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Even today, patients with schizophrenia often have an unfavorable outcome. Negative symptoms and cognitive deficits are common features in many patients and prevent recovery. In recent years, aerobic endurance training has emerged as a therapeutic approach with positive effects on several domains of patients’ health. However, appropriately sized, multicenter randomized controlled trials that would allow better generalization of results are lacking. The exercise study presented here is a multicenter, rater-blind, two-armed, parallel-group randomized clinical trial in patients with clinically stable schizophrenia being conducted at five German tertiary hospitals. The intervention group performs aerobic endurance training on bicycle ergometers three times per week for 40–50 min/session (depending on the intervention week) for a total of 26 weeks, and the control group performs balance and tone training for the same amount of time. Participants are subsequently followed up for 26 weeks. The primary endpoint is all-cause discontinuation; secondary endpoints include psychopathology, cognition, daily functioning, cardiovascular risk factors, and explorative biological measures regarding the underlying mechanisms of exercise. A total of 180 patients will be randomized. With currently 162 randomized participants, our study is the largest trial to date to investigate endurance training in patients with schizophrenia. We hypothesize that aerobic endurance training has beneficial effects on patients’ mental and physical health, leading to lower treatment discontinuation rates and improving disease outcomes. The study results will provide a basis for recommending exercise interventions as an add-on therapy in patients with schizophrenia.The study is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

The continuing evolution of influenza viruses poses a challenge to vaccine prevention, highlighting the need for a universal influenza vaccine. We evaluated the safety and immunogenicity of one such candidate, Multimeric-001 (M-001), when used as a priming vaccine prior to administration of quadrivalent inactivated influenza vaccine (IIV4). Healthy adults 18 to 49 years of age were enrolled in a phase 2 randomized, double-blind placebo-controlled trial. Participants received two doses of either 1.0-mg M-001 or saline placebo (60 per study arm) on Days 1 and 22 followed by a single dose of IIV4 on about Day 172. Safety, reactogenicity, cellular immune responses and influenza hemagglutination inhibition (HAI) and microneutralization (MN) were assessed. The M-001 vaccine was safe and had an acceptable reactogenicity profile. Injection site tenderness (39% post-dose 1, 29% post-dose 2) was the most common reaction after M-001 administration. Polyfunctional CD4+ T cell responses (perforin-negative, CD107α-negative, TNF-α+, IFN-γ+, with or without IL-2) to the pool of M-001 peptides increased significantly from baseline to two weeks after the second dose of M-001, and this increase persisted through Day 172. However, there was no enhancement of HAI or MN antibody responses among M-001 recipients following IIV4 administration. M-001 administration induced a subset of polyfunctional CD4+ T cells that persisted through 6 months of follow-up, but it did not improve HAI or MN antibody responses to IIV4. (clinicaltrials.gov NCT03058692).

Studies in rodents and humans have indicated that omega-3 polyunsaturated fatty acids (n-3 PUFA) may reduce weight. The aim of this meta-analysis was to evaluate evidence for the efficacy of n-3 PUFA in managing overweight and obesity. We performed a systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials until May 2015. Two reviewers independently determined the eligibility of studies and assessed the reporting quality of included randomized controlled trials (RCTs). A total of 11 RCTs involving 617 participants were included in this meta-analysis. Based on the meta-analysis of nine studies, a statistically nonsignificant difference was revealed in weight loss between n-3 PUFA and placebo (p=0.99; weighted mean difference [WMD]: 0.00; 95% confidence interval [CI] −0.42 to 0.43), whereas n-3 PUFA was superior to placebo in reducing serum triglyceride levels (p=0.0007; standard median difference [Std MD]: −0.59; 95% CI −0.93 to −0.25). Based on meta-analysis of seven studies, the analysis of aggregated data showed a significant reduction in waist circumference (p=0.005; WMD: −0.53; 95% CI −0.90 to −0.16). There were no significant differences in body mass index, total serum levels of cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and fasting glucose levels. The evidence from RCTs showed that n-3 PUFA might effectively reduce waist circumference and triglyceride levels in overweight and obese adults, but n-3 PUFA may not effectively reduce body weight. Given the small number and poor quality of RCTs included in the meta-analysis, these results are inconclusive. A large-scale, well-designed RCT is needed to further address this issue..

The effect of a combination of magnesium, vitamins B6, B9, B12, rhodiola and green tea/L-theanine (Mg-Teadiola) on stress was evaluated in chronically stressed, otherwise healthy individuals. Effects on stress-related quality-of-life parameters (sleep and perception of pain) were also explored. Adults with stress for ≥1 month, scoring ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire, were randomized (1:1) to receive oral Mg-Teadiola (n = 49) or a placebo (n = 51), for 28 days, with a follow-up assessment on Day 56 (NCT04391452). The primary endpoint was the change in the DASS-42 stress score from baseline to Day 28 with Mg-Teadiola versus placebo. The DASS-42 stress scores significantly decreased from baseline to Day 28 with Mg-Teadiola versus placebo (effect size, 0.29; 95% CI [0.01, 0.57]; p = 0.04). Similar reductions were observed on Day 14 (p = 0.006) and Day 56 (p = 0.02). A significant reduction in sensitivity to cold pain (p = 0.01) and a trend for lower sensitivity to warm pain was observed (p = 0.06) on Day 28. Improvements in daytime dysfunction due to sleepiness (Pittsburgh Sleep Quality Index-7 component score) were reported on Day 28, and were significant on Day 56 (p < 0.001). Mg-Teadiola is effective in managing stress in otherwise healthy individuals. Its beneficial effects on sleep and pain perception need further investigation.

Heart failure (HF) is associated with a reduction of skeletal muscle mass. Whey protein isolate (WPI) has been beneficial in increasing muscle mass and strength, in addition to improving body composition. The goal of this research was to evaluate the effect of WPI on the body composition, muscle mass, and strength of chronic HF patients. For this purpose, twenty-five patients of both genders with predominantly NYHA I functional class and a median age of 65.5 (60.5–71.0) years were used to conduct a randomized, single-blind, placebo-controlled clinical trial and received 30 g per day of WPI for 12 weeks. Anthropometric measurements, body composition analysis, and biochemical exams were performed at the beginning and end of the study. An increase in skeletal muscle mass was observed in the intervention group after 12 weeks. A reduction in waist circumference, body fat percentage, and an increase in skeletal muscle index was observed when compared to the placebo group. No significant effect on muscle strength was observed after 12 weeks of intervention. These data demonstrate that WPI consumption contributed to the increase of skeletal muscle mass, strength, and reduction of body fat in HF patients.

Purpose This study aimed to investigate the effects of vitamin K 2 supplementation in the form of menaquinone-7 (MK-7) on glucose, insulin, and lipid metabolism in patients with type 2 diabetes mellitus (T2DM). Methods In this double-blinded, placebo-controlled, randomized trial, 68 insulin-independent people with diabetes received either 180 µg MK-7 twice a day or placebo for 12 weeks. We assessed fasting plasma glucose (FPG) and insulin concentrations (primary outcomes), glycated hemoglobin (HbA1c), insulin sensitivity indices, and lipid profiles (secondary outcomes) at baseline and end of the trial. Results At the end of the trial, FPG (effect size (ES) = − 0.68; p -adjusted = 0.031) and HbA1c (ES = − 0.36; p -adjusted = 0.004) were significantly lower in the vitamin K 2 group compared with the placebo at the end of the trial. The number of participants achieved the target levels of glycemic control based on FPG, and HbA1c concentrations were significantly higher in the vitamin K 2 group compared to the placebo group. Insulin concentrations (ES = − 0.29; p  = 0.019) and homeostatic model assessment for insulin resistance (HOMA-IR) significantly decreased in the vitamin K 2 group (ES = − 0.29; p  = 0.019) compared to baseline, but their values were not significantly different compared to the placebo group at the end of the trial. No significant variation was observed in lipid profiles. Conclusion Daily intake of 360 µg Vitamin K 2 in the form of MK-7 for 12-weeks reduces FPG and HbA1c in patients with T2DM but does not have a lipid-lowering effect.

PurposeFatalities due to heart and cerebrovascular diseases caused by uncontrolled hyperlipidaemia increase every year; on the other hand, lipid-lowering drugs are known to cause side effects. The gut microbiota has been thoroughly investigated by researchers and consumers, because they have unique functional properties and littler side effects. However, the effects of the gut microbiota remain controversial. We conducted a meta-analysis to assess the effects of products designed to modulate the gut microbiota on various hyperlipidaemias.MethodsWe systematically searched PubMed, Embase, Cochrane Library (Central), and Web of Science for randomized controlled trials (published before June 2017, and those only in English) to compare treatment (products designed to modulate the gut microbiota) versus placebo. Our main endpoints were total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in serum. We assessed pooled data using a fixed effects model.ResultsOf 1337 identified studies, 21 were eligible and included in our analysis (n = 1436 participants). The combined estimate of effect size for the impact of products designed to modulate the gut microbiota on serum TC (WMD − 11.07 mg/dL, 95% CI − 13.72 to − 8.43, p < 0.001), LDL-C (WMD − 10.96 mg/dL, 95% CI − 13.37 to − 8.56, p < 0.001), and HDL-C (WMD 0.72 mg/dL, 95% CI 0.06–1.38, p = 0.032) were statistically significant, while no significant effect was found on TG concentrations (WMD − 0.56 mg/dL, 95% CI − 5.59 to 4.47, p = 0.828). Subgroup analysis showed parallel trials, probiotics, and long-term intervention had better effects on lowering blood lipid levels.ConclusionProducts designed to modulate the gut microbiota results in changes of the plasma lipid concentrations and these changes may protect against cardiovascular disease.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. This study focused on evaluating the impact of a Mediterranean-type diet combined with physical exercise on CVD risk factors of high-risk individuals. A randomized clinical trial (RCT) recruited individuals (≥50 years old) with no history of acute myocardial infarction, but with high CVD risk criteria according to the SCORE2/SCORE2 OP. Anthropometric and biochemical parameters were assessed at baseline and after 12 weeks of diet and exercise intervention. Participants were randomly assigned into 3 groups: no intervention group (Group 1a), physical exercise group (Group 1b), and physical exercise (±2 h/week) plus diet group (Group 2). Briefly, the dietary intervention was based on the principles of an isocaloric Mediterranean diet (MD), with seven main meals/week centered on plant-based foods (legumes and pulses). The combined effect of exercise and the diet showed significant decrease in WC (p = 0.002), BST (p < 0.001), visceral fat (p < 0.001), and TG (p = 0.029), compared with control groups. The intervention significantly increased legume intake (p < 0.001), as well as adherence to the MD, which associates with WC decrease (p = 0.024) and visceral fat (p = 0.017). A combined intervention of exercise and diet should be endorsed as an efficient modifier of cardiometabolic parameters.

A recent randomized controlled trial (RCT), the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported that high-dose marine omega-3 fatty acids (OM3) significantly reduce cardiovascular disease (CVD) outcomes, yet the mechanisms responsible for this benefit remain unknown. To test the hypothesis that high-dose OM3 is anti-atherosclerotic, we performed a systematic review and meta-analysis of RCT of high-dose OM3 on atherosclerosis. The protocol of this systematic review was registered with PROSPERO (CRD42019125566). PubMed, Embase, Cochran Central Register for Controlled Trials, and Clinicaltrials.gov databases were searched using the following criteria: adult participants, high-dose OM3 (defined as ≥3.0 g/day, or in Japan 1.8 g/day and purity ≥90%) as the intervention, changes in atherosclerosis as the outcome, and RCTs with an intervention duration of ≥6 months. A random-effects meta-analysis was used to pool estimates across studies. Among the 598 articles retrieved, six articles met our criteria. Four RCTs evaluated atherosclerosis in the coronary and two in the carotid arteries. High-dose OM3 significantly slowed the progression of atherosclerosis (standardized mean difference −1.97, 95% confidence interval −3.01, −0.94, p < 0.001). The results indicate that anti-atherosclerotic effect of high-dose OM3 is one potential mechanism in reducing CVD outcomes demonstrated in the REDUCE-IT trial.

Background Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus -derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD. Methods Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis. Results The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks ( p for time < .001, d  = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory ( p  < .001) and scales of subjective memory ( p  < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group ( d  = 0.69 in short-term, and d  = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups ( p for time = .010, d  = 0.21, p time x treatment = .772). Adverse events were balanced between groups. Conclusions In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD. Trial registration The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www.clinicaltrials.gov/ct2/show/NCT04744922 ).