Evidence: universal antioxidant, glucose metabolism

Oral alpha-lipoic acid may reduce sensory symptoms and improve global satisfaction in diabetic neuropathy patients, with higher doses showing a greater effect on some outcomes.

What are the effects of orally administered alpha-lipoic acid (ALA) compared to a placebo in patients with diabetic sensorimotor peripheral neuropathy (DSPN), and what is the optimal dosage?

Hypothesis: The researchers hypothesized that oral ALA would improve symptoms in DSPN patients by reducing oxidative stress and improving microcirculation, and they aimed to determine an optimal dosage.

A meta-analysis of ten randomized controlled trials (RCTs) involving 1242 patients was conducted. The studies were retrieved from PubMed, Embase, and Cochrane databases. Primary outcome was total symptoms' score (TSS), and secondary outcomes included neurological disability score (NDS), neuropathy impaired score (NIS), NIS-lower limb (NIS-LL), vibration perception threshold (VPT), nerve conduction study (NCS) results, and global satisfaction. A subgroup analysis was performed for ALA dosages of 600, 1200, and 1800 mg/day.

ALA treatment showed favorable results for total symptoms' score (TSS), neurological disability score (NDS), and global satisfaction score. A dose-related trend was observed for TSS and global satisfaction. However, ALA did not produce favorable results for VAS, VPT, NIS-LL, and NCS results.

Oral ALA treatment has favorable effects on DSPN by reducing sensory symptoms, with a dose-dependent response observed for TSS and global satisfaction score. Further research is needed to investigate the use of ALA for preventing neurological symptoms.

The abstract does not explicitly state limitations of the meta-analysis itself, but it suggests that further research is needed to investigate ALA's role in preventing neurological symptoms.


Evidence: active folate, methylation cofactor

Folinic acid and l-methylfolate both lower homocysteine, but folinic acid may be more beneficial for individuals with the MTHFR 677CT genotype.

no-difference-cue: "no overall difference" | favorable-cue: "beneficial"

The study investigated the efficacy of folinic acid versus l-methylfolate in lowering total homocysteine (tHcy) levels in healthy Greek adults.

Hypothesis: The study aimed to compare the effectiveness of folinic acid and l-methylfolate in reducing tHcy levels.

Two hundred and seventy-two healthy Greek adults with tHcy levels ≥10 μmol/L were randomized to receive either folinic acid or l-methylfolate orally for three months. Participants with low cobalamin also received hydroxycobalamine. Serum folate, cobalamin, and tHcy levels were measured at the beginning and end of the study, and MTHFR C677T and A1298C gene polymorphisms were genotyped.

Both folinic acid and l-methylfolate significantly increased serum folate and cobalamin, and significantly decreased tHcy levels. Individuals with the MTHFR 677TT genotype showed a greater reduction in tHcy. While folinic acid led to a higher increase in serum folate than l-methylfolate, the reduction in tHcy levels between the two groups was not substantially different overall. However, individuals with the MTHFR 677CT genotype experienced a statistically significant higher reduction in tHcy when supplemented with folinic acid compared to l-methylfolate.

Folinic acid resulted in a greater increase in serum folate levels than l-methylfolate, but there was no overall difference in tHcy reduction between the two treatments. The MTHFR C677T gene polymorphism, but not MTHFR A1298C, influenced tHcy reduction, with MTHFR 677CT individuals benefiting more from folinic acid.

The abstract does not explicitly state any limitations of the study.


Evidence: insulin second-messenger

Inositols are an effective and safe treatment for PCOS, showing similar benefits to metformin for many outcomes.

What is the efficacy and safety of inositols in treating Polycystic Ovary Syndrome (PCOS) compared to metformin or placebo?

Hypothesis: Inositols may be a potential alternative to metformin for treating PCOS, with comparable efficacy and safety.

A systematic review was conducted by searching CENTRAL, MEDLINE, and Embase for randomized controlled trials (RCTs) from inception until October 20th, 2021. Eligible RCTs included women diagnosed with PCOS and compared any inositols with metformin or placebo. Primary outcome was cycle normalization, and secondary outcomes included BMI, carbohydrate metabolism parameters, and clinical/laboratory hyperandrogenism. Results were reported as risk ratios or mean differences (MDs) with 95% confidence intervals (CIs).

Twenty-six RCTs with 1691 patients were identified (806 inositol, 311 placebo, 509 metformin). Inositol treatment resulted in a 1.79 times higher risk of regular menstrual cycles compared to placebo (CI: 1.13; 2.85) and showed non-inferiority to metformin for this outcome. Compared to placebo, inositol treatment led to greater decreases in BMI (MD = -0.45), free testosterone (MD = -0.41), total testosterone (MD = -20.39), androstenedione (MD = -0.69), glucose (MD = -3.14), and AUC insulin (MD = -2081.05). Inositol also significantly increased sex-hormone-binding globulin compared to placebo (MD = 32.06).

Inositol is an effective and safe treatment for PCOS. It demonstrated non-inferiority to metformin in most outcomes.

The abstract does not explicitly state limitations of the systematic review itself, beyond the scope of the included studies.


Evidence: methyl donor, homocysteine remethylation

Daily low-dose B vitamins and betaine supplementation can reduce high homocysteine levels in Chinese adults.

Can daily low-dose B vitamins plus betaine supplementation reduce plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia who are not exposed to mandatory folic acid fortification?

Hypothesis: Daily supplementation with low-dose B vitamins plus betaine will significantly reduce plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia.

One hundred healthy Chinese adults with hyperhomocysteinemia were randomly assigned to either a supplement group (400 μg folic acid, 8 mg vitamin B, 6.4 μg vitamin B, and 1 g betaine daily) or a placebo group for 12 weeks. Fasting blood was collected at baseline, week 4, and week 12 to measure homocysteine, folate, vitamin B, and betaine concentrations. Generalized estimation equations were used for statistical analysis.

The supplement group showed significant increases in blood folate, vitamin B, and betaine concentrations, indicating good compliance. At baseline, homocysteine levels were similar between groups. After 12 weeks, the supplement group had a significant reduction in plasma homocysteine concentrations compared to the placebo group (mean group difference -3.87; reduction rate 10.1%). This decrease was associated with increased blood folate and betaine concentrations.

Daily supplementation with low-dose B vitamins plus betaine for 12 weeks effectively decreased plasma homocysteine concentrations in Chinese adults with hyperhomocysteinemia.


Evidence: catalytic/structural cofactor, immunity

Zinc may shorten the duration of common cold symptoms if taken early at a dose of ≥ 75 mg/day, but it can cause side effects like bad taste and nausea.

Is zinc effective in reducing the incidence, severity, and duration of common cold symptoms, and what are the potential sources of heterogeneity in study results?

Hypothesis: The study aims to assess the efficacy of zinc in reducing common cold symptoms and identify factors influencing study outcomes.

This updated systematic review searched multiple databases for randomized, double-blind, placebo-controlled trials. Trials included used zinc for at least five consecutive days for treatment or five months for prevention of the common cold. Two authors independently extracted data and assessed trial quality.

The review included 16 therapeutic trials (1387 participants) and two preventive trials (394 participants). Zinc intake was associated with a significant reduction in the duration of common cold symptoms (mean difference -1.03 days) and a smaller proportion of participants symptomatic after seven days (odds ratio 0.45). The incidence rate of developing a cold (IRR 0.64), school absence, and antibiotic prescriptions were lower in the zinc group. However, zinc was not associated with a significant reduction in symptom severity. Adverse events, including bad taste (OR 2.31) and nausea (OR 2.15), were higher in the zinc group. High heterogeneity was observed across results.

Zinc administered within 24 hours of symptom onset reduces the duration of common cold symptoms in healthy individuals, but data heterogeneity requires caution. For treatment, zinc lozenges at a dose of ≥ 75 mg/day are suggested. No firm recommendation can be made for prophylactic zinc due to insufficient data. The benefits of zinc lozenges must be weighed against side effects like bad taste and nausea.

The very high heterogeneity across the included studies means that the averaged estimates should be viewed with caution. Insufficient data prevented a firm recommendation for prophylactic zinc supplementation.


Evidence: selenoprotein antioxidant plus CoQ10

Supplementing with selenium and coenzyme Q10 improved thyroid function and related health outcomes in an elderly population with low selenium levels.

unfavorable-cue: "impaired" | favorable-cue: "improved"

Does supplementation with selenium and coenzyme Q10 affect thyroid hormonal status, cardiovascular (CV) mortality, and health-related quality of life (Hr-QoL) in individuals with insufficient selenium intake?

Hypothesis: Supplementation with selenium and coenzyme Q10 will have a beneficial effect on thyroid hormones, CV mortality, and Hr-QoL, particularly in individuals with low baseline selenium concentrations.

This was a randomized, placebo-controlled, double-blind study involving 414 individuals. Participants received either selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) or a placebo for 48 months. Thyroid hormones (Free T3, free T4, reverse T3, TSH), CV mortality, and Hr-QoL (using SF-36) were measured at baseline and after the intervention. Statistical analyses included T-tests, repeated measures of variance, and ANCOVA.

At baseline, individuals with the lowest selenium concentration had significantly higher TSH and lower fT3. After 4 years, supplementation significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo (p = 0.03). In the placebo group, TSH and fT4 values above the median were associated with increased 10-year CV mortality (p < 0.04) and a decline in mental Hr-QoL, which was not observed in the active intervention group.

Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones, which was associated with improved CV mortality and Hr-QoL outcomes. The initial selenium deficiency in the elderly study population was linked to impaired thyroid function, and the observed changes in thyroid hormone levels are likely due to increased deiodinase activity.

The study was retrospectively registered at ClinicalTrials.gov (NCT01443780) because registration was not mandatory when it began.


Evidence: fatty-acid mitochondrial shuttle

Daily L-carnitine doses above or below 3g do not offer additional benefits for mortality or cardiovascular events after a heart attack.

no-difference-cue: "no significant marginal benefit"

What are the effects of various oral maintenance dosages of L-carnitine on all-cause mortality and cardiovascular morbidities in patients with acute myocardial infarction?

Hypothesis: Higher doses of L-carnitine supplementation may not provide additional therapeutic benefits due to strict homeostatic regulation of plasma L-carnitine concentrations.

A meta-analysis of five controlled trials (n = 3108) was conducted after a systematic review of PubMed, EMBASE, and the Cochrane Library up to November 2013. The analysis determined the effects of L-carnitine on all-cause mortality and cardiovascular morbidities in acute MI patients.

There were no significant differences in the effects of 2 g, 3 g, 4 g, and 6 g daily oral L-carnitine doses on all-cause mortality (RR = 0.77, 95% CI [0.57-1.03], P = 0.08). A statistically insignificant trend favored the 3 g dose (RR = 0.48) over the 2 g dose (RR = 0.62), which was favored over the 4 g and 6 g doses (RR = 0.78, 0.78). No significant differences were found between 2 g and 6 g doses for heart failure (RR = 0.53, P = 0.10), unstable angina (RR = 0.90, P = 0.71), or myocardial reinfarction (RR = 0.74, P = 0.50).

There appears to be no significant marginal benefit for oral L-carnitine maintenance doses greater or less than 3 g per day in terms of all-cause mortality, heart failure, unstable angina, or myocardial reinfarction in acute MI patients.

The abstract does not explicitly state limitations of the study.


Evidence: enzymatic cofactor (300+ reactions)

Magnesium Glycinate;Mineral Remineralization Drops

Oral magnesium supplementation can modestly lower both systolic and diastolic blood pressure in adults.

favorable-cue: "lowering blood pressure"

Does oral magnesium supplementation reduce blood pressure in adults?

Hypothesis: The researchers hypothesized that oral magnesium supplementation would reduce blood pressure.

This meta-analysis synthesized evidence from 34 randomized, double-blind, placebo-controlled trials published up to February 1, 2016, involving 2028 normotensive and hypertensive adults. Weighted mean differences of changes in blood pressure and serum magnesium were calculated using a random-effects meta-analysis.

Magnesium supplementation at a median dose of 368 mg/d for a median duration of 3 months significantly reduced systolic blood pressure by 2.00 mm Hg and diastolic blood pressure by 1.78 mm Hg. These reductions were accompanied by a 0.05 mmol/L elevation of serum magnesium. A dose of 300 mg/d or duration of 1 month was found sufficient to elevate serum magnesium and reduce blood pressure, and serum magnesium was negatively associated with diastolic blood pressure.

Magnesium supplementation has a causal effect on lowering blood pressure in adults.

Residual heterogeneity may still exist even after considering factors like trial quality and dropout rates. Further well-designed trials are needed to validate the blood pressure-lowering efficacy of optimal magnesium treatment.


Evidence: carnosine precursor, pH buffer

Beta-alanine supplementation improved exercise endurance and prevented post-exercise cognitive decline in healthy older adults.

Can beta-alanine supplementation improve exercise capacity and executive function in healthy older adults?

Hypothesis: Increasing systemic carnosine levels via beta-alanine supplementation will enhance anti-oxidant, neuro-protective, and pH buffering capabilities, leading to improved exercise capacity and executive function in aging populations.

Twelve healthy adults (average age 60.5 years) were randomized to receive either 2.4 g/d of beta-alanine (BA) or placebo (PL) for 28 days. Exercise capacity was assessed using a cycle ergometer at 70% VOpeak, and executive function was measured by Stroop Tests at four time points relative to exercise. Lactate, heart rate, and Rating of Perceived Exertion (RPE) were also recorded.

Before supplementation, time-to-exhaustion (TTE) was not significantly different between groups. After supplementation, the BA group cycled significantly longer (14.6 minutes) than their pre-supplementation duration (11.1 minutes), while the PL group showed no significant change. Placebo subjects were slower in completing the Stroop test post-exercise at T4 compared to T3, a decline not observed in the BA group. The BA group produced 2.4 mmol/L more lactate than the PL group post-supplementation, showing a trend towards significance.

Beta-alanine supplementation increased exercise capacity and prevented the decline in executive function observed after endurance exercise in the placebo group. The extended exercise duration with similar lactate production suggests an improved ability to sustain exercise. This could allow older adults to maintain exercise benefits with improved safety.

The study involved a small sample size of 12 healthy adults, which may limit the generalizability of the findings.


Evidence: matrix Gla-protein carboxylation

Two years of MK-7 and vitamin D supplementation did not slow aortic valve calcification progression in elderly men, despite improving a biomarker of vitamin K status.

Does menaquinone-7 (MK-7) supplementation, combined with vitamin D, reduce the progression rate of aortic valve calcification (AVC) in men with aortic stenosis?

Hypothesis: Menaquinone-7 (MK-7), a cofactor for carboxylation of proteins inhibiting arterial calcification, may reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis.

This was a randomized, double-blind, multicenter trial involving 365 men from the community with an AVC score >300 arbitrary units (AU). Participants were randomized to receive daily treatment with 720 µg MK-7 plus 25 µg vitamin D or a matching placebo for 24 months. The primary outcome was the change in AVC score, with secondary outcomes including changes in aortic valve area, peak aortic jet velocity, heart valve surgery, aortic and coronary artery calcification, and dp-ucMGP levels. Safety outcomes included all-cause death and cardiovascular events.

The mean increase in AVC score was 275 AU in the intervention group and 292 AU in the placebo group, with a mean difference of 17 AU. There were no significant differences between groups in changes in aortic valve area, peak aortic jet velocity, or progression of aortic and coronary artery calcification. The rates of heart valve surgery (1 vs 2 patients), all-cause death (1 vs 4 patients), and cardiovascular events (10 vs 10 patients) were also not significantly different. However, a significant reduction in dp-ucMGP was observed in the MK-7 plus vitamin D group (-212 pmol/L) compared to the placebo group (45 pmol/L).

In elderly men with an AVC score >300 AU, 2 years of MK-7 plus vitamin D supplementation did not influence the progression of aortic valve calcification, despite a significant reduction in dp-ucMGP.

The study was conducted on elderly men from the community with a specific AVC score, which may limit generalizability to other populations or those with different stages of aortic stenosis.


Evidence: anti-glycation dipeptide antioxidant

This study protocol outlines a trial to investigate if carnosine supplementation improves cardiometabolic health and cognitive function in individuals with pre-diabetes and type 2 diabetes.

Does carnosine supplementation improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes?

Hypothesis: The study aims to investigate if carnosine supplementation improves cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes.

This will be a parallel design randomized controlled trial. Fifty participants aged 18-70 with pre-diabetes or T2DM (HbA1c < 8%) will be randomly assigned to either an intervention group receiving 2g of carnosine daily or a control group receiving an identical placebo for 14 weeks. Baseline and post-intervention measurements will include anthropometrics, oral glucose tolerance, cardiovascular parameters, cognitive function, physical activity, heart rate variability, liver fibroscan, and questionnaires on dietary habits, sleep, depression, and quality of life. Changes in these parameters will be compared between groups.

This is a study protocol, and no results are available yet.

This is a study protocol, and no conclusions can be drawn yet.

This is a study protocol, and limitations of the study design are not discussed in the abstract.


Evidence: Apolipoprotein B particle count

ApoB and non-HDL cholesterol are better indicators of residual risk for death and heart attack in statin-treated patients than LDL cholesterol.

Are elevated apolipoprotein B (apoB) and/or non-high-density lipoprotein (non-HDL) cholesterol superior to elevated low-density lipoprotein (LDL) cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction?

Hypothesis: The study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction.

The study included 13,015 statin-treated patients from the Copenhagen General Population Study with a median follow-up of 8 years. Cox regressions were used to examine associations between apoB, non-HDL cholesterol, and LDL cholesterol with all-cause mortality or myocardial infarction, both on continuous scales and by categories of concordant and discordant values defined by medians.

High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, while high LDL cholesterol showed no such associations. Discordant high apoB with low LDL cholesterol yielded hazard ratios of 1.21 for all-cause mortality and 1.49 for myocardial infarction. Discordant high non-HDL cholesterol with low LDL cholesterol yielded hazard ratios of 1.18 for all-cause mortality and 1.78 for myocardial infarction. Discordant high apoB with low non-HDL cholesterol yielded a hazard ratio of 1.21 for all-cause mortality and 0.93 for myocardial infarction. Dual discordant high apoB and non-HDL cholesterol with low LDL cholesterol showed hazard ratios of 1.23 for all-cause mortality and 1.82 for myocardial infarction.

In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. ApoB is a more accurate marker of all-cause mortality risk than LDL cholesterol or non-HDL cholesterol, and a more accurate marker of myocardial infarction risk than LDL cholesterol.


Evidence: Lipoprotein(a) concentration

Higher lipoprotein(a) levels are modestly and independently associated with an increased risk of coronary heart disease and stroke, but not with nonvascular deaths.

What is the relationship between lipoprotein(a) (Lp[a]) concentration and the risk of major vascular and nonvascular outcomes?

Hypothesis: Circulating concentration of lipoprotein(a) (Lp[a]) may be associated with an increased risk of coronary heart disease (CHD) and stroke.

This study identified 36 long-term prospective studies published between January 1970 and March 2009 that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality. Individual records for 126,634 participants were analyzed, excluding those with preexisting CHD or stroke at baseline. Within-study regression analyses, adjusted for within-person variation, were combined using meta-analysis.

During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded. Lp(a) concentration showed weak correlation with conventional vascular risk factors and was highly consistent within individuals over several years. The rates of CHD in the top and bottom thirds of baseline Lp(a) distributions were 5.6 and 4.4 per 1000 person-years, respectively. The risk ratio for CHD was 1.16 per 3.5-fold higher usual Lp(a) concentration (adjusted for age and sex) and 1.13 after further adjustment for other risk factors. The adjusted risk ratio for ischemic stroke was 1.10, while for nonvascular mortality, cancer deaths, and nonvascular deaths other than cancer, the risk ratios were 1.01, 1.00, and 1.00, respectively.

Lp(a) concentration has continuous, independent, and modest associations with the risk of coronary heart disease and stroke, and these associations appear to be exclusive to vascular outcomes.


Evidence: High-sensitivity C-reactive protein

Higher CTI levels are linked to increased risk of cardiovascular disease and mortality, particularly in individuals without diabetes.

What is the association between the C-reactive protein-triglyceride-glucose index (CTI) and cardiovascular disease (CVD) mortality, CVD incidence, and all-cause mortality?

Hypothesis: The study hypothesized that CTI, an innovative composite marker for metabolic-inflammatory dysregulation, would be associated with CVD mortality, CVD incidence, and all-cause mortality.

This study analyzed data from 8,679 adults from the National Health and Nutrition Examination Survey (NHANES) 2001-2010, 2015-2018. The CTI was calculated as 0.412* Ln (CRP [mg/L]) + Ln (TG [mg/dl] FPG [mg/dl])/2, and participants were divided into quartiles. Kaplan-Meier curves, cox proportional hazards models, logistic regression analyses, and restricted cubic spline (RCS) were used to assess associations across sex-stratified, age-specific, and glycemic subgroups.

CTI was significantly and positively associated with CVD mortality, total CVD incidence, and all-cause mortality. CTI predicted CVD mortality (HR 2.28) and all-cause mortality (HR 2.14). The CTI index correlated with the risk of total CVD (OR 2.85), congestive heart failure (OR 3.66), coronary heart disease (OR 2.82), angina pectoris (OR 2.85), heart attack (OR 2.59), and stroke (OR 2.86). The association was similar across sexes and age groups, but high CTI was linked to increased CVD risk only in individuals without diabetes mellitus.

Elevated CTI levels are significantly associated with CVD incidence and mortality, suggesting CTI could be a unique predictive marker for CVD risk.

The association between high CTI and increased CVD risk was not observed in individuals with diabetes mellitus.


Evidence: Erythrocyte EPA+DHA percentage

Maintaining an optimal Omega-3 Index (8-11%) is linked to better brain health and should be used to guide EPA and DHA supplementation.

What is the significance of the erythrocyte EPA+DHA percentage (Omega-3 Index) for brain health and how does it relate to the design and interpretation of EPA and DHA intervention trials?

Hypothesis: The abstract implies that an optimal Omega-3 Index is crucial for brain health and that using the Omega-3 Index to guide EPA and DHA interventions could improve trial outcomes and clarify their effects.

This is a review article summarizing existing evidence regarding the Omega-3 Index, its association with brain health outcomes from epidemiological studies, and its implications for the design and interpretation of EPA and DHA intervention trials.

The Omega-3 Index ranges from 2% to 20%, with an optimal range of 8-11%. A lower Omega-3 Index is associated with increased risks for total mortality, ischemic stroke, reduced brain volume, impaired cognition, accelerated dementia progression, psychiatric diseases, and compromised complex brain functions. Intervention trials often yield neutral results when not considering baseline blood levels, but when trial results are evaluated using measured blood levels of EPA and DHA, effects are larger and align with epidemiological findings.

The Omega-3 Index is a valuable biomarker for assessing EPA and DHA status, reflecting brain health risks, and should be used to guide the design and interpretation of future EPA and DHA intervention trials for more targeted and effective use.

The abstract does not explicitly state limitations of the Omega-3 Index itself or the reviewed studies, but it highlights that many intervention trials have produced neutral results due to design flaws (e.g., not considering baseline blood levels).


Evidence: Glycated hemoglobin (3-month glucose)

Low glycated hemoglobin levels do not appear to increase mortality risk in a non-diabetic UK population; risk only rises above 5.5%.

Does a low level of glycated hemoglobin (HbA1c) increase mortality risk in a UK population without known diabetes or cardiovascular disease?

Hypothesis: The study aimed to examine the shape of the risk relationship between glycated hemoglobin and mortality, particularly addressing the debate about increased mortality risk associated with low levels of glycaemia.

The study included 17,196 men and women aged 39-82 years from the EPIC-Norfolk Study, all without known diabetes or cardiovascular disease. Hazard ratios (HRs) for total and cause-specific mortality were estimated using Cox regression, comparing categories of glycated hemoglobin (<4.5%, 4.5% to <5.0%, 5.0% to <5.5% [reference], 5.5% to <6.0%, 6.0% to <6.5%, and ">="6.5%).

During a mean follow-up of 11.2 years, 1,953 participants died. The HR for all-cause mortality increased with increasing glycated hemoglobin categories. Spline regression indicated no increased risk at the low end of the distribution, with the HR for all-cause mortality remaining constant in the low range and only beginning to rise at approximately 5.5%. Similar associations were observed for cause-specific mortality, with the strongest link to cardiovascular mortality.

The findings in this large non-diabetic population do not support the concern about increased mortality risk associated with low glycated hemoglobin levels. Differences in population characteristics might account for conflicting results from previous studies and warrant further investigation.

The abstract mentions that differences in population characteristics might explain contrary results of earlier studies, suggesting a potential limitation in generalizability to other populations.


Evidence: Fasting insulin and HOMA-IR

High insulin resistance (HOMA-IR) is linked to increased risk of death from any cause and cardiovascular disease in non-diabetic adults, but high fasting insulin alone is not.

Is elevated fasting insulin or insulin resistance (HOMA-IR) associated with an increased risk of cardiovascular or all-cause mortality in non-diabetic adults?

Hypothesis: The study aimed to evaluate the association of elevated fasting insulin levels or insulin resistance (HOMA-IR) with cardiovascular or all-cause mortality in non-diabetic adults, given conflicting results from previous studies.

This meta-analysis searched PubMed and Embase databases for prospective observational studies published until November 2016. Studies investigating the association of elevated fasting insulin or HOMA-IR with cardiovascular or all-cause mortality in non-diabetic adults were included. Risk ratios (RR) with 95% confidence intervals (CIs) were pooled for the highest compared with the lowest categories of fasting insulin or HOMA-IR.

Seven articles involving 26,976 non-diabetic adults were included. The pooled adjusted RR for all-cause mortality was 1.13 (95% CI: 1.00-1.27) for fasting insulin and 1.34 (95% CI: 1.11-1.62) for HOMA-IR. For cardiovascular mortality, the pooled adjusted RR was 2.11 (95% CI: 1.01-4.41) for HOMA-IR (from two studies) and 1.40 (95% CI: 0.49-3.96) for fasting insulin (from one study).

Insulin resistance as measured by HOMA-IR, but not fasting insulin, appears to be independently associated with a greater risk of cardiovascular or all-cause mortality in non-diabetic adults.

The association of fasting insulin and HOMA-IR with cardiovascular mortality may be unreliable due to the small number of articles included for these specific associations.


Evidence: Plasma homocysteine

Higher homocysteine levels are associated with increased risk of death from cardiovascular causes and all causes, especially in older adults.

Does elevated homocysteine predict coronary heart disease (CHD) mortality, cardiovascular mortality, or all-cause mortality in the general population?

Hypothesis: The study hypothesized that elevated homocysteine levels would be a predictor of increased mortality.

A meta-analysis was conducted by systematically searching PubMed and Embase for prospective observational studies published before October 2013. The studies evaluated the association between baseline homocysteine levels and CHD, cardiovascular, or all-cause mortality. Pooled adjusted risk ratios (RR) and 95% confidence intervals (CI) were calculated for both categorical and continuous risk estimates.

Twelve studies with 23,623 subjects were included. Comparing the highest to lowest homocysteine categories, CHD mortality increased by 66%, cardiovascular mortality by 68%, and all-cause mortality by 93%. For each 5 μmol/L homocysteine increment, the pooled RR was 1.52 for CHD mortality, 1.32 for cardiovascular mortality, and 1.27 for all-cause mortality.

Elevated homocysteine levels are an independent predictor for subsequent cardiovascular mortality and all-cause mortality. The risks were more pronounced in elderly individuals.

The abstract does not explicitly state limitations of the meta-analysis.


Evidence: Serum ferritin (iron stores)

Iron status is linked to mortality risk, with different associations observed in people with and without diabetes, suggesting personalized approaches to iron management.

What is the association between iron status biomarkers and all-cause or cause-specific mortality, and does this association differ between people with and without diabetes mellitus?

Hypothesis: The study aimed to investigate associations between iron metabolic biomarkers and all-cause and cause-specific mortality risk in the general population, and to explore heterogeneities in these associations among populations with and without diabetes mellitus.

The study included 29,166 adults from NHANES III and NHANES 1999-2010, with mortality data linked to the National Death Index up to December 31, 2019. Cox proportional-hazard models and Fine-Gray subdistribution hazard models were used to analyze the associations between iron metabolic biomarkers and mortality outcomes.

During a median follow-up of 18.83 years, 9,378 deaths were observed, including 3,420 cardiovascular disease (CVD) deaths and 1,969 cancer deaths. A linear association between serum ferritin (SF) and all-cause mortality was found in the overall population and those without diabetes. J-shaped associations between transferrin saturation (TSAT) and all-cause and CVD mortality were observed across all populations. In the overall population, the adjusted hazard ratio (HR) for all-cause mortality in the fourth quartile (Q4) of SF was 1.13 (1.05-1.21) compared to the first quartile (Q1), while for TSAT, the HR in Q4 was 0.93 (0.88-0.99). For individuals without diabetes, the adjusted HR of Q4 SF was 1.19 (1.03-1.37) for CVD mortality and 1.25 (1.05-1.48) for cancer mortality. In individuals with diabetes, the adjusted HRs of Q4 TSAT were 0.76 (0.62-0.93) for CVD mortality and 1.47 (1.07-2.03) for cancer mortality.

Abnormalities in iron metabolism increase mortality risk in the general population. The associations between iron status and mortality differ significantly between individuals with and without diabetes mellitus, suggesting a need for tailored strategies for iron homeostasis.


Evidence: TSH and thyroid function

Subclinical thyroid dysfunction is linked to increased cardiovascular risks, with treatment and screening guidelines varying but generally recommending intervention for significant TSH deviations and screening for at-risk populations.

What is the current evidence regarding the association between subclinical thyroid dysfunction and cardiovascular disease, and what are the recommendations for screening and treatment?

Hypothesis: The review aims to update current evidence on the association between thyroid dysfunction and cardiovascular disease, as well as on screening and treatment of subclinical thyroid dysfunction.

This review summarizes evidence from individual participant data (IPD) analyses of prospective cohort studies from the international Thyroid Studies Collaboration and other small studies.

Subclinical hypothyroidism (SHypo) is associated with increased coronary heart disease (CHD) mortality (HR 1.58 for TSH ">=" 10 mIU/L), increased risk of stroke, and heart failure (HF). SHypo also affects carotid intima media thickness (CIMT), diastolic function, peripheral vascular resistance, endothelial function, and lipid profile. Subclinical hyperthyroidism (SHyper) is associated with increased risk of atrial fibrillation (AF) (HR 1.68) and CHD events (HR 1.21).

Subclinical thyroid dysfunction is associated with various cardiovascular risks. Treatment for SHypo is suggested at TSH ">=" 10 mIU/L, and for SHyper at TSH "<" 0.1 mIU/L. Screening is advocated for individuals at risk for hypothyroidism, those over 60, and those with known CHD and HF.

The TSH threshold for initiating treatment is unclear due to the absence of large randomized controlled trials. Recommendations on screening are discordant.


Evidence: Hair cortisol (chronic stress)

Hair cortisol is a promising biomarker for chronic stress linked to cardiovascular disease and its risk factors, but more robust research is needed.

What is the role of hair cortisol as a biomarker for chronic stress in cardiovascular disease (CVD)?

Hypothesis: Hair cortisol may be a reliable biomarker of chronic stress, and elevated levels may be associated with the incidence, prognosis, and cardiometabolic risk factors of CVD.

This is a review article that outlines the cardiovascular consequences of cortisol excess and provides an overview of recent studies investigating the relationship between hair cortisol and CVD. It also discusses clinical implications, limitations, and future research directions.

Hair cortisol provides quantification of total cortisol secreted into hair over several weeks, making it a potential biomarker for chronic stress. Elevated hair cortisol levels are associated with both the incidence of CVD and poorer recovery and treatment outcomes. Increased hair cortisol concentration has also been linked with cardiometabolic risk factors for CVD, including high blood pressure, diabetes, and adiposity.

Hair cortisol is a promising biomarker of chronic cortisol excess that may contribute to both the pathogenesis and prognosis of CVD.

The current evidence relies on small-scale cross-sectional studies.


Evidence: NMR LDL/HDL particle number

Plozasiran significantly reduces harmful triglyceride-rich lipoproteins and shifts LDL to larger, potentially less atherogenic particles, without increasing overall LDL particle count.

unfavorable-cue: "harmful" | favorable-cue: "significantly reduces harmful triglyceride"

What is the impact of plozasiran, an investigational siRNA targeting hepatic apoC-III, on lipoprotein particle concentration and subclass distribution in patients with severe hypertriglyceridemia and mixed hyperlipidemia?

Hypothesis: Reductions in the number of triglyceride-rich lipoprotein particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected.

This study analyzed data from 403 patients across two phase 2 studies, SHASTA-2 (severe hypertriglyceridemia) and MUIR (mixed hyperlipidemia). Patients received two subcutaneous doses of plozasiran (10, 25, or 50 mg) or placebo at baseline and week 12. Lipoprotein profiling was performed using nuclear magnetic resonance (NMR).

In SHASTA-2, plozasiran led to dose-dependent reductions in TRL-P, with total TRL-P decreasing by -46%. Total LDL-P remained unchanged, but large LDL-P increased by +53% and medium LDL-P by +56%, while small LDL-P trended lower (-13%). Total HDL-P increased by +8%, primarily due to a +36% increase in large HDL-P. In MUIR, total TRL-P was reduced by -48% (pooled plozasiran). Total LDL-P was unchanged, but large and medium LDL-P increased by +88% and +46% respectively, and small LDL-P decreased by -28%. Total HDL-P increased by +12%, driven by an +83% increase in large HDL-P.

Plozasiran reduced apoC-III and induced potentially favorable quantitative and qualitative changes in lipoproteins, including a ~50% reduction in TRL-P, a shift in LDL to larger particles, and a modest increase in HDL-P concentration, without increasing total LDL-P or apoB.

The abstract does not explicitly state limitations of the study. It suggests that the potential of plozasiran to lower cardiovascular risk needs to be evaluated in a prospective outcomes trial.


Evidence: Serum uric acid

Higher serum uric acid levels are linked to increased mortality risk in people with diabetes.

Is serum uric acid (SUA) level associated with all-cause and cardiovascular disease (CVD) mortality in individuals with diabetes?

Hypothesis: The study investigates an association between serum uric acid levels and mortality, implying a potential link.

This prospective cohort study analyzed data from 7,101 patients with diabetes from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999-2018. Mortality data were linked to national death records through December 31, 2019. Weighted Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for all-cause and CVD mortality. A meta-analysis of 13 additional cohort studies was also performed.

Among NHANES participants, the weighted mean SUA level was 5.7 mg/dL. During 57,926 person-years of follow-up, there were 1,900 deaths, with 674 attributed to CVD. Patients in the highest SUA quintile had an HR of 1.28 for all-cause mortality and 1.41 for CVD mortality compared to those in the lowest SUA quintile. The meta-analysis of 13 cohort studies showed pooled HRs of 1.08 for all-cause mortality and 1.05 for CVD mortality per 1 mg/dL increment of SUA.

Higher serum uric acid levels are associated with increased risks of both all-cause and cardiovascular disease mortality in individuals with diabetes.

The study design is observational, which means it can identify associations but not prove causation. The abstract does not explicitly state other limitations.


Evidence: Handgrip strength (muscle strength)

Grip-Strength Dynamometer;Hand Grip Dynamometer Pro

Lower grip strength is associated with increased risk of mortality and various diseases, and can improve the accuracy of health risk predictions.

unfavorable-cue: "increased risk" | favorable-cue: "improves"

Does grip strength associate with disease-specific incidence and mortality, and can it improve the predictive ability of an existing office-based risk score?

Hypothesis: The study implicitly hypothesizes that lower grip strength will be associated with higher incidence and mortality from various diseases, and that adding grip strength to an office-based risk score will enhance its predictive power.

This was a prospective population-based study using data from the UK Biobank, involving 502,293 participants (54% women) aged 40-69 years. The study followed participants for a mean of 7.1 years to assess all-cause mortality and incidence/mortality from cardiovascular disease, respiratory disease, COPD, and various cancers.

Over a mean follow-up of 7.1 years, 13,322 (2.7%) participants died. For every 5 kg lower grip strength, hazard ratios were significantly higher for all-cause mortality (1.20 for women, 1.16 for men) and cause-specific mortality from cardiovascular disease (1.19 women, 1.22 men), respiratory disease (1.31 women, 1.24 men), COPD (1.24 women, 1.19 men), all cancer (1.17 women, 1.10 men), colorectal cancer (1.17 women, 1.18 men), lung cancer (1.17 women, 1.08 men), and breast cancer (1.24 women). Prostate cancer showed no significant association (1.05). Muscle weakness (grip strength <26 kg for men, <16 kg for women) was linked to higher hazards for most health outcomes, except colon cancer in women and prostate/lung cancer in both sexes. Adding handgrip strength improved the C-index for predicting all-cause mortality (0.013), cardiovascular mortality (0.012), and cardiovascular disease incidence (0.009).

Higher grip strength is associated with a range of positive health outcomes, and its inclusion significantly improves the predictive ability of an established office-based risk score for several key health indicators.


Evidence: Calcaneal quantitative ultrasound

Lower heel bone density, as measured by ultrasound, is linked to a higher risk of death from any cause and cardiovascular disease in older women, even when accounting for other risk factors.

Is calcaneal quantitative ultrasound (QUS) associated with 15-year all-cause and cardiovascular disease (CVD) mortality in older women?

Hypothesis: The study aims to investigate the association between calcaneal QUS measurements and 15-year all-cause and CVD mortality in older women.

This prospective study followed 1404 older women (mean age 75.2 years) from the Calcium Intake Fracture Outcome study (CAIFOS) for 15 years. Calcaneal bone was measured at baseline in 1998 using QUS. All-cause and CVD mortality were ascertained using linked data from the Western Australia data linkage system.

Over 15 years, 584 women died, with 223 deaths attributed to CVD. For every standard deviation reduction in broadband ultrasound attenuation (BUA), the relative hazard for all-cause mortality increased by 1.15 (multivariable-adjusted HR) and for CVD mortality by 1.20 (multivariable-adjusted HR), independent of cardiovascular risk factors. These associations remained significant even when hip BMD was included in the model, with all-cause mortality HR 1.19 and CVD mortality HR 1.28.

Broadband ultrasound attenuation (BUA) is associated with all-cause and cardiovascular disease mortality in older women, independently of bone mineral density and established cardiovascular disease risk factors.

The abstract does not explicitly state any limitations of the study.


Evidence: Blood pressure level and variability

24h Ambulatory BP Monitor;Validated Home BP Monitor

Variations in blood pressure over long, mid, and short terms are linked to increased risks of cardiovascular disease and mortality, independent of average blood pressure.

What are the associations of long-term, mid-term, and short-term variability in blood pressure, independent of mean blood pressure, with cardiovascular disease events and mortality?

Hypothesis: The study aimed to systematically review existing evidence, implying an expectation that blood pressure variability would be associated with cardiovascular outcomes and mortality.

The researchers conducted a systematic review and meta-analysis of prospective cohort studies and clinical trials in adults, excluding those on hemodialysis patients. They searched Medline, Embase, Cinahl, and Web of Science up to February 15, 2016, for full-text English articles. Standardized hazard ratios were extracted and combined using random effects meta-analysis for main analyses, excluding studies with high confounding risk. Outcomes included all-cause mortality, cardiovascular disease mortality, and cardiovascular disease events, while variability measures included standard deviation, coefficient of variation, variation independent of mean, and average real variability.

The review identified 41 papers (19 observational, 17 clinical trial cohorts) comprising 46 separate analyses. Long-term variability was studied in 24 papers, mid-term in four, and short-term in 15. After excluding 23 analyses due to high confounding risk, increased long-term variability in systolic blood pressure was associated with all-cause mortality (HR 1.15), cardiovascular disease mortality (HR 1.18), cardiovascular disease events (HR 1.18), coronary heart disease (HR 1.10), and stroke (HR 1.15). Increased mid-term and short-term variability in daytime systolic blood pressure were also associated with all-cause mortality (HR 1.15 and HR 1.10, respectively).

Long-term variability in blood pressure is associated with cardiovascular and mortality outcomes, independently of mean blood pressure, with associations similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short-term variability showed similar associations.

The study noted limited data for mid-term and short-term variability. A significant number of analyses (23) were excluded from the main analyses due to high risks of confounding, indicating a common pitfall in existing research.


Evidence: Gamma-glutamyl transferase

Higher GGT levels are linked to an increased risk of death from all causes and specific diseases like heart disease, cancer, respiratory illness, and liver disease.

What is the association between gamma-glutamyl transferase (GGT) levels and all-cause and disease-specific mortality?

Hypothesis: The study aims to examine the association of GGT with all-cause and disease-specific mortality, given inconsistent population-based data.

This study used the Korean nationwide database, including 9,687,066 subjects without viral hepatitis or cirrhosis who underwent a health examination in 2009. Subjects were categorized into three groups based on sex-specific tertiles of serum GGT levels. The underlying causes of death were classified using the 10th Revision of the International Classification of Diseases codes. The median follow-up period was 8.3 years.

During the 8.3-year follow-up, 460,699 deaths were identified. All-cause mortality increased with higher serum GGT levels (HR 1.05 in the middle tertile, 1.33 in the high tertile). Similar trends were observed for cardiovascular disease (HR 1.07 in the middle tertile, 1.29 in the high tertile), cancer (HR 1.08 in the middle tertile, 1.38 in the high tertile), respiratory disease (HR 1.10 in the middle tertile, 1.39 in the high tertile), and liver disease mortality (HR 1.74 in the middle tertile, 6.73 in the high tertile). These associations persisted regardless of smoking, alcohol consumption, and history of previous CVD and cancer.

Higher serum GGT levels are associated with an increased risk of all-cause and disease-specific mortality in the general population. Serum GGT levels may be useful for risk assessment.


Evidence: Cystatin C-based eGFR

Lower kidney function and higher albuminuria are linked to increased risks of kidney failure, cardiovascular disease, and hospitalizations.

unfavorable-cue: "associated with increased"

What are the associations of lower eGFR (based on creatinine alone or combined with cystatin C) and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes?

Hypothesis: Lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria will be associated with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes.

This was an individual-participant data meta-analysis of 114 global cohorts from 1980 to 2021. The study included 27,503,140 individuals for eGFR based on creatinine alone, 720,736 individuals for eGFR based on creatinine and cystatin C, and 9,067,753 individuals for albuminuria. eGFR was estimated using the Chronic Kidney Disease Epidemiology Collaboration 2021 equations, and albuminuria was estimated as urine albumin to creatinine ratio (UACR). The risks of 10 adverse outcomes were analyzed within each cohort and summarized with random-effects meta-analyses.

Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with a higher risk for all 10 adverse outcomes, even in the mildest categories of chronic kidney disease. For example, among individuals with UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared to an eGFR of 90 to 104 mL/min/1.73 m2. This represented an adjusted hazard ratio of 1.3 and an excess absolute risk of 22 events per 1000 person-years.

Lower eGFR, whether based on creatinine alone or combined with cystatin C, and more severe UACR are each associated with increased rates of adverse kidney outcomes, cardiovascular diseases, and hospitalizations.


Evidence: NT-proBNP natriuretic peptide

New Canadian guidelines recommend using NT-proBNP before noncardiac surgery for risk assessment and outline specific pre- and post-operative cardiac management strategies.

What are the updated Canadian Cardiovascular Society guidelines for perioperative cardiac risk assessment and management in patients undergoing noncardiac surgery?

Hypothesis: The Canadian Cardiovascular Society Guidelines Committee and key Canadian opinion leaders believed there was a need for updated guidelines using the GRADE system for perioperative cardiac risk assessment and management.

The Canadian Cardiovascular Society Guidelines Committee, along with key Canadian opinion leaders, developed updated guidelines using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of evidence assessment.

Strong recommendations were made for: 1) measuring BNP or NT-proBNP before surgery in specific patient groups; 2) against several preoperative cardiac tests; 3) against routine acetylsalicylic acid for perioperative cardiac event prevention, with exceptions; 4) against initiating α-agonist or β-blocker within 24 hours before surgery; 5) withholding ACE inhibitor and ARB starting 24 hours before surgery; 6) facilitating smoking cessation before surgery; 7) measuring daily troponin for 48-72 hours after surgery in specific patient groups; and 8) initiating long-term acetylsalicylic acid and statin therapy in patients with postoperative myocardial injury/infarction.

The updated Canadian Cardiovascular Society guidelines provide strong recommendations for perioperative cardiac risk estimation and management, including the use of natriuretic peptides and specific interventions, while advising against certain common practices.

The abstract does not explicitly state any limitations of the guideline development process or the recommendations themselves.


Evidence: near-infrared light to cortex, BDNF

Near-infrared light therapy to the brain improved cognitive function and increased a neuroplasticity biomarker in older adults with mild cognitive impairment.

unfavorable-cue: "impairment" | favorable-cue: "improved"

Can transcranial photobiomodulation (t-PBM) improve cognition, mood, and biomarker levels in individuals with mild cognitive impairment (MCI)?

Hypothesis: Transcranial photobiomodulation (t-PBM) will improve cognition scores, depression, anxiety, resilience scores, and neuroplasticity biomarkers, while not altering neurodegeneration biomarkers, in individuals with MCI compared to a placebo.

A total of 93 older adults with MCI were randomized to either a t-PBM (n=47) or placebo (n=46) group. Clinical assessments and serum biomarker measurements (BDNF, NSE, S100B) were conducted at baseline, 60 days post-treatment, and a 150-day follow-up. Intervention effects were analyzed using repeated measures two-way ANOVA, Tukey post hoc test, Fischer's exact test, and Generalized Estimating Equations.

76 individuals completed the study (t-PBM: 40, placebo: 36). The t-PBM group showed significantly improved cognition (MoCA scores) compared to placebo (p=0.0301), with delta values of 3.20 for t-PBM and 1.97 for placebo. This cognitive improvement persisted until the three-month follow-up and was accompanied by increased BDNF levels in the t-PBM group (p=0.0046), with delta values of 821.94 for t-PBM and 359.41 for placebo. t-PBM did not alter depression, anxiety, resilience scores, or the levels of NSE and S100B.

Transcranial photobiomodulation increases cognitive function and BDNF levels in adults with MCI. It may serve as an adjunctive treatment to help prevent neurodegenerative diseases.

The study had a dropout rate, with 76 out of 93 participants completing the study. The abstract does not specify other limitations.


Evidence: pulsed electromagnetic fields

Pulsed electromagnetic field therapy may improve physical function in knee osteoarthritis but does not significantly reduce pain or stiffness.

Does classical pulsed electromagnetic field (PEMF) therapy effectively treat patients with knee osteoarthritis?

Hypothesis: The study implicitly hypothesizes that classical PEMF therapy will improve outcomes such as pain, stiffness, and physical function in patients with knee osteoarthritis.

A systematic review and meta-analysis were conducted by searching PubMed, EMBASE, Web of Science, and Cochrane Library. The review included randomized controlled trials (RCTs) that compared classical PEMF therapy with placebo in patients with knee osteoarthritis. Data on pain, stiffness, and physical function were extracted from 8 RCTs involving 421 patients.

PEMF therapy improved physical function (weighted mean difference [WMD] = -5.28, 95% confidence interval [CI] -9.45 to -1.11, p = 0.01). However, it showed no significant advantage in reducing Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (WMD = -7.80, 95% CI -16.08 to 0.47, p = 0.06), WOMAC pain score (WMD = -1.06, 95% CI -2.30 to 0.17, p = 0.09), visual analogue scale pain score (WMD = -0.88, 95% CI -2.06 to 0.31, p = 0.15), or WOMAC stiffness score (WMD = -0.50, 95% CI -1.09 to 0.09, p = 0.1).

Pulsed electromagnetic field therapy is beneficial for improving physical function in patients with knee osteoarthritis, but it does not show an advantage in treating pain and stiffness.

Further randomized controlled trials are needed to confirm these findings and to determine the optimal parameters and treatment regimen for pulsed electromagnetic field therapy.


Evidence: vibration-driven muscle contraction

Resistance and mixed training improve muscle strength and gait speed in older adults with sarcopenia, while all three training types improve TUG times.

What are the effects of different exercise modes (resistance training [RT], whole body vibration training [WBVT], and mixed training [MT]) on muscle strength (knee extension strength [KES]) and physical performance (Timed Up and Go [TUG], gait speed [GS], and Chair Stand [CS]) in older people with sarcopenia?

Hypothesis: The study aimed to clarify the effects of different exercise modes on muscle strength and physical performance in older people with sarcopenia, implying an investigation into whether these modes would lead to improvements.

A systematic review and meta-analysis was conducted, retrieving studies published from January 2010 to March 2021 from six electronic databases. Two researchers independently extracted and evaluated studies. Pooled analyses for pre- and post-outcome measurements were performed using Review Manager 5.4 with standardized mean differences (SMDs) and fixed-effect models.

Twenty-six studies, including 1191 older people with sarcopenia, were analyzed. Compared to control, RT and MT significantly improved KES (RT: SMD = 1.36; MT: SMD = 0.62) and GS (RT: SMD = 2.01; MT: SMD = 0.69). WBVT showed no changes in KES (SMD = 0.65) or GS (SMD = 0.12). TUG times were significantly improved with all exercise training modes (SMD = -0.66). There were no changes in CS times with any exercise training modes (SMD = 0.11).

In older people with sarcopenia, KES and GS can be improved by resistance training and mixed training, but not by whole body vibration training. All three training modes improved TUG times, but none improved Chair Stand times.

The abstract does not explicitly state limitations of the systematic review and meta-analysis itself, beyond the inherent variability indicated by I values for some outcomes.


Evidence: quantifies handgrip-force biomarker

Lower handgrip strength is linked to a higher risk of death in dialysis patients.

What is the association between handgrip strength (HGS) and all-cause mortality in patients with chronic kidney disease undergoing dialysis?

Hypothesis: The study hypothesized that there would be an association between handgrip strength and all-cause mortality in patients with chronic kidney disease undergoing dialysis.

This meta-analysis included 9 prospective cohort studies identified by searching PubMed and EMBASE databases up to December 2, 2018. The studies evaluated the association between handgrip strength and all-cause mortality.

Patients with low HGS had a summary risk ratio of all-cause mortality of 1.88 compared to those with high HGS. For every 1-kg unit increase in HGS, the summary risk ratio of all-cause mortality was 0.95.

Low handgrip strength is associated with an increased risk of all-cause mortality in patients with chronic kidney disease undergoing dialysis.

The abstract does not explicitly state any limitations of the meta-analysis.


Evidence: oscillometric arterial pressure

Ambulatory blood pressure monitoring offers more precise cardiovascular risk prediction than traditional office measurements, especially for conditions like white-coat hypertension and gestational hypertension.

What is the prognostic significance of new techniques of automated blood pressure measurement, specifically oscillometric arterial pressure?

Hypothesis: The study aims to reach a consensus on the prognostic significance of new techniques of automated blood pressure measurement.

A Task Force on the prognostic significance of ambulatory blood pressure monitoring wrote a review in preparation for the Eighth International Consensus Conference. This synopsis was amended based on opinions aired at the conference and common ground reached in discussions.

Ambulatory monitoring refines cardiovascular event prediction beyond conventional blood pressure. White-coat hypertension (clinic BP ">= 140/90 mmHg, daytime ambulatory BP < 135/85 mmHg) carries a lower cardiovascular risk than sustained hypertension. A decreased nocturnal blood pressure fall (<10% of daytime level) is associated with worse prognosis. Some studies show an independent relationship between short-term blood pressure variability and cardiovascular outcome. Ambulatory blood pressure monitoring is a better predictor of maternal and fetal complications in gestational hypertension than office measurement. Ambulatory pulse pressure is a strong predictor of cardiovascular outcome, and the QKD interval correlates with left ventricular mass. Self-measurement of blood pressure is effective in identifying the white-coat effect under standardized conditions.

Ambulatory blood pressure measurement provides refined prognostic information compared to conventional readings. Further research is needed on the long-term nature of white-coat hypertension, especially in children, and the prognostic accuracy, applicability, and cost-effectiveness of self-measured blood pressure.

Intermittent ambulatory blood pressure monitoring techniques have limitations in quantifying short-term blood pressure variability. Reference values for ambulatory blood pressure in children are currently based on statistical parameters, and functional definitions of ambulatory hypertension are yet to be developed for this group. The issue of whether white-coat hypertension predisposes to sustained hypertension needs further research. More studies are required to fully elucidate the prognostic accuracy of self-measured blood pressure.


Evidence: auricular vagus stimulation

Daily transcutaneous vagus nerve stimulation reduced postural tachycardia and improved related biomarkers in patients with POTS over two months.

Does low-level transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) reduce postural tachycardia in patients with Postural Tachycardia Syndrome (POTS) over a 2-month period?

Hypothesis: The authors hypothesized that tVNS would be beneficial in patients with POTS, based on preliminary animal studies and the known antiarrhythmic and anti-inflammatory effects of auricular vagus stimulation.

This was a sham-controlled, double-blind, randomized clinical trial. Participants with POTS received either active tVNS (20 Hz, 1 mA below discomfort threshold at the tragus) or sham stimulation (ear lobe) for 1 hour daily over 2 months. Postural tachycardia, heart rate variability, serum cytokines, and antiautonomic autoantibodies were measured at baseline and after 2 months.

At 2 months, the active tVNS group showed significantly less postural tachycardia (mean postural increase in heart rate 17.6 ± 9.9 beats/min) compared to the sham group (31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower, and heart rate variability was better in the active arm. No device-related side effects were observed.

The study concludes that noninvasive neuromodulation with tVNS can treat POTS, likely by reducing antiautonomic autoantibodies and inflammatory cytokines, and improving autonomic tone.

The abstract states that further studies are warranted, implying that this study, while supportive, is not definitive.


Evidence: high-resistance breath loading

Six weeks of high-resistance inspiratory muscle training can lower blood pressure and improve blood vessel function in older adults.

Does high-resistance inspiratory muscle strength training (IMST) improve blood pressure, endothelial function, and arterial stiffness in midlife/older adults with elevated systolic blood pressure?

Hypothesis: The study hypothesized that 6 weeks of high-resistance IMST would improve blood pressure, endothelial function, and arterial stiffness, and also investigated potential mechanisms and long-lasting effects.

A double-blind, randomized, sham-controlled trial was conducted with 36 midlife/older adults (aged 50-79 years) who had systolic blood pressure ≥120 mm Hg. Participants were randomized to either high-resistance IMST (75% maximal inspiratory pressure, n=18) or low-resistance sham training (15% maximal inspiratory pressure, n=18) for 30 breaths/day, 6 days/week for 6 weeks. Blood pressure, endothelial function (brachial artery flow-mediated dilation), and arterial stiffness were measured, along with markers of NO bioavailability, eNOS activation, reactive oxygen species, C-reactive protein, and circulating metabolites.

High-resistance IMST significantly decreased casual systolic blood pressure from 135±2 mm Hg to 126±3 mm Hg, with approximately 75% of this reduction sustained 6 weeks post-training. Casual diastolic blood pressure also modestly decreased from 79±2 mm Hg to 77±2 mm Hg. Twenty-four hour systolic blood pressure was lower after IMST compared to sham training. Brachial artery flow-mediated dilation improved by approximately 45% with IMST. Serum from participants after IMST showed increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity in cultured human umbilical vein endothelial cells. IMST also decreased C-reactive protein and altered select circulating metabolites. Sham training had no effect on blood pressure or endothelial function, and neither IMST nor sham training influenced arterial stiffness.

High-resistance IMST is a safe and highly adherable lifestyle intervention that effectively improves blood pressure and endothelial function in midlife/older adults with above-normal initial systolic blood pressure.


Evidence: device-guided paced breathing

Slow breathing techniques can modestly lower blood pressure in individuals with hypertension or prehypertension.

favorable-cue: "reduction in blood pressure"

What is the impact of device-guided and non-device-guided (pranayama) slow breathing on blood pressure reduction in hypertensive and prehypertensive patients at low cardiac risk?

Hypothesis: The study aims to assess if slow breathing interventions can reduce blood pressure in patients with hypertension or prehypertension.

This meta-analysis included randomized controlled trials or the first phase of randomized cross-over studies. Eligible studies involved subjects with hypertension, prehypertension, or those on antihypertensive medication, with interventions of slow breathing at 10 breaths/minute for 5 minutes on 3 days/week, lasting 4 weeks or more, and with a control group. Data were extracted by two independent authors, bias risk was assessed using the Cochrane Risk of Bias Tool, and data were pooled using the DerSimonian and Laird random effects model. Main outcomes were changes in systolic (SBP) and/or diastolic blood pressure (DBP), heart rate (HR), and/or decreased antihypertensive medication.

Seventeen studies were included in the meta-analysis from 103 eligible citations. Slow breathing interventions resulted in an overall decrease in systolic blood pressure (SBP) by -5.62 mmHg and diastolic blood pressure (DBP) by -2.97 mmHg. High heterogeneity was observed across all analyses.

Slow breathing leads to a modest reduction in blood pressure. It could be considered a reasonable initial treatment option for low-risk hypertensive and prehypertensive patients who prefer not to start medication.

The meta-analysis reported high heterogeneity for all analyses, which may affect the generalizability of the findings.


Evidence: sequential limb compression

Intermittent pneumatic compression on lower limbs may help reduce perceived muscle soreness after exercise, with 20-30 minute sessions at 80 mmHg being common protocols.

What are the effects of lower-limb intermittent pneumatic compression (IPC) on sports recovery, and what are the most effective protocols?

Hypothesis: The study implicitly hypothesizes that lower-limb IPC has beneficial effects on sports recovery and that specific protocols can optimize these effects.

A systematic review and meta-analysis were conducted following PRISMA guidelines, searching PubMed, Web of Science, SportDiscus, Academic Search Complete, and Science Direct. The search terms included variations of "Pneumatic compression" and "Recover*". Data from 17 studies (319 participants) were extracted, and standardized mean differences were calculated using a random-effects model. Methodological quality was assessed with the PEDro scale.

Lower-limb IPC showed a trivial to small benefit for muscular function and a trivial to moderate effect for pain and soreness. The effect on muscle damage markers was highly variable. Protocols of 20 to 30 minutes and pressures of about 80 mmHg were the most frequently used options for optimizing recovery.

Lower-limb IPC has potential effects for sports recovery, primarily by reducing perceived soreness.

The methodological quality of the included studies ranged from fair to good, and the effect on muscle damage markers was highly variable, suggesting inconsistencies or limited efficacy in this area.


Evidence: rapid percussion, neuromuscular recovery

Percussion massage did not improve recovery from muscle damage caused by intense eccentric exercise.

Does percussion massage accelerate neuromuscular recovery and performance after eccentric exercise-induced muscle damage?

Hypothesis: The study implicitly hypothesized that percussion massage would accelerate recovery after high-intensity muscle damaging eccentric exercise.

Twenty healthy, active volunteers performed eccentric elbow flexion exercise on their nondominant arm. They were randomized into a percussion massage group (n=10) or a control group (n=10). The percussion group received 5 minutes of massage immediately, 24 hours, and 48 hours post-exercise. Muscle soreness, range of motion, arm circumference, isometric strength, voluntary activation, and resting twitch were measured at baseline, immediately after exercise, and at 24, 48, and 168 hours post-exercise.

Significant main effects for time were observed in all measured variables, indicating changes over time. However, no significant interactions between time and group, or overall group differences, were found for any of the muscle damage markers.

Percussion massage does not accelerate recovery after high-intensity muscle-damaging eccentric exercise.


Evidence: progressive balance and power training

This study protocol outlines a trial to evaluate a fall prevention exercise program for older adults, including supervised and home-based versions, and will assess detraining effects.

What are the effects of a fall prevention program on balance, strength/power, body composition, cognition, psychosocial well-being, and falls self-efficacy in healthy older adults, and what are the time-related effects of detraining?

Hypothesis: The supervised combination of balance and strength/power training will improve performance in variables of balance, strength/power, body composition, cognitive function, psychosocial well-being, and falls self-efficacy in older adults.

Healthy older adults (n=54, aged 65-80 years) will be randomized into two intervention groups or a control/waiting group. Intervention groups will complete a 12-week balance and strength/power exercise intervention 3 times per week for 30 minutes per session. One intervention group will receive extensive supervised training, while the other will complete a home-based short version ('3 times 3') controlled by weekly phone calls. The control group will not receive an intervention during the experimental period. Measures of static/dynamic steady-state balance, proactive balance, reactive balance, strength, power, body composition, psychosocial well-being, cognition, and fall self-efficacy will be assessed at baseline, immediately post-intervention, and 12 weeks after program cessation to evaluate detraining effects.

This abstract describes the study protocol and does not present any results from the trial.

This abstract outlines the design of a study to assess the effects of a fall prevention program on various health outcomes in older adults, as well as detraining effects. No conclusions can be drawn as the study has not yet been conducted or reported its findings.

This abstract describes a study protocol and does not discuss limitations of the study itself, as no results have been presented.


Evidence: gate-control nerve stimulation

TENS effectively reduces pain intensity compared to placebo with generally mild side effects.

What is the efficacy and safety of transcutaneous electrical nerve stimulation (TENS) for pain relief in adults?

Hypothesis: The study implicitly hypothesizes that TENS is effective and safe for pain relief in adults compared to placebo or other treatments.

This systematic review and meta-analysis included 381 randomized controlled trials (RCTs) with 24,532 participants. Reviewers independently screened, extracted data, and assessed risk of bias and certainty of evidence. Random effect models were used to calculate standardized mean differences (SMD) and risk ratios for mean pain intensity and proportions of participants achieving pain reductions (≥30% or ≥50%) during or immediately after TENS.

Pain intensity was lower during or immediately after TENS compared with placebo (91 RCTs, 4841 participants, SMD=-0.96, moderate-certainty evidence). This effect was not modified by methodological or pain characteristics. Pain intensity was also lower during or immediately after TENS compared with pharmacological and non-pharmacological standard care treatments (61 RCTs, 3155 participants, SMD=-0.72, low-certainty evidence). Adverse events were poorly reported but generally mild and similar to comparators.

There is moderate-certainty evidence that pain intensity is lower during or immediately after TENS compared with placebo, and TENS is not associated with serious adverse events.

The certainty of evidence was downgraded due to small-sized trials contributing to imprecision in magnitude estimates. Data on adverse events were limited and poorly reported.


Evidence: microcurrent for sleep and mood

A microcurrent device improved depression and physical well-being, and altered brain activity, in people with subclinical insomnia, but did not significantly improve sleep more than a sham device.

no-difference-cue: "did not significantly improve" | favorable-cue: "improve"

Can a novel microcurrent device improve sleep and mood symptoms in individuals with subclinical insomnia?

Hypothesis: The researchers hypothesized that a novel cranial electrotherapy stimulation device providing stable electronic stimulation would improve sleep and accompanying mood symptoms in people with subclinical insomnia.

Participants with subclinical insomnia were randomly assigned to either an active or a sham device group. They used the device for 30 minutes, twice daily, for two weeks. Outcome measures included questionnaires for sleep, depression, anxiety, and quality of life, 4-day actigraphy, and 64-channel electroencephalography.

The active device group showed significant improvement in depression (p = 0.032) and physical well-being (p = 0.041) compared to the sham group. Anxiety also improved in the active group, but not significantly (p = 0.090). Both groups reported significant subjective sleep improvement, with no significant difference between groups. Electroencephalography changes after two weeks were significantly different between groups, particularly for occipital delta (p = 0.008), beta power (p = 0.012), and temporo-parieto-occipital theta (p = 0.022).

Cranial electrotherapy stimulation may be an adjunctive therapy to improve psychological symptoms and alter brain activity.

The study's limitations include the need for further investigation into the device's effects in a clinical population and the optimal stimulation parameters.


Evidence: self-myofascial release

Self-myofascial release can acutely improve flexibility, reduce muscle soreness, and aid recovery, but its long-term effects on flexibility are unclear.

What are the acute and chronic clinical effects of self-myofascial release (SMFR)?

Hypothesis: The study aimed to review existing literature to understand the effects of SMFR.

PubMed and Google Scholar databases were searched in February 2015 for studies related to self-myofascial release.

Acutely, SMFR appears to increase flexibility, reduce muscle soreness, and does not hinder athletic performance. It may also acutely improve arterial function, vascular endothelial function, and increase parasympathetic nervous system activity. Long-term effects on flexibility show conflicting evidence.

SMFR has a range of potentially valuable acute effects for athletes and the general population, including increased flexibility and enhanced recovery. Long-term effects on flexibility are not consistently supported by current evidence.

The review did not specify the number or type of studies included, nor did it detail the specific tools or protocols used in the SMFR studies reviewed. The search was limited to two databases and a specific timeframe.


Evidence: low-load occlusion training

Low-load resistance training and walking combined with blood flow restriction effectively increase muscle mass and strength in older adults, with similar hypertrophy but lower strength gains compared to high-load training.

How does low-load blood flow restriction (LL-BFR) training influence muscle mass and strength in older adults compared to conventional resistance training, and what is the effectiveness of walking with and without BFR?

Hypothesis: The study aims to quantitatively identify the effects of LL-BFR training on muscle mass and strength in older individuals.

A PRISMA-compliant systematic review and meta-analysis was conducted. Electronic databases (PubMed, Web of Science, Scopus, CINAHL, SPORTDiscus, CENTRAL) were searched until June 1, 2018. A random-effects meta-analysis with inverse variance weighting was performed on 11 included studies with a total of 238 participants.

Adding BFR to low-load training and walking significantly improved muscular strength, with pooled effect sizes of 2.16 and 3.09, respectively. Muscle mass also increased when comparing walking with and without BFR (ES 1.82). Compared to high-load training, LL-BFR promoted similar muscle hypertrophy (ES 0.21) but resulted in lower strength gains (ES -0.42).

LL-BFR and walking with BFR are effective interventions for stimulating muscle hypertrophy and strength gains in older populations.

The BFR literature is still scarce regarding potential moderator variables such as sex, cuff pressure, or training volume/frequency, indicating a need for further research.


Evidence: electrical muscle contraction

Intradialytic electrical muscle stimulation improved muscle strength, size, and physical function in hemodialysis patients.

Can intradialytic electrical muscle stimulation (EMS) improve muscle wasting, weakness, and sarcopenia in hemodialysis (HD) patients?

Hypothesis: Intradialytic EMS will improve quadriceps muscle strength and size, and physical function in HD patients.

This was a prospective, open-label, randomized controlled trial. Twenty-nine HD patients were randomly assigned to either an EMS group or a control group, with 13 patients in each group analyzed. The EMS group received intradialytic EMS over an 8-week period. Measurements included isometric knee extensor strength, quadriceps cross-sectional area (CSA) via MRI, Timed Up and Go Test (TUG), SF-8 Health Survey, and blood tests, performed before and after the intervention.

The EMS group showed significant improvement compared to the control group in knee extensor strength (right: 22.3 vs. -10.8 N; left: 26.1 vs. -8.3 N), quadriceps CSA at three positions (25% right: 1.7 vs. -0.4 cm; 25% left: 1.3 vs. -0.6 cm; 50% right: 2.0 vs. -0.7 cm; 50% left: 2.7 vs. -0.7 cm; 75% right: 1.8 vs. -0.7 cm; 75% left: 2.1 vs. -0.4 cm), and TUG time (-0.8 vs. 0.2 s). Improvements in SF-8 components in the EMS group were not statistically significant.

Intradialytic electrical muscle stimulation (EMS) can be an effective exercise training tool for hemodialysis patients experiencing muscle wasting, weakness, or sarcopenia.

The study was open-label, which might introduce bias. The sample size for analysis was relatively small, with 13 patients in each group.


Evidence: paced breathing raises HRV

HRV biofeedback training shows promise for reducing self-reported stress and anxiety.

favorable-cue: "reduction in self-reported stress and anxiety"

Does heart rate variability (HRV) biofeedback effectively treat symptoms of anxiety and stress?

Hypothesis: HRV biofeedback might be an effective way to treat anxiety and stress symptoms.

A meta-analysis was conducted using studies from PubMed, PsycINFO, and the Cochrane Library. The search identified 24 studies with a total of 484 participants who underwent HRV biofeedback training for stress and anxiety. A random-effects meta-analysis was performed.

The pre-post within-group effect size (Hedges' g) was 0.81. The between-groups analysis comparing biofeedback to a control condition showed a Hedges' g of 0.83. Moderator analyses indicated that treatment efficacy was not influenced by study year, risk of study bias, percentage of females, number of sessions, or presence of an anxiety disorder.

HRV biofeedback training is linked to a significant reduction in self-reported stress and anxiety.

More well-controlled studies are needed to further confirm the efficacy of HRV biofeedback.


Evidence: reflective photoplethysmography

The EmbracePlus wristband accurately measures blood oxygen levels in healthy adults, including those with darker skin, under controlled conditions.

Can the EmbracePlus wristband accurately measure peripheral oxygen saturation (SpO2) using reflective pulse oximetry during controlled hypoxia in healthy adults, including those with darker skin pigmentation?

Hypothesis: The EmbracePlus wristband will demonstrate clinically acceptable accuracy in measuring SpO2 during controlled hypoxia, meeting FDA guidelines and showing consistent performance across different skin pigmentations and sexes.

Healthy adult participants underwent a controlled desaturation protocol to achieve SaO2 levels from 100% to 70%. The EmbracePlus wristband measured SpO2, while reference SaO2 was obtained from blood samples analyzed by a co-oximeter. The study followed ISO 80601-2-61:2017 and FDA guidance, including 30% participants with dark skin pigmentation (Fitzpatrick V-VI).

The study yielded 373 measurements from 15 subjects. The accuracy root mean square (Arms) error was 2.4%, which is within the FDA's 3.5% limit. A strong positive correlation (r = 0.96, p < 0.001) was found between wristband SpO2 and reference SaO2. Bland-Altman analysis showed good concordance (bias, 0.05%; standard deviation, 1.66; lower limit, -4.7%; upper limit, 4.8%). Accuracy was acceptable when stratified by skin pigmentation (2.2% in Fitzpatrick V-VI, 2.5% in Fitzpatrick I-IV) and sex (1.9% in females, 2.9% in males).

The EmbracePlus wristband can assess SpO2 with clinically acceptable accuracy under no-motion and high perfusion conditions in healthy individuals of different ethnicities across the claimed range.

The study was conducted under no-motion and high perfusion conditions in healthy subjects. Further evaluations are needed for unhealthy subjects and during prolonged use in ambulatory settings.


Evidence: deep-pressure stimulation

Weighted blankets effectively reduce insomnia and improve daytime symptoms and activity in individuals with certain psychiatric disorders.

What is the effect of weighted chain blankets on insomnia and sleep-related daytime symptoms in patients with major depressive disorder, bipolar disorder, generalized anxiety disorder, and attention deficit hyperactivity disorder?

Hypothesis: The study hypothesized that weighted chain blankets would improve insomnia and sleep-related daytime symptoms in the target patient population.

One hundred twenty patients were randomized (1:1) to either a weighted metal chain blanket or a light plastic chain blanket for 4 weeks. The primary outcome was the Insomnia Severity Index, with secondary outcomes including day and night diaries, Fatigue Symptom Inventory, Hospital Anxiety and Depression Scale, and wrist actigraphy for sleep and daytime activity levels. A 12-month open follow-up phase was also conducted.

At 4 weeks, the weighted blanket group showed a significant advantage in Insomnia Severity Index ratings compared to the light blanket group (P < .001) with a large effect size (Cohen's d 1.90). The weighted blanket also led to better sleep maintenance, higher daytime activity, and reduced daytime fatigue, depression, and anxiety. No serious adverse events were reported. During the 12-month follow-up, the positive effects on sleep were maintained by continuous users, and those who switched from a light to a weighted blanket experienced similar improvements.

Weighted chain blankets are an effective and safe intervention for insomnia in patients with major depressive disorder, bipolar disorder, generalized anxiety disorder, or attention deficit hyperactivity disorder, also improving daytime symptoms and activity levels.

The abstract does not explicitly state any limitations of the study.


Evidence: retinoic-acid precursor boosts collagen

Topical retinaldehyde is an effective and safe treatment for photoaged skin.

Can topical retinaldehyde improve the signs of photoaged skin?

Hypothesis: Retinaldehyde, as a precursor to retinoic acid, should have similar beneficial effects on photoaged skin.

The study used open and controlled clinical studies. Efficacy was assessed through image analysis of silicone skin replicas.

Topical retinaldehyde was found to be both efficient and safe.

Retinaldehyde is an efficient and well-tolerated treatment for improving the signs of photoaging.

The abstract does not specify any limitations of the study.


Evidence: collagen biosynthesis, photoprotection

A 5% vitamin C cream applied topically improved the appearance and structure of sun-damaged skin over 6 months.

Can topical application of a 5% vitamin C cream improve photoaged skin and is it well-tolerated?

Hypothesis: Topical vitamin C, known for its antioxidant and collagen-biosynthetic properties, may prevent and treat skin aging.

A 6-month double-blind, randomized trial compared a 5% vitamin C cream to an excipient on photoaged skin of healthy female volunteers' low-neck and arms. Clinical assessments by investigators and self-assessments by volunteers were performed at baseline, 3, and 6 months. Skin relief was measured using silicone replicas, and biopsies at the trial's end were analyzed with immunohistochemistry and electron microscopy.

Clinical and self-assessments showed significant improvement in the 'global score' on the vitamin C-treated side compared to the control. There was a highly significant increase in skin microrelief density and a decrease in deep furrows. Ultrastructural evidence of elastic tissue repair was also observed.

Topical application of 5% vitamin C cream was an effective and well-tolerated treatment, leading to clinically apparent improvement in photodamaged skin and inducing positive modifications in skin relief and ultrastructure, suggesting a beneficial effect on sun-induced skin aging.


Evidence: barrier and pigment modulation

Topical niacinamide improves multiple signs of facial aging, including wrinkles, hyperpigmentation, redness, yellowing, and elasticity.

What are the effects of topical niacinamide on skin appearance and properties, specifically wrinkles, yellowing, and elasticity?

Hypothesis: Topical niacinamide will improve the appearance of aging facial skin, including reductions in fine lines, wrinkles, hyperpigmented spots, red blotchiness, and skin sallowness, and will improve elasticity.

Fifty female white subjects with facial photoaging applied 5% niacinamide to half of their face and a vehicle control to the other half twice daily for 12 weeks. The study was double-blind and left-right randomized. Facial images and instrumental measures were taken at baseline and every 4 weeks.

Topical niacinamide significantly reduced fine lines and wrinkles, hyperpigmented spots, red blotchiness, and skin sallowness (yellowing). Skin elasticity, measured by cutometry, also improved.

Topical niacinamide provides additional benefits beyond previously observed effects, including improved appearance of skin wrinkles and yellowing, and improved elasticity.


Evidence: retinoid-mimicking gene expression

Bakuchiol is as effective as retinol for reducing wrinkles and hyperpigmentation, but causes less irritation.

Can bakuchiol provide similar anti-aging benefits to retinol with fewer side effects?

Hypothesis: Bakuchiol will demonstrate comparable efficacy to retinol in improving signs of facial aging, but with a better tolerability profile.

This was a 12-week, randomized, double-blind study involving 44 patients. Participants applied either 0.5% bakuchiol cream twice daily or 0.5% retinol cream daily. Facial photographs were analyzed at weeks 0, 4, 8, and 12. Patients also completed tolerability assessments, and a blinded dermatologist graded pigmentation and redness during visits.

Both bakuchiol and retinol significantly reduced wrinkle surface area and hyperpigmentation, with no statistical difference in efficacy between the two compounds. Retinol users reported more instances of facial skin scaling and stinging compared to bakuchiol users.

Bakuchiol is comparable to retinol in improving photoaging and is better tolerated, suggesting it could be a promising alternative to retinol.


Evidence: anti-inflammatory, antioxidant

Topical azelaic acid effectively reduces inflammatory lesions and erythema in papulopustular rosacea and is comparable to metronidazole.

What is the clinical efficacy of topical 20% azelaic acid cream and 15% azelaic acid gel compared with their respective vehicles and metronidazole gel in treating papulopustular rosacea?

Hypothesis: The study aims to evaluate the efficacy of azelaic acid formulations for papulopustular rosacea.

Electronic searches of MEDLINE, EMBASE, BIOSIS, SciSearch, and the Cochrane Central Register of Controlled Trials were conducted through July or August 2004. Hand searches of reference lists, conference proceedings, and clinical trial databases were also performed, and experts were contacted. Randomized controlled trials comparing topical azelaic acid (cream or gel) with placebo or other topical treatments for rosacea were included. Two authors independently identified studies, extracted data, and assessed methodological quality. Five studies involving 873 patients were included.

A meta-analysis could not be conducted due to a lack of standard deviation data for four of the five studies. Four of the five studies showed significant decreases in mean inflammatory lesion count and erythema severity after azelaic acid treatment compared with vehicle. No studies demonstrated a significant decrease in telangiectasia severity.

Topical 20% azelaic acid cream and 15% azelaic acid gel are effective for treating papulopustular rosacea, particularly in reducing inflammatory lesion count and erythema severity. Azelaic acid appears to be as effective as, or potentially better than, metronidazole.

A meta-analysis could not be performed because standard deviation data were unavailable for four out of five included studies.


Evaluating the Efficacy and Safety of Alpha-Hydroxy Acids in Dermatological Practice: A Comprehensive Clinical and Legal Review.

Alpha-hydroxy acids are effective for skin rejuvenation and treating various skin conditions, but more research is needed to determine optimal concentrations for safety and efficacy, and regulatory compliance is crucial.

What is the efficacy and safety of alpha-hydroxy acids (AHAs) in dermatological practice?

Hypothesis: AHAs are effective in skin rejuvenation and treating various skin conditions, but their optimal concentrations and safety require further research and regulatory adherence.

This study was a comprehensive clinical and legal review of the dermatological applications of AHAs, focusing on their use in cosmetic formulations like chemical peels.

AHAs, including glycolic and lactic acids, enhance skin rejuvenation by promoting apoptosis in skin cells, boosting collagen and elastin synthesis, and improving skin texture and luminosity. They are useful in treating conditions such as acne, hyperpigmentation, and photoaging. However, the precise optimal concentrations for therapeutic efficacy with minimal side effects are not yet defined.

AHAs are effective in cosmetic dermatology, but continued research is needed to define optimal concentrations, and rigorous regulatory adherence is essential for their safe and beneficial application.

The review indicates that optimal concentrations for therapeutic efficacy with minimal side effects are yet to be precisely defined, necessitating further research.


Benefits of topical hyaluronic acid for skin quality and signs of skin aging: From literature review to clinical evidence.

Topical hyaluronic acid improves skin hydration and rejuvenation and can extend the effects of Botulinum toxin type A in reducing wrinkles.

What are the benefits of topical hyaluronic acid (HA) for skin quality and signs of skin aging, and does it enhance the effects of Botulinum toxin type A (BoNTA)?

Hypothesis: Topical hyaluronic acid (HA) is an important component of the extracellular matrix and is expected to have hydration and anti-aging properties. It may also lengthen the duration of BoNTA's effect in reducing wrinkles.

A literature review was conducted using terms such as HA, hyaluronan, topical, dermatology, cosmetic, aging treatment, exposome, and cosmeceuticals. Additionally, results from a randomized controlled trial (RCT) were presented. In the RCT, subjects were randomized into two groups: one received HA-filler serum twice daily for 24 weeks starting 24 hours after a Botulinum toxin type A (BoNTA) injection, and the control group received only BoNTA.

HA is a key ingredient in cosmeceuticals due to its hydration and anti-aging properties (hygroscopic, rheological, and viscoelastic). Clinical studies indicate that HA is well tolerated and effective as an adjuvant to post-surgical and facial rejuvenation procedures. In the RCT, the HA-filler serum lengthened the duration of BoNTA's effect in reducing wrinkles.

HA-based cosmeceuticals are a noninvasive, effective solution for improving skin hydration and rejuvenation. Topical HA can also extend the duration of BoNTA's wrinkle-reducing effects.

The abstract does not explicitly state limitations of the literature review or the randomized controlled trial.


Sunscreen and prevention of skin aging: a randomized trial.

Daily sunscreen use significantly reduces skin aging, while β-carotene supplements showed no overall benefit.

Does regular use of sunscreen or β-carotene supplements retard skin aging, as measured by photoaging, compared to discretionary use or placebo?

Hypothesis: Regular use of sunscreen and/or β-carotene supplements will retard skin aging.

This was a randomized, controlled, community-based intervention conducted in Nambour, Australia. 903 adults younger than 55 years were randomly assigned to one of four groups: daily broad-spectrum sunscreen and 30 mg β-carotene, daily sunscreen and placebo, discretionary sunscreen and 30 mg β-carotene, or discretionary sunscreen and placebo. The change in microtopography between 1992 and 1996 was graded by blinded assessors to measure skin aging.

The daily sunscreen group showed no detectable increase in skin aging after 4.5 years. Skin aging from baseline to the end of the trial was 24% less in the daily sunscreen group compared to the discretionary sunscreen group. β-carotene supplementation had no overall effect on skin aging.

Regular sunscreen use retards skin aging in healthy, middle-aged men and women. No overall effect of β-carotene on skin aging was identified.

Some outcome data were missing, and the study's power to detect moderate treatment effects was modest.