Clinical effects and safety of edaravone in treatment of acute ischaemic stroke: A meta-analysis of randomized controlled trials.

WHAT IS KNOWN AND OBJECTIVE: Edaravone is a new antioxidant and hydroxyl radical scavenger. Although there is evidence that it improves clinical outcomes of patients with acute ischaemic stroke (AIS), it is not yet widely accepted for treatment of AIS in Western countries. We further investigated the efficacy and safety of edaravone through this meta-analysis of randomized controlled clinical trials (RCTs). METHOD: Pubmed, Embase, Web of Science and Cochrane Library were screened up to December 2020 for original articles from SCI journals that published in English. RCTs that compared edaravone versus placebo or no intervention in adult patients and reported the efficacy or safety of edaravone were regarded as eligible. Mortality was regarded as the primary outcome and the improvement of neurological impairment was regarded as the secondary outcome. Safety evaluation was conducted according to the incidence of adverse events. Review Manager 5.3 was employed to perform the assessment of the risk of bias and data synthesis. The Cochrane risk of bias tool for randomized controlled trials was employed to assess the risk of bias. RESULTS AND DISCUSSION: Seven randomized controlled trials with 2069 patients were included. For the incidence of mortality, the pooled RR for studies that evaluated edaravone after three-month follow-up was 0.55 (95% Cl, 0.43-0.7, I2  = 0, P < 0.01). The pooled RR for improvement of neurological impairment at the three months follow-up was 1.54 (95% CI, 1.27-1.87, I2  = 0, P < 0.01) in four RCTs. On subgroup analysis of studies that were conducted in Asia, the RR was 1.56 (95% CI, 1.27-1.90, I2  = 0%; P < 0.01); the pooled RR for studies that conducted in Europe was 1.32 (95% CI, 0.64-2.72; P = 0.45); the pooled RR for studies that used edaravone for two weeks was 1.42 (95% CI, 1.10 to 1.83, I2  = 0%; P < 0.01); the pooled RR for studies that used edaravone for one week was 1.64 (95% CI, 1.24-2.16, I2  = 0%; P < 0.01); the pooled RR for studies that conducted in patients with mean age equal to or over 60 years was 1.52 (95% CI, 1.24-1.87, I2  = 0%; P < 0.01); and the pooled RR for studies that conducted in patients with mean age less than 60 was 1.80 (95% CI, 1.05-3.08, I2  = 0%; P = 0.03). For the incidence of any treatment-related adverse events, the pooled RR for studies that evaluated edaravone during treatment was 0.83 (95% CI, 0.51-1.34, I2  = 0, P = 0.43). The difference of the incidence of any treatment-related adverse events between two groups was not statistically significant. WHAT IS NEW AND CONCLUSION: The limited studies indicate that edaravone can improve neurological impairment with a survival benefit at three-month follow-up, regardless of the mean age and course of treatment. It is worthy of promotion in the clinical treatment of AIS in Asian countries. More well-designed RCTs with larger sample sizes are needed to determine the benefits of edaravone in patients from Western countries.

Effectiveness of photobiomodulation in the treatment of primary burning mouth syndrome-a systematic review and meta-analysis.

To evaluate the effectiveness of photobiomodulation (PBM) on primary burning mouth syndrome (pBMS). We searched Chinese and English studies published before February 10, 2020. The databases used include PubMed, EMBASE, the Cochrane Library, Web of Science, Wanfang Database, and China National Knowledge Infrastructure (CNKI). Randomized controlled clinical trials (RCTs) that used the PBM to treat pBMS and reported specific treatment outcomes were considered for inclusion. We eventually included 12 RCTs, and 574 samples were included in these studies. The primary outcomes investigated were pain reduction and life quality improvement. A meta-analysis performed on 9 groups in 5 trials showed that PBM was effective in reducing pain compared with placebo (MD - 1.86, 95% CI - 2.59 to - 1.13, Z = 4.99, P < 0.00001). Meta-analysis was also performed on 7 groups in 4 trials and showed that PBM was effective in improving life quality compared with placebo (MD - 3.43, 95% CI - 5.11 to - 1.75, Z = 4.00, P < 0.0001). Qualitative analysis of the included RCTs found that PBM might also play a role in the decrease of TNF-α and IL-6 in saliva. Three studies that compared PBM with medications were evaluated by descriptive analysis. None of the treatment-related adverse event was reported. Up to date, PBM appears to have an effect on pain reduction and life quality improvement in pBMS patients. However, more evidence is still required to warrant its efficacy and safety in treating pBMS.

The comparison of albumin and 6% hydroxyethyl starches (130/0.4) in cardiac surgery: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: Fluid administration is a key tool in the maintenance of normovolemia in patients with cardiac surgery. The trials that evaluated the safety of 6% hydroxyethyl starch (HES) 130/0.4 in cardiac surgical patients were inconsistent. It is necessary to compare the efficacy and safety of albumin and 6% HES (130/0.4). METHOD: We searched for the randomized controlled clinical trials that compared human albumin with 6% HES (130/0.4) in cardiac surgery in PubMed, Cochrane, and Embase. RESULTS: Ten studies involved a total of 1567 patients were included in our meta-analysis. For the efficiency, there was no difference in total volume of infusion between compared groups [P = 0.64, Fixed Effect Model (FEM): standardized mean difference (SMD) = 0.04, 95% confidence interval (CI) (- 0.12, 0.20)]. As for safety, the albumin show more risk than hydroxyethyl starch 130/0.4 in blood loss [P = 0.02, FEM: SMD: 0.22, 95% CI (0.03, 0.41)]. There was no difference in the frequency of transfusions (P = 0.20, RR = 1.11; 95% CI (0.95, 1.27)) between the two groups. No difference was observed for the days in intensive care unit [P = 0.05, FEM: SMD = - 0.18, 95% CI (- 0.36, 0.00)], and the days in hospital [P = 0.32, FEM: SMD = - 0.11, 95% CI (- 0.32, 0.10)]. Furthermore, both the incidence of AKI, RRT, and mortality were comparable in the two groups. CONCLUSION: This study provided evidence that the 6% HES (130/0.4) might be the substitute for HA, which reduced the economic burden for patients with cardiac surgery. However, the effect of 6% HES (130/0.4) and HA on AKI still needs to be further studied.

A randomized clinical trial of class II composite restorations using direct and semidirect techniques.

OBJECTIVE: This prospective study evaluated the clinical performance of large class II restorations made with different techniques over 24 months. MATERIALS AND METHODS: Thirty patients received two class II restorations (n = 60) using a nanohybrid composite and different restorative techniques (direct (DT), semidirect (SDT)), in a split-mouth randomized design. The same adhesive system was applied for all restorations. For DT, the restorative material was applied directly inside the tooth preparation. For SDT, a tooth preparation impression was obtained using alginate and a silicone flexible die was prepared. The restoration was made chairside on the model and additionally light cured. After that, it was cemented in preparation using resinous cement. All restorations were evaluated using the FDI criteria after 7 days, 6, 12, and 24 months postoperatively. RESULTS: After 24 months, 24 patients attended the recall and 48 restorations were evaluated. Fisher's statistical analysis (5%) showed no difference between the techniques. Nevertheless, Friedman's test showed significant differences for some criteria after 12 months of evaluation for both techniques. Postoperative sensitivity was reported in one DT restoration. Also, after 24 months, one SDT restoration presented marginal fracture, which was deemed unsatisfactory. CONCLUSIONS: After a 24-month follow-up, no significant difference between the tested techniques was detected. The restorations performed with both techniques produced clinically acceptable restorations. CLINICAL RELEVANCE: This study demonstrated the viability of applying two different operatory techniques (direct and semidirect) for class II resin composite restorations.

Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System.

BACKGROUND: Deep brain stimulation (DBS) is the most commonly performed surgery for the debilitating symptoms of Parkinson disease (PD). However, DBS systems remain largely unaffordable to patients in developing countries, warranting the development of a safe, economically viable, and functionally comparable alternative. OBJECTIVE: To investigate the efficacy and safety of wirelessly programmed DBS of bilateral subthalamic nucleus (STN) in patients with primary PD. METHODS: Sixty-four patients with primary PD were randomly divided into test and control groups (1:1), where DBS was initiated at either 1 month or 3 months, respectively, after surgery. Safety and efficacy of the treatment were compared between on- and off-medication states 3 months after surgery. Outcome measures included analysis of Unified Parkinson's Disease Rating Scale (UPDRS) scores, duration of "on" periods, and daily equivalent doses of levodopa. All patients were followed up both 6 and 12 months after surgery. RESULTS: Three months after surgery, significant decrease in the UPDRS motor scores were observed for the test group in the off-medication state (25.08 ± 1.00) versus the control group (4.20 ± 1.99). CONCLUSIONS: Bilateral wireless programming STN-DBS is safe and effective for patients with primary PD in whom medical management has failed to restore motor function.

Efficacy and safety of blood transfusion in obstetric patients: systematic review of the literature.

OBJECTIVES: To evaluate the efficacy of blood transfusion compared to no intervention in obstetric patients. MATERIAL AND METHODS: A systematic review was performed with Cochrane Database of Clinical Trials, PubMed, EMBASE and LILACS databases searched as of September, 2016. Two authors independently selected relevant clinical trials, assessed their methodological quality and extracted data, using the GRADE approach. RESULTS: Five studies within a total of 6,297 met the inclusion criteria, with women generally aged 20-40 years. Three included studies allocated women to receive blood transfusion or no intervention. Two other studies allocated women with either restricted or full blood supplies. The major issue regarding risk of bias was the extent of concealment of randomization and blinding. There was no statistically significant difference between blood transfusion versus no transfusion or restricted blood supply on mortality (relative risk 0.82 [95% confidential interval 0.32 to 2.09], p = 0.68; two studies; I2 = not applicable). CONCLUSIONS: Very low-quality evidence suggests no significant difference between blood transfusion and no intervention in obstetric patients, underlining the need for more robust clinical trials evaluating this area.

The effect of renal denervation on resistant hypertension: Meta-analysis of randomized controlled clinical trials.

BACKGROUND: This meta-analysis was conducted to evaluate the efficiency of renal denervation (RDN) on resistant hypertension. METHODS: PubMed, EMBASE, and the Cochrane Central database were searched for eligible randomized controlled clinical trials (RCTs). Changes from the baseline of the office blood pressure and the 24-h ambulatory blood pressure were extracted. RESULTS: Nine RCTs were included. RDN reduced the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) by -8.23 mm Hg (95%CI: -16.86, 0.39) and -3.77 mm Hg (95%CI: -7.21, -0.32), respectively, compared with the control. In the population with a baseline SBP more than 170 mm Hg, the RDN reduced SBP by -17.77 mm Hg (95%CI: -33.73, -1.82) and DBP by -7.51 mm Hg (95%CI: -12.58, -2.44). In the subgroup with no medication adjustment, the RDN reduced SBP by -15.56 mm Hg (95%CI: -26.33, -4.80) and DBP by -6.89 mm Hg (95%CI: -9.99, -3.79). The proportion of patients with SBP decrease of 10 mm Hg or more and the controlled office BP were not different between two groups. RDN reduced 24-h mean SBP and DBP by -3.34 mm Hg (95%CI: -5.30, -1.38) and -1.56 mm Hg (95%CI: -2.71, -0.41), respectively. The SBPs in the subgroups with higher baseline SBP and with no medication adjustment were significantly decreased after the HTN-3 was omitted. CONCLUSION: Radiofrequency RDN in a randomized manner did not have superiority compared with medical treatment at 6-month follow-up in general population. Current evidence provides insufficient evidence to support the use of such RDN strategy in the treatment of resistant hypertension. The result could not be used to extrapolate other strategies' effect.

Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials.

BACKGROUND AND PURPOSE: No subgroups of patients with higher treatment effects have been clearly detected in multiple sclerosis (MS). The aim of the present work was to evaluate whether there are subgroups of relapsing-remitting MS (RRMS) patients who are more responsive to treatments. METHODS: All published randomized clinical trials in RRMS reporting a subgroup analysis of treatment effect were collected. Two main outcomes, the annualized relapse rate (ARR) and the disability progression, were studied. The treatment effect in each subgroup was reported as a relative effect (RE), defined as the treatment effect in the subgroup relative to the overall effect. A meta-analysis was run to compare the RE between subgroups. RESULTS: Six trials (6693 RRMS patients) were included. Treatment effects on ARR were significantly higher in younger than in older subjects (RE = 0.83 vs. RE = 1.30, P < 0.001), in patients with than those without gadolinium activity (RE = 0.86 vs. RE = 1.15, P = 0.005) and in patients with lower than in those with higher Expanded Disability Status Scale (RE = 0.96 vs. RE = 1.23, P = 0.02), and on disability progression in younger than in older subjects (RE = 0.82 vs. RE = 1.28, P = 0.017). CONCLUSIONS: This study formally shows that in RRMS higher treatment effects are associated with characteristics of earlier (lower age and Expanded Disability Status Scale) and more active (higher gadolinium activity) disease.

Adjusting for misclassification in a stratified biomarker clinical trial.

Clinical trials utilizing predictive biomarkers have become a research focus in personalized medicine. We investigate the effects of biomarker misclassification on the design and analysis of stratified biomarker clinical trials. For a variety of inference problems including marker-treatment interaction in particular, we show that marker misclassification may have profound adverse effects on the coverage of confidence intervals, power of the tests, and required sample sizes. For each inferential problem, we propose methods to adjust for the classification errors.

Evaluation of Pain Perception During Orthodontic Debonding of Metallic Brackets with Simultaneous Application of TENS Therapy.

Objective: The objective of the present study was to evaluate the effectiveness of transcutaneous electrical nerve stimulation (TENS) therapy on pain during the debonding procedure. Methods: A placebo-controlled, randomized split - mouth study was conducted on 30 orthodontic patients. The right and left anterior teeth in the maxilla and mandible were randomly allocated to the control and experimental groups (EG) and were stimulated. TENS application was made through a modified electrode probe that was used from an ammeter. The control group (CG) received the mechanical application of the device with no current, whereas the EG received progressively increasing current from 0.1 mA to the point where the patient experienced a mild tingling sensation for 60 s for each tooth. This was followed by a debonding procedure using an orthodontic debonding plier. Pain perception was recorded on a numerical rating scale after debonding each tooth. Results: The mean pain score was higher in the CG than in the EG, and the difference between the two groups was significant (p=0.001). The pain score was higher in the mandibular teeth than in the maxillary teeth, and the difference between the two groups was also significant (p=0.021). Pain score was higher in female subjects than in male subjects, and the difference between the two groups was significant (p=0.015). Conclusion: The application of TENS therapy results in pain reduction during the debonding procedure. The female subjects experienced more pain. Higher pain scores were recorded for the mandibular anterior teeth than for the maxillary teeth.

Effects of cinnamon supplementation on metabolic biomarkers in individuals with type 2 diabetes: a systematic review and meta-analysis.

CONTEXT: The global prevalence of type 2 diabetes mellitus (DM2) has been rising significantly over the years. Recent studies have shown beneficial effects of cinnamon on metabolic biomarkers. OBJECTIVE: The objective of this review was to assess the effect of cinnamon supplementation on metabolic biomarkers in patients with DM2. DATA SOURCES: The Pubmed/MEDLINE, Cochrane CENTRAL, and Embase databases were searched up to November 10, 2022. DATA EXTRACTION: A systematic search was performed for randomized controlled trials (RCTs) evaluating the effect of cinnamon supplementation on metabolic biomarkers, in adults and the elderly with DM2, and comparing the data for a cinnamon intervention group with that for a placebo group or a control group. The main exclusion criteria were studies (1) with other types of diabetes (ie, gestational diabetes or type 1 diabetes), (2) without cinnamon consumption, (3) that did not evaluate metabolic biomarkers, or (4) in vitro and animal studies. Two researchers independently screened 924 records, evaluated full-text studies, extracted data, and appraised their quality. A third researcher was consulted to resolve any discrepancies. The data were pooled using random-effects models and expressed as the weighted mean difference (WMD) with 95% CI. Heterogeneity was assessed using Cochran's Q test and quantified using I2 statistics. Risk of bias was assessed using the Joanna Briggs Institute (JBI) instrument. Sensitivity analysis and the GRADE system were used to assess the robustness and certainty of the findings. DATA ANALYSIS: In total, 28 RCTs with a duration ranging from 30 to 120 days and a total enrollment of 3054 patients with DM2 were included. Participants consuming cinnamon showed a significant reduction in fasting blood glucose (FBG) (WMD: -15.26 mg/dL; 95% CI: -22.23 to -8.30; I2 = 88%), postprandial glucose (WMD: -39.22 mg/dL; 95% CI: -63.90 to -14.55; I2 = 100%), HbA1c (WMD: -0.56 mg/dL; 95% CI: -0.99 to -0.13; I2 = 94%), and HOMA-IR (WMD = -0.76, 95% CI: -1.13 to -0.39; I2 = 22%) compared with the control group. An intervention of cinnamon in capsule form reduced FBG (WMD:-18.43 mg/dL, 95% CI: -26.32 to -10.53; I2 = 89%), postprandial glucose (WMD: -44.83 mg/dL, 95% CI: -70.67 to -18.99; I2 = 100%), HbA1c (WMD: -0.56 mg/dL, 95% CI: -1.02 to -0.09; I2 = 94%), total cholesterol (WMD: -13.39 mg/dL; 95% CI: -24.71 to -2.07; I2 = 96%), LDL-C (WMD: -6.49 mg/dL, 95% CI: -12.69 to -0.29; I2 = 92%), and triglycerides (WND: -19.75 mg/dL; 95% CI, -33.71 to -5.80; I2 = 88%). Both doses (≤2 g/day and >2 g/day) reduced FBG and postprandial glucose. Only cinnamon doses of ≤2 g/day reduced HbA1c (WMD: -0.68 mg/dL, 95% CI: -1.16 to -0.1; I2 = 92%), HOMA-IR (WMD: -0.94 mg/dL; 95% CI: -1.21 to -0.67; I2 = 0%), and BMI (WMD: -1.18 kg/m2; 95% CI: -1.97 to -0.39; I2 = 0%). CONCLUSION: The data suggest that cinnamon improves the glycemic and lipid profile and reduces the BMI, particularly in DM2 patients who receive cinnamon supplementation in capsule form and at a dose of ≤2 g/day. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022370332.

Tenecteplase for the treatment of acute ischemic stroke in the extended time window: a systematic review and meta-analysis.

Background: Outcome data regarding the administration of tenecteplase (TNK) to acute ischemic stroke (AIS) patients presenting in the extended time window are limited. Objectives: We aimed to assess the current evidence regarding the efficacy and safety of TNK at a dose of 0.25 mg/kg for AIS treatment in the extended time window. Design: A systematic review and meta-analysis was conducted including all available randomized-controlled clinical trials (RCTs) that compared TNK 0.25 mg/kg versus no thrombolysis in AIS patients presenting in the extended time window (>4.5 h after last-seen-well or witnessed onset). Data sources and methods: Eligible studies were identified by searching Medline, Scopus, and international conference abstracts. The predefined efficacy outcomes of interest were 3-month excellent functional outcome [defined as the modified Rankin Scale (mRS) score ⩽1; primary outcome], 3-month good functional outcome (mRS ⩽ 2), 3-month reduced disability (⩾1-point reduction across all mRS scores). We determined symptomatic intracranial hemorrhage (sICH), any ICH and 3-month mortality as safety endpoints. A random-effects model was used to calculate risk ratios (RRs) and common odds ratios (cORs) with corresponding 95% confidence intervals (CIs). Results: Three RCTs were included comprising 556 patients treated with TNK versus 560 controls. TNK 0.25 mg/kg was associated with a higher likelihood of 3-month excellent functional outcome compared to controls (RR = 1.17; 95% CI = 1.01-1.36; I2 = 0%), whereas there was no difference regarding good functional outcome (RR = 1.05; 95% CI = 0.94-1.17; I2 = 0%) and reduced disability (adjusted cOR = 1.14; 95% CI = 0.92-1.40; I2 = 0%) at 3 months. The risks of sICH (RR = 1.67; 95% CI = 0.70-4.00; I2 = 0%), any ICH (RR = 1.08; 95% CI = 0.90-1.29; I2 = 0%) and 3-month mortality (RR = 1.10; 95% CI = 0.81-1.49; I2 = 0%) were similar between the groups. Conclusion: Based on data from three RCTs showing increased efficacy and a favorable safety profile of TNK in the treatment of AIS in the extended time window, continuing efforts of ongoing RCTs in the field are clearly supported. Trial registration: PROSPERO registration ID: CRD42023448707.

Exploring the mechanism of anti-chronic heart failure effect of qiweiqiangxin І granules based on metabolomics.

Background: Qiweiqiangxin І granules (QWQX І) is a traditional Chinese medicine preparation based on the basic theory of traditional Chinese medicine, which produces a good curative effect in treating chronic heart failure (CHF). However, its pharmacological effect and potential mechanism for CHF remain unknown. Aim of the study: The purpose of this study is to clarify the efficacy of QWQX І and its possible mechanisms. Materials and methods: A total of 66 patients with CHF were recruited and randomly assigned to the control or QWQX І groups. The primary endpoint was the effect of left ventricular ejection fraction (LVEF) after 4 weeks of treatment. The LAD artery of rats was occluded to establish the model of CHF. Echocardiography, HE and Masson staining were performed to evaluate the pharmacological effect of QWQX І against CHF. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) untargeted metabolomics was to screen endogenous metabolites in rat plasma and heart and elucidate the mechanism of QWQX І against CHF. Results: In the clinical study, a total of 63 heart failure patients completed the 4-week follow-up, including 32 in the control group and 31 in QWQX І group. After 4 weeks of treatment, LVEF was significantly improved in QWQX І group compared with the control group. In addition, the patients in QWQX І group had better quality of life than the control group. In animal studies, QWQX І significantly improved cardiac function, decreased B-type natriuretic peptide (BNP) levels, reduced inflammatory cell infiltration, and inhibited collagen fibril rate. Untargeted metabolomic analysis revealed that 23 and 34 differential metabolites were screened in the plasma and heart of chronic heart failure rats, respectively. 17 and 32 differential metabolites appeared in plasma and heart tissue after QWQX І treatment, which were enriched to taurine and hypotaurine metabolism, glycerophospholipid metabolism and linolenic acid metabolism by KEGG analysis. LysoPC (16:1 (9Z)) is a common differential metabolite in plasma and heart, which is produced by lipoprotein-associated phospholipase A2 (Lp-PLA2), hydrolyzes oxidized linoleic acid to produce pro-inflammatory substances. QWQX І regulates the level of LysoPC (16:1 (9Z)) and Lp-PLA2 to normal. Conclusion: QWQX І combined with western medicine can improve the cardiac function of patients with CHF. QWQX І can effectively improve the cardiac function of LAD-induced CHF rats through regulating glycerophospholipid metabolism and linolenic acid metabolism-mediated inflammatory response. Thus, QWQX I might provide a potential strategy for CHF therapy.

Efficacy and Safety of Oral Factor XIa Inhibitors in Stroke Prevention: A Systematic Review and Meta-Analysis.

INTRODUCTION: Despite preventive measures, stroke rates remain high in the primary and secondary prevention settings. Factor XIa inhibition may offer a novel, safe and effective antithrombotic option for stroke prevention. METHODS: We conducted a systematic review and meta-analysis including all available randomized controlled clinical trials (RCTs) that investigated the efficacy and safety of factor XIa inhibitors versus controls in primary or secondary stroke prevention. The primary efficacy and safety outcomes of interest were symptomatic ischemic stroke (IS) and the composite of major bleeding and clinically relevant non-major bleeding. RESULTS: Four phase II dose-finding RCTs were included, comprising a total of 4732 patients treated with factor XIa inhibitors versus 1798 controls. Treatment with factor XIa inhibitors did not reduce the risk of IS compared to controls (RR: 0.89; 95% CI: 0.67-1.17). The composite of symptomatic IS and covert infarcts on brain MRI (RR: 1.01; 95% CI: 0.87-1.18), the composite of symptomatic IS and transient ischemic attack (TIA; RR: 0.78; 95% CI: 0.61-1.01), and the composite of major adverse cardiovascular events (RR: 1.07; 95% CI: 0.87-1.31) did not differ between the treatment groups. Treatment with factor XIa inhibitors did not increase the risk of the composite of major bleeding and clinically relevant non-major bleeding (RR: 1.19; 95% CI: 0.65-2.16), major bleeding alone (RR: 1.19; 95% CI: 0.64-2.22), intracranial bleeding (RR: 0.91; 95% CI: 0.26-3.19) or all-cause mortality (RR: 1.21; 95% CI: 0.77-1.90). CONCLUSION: This meta-analysis provides reassuring evidence regarding the safety of factor XIa inhibitors. These findings, coupled with potential signals of efficacy in reducing IS (and TIA), underscore the importance of ongoing phase III RCTs for providing definitive data regarding the effect of factor XIa inhibition on stroke prevention.

Endovascular Treatment for Acute Basilar Artery Occlusion: A Fragility Index Meta-Analysis.

INTRODUCTION: High-quality evidence regarding the use of endovascular treatment (EVT) in patients with acute basilar artery occlusion (BAO) has been provided by recently completed randomized controlled clinical trials (RCTs). METHODS: We conducted a systematic review and meta-analysis including all available RCTs that investigated efficacy and safety of EVT in addition to best medical treatment (BMT) versus BMT alone for BAO. The random-effects model was used, while the fragility index (FI) was calculated for dichotomous outcomes of interest. RESULTS: Four RCTs were included comprising a total of 988 patients with acute BAO (mean age: 65.6 years, 70% men, median NIHSS: 24, 39% pretreatment with intravenous thrombolysis). EVT was related to higher likelihood of good functional outcome (RR: 1.54; 95% CI: 1.16-2.05; I2 = 60%), functional independence (RR: 1.83; 95% CI: 1.08-3.08; I2 = 79%) and reduced disability at 3 months (adjusted common OR: 1.96; 95% CI: 1.26-3.05; I2 = 59%) compared to BMT alone. Despite that EVT was associated with a higher risk for symptomatic intracranial hemorrhage (RR: 7.78; 95% CI: 2.36-25.61; I2 = 0%) and any intracranial hemorrhage (RR: 2.85; 95% CI: 1.50-5.44; I2 = 16%), mortality at 3 months was lower among patients that received EVT plus BMT versus BMT alone (RR: 0.76; 95% CI: 0.65-0.89; I2 = 0%). However, sufficient robustness was not evident in any of the reported associations (FI < 10) including the overall effect regarding the primary outcome. The former associations were predominantly driven by RCTs with recruitment limited in China. CONCLUSIONS: EVT combined with BMT is associated with a higher likelihood of achieving good functional outcomes and a lower risk of death at 3 months compared to BMT alone, despite the higher risk of sICH. An individual-patient data meta-analysis is warranted to uncover and adjust for potential sources of heterogeneity and to provide further insight.

A comprehensive quality analysis of randomized controlled clinical trials of Asian ginseng and American ginseng based on the CONSORT guideline.

Ginseng is an international herb that has been used for thousands of years. Two species most commonly applied and investigated in the ginseng family are Asian ginseng and American ginseng. The number of randomized controlled clinical trials (RCTs) has conspicuously increased, driven by the rapid development of ginseng. However, the reporting of RCT items of ginseng is deficient because of different trial designs and reporting formats, which is a challenge for researchers who are looking for the data with high quality and reliability. Thus, this study focused on providing an extensive analysis of these two species and examined the quality of the RCTs, based on the Consolidated Standards of Reporting Trials (CONSORT) guideline. Ninety-one RCTs conducted from 1980 to 2019 that were related to Asian ginseng and American ginseng used singly met our inclusion criteria. We found that the reporting quality of the two species has improved during the past 40 years. Publication date and sample size were significantly associated with the reporting quality. Rigorous RCTs designed for the species of ginseng are warranted, which can shed light on product research and development of ginseng in the future.

Effectiveness of treatments for people living with severe dementia: A systematic review and meta-analysis of randomised controlled clinical trials.

BACKGROUND: Dementia is a progressive neurodegenerative syndrome that has no cure. Although a significant proportion of people with dementia progress into the severe stages of the disease, evidence on the clinical effectiveness of treatments for people with severe dementia remains limited. AIMS: To systematically review the effectiveness of pharmacological and non-pharmacological treatments for people living with severe dementia and assess the quality of the evidence. METHOD: We searched MEDLINE, EMBASE, PsycINFO, CINAHL and online clinical trial registers up to January 2022, for Randomised Controlled Trials (RCT) in people living with severe dementia. Quality and risk of bias were assessed independently by two authors. RESULTS: A total of 30 trials met our inclusion criteria of which 14 evaluated the effectiveness of pharmacological treatments, and 16 evaluated a non-pharmacological intervention. Pharmacological treatments: Meta-analyses indicated that pharmacological treatments (donepezil: 10 mg, 5 mg; galantamine: 24 mg; memantine: 10 mg) are associated with better outcomes compared to placebo for: severity of symptoms (standardized mean difference (SMD) 0.37, 95% CI 0.26-0.48; 4 studies; moderate-certainty evidence), activities of daily living (SMD 0.15, 95% CI 0.04-0.26; 5 studies; moderate-certainty evidence), and clinical impression of change (Relative Risk (RR) 1.34, 95% CI 1.14-1.57; 4 studies; low-certainty evidence). Pharmacological treatments were also more likely to reduce mortality compared to placebo (RR 0.60, 95% CI 0.40-0.89; 6 studies; low-certainty evidence). Non-pharmacological treatments: Five trials were included in the meta-analyses of non-pharmacological interventions (multi-sensory stimulation, needs assessment, and activities-based interventions); results showed that non-pharmacological interventions may reduce neuropsychiatric symptoms of dementia compared to usual care (SMD -0.33, 95% CI -0.59 to -0.06; low certainty evidence). CONCLUSIONS: There is moderate-certainty evidence that pharmacological treatments may decrease disease severity and improve function for people with severe dementia. Non-pharmacological treatments are probably effective in reducing neuropsychiatric symptoms but the quality of evidence remains low. There is an urgent need for high-quality evidence for other outcomes and for developing service-user informed interventions for this under-served group.

Preventing Gestational Diabetes Mellitus by Improving Healthy Diet and/or Physical Activity during Pregnancy: An Umbrella Review.

Several epidemiological studies have analyzed the effects of lifestyle modification on reducing the risk of gestational diabetes mellitus (GDM); however, their results remain inconsistent. This umbrella review aims to evaluate the effects of diet and/or physical activity interventions during pregnancy on preventing GDM. Systematic reviews and meta-analysis of randomized clinical trials reporting preventive effects of diet and/or physical activity in reducing the incidence of GDM were included from PubMed, Web of Science, Scopus and Cochrane library. Two authors independently assessed the overlapping and quality of the 35 selected reviews using AMSTAR 2. The results, although variable, tend to defend the protective role of diet and physical activity interventions separately and independently of each other in the prevention of GDM. However, the results for the combined interventions show a possible protective effect; however, it is not entirely clear because most of the analyzed meta-analyses tend to approach 1, and heterogeneity cannot be ruled out. Establishing conclusions about the most efficient type of intervention and a dose-effect relationship was not feasible given the low quality of systematic reviews (83% low to critically low) and the variability in reporting interventions. Therefore, more studies with better quality and definition of the interventions are required. The protocol was previously registered in PROSPERO as CRD42021237895.

Study Criteria Applied to Real Life-A Multicenter Analysis of Stroke Patients Undergoing Endovascular Treatment in Clinical Practice.

Background Randomized controlled clinical trials (RCT) have demonstrated the efficacy of endovascular treatment in anterior circulation large vessel occlusions. However, outcome of patients treated in daily practice differs from the results of the clinical trials. We hypothesize that this is attributable to the study criteria and that application of the criteria on patients undergoing endovascular therapy in daily routine would improve their outcome. Methods and Results Data from a multicenter prospective registry of GSR-ET (German Stroke Registry - Endovascular Treatment) was used. Inclusion criteria and selectivity of SWIFT-PRIME (Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment trial), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial), ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times trial), DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo trial) and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke trial) trials were analyzed. Baseline characteristics, procedural and outcome data of patients from GSR-ET before and after selection were compared with the results of the RCTs. Furthermore, outcome of patients who underwent endovascular treatment despite not fulfilling the RCT criteria was analyzed. A total of 2611 patients were included (median age, 75 years; 49.6% women; median National Institute of Health Stroke Scale, 16). A minority of patients met all inclusion criteria, ranging from 3% (DEFUSE-3 criteria) to 35% (MR CLEAN criteria). Of the patients fulfilling the MR CLEAN criteria, 41% of patients had a good clinical outcome, compared with 34% of patients that did not fulfill MR CLEAN criteria. Conclusions The RCTs represent a selected population with higher rates of good clinical outcome compared with daily practice. The good outcomes of RCTs can be reproduced in clinical routine in patients who fulfill the RCT inclusion criteria. Furthermore, patients who did not meet the criteria of the RCT still had substantial rates of good clinical outcome.

Impact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS.

INTRODUCTION: The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. METHODS: World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. RESULTS: The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within-site stratification, interim power projections, and sensitivity analyses. DISCUSSION: Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world-wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.