Results Of Trial Sequential Analysis Research Articles

Efficacy of acupuncture in ameliorating anxiety in Parkinson's disease: a systematic review and meta-analysis with trial sequential analysis

BackgroundAlthough numerous studies have explored acupuncture for alleviating Parkinson's disease (PD) symptoms, specific methods focusing on reducing anxiety in these patients are lacking. Preliminary research indicates that acupuncture may improve anxiety in patients with Parkinson's; however, high-quality evidence is lacking. Therefore, we conducted a meta-analysis and trial sequential analysis (TSA) to assess the efficacy of acupuncture in managing anxiety symptoms in PD.MethodsWe systematically searched eight databases for randomized controlled trials (RCTs) evaluating the efficacy of acupuncture for the treatment of anxiety in patients with PD. Primary outcomes were measured using the Hamilton Anxiety Scale (HAMA) and the Self-Rating Anxiety Scale (SAS). Secondary outcomes included the Parkinson's Disease Questionnaire-39 (PDQ-39) and the Unified Parkinson's Disease Rating Scale (UPDRS). Risk of bias was assessed using the Cochrane RoB 2.0 tool, and certainty of evidence was assessed using the GRADE system. The Trial Sequential Analysis (TSA) was used to assess the sufficiency of the evidence.ResultsOur meta-analysis included 14 studies. The Manual acupuncture (MA) + routine drug treatment (RDT) group improved more than the RDT alone group. MA was more effective than sham acupuncture. MA+ traditional Chinese medicine (TCM) was also more effective than TCM. Auricular therapy (AT) was not as effective as control therapy (CT). The Electroacupuncture (EA) + routine drug treatment (RDT) group was not as effective as RDT. PDQ-39 and UPDRS subgroup analysis showed that the acupuncture group had better clinical efficacy than CT. The GRADE assessment rated the overall certainty of evidence for anxiety outcomes as low, PDQ-39 as very low and UPDRS as low. TSA results indicate insufficient evidence; further high-quality RCTs are needed to substantiate these findings.ConclusionOur analysis suggests that MA combined with RDT may help ameliorate anxiety in PD patients, although the evidence is weak due to low quality RCTs. EA and AT showed no significant effects, highlighting the need for more rigorous studies with better controls and longer follow-up. The potential of acupuncture for PD-related anxiety should be considered with caution until stronger evidence becomes available.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/.

Is Thrombectomy Effective for Large Vessel Occlusion Stroke Patients with Mild Symptoms? Meta-Analysis and Trial Sequential Analysis

Background: Endovascular treatment (EVT) is an established method for managing large vessel occlusion (LVO), but its efficacy in patients with mild stroke (National Institutes of Health Stroke Scale [NIHSS] score < 6) remains debated. Given the clinical problem of early neurological deterioration in approximately 10% of mild stroke patients, understanding the role of EVT in managing these patients is crucial. Our objective was to perform a meta-analysis with trial sequential analysis (TSA) focusing on mild stroke patients with LVO to determine whether EVT offers better outcomes than best medical therapy alone. Methods: A comprehensive search of PubMed, Cochrane, and Embase databases up to 12 December 2023 identified 14 retrospective and prospective cohort studies, including a total of 4436 patients with NIHSS scores less than 6 and presenting with LVO. Studies were categorized into crossover and non-crossover groups to prevent overestimation of the treatment effect. In the crossover group, patients initially treated with BMT were moved to EVT upon clinical deterioration. In the non-crossover group, patients remained in their initially assigned treatment. Meta-analysis and data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary outcome was achieving an excellent functional outcome, defined as a modified Rankin scale (mRS) score of 0–1 at 3 months. Secondary outcomes included good (mRS 0–2) and favorable (mRS 0–3) functional outcomes. Safety outcomes were symptomatic intracerebral hemorrhage (sICH) and mortality at 3 months. Results: In the crossover group, EVT did not significantly improve excellent functional outcomes, and TSA results were inconclusive. Conversely, in the non-crossover group, EVT significantly improved the excellent functional outcome rates at 3 months (65.0% vs. 53.7%; OR 1.62; 95% CI 1.13 to 2.32), supported by TSA. EVT increased the risk of sICH in both crossover and non-crossover groups, while mortality rates did not significantly differ between EVT and BMT groups. Conclusions: Our research indicates that thrombectomy may not significantly help mild stroke patients in recovering functional status and could increase the risk of sICH. The disparity in results between crossover and non-crossover studies highlights the critical need for the prompt identification of patients at risk of early neurological deterioration to minimize negative outcomes. Additional randomized controlled trials are essential to optimize the application of EVT in this patient population.

Is Thrombectomy Worth It for Isolated Posterior Cerebral Artery Occlusion? Meta‐Analysis and Trial Sequential Analysis

Background Thrombectomy is well‐established management for acute ischemic stroke involving large vessel occlusion. However. the potential efficacy of thrombectomy for isolated posterior cerebral artery occlusion remains limited. The study aims to evaluate the benefits of thrombectomy for isolated posterior cerebral artery occlusion. Methods We searched PubMed, Cochrane, and Embase for articles published until September 2023. The primary outcome was good functional outcome at 3 months. The secondary outcomes included excellent functional outcome at 3 months and early neurological improvement. The safety outcomes were symptomatic intracerebral hemorrhage, and mortality at 3 months. Results Seven retrospective studies involving 2560 patients with isolated posterior cerebral artery occlusion were included (876 patients receiving thrombectomy). The odds ratio (OR) of good functional outcome at 3 months was 0.93 (95% CI, 0.68–1.28) between 2 groups. The OR of excellent functional outcome (OR 1.23; 95% CI 0.92–1.64) and early neurological improvement (OR 1.82; 95% CI 0.97–3.40) were not different between the 2 groups. Compared with patients with best medical management, those with thrombectomy demonstrated a significantly increased risk of mortality (OR 1.81; 95% CI 1.24–2.65), whereas the risk of symptomatic intracerebral hemorrhage (OR 2.033; 95% CI 0.996–4.148) did not show an increase. Additionally, the results of trial sequential analysis indicated all outcomes were inconclusive. Conclusion Thrombectomy stands as an available procedure for patients with isolated posterior cerebral artery occlusion; however, it shows no notable benefits in reducing symptomatic intracerebral hemorrhage risk or enhancing function and may raise mortality compared with standard medical management. Further randomized controlled trials are necessary to yield more conclusive evidence.

A comprehensive meta-analysis to identify susceptibility genetic variants for precocious puberty.

Currently, several genetic variants in ERα gene (rs2234693 and rs9340799), ERβ gene (rs1256049 and rs4986938), KISS1 gene (rs4889, rs1132506 and rs5780218), LIN28B gene (rs314263, rs314276 and rs314280), and MKRN3 gene (rs2239669) have been repeatedly explored for their contribution to precocious puberty (PP) susceptibility. However, the results remain conflicting rather than conclusive. We here performed a meta-analysis to identify the real susceptibility genetic variants for PP. After screening by inclusion criteria, 20 related studies were finally included in this meta-analysis. The odds ratios and 95% confidence intervals were calculated to assess the strength of association. Sensitive analysis, publication bias, and trial sequential analysis (TSA) were performed to evaluate the stability and reliability of results. Rs2234693, rs9340799, and rs1256049 were significantly associated with PP susceptibility (p<0.0084). Stratified analysis according to ethnicity showed that rs2234693 and rs9340799 were significantly associated with PP susceptibility in Asian and Chinese populations. Stratified analysis according to PP subtype showed that rs2234693 and rs9340799 were significantly associated with idiopathic central PP susceptibility in Asian and Chinese populations (p<0.0084). The results of publication bias, sensitivity analysis, and TSA provided solid evidence for the association between these three variants and PP susceptibility. Rs2234693 and rs9340799 in ERα gene and rs1256049 in ERβ gene may serve as susceptive factors for PP development. The present finding should be confirmed in replication studies and reinforced in functional studies, which will ultimately improve the feasibility of the application of these three PP-susceptible loci in clinical practice.

Serum prolactin and gonadal hormones in hemodialysis women: a meta-analysis

BackgroundA meta-analysis followed by PRISMA 2020 statement was performed aiming to present a whole prolactin and sex hormone profile in hemodialysis women.MethodsLiteratures were searched in PubMed, Cochrane library, Embase, and Web of science before March 11, 2023. Trial sequential analysis (TSA) was performed to test the conclusiveness of this meta-analysis. Egger’s test and trim-and-fill analysis was used to test publication bias. We took standardized mean difference (SMD) as pool effect of hormones values including prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and progesterone (P). This study was registered in PROSPERO and the number was CRD42023394503.ResultsTwenty-two articles from 13 countries were analyzed. Combining the results of TSA and meta-analysis, we found that compared with healthy control, hemodialysis women had higher PRL, follicular FSH and LH values and lower P levels (PRL: I2 = 87%, SMD 1.24, 95% CI: 0.79–1.69, p < 0.00001; FSH: I2 = 0%, SMD 0.34, 95% CI: 0.13–0.55, p = 0.002; LH: I2 = 39%, SMD 0.64, 95% CI: 0.34–0.93, p < 0.00001; P: I2 = 30%, SMD − 1.62, 95% CI: -2.04 to -1.20, p < 0.00001). What’s more, compared with women after renal transplantation, hemodialysis women had higher PRL levels (I2 = 0%, SMD 0.51, 95% CI: 0.25–0.78, p = 0.0001). There was not enough evidence to draw a conclusion on the comparison of hormones between regular and irregular menses hemodialysis women. Egger’s test and trim-and-fill analysis didn’t show significant publication bias.ConclusionsHemodialysis women had higher serum PRL, follicular phase FSH, LH and lower serum P values compared with healthy control. PRL values of hemodialysis women were also higher than that of women after renal transplantation.

EVALUATING THE OUTCOMES OF MINIMALLY INVASIVE THERAPY VS SURGERY FOR ORAL MUCOCELES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Oral mucoceles could be managed with minimally invasive therapy (MIT) or conventional surgery, and both modalities reportedly possess advantages and demerits. This review aims to investigate and compare the postoperative disease recurrence and complications of these interventions with each other. Relevant studies were searched in 5 databases (PubMed, Embase, Scopus, Web of Science and Cochrane Library) from inception to December 17, 2022. The pooled relative risks (RRs) with 95% confidence intervals (CIs) of disease recurrence, overall complications, nerve injury and bleeding/hematoma in MIT vs conventional surgery were calculated in meta-analysis. Trial Sequential Analysis (TSA) was performed to confirm our conclusions and assess the need for future trials. Six studies (1 randomized controlled trial and 5 cohort studies) were included for systematic review and meta-analysis. The results showed no significant difference in recurrence between MIT and conventional surgery (RR=0.80; 95% CI, 0.39-1.64; P = .54; I2=17%), and the results of the subgroup analysis were consistent. The incidence of the overall complications (RR=0.15; 95% CI, 0.05-0.47; P = .001; I2=0%) and nerve injury (RR=0.22; 95% CI, 0.06-0.82; P = .02; I2=0%) was significantly lower in MIT than in conventional surgery, but the incidence of bleeding/hematoma presented no significant difference (RR=0.34; 95% CI, 0.06-2.07; P = .24; I2=0%). The results of TSA suggested that the conclusion of MIT significantly reducing the risk of overall complications was stable; and additional clinical trials were need in the future for confirming the conclusions regarding disease recurrence, nerve injury and bleeding/hematoma. For mucoceles in the oral cavity, MIT is less likely to induce complications (i.e., nerve injury) compared with surgical removal, and the control of disease recurrence is comparable to that of conventional surgery. Therefore, the application of MIT for mucoceles could be a promising alternative to conventional surgery when the latter is not applicable.

Invasive Versus Conservative Management of NSTEMI Patients Aged ≥ 75 Years.

The efficiency of invasive management in older patients (≥75 years) with non-ST-segment elevation myocardial infarction (NSTEMI) remains ambiguous. To assess the efficiency of invasive management in older patients with NSTEMI based on meta-analysis and trial sequential analysis (TSA). Relevant randomized controlled trials (RCT) and observational studies were included. The primary outcomes were all-cause death, myocardial infarction, stroke, and major bleeding. Pooled odd ratio (OR) and 95% confidence interval (CI) were calculated. P <0.05 was considered statistically significant. Five RCTs and 22 observational studies with 1017374 patients were included. Based on RCT and TSA results, invasive management was associated with lower risks of myocardial infarction (OR: 0.51; 95% CI: 0.40-0.65; I2=0%), major adverse cardiovascular events (MACE; OR: 0.61; 95% CI: 0.49-0.77; I2=27.0%), and revascularization (OR: 0.29; 95% CI: 0.15-0.55; I2=5.3%) compared with conservative management. Pooling results from RCTs and observational studies with multivariable adjustment showed consistently lower risks of all-cause death (OR: 0.57; 95% CI: 0.50-0.64; I2=86.4%), myocardial infarction (OR: 0.63; 95% CI: 0.56-0.71; I2=0%), stroke (OR: 0.59; 95% CI: 0.51-0.69; I2=0%), and MACE (OR: 0.64; 95% CI: 0.54-0.76; I2=43.4%). The better prognosis associated with invasive management was also observed in real-world scenarios. However, for patients aged ≥85 years, invasive management may increase the risk of major bleeding (OR: 2.68; 95% CI: 1.12-6.42; I2=0%). Invasive management was associated with lower risks of myocardial infarction, MACE, and revascularization in older patients with NSTEMI, yet it may increase the risk of major bleeding in patients aged ≥85 years.

Moxibustion at Baihui combined with acupuncture for cervical vertigo: a Meta-analysis and trial sequential analysis

To evaluate the efficacy and safety of moxibustion at Baihui (CV20) combined with acupuncture in treatment of cervical vertigo. From the databases, such as CNKI, VIP, WanFang, CBM, PubMed, Cochrane Library and Embase, the studies of randomized controlled trials (RCTs) on moxibustion at CV20 combined with acupuncture for cervical vertigo were searched from inception to September 15th, 2021. The Cochrane risk of bias assessment tool was utilized to evaluate the quality of the included literature. Using RevMan5.3, Stata12.0 and TSA0.9.5.0 10 Beta software, the Meta-analysis and trial sequential analysis (TSA) were performed. Seventeen RCTs with 1 232 patients were included. Meta-analysis showed that in the trial group (moxibustion at CV20 combined with acupuncture), the total effective rate (RR=1.17, 95%CI［1.12, 1.22］, P<0.000 1), the curative and remarkably-effective rate (RR＝1.28，95%CI［1.20，1.36］，P<0.000 1) and the score of cervical vertigo (WMD=2.88, 95%CI［1.87, 3.89］, P<0.000 1) were all better when compared with the control group (simple acupuncture or electroacupuncture group). The results of trial sequential analysis indicated that for the cumulative Z-score of each RCT, the Z-curve crossed the conventional test boundary and TSA boundary, which further confirmed the clinical efficacy of moxibustion at CV20 combined with acupuncture on cervical vertigo. The clinical efficacy of moxibustion at CV20 combined with acupuncture is determined in treatment of cervical vertigo.

Causal relationships of excessive daytime napping with atherosclerosis and cardiovascular diseases: a Mendelian randomization study.

Previous observational studies have found conflicting evidence on the relationship between daytime napping and incident cardiovascular diseases (CVDs), but it remains unclear whether these associations present causality. This study aims to verify whether and why there is a causal relationship between these parameters, and whether there is an etiological basis. A two-sample Mendelian randomization analysis was performed using 79 single nucleotide polymorphisms associated with daytime napping. Summary-level data for coronary atherosclerosis, peripheral atherosclerosis, total CVD, and five CVD outcomes were obtained from the FinnGen study. Meta-analyses were aimed at investigating the relationships of excessive daytime napping with total CVD, coronary heart disease, myocardial infarction (MI), and stroke incidence. Subgroup, network meta-analysis (NMA) and trial sequential analysis (TSA) were also performed in this study. The inverse-variance weighted method demonstrated that a genetic predisposition to more frequent daytime napping was significantly associated with higher odds of coronary atherosclerosis (odds ratio [OR] = 1.55, 95% confidence interval [CI]: 1.11 to 2.17), MI (OR = 1.63, 95% CI: 1.06 to 2.50), and heart failure (OR = 1.80, 95%CI: 1.28 to 2.52). In NMA, an increased risk of developing CVD in people who napped for more than 60 min a day than those who did not nap was demonstrated and then supported by TSA results (summary relative risk = 1.98, 95% CI: 1.39 to 2.82). Habitual daytime napping is causally associated with an increased risk of incident CVD primarily via the development of coronary atherosclerosis. An average napping duration of more than 60 min is associated with an elevated risk of CVD in all participants.

Mepivacaine Versus Bupivacaine in Adult Surgical Patients: A Meta-analysis, Trial Sequential Analysis of Randomized Controlled Trials

PurposeEvidence supporting the choice between mepivacaine and bupivacaine is inconclusive. This meta-analysis aims to determine whether mepivacaine can reach a similar effect to bupivacaine after surgeries. DesignA meta-analysis, trial sequential analysis of randomized controlled trials (RCTs). MethodsRCTs were identified in PubMed, EMBASE (Ovid), Medline (Ovid), and Cochrane Library using a controlled vocabulary (MeSH) and keywords. There were no date and language restrictions. We strictly included RCTs comparing mepivacaine with bupivacaine. The primary outcome was motor function recovery time. Secondary outcomes included postoperative analgesic requirement, transient neurologic symptoms (TNS), pain score at 24 hours, length of stay (LOS), duration of analgesia, complications, and patient satisfaction. A trial sequential analysis (TSA) was performed for motor function recovery time, postoperative analgesic requirement, and TNS. FindingsSeven RCTs with a total of 672 patients were included. Return of motor function was quicker in patients who received mepivacaine than in those who received bupivacaine (weighted mean differences [WMD] = -2.23 minutes; 95% confidence intervals [CI], -3.58 to -0.88; P = .02; I2 = 97.08%; TSA adjusted CI -17.52 to -10.9). Postoperative analgesic requirement was significantly more with mepivacaine (risk ratio [RR] = 3.23; 95% CI, 1.37-7.62; P = .01; I2 = 55.11%; TSA adjusted CI 5.73-63.27). Duration of analgesia (WMD = -8.83 hours; 95% CI, -11.75 to -7.90; P < .001; I2 = 0%) and LOS (WMD = -3.95 hours; 95% CI, -4.83 to -3.07; P < .001; I2 = 0%) in group mepivacaine was significantly shorter compared with bupivacaine. There were no differences for TNS (RR = 3.90; 95% CI, 0.94-16.22; P = .062; I2 = 72.23%), postoperative pain score (standard mean differences [SMD] = 0; 95% CI, −0.10 to 0.10; P = .972; I2 = 0%), complications (RR = 1; 95% CI, 0.70-1.43; P = .998; I2 = 0%), and satisfaction (RR = 0.97; 95% CI, 0.85-1.11; P = .40; I2 = 45%) between bupivacaine and mepivacaine. ConclusionsMepivacaine appears to yield a faster return of motor function and shorter LOS compared with bupivacaine. and may be more popular in short-stay and outpatient surgery. However, the results of TSA indicate that more high-quality trials are needed to confirm the true effects.

Probiotic in the prevention of ventilator-associated pneumonia in critically ill patients: evidence from meta-analysis and trial sequential analysis of randomized clinical trials

BackgroundProbiotic might have a role in the prevention of ventilator-associated pneumonia (VAP) among mechanically ventilated patients, but the efficacy and safety remained inconsistent. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of probiotic (prebiotic, synbiotic) versus placebo in preventing VAP in critically ill patients undergoing mechanical ventilation.MethodsPubMed, Embase and the Cochrane library databases were searched to 10 October 2021 without language restriction for randomized or semi-randomized controlled trials evaluating probiotic (prebiotic, synbiotic) vs. placebo in prevention of VAP in critically ill mechanically ventilated patients. The pooled relative risk (RR) along with 95% confidence intervals (CI) were combined using a random-effects model. Furthermore, the trial sequential analysis (TSA) and subgroup analyses were performed. Statistical significance was regarded as P < 0.05.ResultsTwenty-three trials involving 5543 patients were eligible for this meta-analysis. The combined RR of decreasing the risk of VAP by probiotic was 0.67 (0.56, 0.81) for all eligible studies, 0.69 (n = 5136; 95% CI = 0.57 to 0.84; P < 0.01) for adults studies and 0.55 (n = 407; 95%CI = 0.31 to 0.99; P = 0.046) for neonates/children studies. Additionally, the above-mentioned positive finding in 20 adults studies was verified by the results of TSA, subgroup analyses and cumulative meta-analysis. Ample evidences demonstrated a 31% decrease in RR of incidence of VAP was noted when prophylactic probiotic therapy was administrated among adult patients. Finally, there were no effects on the ICU/hospital/28-/90-day mortality, bacteremia, CRBSI, diarrhea, ICU-acquired infections, infectious complications, pneumonia, UTI and wound infection between two groups (P > 0.05 for all).ConclusionsBased on the results of our study, the current evidences suggested that prophylactic administration of probiotic might be utilized as a preventive method for VAP in neonates/children and adults patients who required mechanical ventilation. However, further large, high-quality RCTs are warranted to assess the efficacy and safety of probiotic treatment in critically ill patients, especially for the neonates/children studies and the long-term consequences of this therapy.

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis

BackgroundStudies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying.MethodsThis systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes.ResultsEight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22–0.75; P = 0.004). Furthermore, any LOF allele carriers didn’t yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76–1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99–2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17–4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27–1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30–2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33–2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required.ConclusionsThis qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included.

The minor T allele of the MUC5B promoter rs35705950 associated with susceptibility to idiopathic pulmonary fibrosis: a meta-analysis

MUC5B promoter rs35705950 T/G gene polymorphism has been associated with the risk of IPF, but the influence of this relationship varies among different populations. In the past 2 years, there were new clinical studies with different results, but none of them reached unified conclusions. Therefore, this study further included the latest case–control studies, integrated their results and carried out meta-analysis on them to draw reliable conclusions. PubMed, EMBASE, CNKI, Wanfang database and VIP Chinese science were searched by a computer to collect the related literatures of MUC5B gene polymorphism and IPF susceptibility published before June 15, 2021. The first author, year of publication, diagnostic criteria and gene frequency were extracted after screened them. Forest plot was drawn and the trial sequential analysis (TSA) was carried out to confirm the stability of the meta-analysis results. Registration number: CRD42021272940. A total of 24 case–control studies (13 studies on the Caucasian, 7 studies on the Asian and 4 studies on the mixed population), and a total of 6749 IPF patients and 13,898 healthy controls were included in this study. The T vs.G, TT vs. GG, GT vs. GG, GT + TT vs. GG and TT vs. GG + GT genetic models of MUC5B promoter rs35705950 T/G polymorphism were associated with IPF risk in all populations, and the effect values were ([OR] 4.12, 95% CI [3.64, 4.67]), ([OR] 10.12, 95% CI [7.06, 14.49]), ([OR] 4.84, 95% CI [3.85, 6.08]), ([OR] 4.84, 95% CI [3.79, 6.19]) and ([OR] 5.11, 95% CI [4.02, 6.49]), respectively. The results of TSA confirmed the stability of the results. Subgroup analysis showed that T vs.G, TT vs. GG, GT vs. GG, GT + TT vs. GG and TT vs. GG + GT genetic models of MUC5B polymorphism were associated with IPF risk in Caucasian population. The effect values were ([OR] 4.50, 95% CI [3.93, 5.16]), ([OR] 10.98, 95% CI [7.59, 15.89]), ([OR] 6.27, 95% CI [5.37, 7.32]), ([OR] 6.30, 95% CI [5.19, 7.64]) and ([OR] 5.15, 95% CI [4.01, 6.61]), respectively. Similar results were also found in Asian and mixed populations. The association strength of the minor T allele in the Caucasian was more significant than that of the Asian population ([OR] 4.50 vs. [OR] 2.39), and the association strength of all genetic models carrying "T" was more significant than that of the Asian population ([OR] 10.98 vs. [OR] 4.29). In Caucasian, Asian and mixed populations, T minor allele carriers were more likely to be susceptible to pulmonary fibrosis, and TT genotype carriers were more likely to be susceptible to IPF than GT genotype carriers. The association between IPF and Caucasian population with minor T allele and all "T" genetic model was more significant than that of Asian population.

Association of interleukin-6 promoter polymorphism with rheumatoid arthritis: a meta-analysis with trial sequential analysis.

The association of interleukin-6 (IL-6) -174G/C (rs1800795) and IL-6 -572G/C (rs1800796) single-nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) was inconsistent among previous studies. This paper aims to investigate the association between IL-6 promoter polymorphism with RA in different ethnics. Relevant studies were searched using Medline and Google Search engines; STATA software was used to perform the meta-analysis. Pooled odds ratios (OR) were calculated to estimate the potential genetic associations. Subgroup analysis and sensitivity analysis were applied to explore the sources of heterogeneity. Lastly, we used TSA (trial sequential analysis) software to verify the reliability of meta-analysis results. A total of 18 studies were included, involving 8116 subjects (3820 RA patients and 4296 controls). We found a tendency to associate RA with the IL-6 -174G/C allele in Asians (C vs G: OR = 4.56, 95% CI = 1.85-11.23; P < 0.001); with IL-6 -572G/C genotype or allele frequencies, there was no statistical differences between RA patients and controls (P > 0.05). TSA results indicate that the current meta-analysis can draw conclusions. IL-6-174G/C gene polymorphism were associated with increased risk of RA in Asians, but not in Caucasians. There was no association between IL-6 -572G/C gene polymorphism and the risk of RA. Key Points • Although the association between interleukin-6 (IL-6) promoter polymorphism and rheumatic arthritis (RA) has been discussed in the previous meta-analysis, their conclusions are inconsistent. • In this study, trial sequential analysis (TSA) was introduced into the meta-analysis, and the following two important conclusions were confirmed: (1) IL-6-174G/C gene polymorphism was associated with increased risk of RA in Asians, but not in Caucasians. (2) There was no association between IL-6 -572G/C gene polymorphism and the risk of RA.

A meta-analysis and trial sequential analysis of serum copeptin level in adult patients with Obstructive Sleep Apnoea Syndrome

Copeptin can act as a stable biomarker in inflammation and stress response that obstructive sleep apnoea syndrome (OSAS), can induce oxidative stress and consequently promotes systemic inflammation. The purpose of the study is to appraise serum copeptin level in adult patients with OSAS compared to the controls. Electronic search was done in the databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library until June 2021, without any restrictions. For comparison of the serum copeptin level between groups, the mean difference (MD) and 95% confidence interval (CI) were calculated by the Review Manager 5.3 software. Trial sequential analysis (TSA) was used by applying TSA software. Among the databases, five articles (involving 495 OSAS patients and 135 controls) were included. To report the serum copeptin level in OSAS patients compared to controls, the pooled OR became 12.21pg/mL (95%CI: 2.31 to 22.11; P=0.02) and also the pooled OR for comparison of serum copeptin level in severe versus moderate/mild OSAS patients was 5.96pg/mL (95%CI: 1.46 to 10.47; P=0.009). The results of TSA illustrated that the Z-curve has not crossed the monitoring boundary curves and did not reach the required information size. The main findings recommended that copeptin had a significantly higher serum level in OSAS patients compared to controls, as well as a significantly higher level in severe patients compared to mild/moderate OSAS patients for the serum level of copeptin.

Efficacy and airway complications of Parker Flex-Tip tubes and standard endotracheal tubes during airway manipulation: A meta-analysis and trial sequential analysis.

Despite reported superior intubation outcomes associated with Parker Flex-Tip (PFT) tubes compared with those associated with standard polyvinylchloride tubes, the efficacy and safety of PFT tubes remain uncertain. To compare the intubation outcomes between PFT and conventional standard polyvinylchloride tubes. Meta-analysis of randomised controlled trials. Embase, Medline, Google Scholar, PubMed and the Cochrane controlled trials register from inception until 3 January 2021. All randomised trials comparing intubation outcomes between PFT (PFT group) and standard polyvinylchloride (standard polyvinylchloride group) tubes. Analysis of the 13 eligible trials showed no significant difference in successful first-attempt intubation rate [risk ratio (RR) 1.20, 95% confidence interval (CI) 0.99 to 1.44] (6 trials, 568 participants), trauma risk (RR 0.83, 95% CI 0.67 to 1.03) (5 trials, 501 participants) as well as the overall risks of epistaxis (RR 0.58, 95% CI 0.26 to 1.31) (3 trials, 262 participants), sore throat (RR 0.90, 95% CI 0.70 to 1.17) (4 trials, 451 participants) and hoarseness (RR 0.71, 95% CI 0.44 to 1.14) (4 trials, 451 participants) between the two groups. However, the intubation time was slightly shorter (weighted mean difference -4.2 s, 95% CI -7.4 to -1.0 s) (8 trials, 759 participants) and the risks of severe epistaxis (RR 0.15, 95% CI 0.03 to 0.84) (3 trials, 262 participants) and overall difficulty in airway manipulation (RR 0.48, 95% CI 0.29 to 0.80) (8 trials, 647 participants) were lower in the PFT group than those in the standard polyvinylchloride group. Trial sequential analysis conclusively confirmed a shorter intubation time with PFT tubes than with standard polyvinylchloride tubes, whereas other intubation outcomes were inconclusive. The use of PFT tubes for airway manipulation was associated with a shorter intubation time compared with the standard polyvinylchloride tubes. The results of trial sequential analysis suggest the need for further trials and meta-analysis to compare other intubation outcomes associated with the two devices. PROSPERO CRD42020197670.

Extracorporeal membrane oxygenation versus mechanical ventilation alone in adults with severe acute respiratory distress syndrome: A systematic review and meta-analysis.

COVID-19 can lead to acute respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) is considered to be a salvage strategy for severe ARDS. However, the effect of ECMO therapy on severe ARDS remains inconclusive. We aimed to evaluate the effects of ECMO for adults with severe ARDS. We searched six databases (EMBASE, Medline, the Cochrane Library, Web of Science, Wanfang databases and CNKI) from inception to May 2020 to screen relevant high-quality observational studies and randomised controlled trials. We used the random effects model for outcome calculation. Trial sequential analysis (TSA), heterogeneity, sensitivity analysis and publication bias were explored. The primary outcome was 90-day mortality. Seven studies (two RCTs and five observational studies) with a total of 867 patients were included. Compared with MV therapy alone, ECMO therapy significantly reduced the mortality at 90days (based on RCT studies, Risk Ratio [RR] 0.74, 95% confidence Interval (CI) 0.59-0.93, P=.01, I2 =0%, moderate quality; based on observational studies, RR 0.61, 95% CI 0.46-0.81, P<.001, I2 =0%, low quality) and at 30 and 60days. TSA results were consistent with the primary outcome. Furthermore, device-related adverse events were similar between the ECMO group and MV alone group (RR, 2.09; 95% CI, 0.27-16.03, P=.48, I2 =0%, moderate quality). This study showed that the ECMO group exhibited a significantly lower mortality rate compared with the MV alone group at 90, 30 and 60days for severe ARDS patients.

Bisphosphonates and Breast Cancer Survival: A Meta-Analysis and Trial Sequential Analysis of 81508 Participants From 23 Prospective Epidemiological Studies

Background: We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment. Methods: We performed a meta-analysis and trial sequential analysis (TSA) of prospective studies including randomized controlled trials (RCTs) and cohort studies and reported effect estimates with 95% confidence intervals (CIs). We performed extensive sensitivity analyses to assess the robustness of the findings.\ Results: Seventeen RCTs and eight cohorts with 81508 BCa patients were identified. A significant beneficial effect of BPs on BCa survival was found (RR, 0·725; 95%CI, 0·627-0·839), and TSA results also suggested firm evidence for this beneficial effect. Both summarized results from RCTs and cohorts provides firm evidence for this effect, though the effect estimates were stronger from cohorts than RCTs (RR, 0·892; 95%CI, 0·829-0·961; 0·570; 95%CI, 0·436-0·745; respectively). This beneficial effect was confirmed for bone-metastases (RR, 0·713; 95%CI, 0·602-0·843) and postmenopausal women (RR, 0·737; 95%CI, 0·640-0·850). Importantly, our results demonstrated that this beneficial effect retained at least 1-2 years after treatment completion (RR, 0·780; 95%CI, 0·638-0·954) and could persist for up to more than 4 years after treatment completion (RR, 0·906; 95%CI, 0·832-0·987). Extensive sensitivity analyses showed the robustness of our results. The GRADE quality of evidence was generally judged to be moderate to high. Conclusions: The present study provides firm evidence for a significant beneficial effect of BPs on BCa survival in patients with early-stage BCa, particularly for bone metastases and postmenopausal patients; and this effect retained at least 1-2 years after BP treatment completion. Systematic Review Registration: PROSPERO CRD42014014699. Funding Statement: This work was supported by the China Postdoctoral Science Foundation (grant number 2018M641875 to YPL); the Natural Science Foundation of Heilongjiang Province (grant number YQ2019H021to YPL); the National Key Research and Development Program of China (grant number 2017YFC0108602 to XDL). Declaration of Interests: None.

Therapeutic effect of nebulized hypertonic saline for muco-obstructive lung diseases: a systematic review and meta-analysis with trial sequential analysis

Overproduction of mucus and impaired clearance play important roles in the pathogenesis of muco-obstructive lung diseases (MOLDs). This study aims to evaluate the therapeutic effect and safety of nebulized hypertonic...

Use of the GlideScope does not lower the hemodynamic response to tracheal intubation more than the Macintosh laryngoscope: a systematic review and meta-analysis.

Background:It is presently unclear whether the hemodynamic response to intubation is less marked with indirect laryngoscopy using the GlideScope (GlideScope) than with direct laryngoscopy using the Macintosh laryngoscope. Thus, the aim of this study was to determine whether using the GlideScope lowers the hemodynamic response to tracheal intubation more than using the Macintosh laryngoscope.Methods:We performed a comprehensive literature search of electronic databases for clinical trials comparing hemodynamic response to tracheal intubation. The primary aim was to determine whether the heart rate (HR) and mean blood pressure (MBP) 60 s after tracheal intubation with the GlideScope were lower than after intubation with the Macintosh laryngoscope. We expressed pooled differences in HR and MBP between the devices as the weighted mean difference with 95% confidence interval and also performed trial sequential analysis (TSA). Second, we examined whether use of the GlideScope resulted in lower post-intubation hemodynamic responses at 120, 180, and 300 s compared with use of the Macintosh laryngoscope. For sensitivity analysis, we used a multivariate random effects model that accounted for within-study correlation of the longitudinal data.Results:The literature search identified 13 articles. HR and MBP at 60 seconds post-intubation was not significantly lower with the GlideScope than with the Macintosh (HR vs MBP: weighted mean difference = 0.22 vs 2.56; 95% confidence interval −3.43 to 3.88 vs −0.82 to 5.93; P = .90 vs 0.14; I2 = 77% vs 63%: Cochran Q, 52.7 vs 27.2). Use of the GlideScope was not associated with a significantly lower HR or MBP at 120, 180, or 300 s post-intubation. TSA indicated that the total sample size was over the futility boundary for HR and MBP. Sensitivity analysis indicated no significant association between use of the GlideScope and a lower HR or MBP at any measurement point.Conclusions:Compared with the Macintosh laryngoscope, the GlideScope did not lower the hemodynamic response after tracheal intubation. Sensitivity analysis results supported this finding, and the results of TSA suggest that the total sample size exceeded the TSA monitoring boundary for HR and MBP.