UNASSIGNED: Alzheimer\'s disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD.
UNASSIGNED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms \'ALZ-801\' or \'valiltramiprosate.\' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate\'s active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aβ42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate\'s phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion.
UNASSIGNED: Valiltramiprosate\'s clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

UNASSIGNED: Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population.
UNASSIGNED: We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords \"tardive dyskinesia\" AND (\"valbenazine\" [all fields] OR \" deutetrabenazine \" [all fields]) AND \"clinical trial\". The reviewed articles were studied for efficacy and side effects.
UNASSIGNED: An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated.
UNASSIGNED: The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality.
UNASSIGNED: The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.

OBJECTIVE: We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines.
METHODS: We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach.
RESULTS: A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%).
CONCLUSIONS: All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes.
UNASSIGNED: CRD42020146752.

The present study aimed to investigate the association of dietary branched-chain amino acids (BCAAs) and its components with cancer, cancer mortality, and all-cause mortality in a meta-analysis of observational studies. A comprehensive search was conducted between electronic databases (PubMed, Scopus, and Web of Science) until September 2022. Odds ratios (OR), hazard ratios (HR), and relative risks (RR) were extracted. Eight articles (six studies on breast cancer (BC) and digestive cancers risk, and three studies on both BC and digestive cancers mortality, and all-cause mortality) were included. The present study showed no statistically significant association between dietary BCAAs and its components with BC and digestive cancers (RRBCAA: 0.87, 95% CI: 0.68-1.10, RRLeucine: 0.74, 95% CI: 0.52-1.04, RRIsoleucine: 0.98, 95% CI: 0.93-1.04, RRValine: 0.76, 95% CI: 0.55-1.05). Also, no statistically significant relationship between dietary BCAAs and its components with both BC and digestive cancers mortality (RRBCAA: 0.95, 95% CI: 0.68-1.33, RRLeucine: 0.95, 95% CI: 0.79-1.15, RRIsoleucine: 0.95, 95% CI: 0.79-1.14, RRValine: 1.01, 95% CI: 0.84-1.21) and all-cause mortality (RRBCAA: 0.98, 95% CI: 0.73-1.32, RRLeucine: 1.02, 95% CI: 0.81-1.29, RRIsoleucine: 0.96, 95% CI: 0.73-1.27, RRValine: 1.02, 95% CI: 0.79-1.32) were observed. Our findings showed no significant association between dietary BCAAs and its components with BC and digestive cancers, BC and digestive cancers mortality, and all-cause mortality.

Recently, the serum levels of branched-chain amino acids (BCAAs) have been considered as an indicator to evaluate health status and predict chronic diseases risk. This systematic review and meta-analysis aimed to assess the relationship between Serum BCAAs and the risk of all-cause mortality. We carried out a comprehensive and systematic search in various important databases, including PubMed, Scopus, and Web of Science databases to find the relevant studies published up to October 2022 with no language, design, or time limitation. We extracted the reported hazard ratio (HR) with 95% confidence interval (CI) and odds ratio (OR) with 95%CI in cohorts and case-control studies, respectively, and computed the log HR or OR and its standard error. Then, we used the random-effects model with inverse variance weighting method for the present meta-analysis, to calculate the pooled effect size. Ten observational studies, including nine cohort studies and one case-control study, were included in the present meta-analysis. The number of participants ranges from 53 to 26,711, with an age range of 18-99 years. During 6 months to 24 years of follow-up, 3599 deaths were ascertained. The pooled results indicated that there was no significant association between serum BCAAs (RR: 1.17; 95% CI 0.85-1.60), isoleucine (RR: 1.41; 95%CI 0.92-2.17), leucine (RR: 1.13; 95% CI 0.94-1.36), and valine (RR: 1.02; 95%CI 0.86-1.22) and all-cause mortality. Also, there was significant heterogeneity between studies for serum BCAAs (I2 = 74.1% and P-heterogeneity = 0.021), isoleucine (I2 = 89.4% and P-heterogeneity < 0.001), leucine (I2 = 87.8% and P-heterogeneity < 0.001), and valine (I2 = 86.6% and P-heterogeneity < 0.001). Our results suggested that the serum BCAAs and its components, including isoleucine, leucine, and valine, were not associated with the risk of all-cause mortality.

This study aimed to evaluate the efficacy of single-pill combination (SPC) antihypertensive drugs in patients with uncontrolled essential hypertension. Through Searching Pubmed, EMBASE, the Cochrane Library, and Web of Science collected only randomized controlled trials on the efficacy of single-pill combination antihypertensive drugs in people with uncontrolled essential hypertension. The search period is from the establishment of the database to July 2022. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias Assessment, and statistical analyses were performed using Review Manage 5.3 and Stata 15.1 software. This review ultimately included 32 references involving 16 273 patients with uncontrolled essential hypertension. The results of the network meta-analysis showed that a total of 11 single-pill combination antihypertensive drugs were included, namely: Amlodipine/valsartan, Telmisartan/amlodipine, Losartan/HCTZ, Candesartan/HCTZ, Amlodipine/benazepril, Telmisartan/HCTZ, Valsartan/HCTZ, Irbesartan/amlodipine, Amlodipine/losartan, Irbesartan/HCTZ, and Perindopril/amlodipine. According to SUCRA, Irbesartan/amlodipine may rank first in reducing systolic blood pressure (SUCRA: 92.2%); Amlodipine/losartan may rank first in reducing diastolic blood pressure (SUCRA: 95.1%); Telmisartan/amlodipine may rank first in blood pressure control rates (SUCRA: 83.5%); Amlodipine/losartan probably ranks first in diastolic response rate (SUCRA: 84.5%). Based on Ranking Plot of the Network, we can conclude that single-pill combination antihypertensive drugs are superior to monotherapy, and ARB/CCB combination has better advantages than other SPC in terms of systolic blood pressure, diastolic blood pressure, blood pressure control rate, and diastolic response rate. However, due to the small number of some drug studies, the lack of relevant studies has led to not being included in this study, which may impact the results, and readers should interpret the results with caution.

Introduction: Recent studies have concluded that elevated circulating branched chain amino acids (BCAA) are associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. However, the development of this association over time and the quantification of the strength of this association for individual BCAAs prior to T2DM diagnosis remains unexplored. Methods: A systematic search was conducted using the Healthcare Databases Advance Search (HDAS) via the National Institute for Health and Care Excellence (NICE) website. The data sources included EMBASE, MEDLINE and PubMed for all papers from inception until November 2021. Nine studies were identified in this systematic review and meta-analysis. Stratification was based on follow-up times (0−6, 6−12 and 12 or more years) and controlling of body mass index (BMI) through the specific assessment of overweight cohorts was also undertaken. Results: The meta-analysis revealed a statistically significant positive association between BCAA concentrations and the development of T2DM, with valine OR = 2.08 (95% CI = 2.04−2.12, p < 0.00001), leucine OR = 2.25 (95% CI = 1.76−2.87, p < 0.00001) and isoleucine OR = 2.12, 95% CI = 2.00−2.25, p < 0.00001. In addition, we demonstrated a positive consistent temporal association between circulating BCAA levels and the risk of developing T2DM with differentials in the respective follow-up times of 0−6 years, 6−12 years and ≥12 years follow-up for valine (OR = 2.08, 1.86 and 2.14, p < 0.05 each), leucine (OR = 2.10, 2.25 and 2.16, p < 0.05 each) and isoleucine (OR = 2.12, 1.90 and 2.16, p < 0.05 each) demonstrated. Conclusion: Plasma BCAA concentrations are associated with T2DM incidence across all temporal subgroups. We suggest the potential utility of BCAAs as an early biomarker for T2DM irrespective of follow-up time.

Periodontitis is resulted from a complex interaction between genetics and epigenetics, microbial factors, and the host response. Metabolomics analyses reflect both the steady-state physiological equilibrium of cells or organisms as well as their dynamic metabolic responses to environmental stimuli.
This systematic review of the literature aimed to assess which low molecular weight metabolites are more often found in biological fluids of individuals with periodontitis compared to individuals with gingivitis or periodontal health.
All the included studies employed untargeted analysis. One or more biological fluids were analyzed, including saliva (n = 14), gingival crevicular fluid (n = 6), mouthwash (n = 1), serum (n = 3) and plasma (n = 1). Fifty-six main metabolites related to periodontitis have been identified in at least two independent studies by NMR spectroscopy or MS-based metabolomics. Saliva was the main biological fluid sampled. It is noteworthy that 14 metabolites of the 56 detected were identified as main metabolites in all studies that sampled the saliva. The majority of metabolites found consistently among studies were amino acids, organic acids and derivates: acetate, alanine, butyrate, formate, GABA, lactate, propionate, phenylalanine and valine. They were either up- or down-regulated in the studies or this information was not mentioned. The main metabolic pathway was related to phenylalanine, tyrosine and tryptophan biosynthesis. Metabolites more frequently found in individuals with periodontitis were related to both the host and to microorganism responses. Future studies are needed, and they should follow some methodological standards to facilitate their comparison.

UNASSIGNED: This study investigated the clinical efficacy sofosbuvir/daclatasvir (SOF-DCV) in patients with COVID-19.
UNASSIGNED: PubMed, Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before January 6, 2022. Only randomized controlled trials (RCTs) comparing the clinical efficacy of SOF-DCV (study group) with alternative treatments (control group) in patients with COVID-19 were included.
UNASSIGNED: A total of 9 RCTs were included. The all-cause mortality rate in the study group was 10.7% (96/898), which was lower than that in the control group (12.3%, 108/871). However, this difference was not statistically significant (odds ratio [OR] = 0.83; 95% CI, 0.62-1.12; I2 = 49%). The overall clinical recovery rate was significantly higher in the study group than in the control group (OR = 2.34; 95% CI, 1.47-3.72; I2 = 20%). Furthermore, the average length of hospital stay was shorter in the study group than in the control group (mean deviation = -1.84; 95% CI, -3.42 to -0.26, I2 = 68%).
UNASSIGNED: Although SOF-DCV did not confer a survival benefit in patients with COVID-19, it may increase a patient\'s odds of clinical recovery, and shorten the length of their hospital stay.

We conducted a systematic review with meta-analysis of non-prospective and prospective clinical studies to assess the effects of circulating branched-chain amino acids (BCAA), including Isoleucine, Valine and Leucine, on cardiovascular disease (CVD) risk.
PubMed, Embase, Cochrane and CNKI databases were searched for publications reporting the relationship between BCAAs and CVD. Relative risk (RR) and odd ratios (OR) were extracted and pooled. Subgroup analysis and meta-regression were performed to identify potential sources of heterogeneity, sensitivity analysis was conducted to assess the robustness of pooled estimates.
11 non-prospective studies involving 2806 participants and 10 prospective studies involving 43,895 participants reported correlations between BCAAs and CVD risk. Levels of circulating BCAAs changed in individuals with CVD compared with those in the control group. Nine prospective studies were meta-analyzed and highlighted a 10% higher risk of CVD per study-specific SD difference for Isoleucine (pooled relative risk 1.10 [1.03-1.18]; I2 = 63.5%). Valine and Leucine do not appear to be associated with CVD incidence. Subgroup analysis based on age suggested that among adults ≤60 years, there is a 15%, 13%, and 9% higher risk of developing CVD per study-specific SD difference for Isoleucine (RR 1.15 [1.11-1.19]; I2 = 0.0%), Valine (RR 1.13 [1.09-1.17]; I2 = 0.0%), and Leucine (RR 1.09 [1.03-1.16]; I2 = 40.5%), respectively. No such associations were observed for adults older than 60 years.
Evidence suggests that elevated concentrations of circulating Isoleucine were associated with increased risks of CVD, independent of traditional risk factors.