UNASSIGNED: The overall prevalence of dyslipidemia continues to increase, which poses a significant risk for coronary artery disease. Some patients with dyslipidemia do not respond to or benefit from conventional lipid-lowering therapy, which warrants the need for alternative and complementary therapies. Chinese patent medicine (CPM) has shown great potential in the treatment of dyslipidemia, but its clinical value needs to be further explored. This study aims to systematically evaluate the efficacy and safety of CPM in treating dyslipidemia.
UNASSIGNED: This study was registered in INPLASY as INPLASY202330090. The randomized controlled trials included in this study were published in January 2013 to March 2023 and retrieved from the Web of Science, PubMed, Embase, Cochrane Library, SinoMed, China National Knowledge Internet, WanFang, and VIP. The bias risk in the study was independently evaluated by two reviewers using the Cochrane Randomized Trial Bias Risk Tool (RoB 2) Review Manager 5.4 software was used for the overall effect analysis and subgroup analysis of four blood lipids, and the trial sequential analysis (TSA) was conducted to check the results.
UNASSIGNED: A total of 69 studies were included, involving 6,993 participants. The methodological quality was in the middle level. Meta-analysis showed that CPM markedly improved the levels of total cholesterol (TC) [mean difference (MD) =-0.54 mmol/L; 95% confidence interval (CI): -0.71 to -0.37; P<0.001], triglyceride (TG) (MD =-0.43 mmol/L; 95% CI: -0.53 to -0.33; P<0.001), low-density lipoprotein cholesterol (LDL-C) (MD =-0.40 mmol/L; 95% CI: -0.50 to -0.30; P<0.001) and increased levels of high-density lipoprotein cholesterol (HDL-C) (MD =0.23 mmol/L; 95% CI: 0.18 to 0.27; P<0.001), in patients with dyslipidemia. Though CPM did not differ significantly from statins when used alone, it could improve lipid profile better in all cases when used in combination with statins and with drugs used for comorbidities or co-morbidities. Subgroup analysis found that the efficacy of pill formulations was superior to other formulations, and CPM showed better lipid-lowering response in the context of comorbidity. The TSA confirmed the robustness of the analysis of the LDL-C level. No significant difference was observed in the incidence of adverse events between the treatment group and the control group [risk ratio (RR) =0.89; 95% CI: 0.69-1.16; P=0.40].
UNASSIGNED: CPM can yield superior therapeutic effects in ameliorating dyslipidemia without exacerbating adverse effects as an alternative and complementary therapy. In addition, the therapeutic effect can be improved by emphasizing pill formulation and strengthening the standardization of syndromes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of obesity.
To assess the weight-loss effects of GLP-1RAs in the treatment of patients with overweight or obesity without diabetes.
This is a systematic review with meta-analysis and trial sequential analysis. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from their inception to January 1, 2022. Eligible trials report on outcomes including body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), or total body fat (TBF). Mean differences (MDs) and standardized mean differences (SMDs) were summarized using random-effects models.
Forty-one trials involving 15,135 participants were included. Compared with controls, GLP-1RAs significantly reduced BW (MD -5.319 kg, 95% CI: -6.465, -4.174), BMI (MD -2.373 kg/m2, 95% CI: -2.821, -1.924), WC (MD -4.302 cm, CI:-5.185 to -3.419), WHR (MD -0.011, CI -0.015 to -0.007), but not TBF (MD -0.320%, CI -1.420 to -0.780). Trial sequential analysis (TSA) supported conclusive evidence of the effects of GLP-1RAs on BW, BMI, and WC for weight loss. GLP-1RAs had nonlinear dose-response relationships with weight loss. Extensive sensitivity analyses demonstrated the robustness of the results, though the GRADE certainty of the evidence ranged from high to very low. High to moderate GRADE certainty of evidence suggested semaglutide as the most effective GLP-1RA agent, with the best efficacy and low to moderate risk of adverse effects.
The present study provides conclusive evidence for the effect of GLP-1RAs on weight loss in a nonlinear dose-response manner in patients with obesity or overweight without diabetes. In terms of changes in BW, BMI, and WC, there is firm evidence for the overall weight-loss effects of GLP-1RAs. Of the GLP-1RAs, semaglutide might be the most effective agent.

UNASSIGNED: There is insufficient evidence to support the use of acupuncture for mild cognitive impairment (MCI), and there is no consensus on its efficacy. This review aimed to determine the acupuncture effect in patients with MCI.
UNASSIGNED: Relevant and potentially eligible randomized controlled trials (RCTs) of acupuncture for MCI were obtained from four Chinese databases, four English databases, and additional resources up to 1 August 2022. The primary outcome was the improvement in overall cognitive function (OCF). Secondary outcomes were improved memory function (MF) and activities of daily living (ADLs). The revised Cochrane collaboration risk of bias (ROB) assessment tool (ROB 2.0) was applied to evaluate their methodological quality. The Review Manager software v 5.4 was used for analyses. Trial sequential analysis (TSA) 0.9.5.10 β software was used to estimate the required sample size and test the reliability of the pooled outcome. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool.
UNASSIGNED: This meta-analysis included 11 RCTs with a total of 602 patients. The methodological quality of all trials was moderate. Low-quality evidence showed that acupuncture significantly improved OCF (Mini-Mental State Examination (MMSE): mean difference (MD) = 1.22, 95% confidence interval (CI): 0.78-1.66; the Montreal Cognitive Assessment Scale (MoCA): MD = 1.22, 95% CI: 0.47-1.97). In subgroup analyses, it was revealed that acupuncture significantly increased OCF in patients with MCI when compared to conventional medicine (CM) and sham acupuncture (SA). TSA\'s findings indicated that the evidence of improving OCF with acupuncture for patients with MCI was conclusive. Meanwhile, there is no statistical difference in the improvement of MF and ADL between acupuncture and CM. TSA showed that the evidence of improving MF and ADL for patients who had MCI and received acupuncture was inconclusive. The shreds of evidence of improving MF and ADL were ranked from low to critically low.
UNASSIGNED: Acupuncture appears to be an effective clinical application method for improving OCF in patients with MCI. However, due to low-quality evidence, more relevant and high-quality research is needed in this field.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021291284, PROSPERO, No. CRD42021291284.

The γ-aminobutyric acid type A receptors (GABAAR) have been reported to contribute to the pathogenesis of epilepsy and the recurrence of chronic seizures. Genetic polymorphisms in GABRA1 and GABRA6 may confer a high risk of epilepsy and multiple drug resistance, but with conflicting results. We aimed to assess the association of GABRA1 rs2279020 and GABRA6 rs3219151 with epilepsy risk using a meta-analysis. The databases of Pubmed, Ovid, Web of Science, and China National Knowledge Infrastructure were searched. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were computed to evaluate the association between the polymorphisms and epilepsy risk using a fixed- or random-effect model. Trial sequential analysis (TSA) was performed to assess the results of the meta-analysis. No significant association between the GABRA1 rs2279020 and GABRA6 rs3219151 and the risk of epilepsy was found in the Asian and Arabic populations. The negative results were also observed when comparing the GABRA1 rs2279020 and GABRA6 rs3219151 polymorphism to antiepileptic drug responsiveness. The trial sequential analysis confirmed the results of the meta-analysis. This meta-analysis suggests that GABRA1 rs2279020 and GABRA6 rs3219151 are not risk factors for the etiology of epilepsy and antiepileptic drug responsiveness in the Asian and Arabic populations.

The etiopathogenetic mechanisms involving tumor genesis, including alteration of cell proliferation, apoptosis, invasion, migration, and death, may lead to alterations in microRNAs (miR) expression. The hypothesis is that with the presence in the literature of recent studies conducted on miR-196a and miR-196b, it is possible to clearly determine, by aggregating the results, whether miR-196 upregulation in head and neck squamous cell carcinoma (HNSCC) tissues can represent a prognostic biomarker of survival through hazard ratio (HR) analysis. The systematic review was conducted following the indications of the PRISMA, and four electronic databases were used (Science Direct, SCOPUS, PubMed, and Cochrane Central), with the addition of gray literature. Combinations of keywords were used, such as miR-196, miR-196 AND HNSCC, microRNA AND HNSCC, LSCC AND miR-196, OSCC AND miR-196, OPSCC AND miR-196, HSCC AND miR-196. The meta-analysis and trial sequential analysis (TSA) were performed using RevMan 5.41 software and Stata 13 (StataCorp, College Station, TX, USA) with the implementation of the R 4.2 software. This search identified 1593 reports and, at the end of the selection, five articles were inserted. The results of the meta-analysis report an aggregate HR for overall survival (OS), between the highest and lowest miR-196 expression of 1.67, 95% CI: [1.16, 2.49]. In this meta-analysis, we found that the forest plot is in favor of higher OS in HNSCC patients, compared with the control, with low miR-196 expression, correlating this data with a favorable prognosis, which indicated the potential role of this miRNA in strengthening the therapy sensitiveness of the HNSCC patients. Consequently, the present systematic review places itself, together with other systematic reviews on this topic, in a key role to the finding of Phase 3 clinical trials studies, in search for a prognostic model of miR-196 for HNSCC. In conclusion, with the limitations of the meta-analysis, it can be argued that miRs of the miR-196 family could be independent prognostic biomarkers of survival for HNSCC.

Background: the impact of knee osteoarthritis (OA) poses a formidable challenge to older adults. Studies have reported that genetic factors, such as MMP1, are one of important risk factors for knee OA. Although the relationship between the genetic polymorphism of MMP1 rs1799750 and the risk of knee OA has been explored, conclusions have been nonunanimous and pending due to research sample sizes, one of determinants in studying genetic polymorphisms associated with disease. Objective: to establish a model to assess whether the genetic polymorphism of MMP1 rs1799750 is associated with knee OA based on an estimation of sample sizes. Methods: samples were collected from a case−control and meta-analysis study. In the case−control study, patients who underwent knee X-ray examinations based on the Kellgren−Lawrence Grading System (KL) as diagnostic criteria were recruited at the Health Examination Center of the Tri-Service General Hospital from 2015 to 2019. Gene sequencing was conducted using iPLEX Gold. Those with unsuccessful gene sequencing were excluded. Finally, there were 569 patients in the knee OA group (KL ≥ 2) and 534 participants in the control group (KL < 2). In the meta-analysis, we used the databases PubMed, EMBASE, and Cochrane to search for studies on the relationship between MMP1 rs1799750 and knee OA. Next, we adopted the trial sequential analysis (TSA) method to assess whether sample sizes were sufficient or not to determine the risk of the genetic polymorphism of MMP1 rs1799750 on knee OA in Caucasians and Asians. Results: in Caucasians, the MMP1 rs1799750 was not significantly associated with knee OA with an odds ratios (OR) of 1.10 (95% confidence interval, CI: 0.45−2.68). Some extra 8559 samples were needed to conclude this relationship in Caucasians by the TSA model. In Asians, neither our case−control study results (n = 1103) nor a combination of samples from the case−control and meta-analysis results showed an association between MMP1 rs1799750 and knee OA. The OR (95% CI) was 1.10 (0.81−1.49) in a combination of Asian samples. Some extra 5517 samples were needed to justify this relationship in Asians by the TSA model. Conclusions: this research shows that an extra 8559 and 5517 samples are needed in Caucasians and Asians, respectively, in order to justify the association between MMP1 rs1799750 and knee OA.

The efficacy and safety of early renal replacement therapy (eRRT) for critically ill patients with acute kidney injury (AKI) remain controversial. Therefore, the purpose of our study was to perform an up-to-date meta-analysis with the trial sequential analysis (TSA) of randomized controlled trials (RCTs) to evaluate the therapeutic effect of eRRT on patients in an intensive care unit (ICU). We extensively searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov, Gray Literature Report, and Bielefeld Academic Search Engine (BASE), and conducted an updated search on December 27, 2021. The included studies were RCTs, which compared the efficacy and safety of eRRT and delayed renal replacement therapy (dRRT) on critically ill patients with AKI. We adopted TSA and sensitivity analysis to strengthen the robustness of the results. About 12 RCTs with a total of 5,423 participants were included. Patients receiving eRRT and dRRT had the similar rate of all-cause mortality at day 28 (38.7% vs. 38.9%) [risk ratio (RR), 1.00; 95%CI, 0.93-1.07, p = 0.93, I 2 = 0%, p = 0.93]. A sensitivity and subgroup analysis produced similar results for the primary outcome. TSA showed that the required information size was 5,034, and the cumulative Z-curve crossed trial sequential monitoring boundaries for futility. Patients receiving eRRT had a higher rate of renal replacement therapy (RRT) (RR, 1.50, 95% CI: 1.28-1.76, p < 0.00001, I 2 = 96%), and experienced more adverse events comparing to those receiving dRRT (RR: 1.41, 95% CI: 1.22-1.63, p < 0.0001, heterogeneity not applied). The most remarkable and important experimental finding is that, to our knowledge, the current meta-analysis included the largest sample size from the RCTs, which were published in the past 10 years to date, show that eRRT had no significant survival benefit for ill patients with AKI compared with dRRT and TSA indicating that no more studies were needed to confirm it.
UNASSIGNED: INPLASY, INPLASY2020120030. Registered 04 December 2020.

BACKGROUND: Proton pump inhibitors (PPIs) have been used to treat Barrett\'s esophagus (BE), but there seems to be insufficient evidence that PPIs can prevent esophageal adenocarcinoma (EAC) and high grade dysplasia (HGD). This study aimed to evaluate the effects of PPIs in BE patients.
METHODS: PubMed and EMBASE were systematically searched. Stata13 and trial sequential analysis (TSA) software were used to carry out related statistics. Pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.
RESULTS: Using PPIs to reduce the incidence of EAC and HGD has not been confirmed (OR, 0.61; 95% CI, 0.29-1.26). The pooled results of three cohort studies reported that PPIs use was protective (OR 0.48; 95% CI, 0.33-0.70). But the pooled results of five case-control study indicating PPIs use does not prove this protective effect (OR 0.73; 95% CI, 0.21-2.48). On pooled analysis of 4 US studies 2 Netherlands, protective effect on development of EAC and HGD was noted (OR, 0.59; 95% CI, 0.43-0.80) and (OR, 0.16; 95% CI, 0.03-0.75).
CONCLUSIONS: According to the Meta analysis and TSA of existing studies, the protective effect of PPIs on the progression of BE patients to EAC and/or HGD has not been confirmed. TSA shows that more patients are needed before a clear conclusion can be reached.

BACKGROUND: The effectiveness of corticosteroids in acute respiratory distress syndrome (ARDS) and COVID-19 still remains uncertain. Since ARDS is due to a hyperinflammatory response to a direct injury, we decided to perform a meta-analysis and an evaluation of robustness of randomised clinical trials (RCTs) investigating the impact of corticosteroids on mortality in ARDS in both COVID-19 and non-COVID-19 patients. We conducted a systematic search of the literature from inception up to 30 October 2020, using the MEDLINE database and the PubMed interface. We evaluated the fragility index (FI) of the included RCTs using a two-by-two contingency table and the p-value produced by the Fisher exact test; the fragility quotient (FQ) was calculated by dividing the FI score by the total sample size of the trial.
RESULTS: Thirteen RCTs were included in the analysis; five of them were conducted in COVID-19 ARDS, including 7692 patients, while 8 RCTS were performed in non-COVID ARDS with 1091 patients evaluated. Three out of eight RCTs in ARDS had a FI > 0 while 2 RCTs out of five in COVID-19 had FI > 0. The median of FI for ARDS was 0.625 (0.47) while the median of FQ was 0.03 (0.014). The median of FI for COVID-19 was 6 (2) while the median of FQ was 0.059 (0.055). In this systematic review, we found that FI and FQ of RCTs evaluating the use of corticosteroids in ARDS and COVID-19 were low.

UNASSIGNED: The CDK5 regulatory subunit-associated protein 1-like 1 (CDKAL1) contributes to islet β-cell function and insulin secretion by inhibiting the activation of CDK5. The current studies on the relationship between CDKAL1 polymorphisms rs7756992 A>G and rs7754840 C>G and the risk of gestational diabetes mellitus (GDM) have drawn contradictory conclusions.
UNASSIGNED: A meta-analysis with a fixed- or random-effects model was conducted to estimate the correlation between studied CDKAL1 polymorphisms and GDM risk with the summary odds ratio (OR) and 95% confidence interval (CI). In addition, trial sequential analysis (TSA) and false-positive report probability (FPRP) analysis were performed to confirm the study findings.
UNASSIGNED: A total of 13,306 subjects were included in the present study. Meta-analysis results showed that the variant heterozygous and homozygous genotypes of the two polymorphisms were associated with increased GDM risk in comparison with the wild-type AA genotype (AG vs. AA: OR = 1.23, 95% CI = 1.08, 1.41, p = 0.002; GG vs. AA: OR = 1.47, 95% CI = 1.05, 2.05, p = 0.024 for rs7756992; and CG vs. GG: OR = 1.36, 95% CI = 1.13, 1.65, p = 0.002; CC vs. GG: OR = 1.76, 95% CI = 1.37, 2.26, p < 0.001 for rs7754840). The TSA confirmed a significant association between rs7754840 and the susceptibility to GDM because the cumulative Z-curve crossed both the conventional cutoff value and the TSA boundaries under the heterozygote and homozygote models.
UNASSIGNED: This study supported the finding that rs7756992 and rs7754840 are associated with susceptibility to GDM. However, further functional studies are warranted to clarify the mechanism.