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Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so \"Mendelian randomization\" studies using this variant as an instrumental variable could help test causality. Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases). The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.

To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (-2.57 vs. -1.80; adjusted mean difference: -0.77; 95% CI: -1.11 to -0.43; <0.0001). Secondary efficacy endpoints and most HRQoL scales showed greater improvements in the duloxetine group than the placebo group. Adverse events observed in ≥5% of patients that were more frequent in the duloxetine than placebo group were somnolence, constipation, dry mouth, nausea, malaise, and decreased appetite. There were no marked changes in range of motion of the knee joint (efficacy), X-ray images, or Kellgren-Lawrence grade (safety) in either group. Duloxetine reduced pain and improved function in patients with knee osteoarthritis, without causing X-ray abnormalities or altered knee joint mobility. Reduced pain was associated with improved HRQoL. Adverse events were consistent with duloxetine's known safety profile.

This study found that supplementing exclusively breastfed infants with a probiotic, Bifidobacterium infantis EVC001, between 2 and 4 months of age can successfully restore beneficial bacteria in their gut, even after the newborn period. Although previous research showed this effect in newborns, this is the first study to demonstrate that older infants, whose gut microbiomes are typically more stable, can still benefit. The probiotic was effective at all tested doses, with higher levels of B. infantis and overall Bifidobacteriaceae in infants' stool during and even 1 month after supplementation. This study demonstrates that B. infantis can take hold in the gut and potentially improve gut health in older breastfed babies, offering a promising approach to support infant health in settings where beneficial gut bacteria are often missing. This study was registered at clinicaltrials.gov as NCT03476447 .

Green tea bioactive compounds show promise as a potential functional food to improve blood lipid profiles and ameliorate cardiovascular diseases. To determine the effect of 6 weeks of green tea compared to the placebo beverage consumption on blood cardiometabolic biomarkers. A randomized double‐blinded placebo‐controlled trial was conducted on dyslipidemia participants and randomly allocated in green tea beverage (n = 30) and placebo beverage (n = 30) groups. Sixty dyslipidemia adults with age 30–60 years old participated. Change in blood parameters, including lipid profiles, liver and kidney functions, oxidative stress and antioxidant markers, gene expressions, and anthropometric parameters, was measured. After 6 weeks of green tea intervention, blood total cholesterol and low‐density lipoprotein cholesterol (LDL) decreased in the green tea group by 4.96% and 7.98%, respectively. Plasma malondialdehyde (MDA), a lipid peroxidation marker, decreased, whereas antioxidant capacities measured by the ferric ion reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays were maintained in the green tea beverage group. The lipid‐related gene expression of peripheral blood mononuclear cells (PBMC) was observed by real‐time polymerase chain reaction. The LDL receptor gene was upregulated in the green tea beverage group. The liver and kidney function tests showed no alterations among the subjects in the green tea beverage and placebo groups. Six weeks of green tea beverage intervention showed potential as a treatment to reduce cardiometabolic risk in dyslipidemia subjects. Trial Registration: Thai Clinical Trial Registry: TCTR20250104003 This study is the first randomized double‐blind placebo‐controlled trial focusing on nutrigenomics to investigate the effects of 6 weeks in green tea consumption on dyslipidemia subjects. Green tea beverages containing 898.1 mg of total catechins improved lipid profiles, reduced oxidative stress parameters, and modulated lipid‐related gene expressions.

Objective The primary objective of this study is to review the evidence for aspirin use to prevent the growth of vestibular schwannomas (VS) and to propose a prospective trial to determine the progression‐free survival of VS patients after up to 42 months of treatment with aspirin. Secondary study objectives are to determine the effect of aspirin on VS growth, hearing function, serum biomarker levels, and the quality of life, as well as to determine the tolerability of aspirin treatment and whether serum biomarker and salicylate levels predict the response to aspirin. Study Design Literature review. Setting Six academic and private medical centers. Methods Review of recent English literature regarding prophylactic aspirin use for VS. Results The retrospective reviews on the utility of aspirin to prevent VS growth are inconclusive. Eighty‐four patients have been enrolled in a prospective double‐blinded, placebo‐controlled trial thus far to determine the effect of aspirin on VS. Conclusions Completion of a robust study design is necessary. The current aspirin dose has been well tolerated, with minimal adverse events to date. Level of Evidence Review of retrospective studies: Level 4; Proposed randomized, placebo‐controlled, double‐blinded clinical trial: Level 2. This article reviews the data for and against the use of aspirin to prevent the growth of vestibular schwannomas. It then proposes a randomized placebo‐controlled double‐blinded study to clarify contradictory retrospective findings.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist–C when subjects were taking simvastatin. This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol–to–total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS. Genet Med19 3, 297–305.

Violet light (VL), 360–400 nm wavelength, is contained in the sunlight and is an effective element for myopia suppression. This study is to investigate the safety and efficacy of novel eyeglasses that emit VL from the frames. This is a double-masked, randomized, pilot clinical trial conducted in a clinic in Japan. Forty-three children with myopia were enrolled. Participants were randomly assigned to two groups, wearing VL-emitting eyeglass frames (VLf) that emitted VL of 310 μW/cm2 (VLf group, n = 22) or pseudo-placebo eyeglass frames with a minimal emission of VL (<10 μW/cm2) (control group, n = 21). The exposure time was 3 h per day. The primary outcomes were visual acuity, tear film break-up time, corneal endothelial cell density, and the slit-lamp/fundus examinations. The secondary outcome was the 6-month changes in the axial lengths and cycloplegic refractions. Forty-one (95%) participants were included; twenty-one in the VLf group and twenty in the control group. No significant differences were seen in any safety evaluation. Significant changes were seen in axial elongation, choroidal thickness, and cycloplegic refractions in the subgroup analysis of 8- to 10-year-old children (p < 0.05), but otherwise no significant differences were seen. The VLf showed short-term safety and effectiveness against myopia progression.

Background Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80–90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10–20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome. Methods We conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000–1200mg/m2/day (maximum 2g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance).Discussion The results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in'complicated'FRNS/SDNS cases. Trial registration This trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347).

Muscle Stem Cells (MuSCs) drive muscle regeneration and slow pathological progression of muscle diseases. In preclinical models, nicotinamide (NAM) and pyridoxine (PN) synergistically increased MuSC proliferation and differentiation, and accelerated muscle regeneration. Herein we tested if NAM/PN could enhance MuSC activity and muscle regeneration in a randomized, placebo‐controlled clinical trial. Men aged 18–49 years were supplemented daily with 714 mg NAM and 19 mg PN, or placebo, for 9 days following one session of damaging unilateral eccentric muscle contractions. The primary endpoint was MuSC activity via immunohistofluorescence on biopsy sections from the vastus lateralis muscle. Histological markers of muscle regeneration constituted secondary outcomes, and muscle damage was validated with clinical markers. 39 out of 43 enrolled participants completed the study. Supplementation of NAM/PN was well tolerated and increased blood concentrations of NAM and PN vitamers. 8 days after the contraction protocol, the number of Pax7, MyoD, and myogenin positive cells per damaged fiber was significantly higher in NAM/PN vs placebo groups (+29%–67%). NAM/PN also increased the proportion of regenerating fibers (+37%). Daily oral NAM/PN supplementation after high intensity muscle contractions enhances MuSC activity and accelerates muscle regeneration and repair, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders. In a randomized clinical trial, we test the potential of combined nicotinamide (NAM) and pyridoxine (PN) to improve muscle recovery through muscle stem cell (MuSC) activity. Daily oral NAM and PN supplementation after high intensity muscle contractions enhances MuSC activation and differentiation, and accelerates muscle regeneration, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

In this trial evaluating mepolizumab, an anti–interleukin-5 antibody, the rate of COPD exacerbations among patients whose COPD was characterized by an increased number of eosinophils in the circulating blood was lower with mepolizumab than with placebo.