient combination as studied, separate from Boswellia serrata alone, which holds its own Grade B. One randomized, placebo-controlled trial of 62 adults with knee osteoarthritis (Vaidya et al., Pharm Res 2025; PMID 39875757) found less pain and stiffness over 90 days. The trial was funded by the company that sells the ingredient and has not been repeated by an independent group, so the record holds at C.

New record. Two randomized trials have given C15:0 to people. In the TANGO trial (Chooi et al., Am J Clin Nutr 2024; PMID 38035997), 300 mg a day in soymilk lowered LDL cholesterol beyond what a weight-loss diet achieved in 88 women with fatty liver disease. In a 30-person trial of 200 mg a day (Robinson et al., J Nutr 2024; PMID 39069269), the pre-specified outcome was the blood level of C15:0, which rose; the liver-enzyme changes it reported compare responders rather than randomized arms. One surrogate result, not yet repeated, and no clinical endpoint: Grade C. The common retail serving of 100 mg is below both studied doses.

STOP-NIDDM (PMID 12086760) randomized adults with impaired glucose tolerance to acarbose or placebo, with conversion to type 2 diabetes as the primary endpoint. One landmark trial supports B and not A under Rule 03. Acarbose appears on longevity lists because it extended median lifespan in the NIA Interventions Testing Program in mice. Animal lifespan data does not move a grade here at any effect size How large a difference the treatment made, as distinct from whether the difference could be detected at all., and there is no randomized human trial of acarbose on mortality, healthspan, or in a healthy population.

EMPA-REG OUTCOME (PMID 26378978), DAPA-HF (PMID 31535829) and DAPA-CKD (PMID 32970396) are three independent randomized trials in three different populations, all on hard clinical outcomes. That is the replicated-hard-outcome route to Grade A. The record states the boundary in the same breath as the letter: every one of those trials enrolled people who already had cardiovascular, cardiac or renal disease. No trial has given an SGLT2 inhibitor to a healthy adult to see whether they live longer.

Metformin is the most-cited longevity drug and had no graded record on EBL. It has one now, and the letter is D. Walton et al. (PMID 31557380, the MASTERS trial) randomized 94 adults aged 65 and over without diabetes to metformin 1,700 mg/day or placebo through 14 weeks of progressive resistance training. The stated hypothesis was that metformin would augment the muscle response; it blunted it. Konopka et al. (PMID 30548390) found metformin inhibited the mitochondrial adaptations to aerobic training in the same population. TAME, the trial designed to test metformin against age-related disease, has not reported, and the observational survival signal is not randomized. So the D is Route 2: tested in humans on the actual molecule, in the target population, result adverse on the endpoint that matters.

PMID 42172592 screened 1,960 publications and found 15 randomized trials of multidimensional healthspan in 4,656 people, 11 of them testing exercise, with the supplement and caloric restriction evidence too sparse to support a conclusion. PMID 42494770 reaches the same position from dietary patterns and cognition. Cited as methodology. Neither sets a letter for any entity.

Kell et al. (Aging Cell, 2026; PMID 41524558) randomized healthy older men to 1 mg/day or placebo for four months and reported no difference in white cell counts at eight weeks. A safety and mechanism result in a small randomized sample. No randomized human trial has tested rapamycin against a clinical aging endpoint, so the grade does not move.

A randomized trial of 3 g/day for 8 weeks in 120 adults with type 2 diabetes (PMID 35870947) named fasting blood glucose as a primary outcome and did not improve it, nor HbA1c, nor the lipid profile. Serum insulin and HOMA-IR, secondary outcomes, did improve, as did endothelial and inflammatory markers listed alongside glucose as primary. Glycemic control is filed as D Route 2, tested and not supported on the primary endpoint. Endothelial and inflammatory markers are filed separately at C. The headline aging grade is unchanged at D Route 1.

Two phase 2 randomized trials (PMID 37366315, PMID 37385280) met their pre-specified primary endpoints of body weight and HbA1c, with large dose-dependent effects. Phase 2 trials on anthropometric and biomarker endpoints cap at B however large the effect, and no phase 3 outcome trial had reported at review. The material sold online under this name sits outside any pharmacy supply chain and none of this evidence applies to an unverified vial.

SURMOUNT-1 (PMID 39536238) reports a reduction in incident type 2 diabetes over 176 weeks against placebo, a hard clinical outcome from a single trial. SURPASS-CVOT (PMID 41406444) is a non-inferiority trial against dulaglutide, which shows tirzepatide is not worse than a drug that works rather than that it beats placebo. That combination is B, not A.

Graded A on the cardiovascular composite, not on weight loss. SELECT (PMID 37952131) and SUSTAIN-6 (PMID 27633186) are two independent randomized trials in different populations, both reporting a reduction in cardiovascular death, myocardial infarction or stroke. Weight reduction is the reason most readers arrive at this record and is not what earns the letter.

Added as a device modality separate from 40Hz Gamma Sensory Stimulation, which sits in the same category and shares none of its literature. Three meta-analyses of randomized trials carry the letter, all of binaural beats delivered through headphones: pooled g = 0.45 across cognition, anxiety and pain (Garcia-Argibay 2019, PMID 30073406), g = 0.40 on memory and attention (Basu 2023, PMID 35842538), and SMD -1.38 on perioperative anxiety at 91.6 percent heterogeneity How much the results of the pooled trials differ from each other. High heterogeneity makes a combined estimate less reliable. (Xiong 2025, PMID 41176178). Every pooled endpoint is self-report or a cognitive test score, so B is the ceiling before anything else is weighed. Graded C rather than B for three reasons: a systematic review of EEG recordings during stimulation found five studies supporting entrainment and eight contradicting it (Ingendoh 2023, PMID 37205669), so the named mechanism is not established; the comparator in these trials is blank audio or music and cannot be blinded; and no trial has reported a longevity endpoint. The graded form is tones alone. No light-and-sound headset has been tested as a unit in any pooled trial, which is why the one consumer product listed under this modality carries a low delivery fidelity.

A new graded protocol covers compressing the week's vigorous exercise into a single session. Siu et al. 2026 randomized 315 inactive adults with overweight and central obesity to once-weekly HIIT, thrice-weekly HIIT, or control, both training arms performing 75 minutes of high-intensity interval work per week for 16 weeks. Against control, the once-weekly arm lost 0.8 kg of fat mass and the thrice-weekly arm 1.0 kg. The comparison usually quoted from this trial, once weekly against three times weekly, is not a finding: that between-arm difference did not reach significance. Grade C on a single trial.

A new graded protocol covers the order of resistance and aerobic work inside a single session. Three independent syntheses agree on the direction: lower-body 1RM higher by 3.96 kg when resistance work came first (Murlasits and Kneffel, 2018), lower-body dynamic strength higher by 6.91 percent (Eddens and van Someren, 2018), and a pooled SMD of 0.19 across 19 randomized trials (Gao and Yu, 2023). All three report no difference in VO2max in either order. Graded B rather than A because the endpoint is performance rather than a hard clinical outcome, and the lower confidence bound sits close to zero.