METHODS: We searched Medline and the Cochrane Database of Systematic Reviews from 1 January 2018 to 31 December 2021 for systematic reviews and meta-analysis reports that include a trial sequential analysis. Only studies with at least two randomised clinical trials analysed in a forest plot and a trial sequential analysis were included. Two independent investigators assessed the studies. We evaluated protocolisation, reporting, and interpretation of the analyses, including their effect on any GRADE evaluation of imprecision.
RESULTS: We included 270 systematic reviews and 274 meta-analysis reports and extracted data from 624 trial sequential analyses. Only 134/270 (50%) systematic reviews planned the trial sequential analysis in the protocol. For analyses on dichotomous outcomes, the proportion of events in the control group was missing in 181/439 (41%), relative risk reduction in 105/439 (24%), alpha in 30/439 (7%), beta in 128/439 (29%), and heterogeneity in 232/439 (53%). For analyses on continuous outcomes, the minimally relevant difference was missing in 125/185 (68%), variance (or standard deviation) in 144/185 (78%), alpha in 23/185 (12%), beta in 63/185 (34%), and heterogeneity in 105/185 (57%). Graphical illustration of the trial sequential analysis was present in 93% of the analyses, however, the Z-curve was wrongly displayed in 135/624 (22%) and 227/624 (36%) did not include futility boundaries. The overall transparency of all 624 analyses was very poor in 236 (38%) and poor in 173 (28%).
CONCLUSIONS: The majority of trial sequential analyses are not transparent when preparing or presenting the required parameters, partly due to missing or poorly conducted protocols. This hampers interpretation, reproducibility, and validity.
STUDY REGISTRATION: PROSPERO CRD42021273811.
METHODS: A cohort of 4,240 Sepsis-3 patients was analyzed, with 783 experiencing 30-day mortality and 3,457 surviving. Fifteen biomarkers were selected using feature ranking methods, including Extreme Gradient Boosting (XGBoost), Random Forest, and Extra Tree, and the Logistic Regression (LR) model was used to assess their individual predictability with a fivefold cross-validation approach for the validation of the prediction. The dataset was balanced using the SMOTE-TOMEK LINK technique, and a stacking-based meta-classifier was used for 30-day mortality prediction. The SHapley Additive explanations analysis was performed to explain the model's prediction.
RESULTS: Using the LR classifier, the model achieved an area under the curve or AUC score of 0.99. A nomogram provided clinical insights into the biomarkers' significance. The stacked meta-learner, LR classifier exhibited the best performance with 95.52% accuracy, 95.79% precision, 95.52% recall, 93.65% specificity, and a 95.60% F1-score.
CONCLUSIONS: In conjunction with the nomogram, the proposed stacking classifier model effectively predicted 30-day mortality in Sepsis patients. This approach holds promise for early intervention and improved outcomes in treating Sepsis cases.
METHODS: A total of 78 first-year students from a public university in Henan Province were recruited for this study via a cluster randomized controlled trial (CRCT) design. The participants were divided into an experimental group (blended learning) and a control group (traditional learning). The intervention lasted for 16 weeks, and physical fitness indices such as body mass index (BMI), lung capacity, sit and reach, pull-ups/sit-ups, standing long jumps, 50-meter runs, and 1000/800-meter runs were measured before and after the intervention. Statistical analyses were conducted via generalized estimating equation (GEE) modeling, with the significance level set at P
METHODS: We developed nine scales to quantify different facets of lifestyle (e.g., urban infrastructure, market-integration, acculturation) in two Indigenous, transitioning subsistence populations currently undergoing rapid change in very different ecological and sociopolitical contexts: Turkana pastoralists of northwest Kenya (n = 3,692) and Orang Asli mixed subsistence groups of Peninsular Malaysia (n = 688). We tested the extent to which these lifestyle scales predicted 16 measures of cardiometabolic health and compared the generalizability of each scale across the two populations. We used factor analysis to decompose comprehensive lifestyle data into salient axes without supervision, sensitivity analyses to understand which components of the multidimensional scales were most important, and sex-stratified analyses to understand how facets of lifestyle variation differentially impacted cardiometabolic health among males and females.
FINDINGS: Cardiometabolic health was best predicted by measures that quantified urban infrastructure and market-derived material wealth compared to metrics encompassing diet, mobility, or acculturation, and these results were highly consistent across both populations and sexes. Factor analysis results were also highly consistent between the Turkana and Orang Asli and revealed that lifestyle variation decomposes into two distinct axes-the built environment and diet-which change at different paces and have different relationships with health.
INTERPRETATION: Our analysis of comparable data from Indigenous peoples in East Africa and Southeast Asia revealed a surprising amount of generalizability: in both contexts, measures of local infrastructure and built environment are consistently more predictive of cardiometabolic health than other facets of lifestyle that are seemingly more proximate to health, such as diet. We hypothesize that this is because the built environment impacts unmeasured proximate drivers like physical activity, increased stress, and broader access to market goods, and serves as a proxy for the duration of time that communities have been market-integrated.
METHODS: Here, we tested whether the deuterated analogues of Compound 6, namely DK-1-56-1 and RV-I-29, known to have longer half-lives than the parent compound, can exert a similar therapeutic effect in the same model. The activation of TGVS was triggered by intra-cisternal (i.c.) instillation of capsaicin in male Wistar rats. Centrally, i.c. capsaicin increased the quantity of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminal cervical complex (TCC). Peripherally, it increased the calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG, and caused CGRP release, leading to CGRP depletion in the dura mater.
RESULTS: DK-I-56-1 and RV-I-29, administered intraperitoneally (i.p.), significantly ameliorated the TCC neuronal activation, TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin, with DK-I-56-1 demonstrating better efficacy. The therapeutic effects of 3 mg/kg DK-I-56-1 are comparable to that of 30 mg/kg topiramate. Notably, i.p. administered furosemide, a blood-brain-barrier impermeable α6GABAAR-selective antagonist, prevented the effects of DK-I-56-1 and RV-I-29. Lastly, orally administered DK-I-56-1 has a similar pharmacological effect.
DISCUSSION: These results suggest that DK-I-56-1 is a promising candidate for novel migraine pharmacotherapy, through positively modulating TG α6GABAARs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.