OBJECTIVE:Identifying stroke patients at different disease stages is a prerequisite for clinical research using electronic medical records (EMRs), whereas an artificial intelligence-based model that can be directly applied remains lacking. We therefore develop a large language model (LLM) pipeline for stroke staging model (StrokeSM) in retrospective clinical research. METHODS:StrokeSM was developed using a Chinese national stroke database comprising EMRs from 33,637 patients. A total of 2000 patients were randomly selected from the Tianjin regional stroke database for external validation. StrokeSM comprised three phases: stroke hospitalization identification based on BERT and a bidirectional cross-attention network to fuse present illness history and discharge diagnosis, symptom-time extraction based on chief complaint through a UIE-base LLM, and stroke staging classification according to the predefined rules. RESULTS:On the test set, StrokeSM achieved accuracy, F1 score, precision, and recall of 0.90, 0.91, 0.91, and 0.90, respectively. The F1 score, precision, and recall of StrokeSM for acute phase was 0.91, 0.89, and 0.93, respectively. On the external validation set, StrokeSM had an accuracy, F1 score, precision, and recall of 0.92, 0.93, 0.93, and 0.92, respectively. Moreover, StrokeSM performed remarkably well in acute phase, with F1 score, precision, and recall of 0.97, 0.98, and 0.96, respectively. CONCLUSIONS:StrokeSM had achieved state-of-the-art performance, providing an accurate method of classifying stroke populations with different disease stages in EMRs, especially in the acute phase. StrokeSM heralds automatic and accurate identification of disease stage phenotypes based on LLM in EMRs, laying the foundation for drawing reliable conclusions in clinical research.

Importance Randomized clinical trials (RCTs) provide the optimal design for evaluating the effects of Chinese herbal medicine (CHM) on patient outcomes. However, how trialists have designed, conducted, and analyzed CHM RCTs remains largely unknown. Objective To investigate the design, conduct, and analysis of CHM RCTs; to examine whether there are differences between RCTs published in English and Chinese and between higher-impact and lower-impact English journals; and to determine whether CHM RCTs have improved over time. Design, Setting, and Participants In this cross-sectional study, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and 4 Chinese databases were searched from inception to April 2024. Parallel CHM RCTs published in journals covered in the Journal Citation Reports or Chinese core journals were included. Main Outcomes and Measures The primary outcomes were the general and methodological characteristics of included RCTs published in English vs Chinese, publication year up to vs after 2015, and higher-impact vs lower-impact English journals. To compare characteristics of included RCTs published in different journals, χ 2 or Fisher exact test was use for dichotomous variables, and t test was used for continuous variables when the distribution proved normal or Mann-Whitney U test when it did not. Results The 400 CHM RCTs (200 from Chinese language journals and 200 from English language journals) enrolled 100 to 4870 patients. Most RCTs (370 RCTs [92.5%]) did not specify the study hypothesis; approximately one-third (102 RCTs [30.6%]) were registered. The protocols were available for 15 RCTs (3.8%), and statistical analysis plans were available for 4 RCTs (1.0%). Approximately two-fifths (159 RCTs [39.8%]) reported inadequate methods of allocation sequence generation, and three-fifths (242 RCTs [60.2%]) described inadequate methods of allocation concealment. More than one-third (138 RCTs [34.5%]) explicitly specified a primary outcome, and 115 RCTs (28.8%) reported sample size estimation. Ony 10 RCTs (2.5%) had an independent data monitoring committee. More than two-thirds (254 RCTs [73.5%]) stated reasons for prescribing CHM, most commonly the limited or no effect of Western medicine (215 RCTs [53.8%]) and adverse effects of Western medicine (80 RCTs [20.0%]). Most RCTs did not mention whether there was prior clinical (279 RCTs [69.8%]), pharmacological (201 RCTs [50.2%]), or toxicological (388 RCTs [97.0%]) evidence to support the trial hypotheses. A minority (146 RCTs [36.5%]) specified the prescription of CHM according to traditional Chinese medicine syndrome diagnosis. Most RCTs with missing data conducted only a complete case analysis (70 RCTs [77.8%] for dichotomous outcomes and 79 RCTs [84.0%] for continuous outcomes). A small proportion of RCTs (62 RCTs [15.5%]) used an intention-to-treat analysis, and trialists rarely performed sensitivity analysis (29 RCTs [7.2%]) and subgroup analysis (30 RCTs [7.5%]). The design, conduct, and analysis of CHM RCTs improved over time, and were superior in English-language journals, especially higher-impact English-language journals. Conclusions and Relevance These findings suggest that the conduct and analysis of CHM RCTs are generally suboptimal, highlighting areas that urgently need improvement, including statement of study hypothesis and provision of a protocol; registration of the trial; implementation of allocation concealment; specification of primary outcome and sample size estimation; mention of prior clinical, pharmacological, and toxicological support for the trial hypotheses; and satisfactory conduct of sensitivity analysis or subgroup analysis. Although improvements occurred over time, further enhancing the fundamental research capabilities and developing methodological guidelines remains necessary.

Objective Atherosclerosis (AS) is a chronic inflammatory cardiovascular disease. The sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling axis plays a key role in inflammation regulation, but its precise role in AS pathogenesis remains unclear. Puerarin (Pue), an isoflavone derived from the medicinal and dietary plant Pueraria lobata, exhibits cardiovascular protective effects, though its pharmacological mechanisms remain to be elucidated. This study aimed to investigate the involvement of the SphK1/S1P/S1P receptor (S1PRs) pathway in AS progression and to evaluate the therapeutic effects of Pue. Methods ApoE−/− and SphK1−/− mice were bred to generate ApoE−/−SphK1−/− mice. C57BL/6J, ApoE−/−, SphK1−/−, and ApoE−/−SphK1−/− mice were fed a high-fat diet to induce atherosclerosis and evaluate the effects of SphK1 deficiency. High-fat diet-induced ApoE−/− mice received oral administration of Pue at low and high doses to assess its therapeutic effects. AS progression was evaluated by monitoring serum biochemical parameters, performing histological analyses (H&E staining, Oil Red O staining, Masson's trichrome, and Von Kossa staining), and detecting the expression of S1PR1 and NLRP3 inflammasome-related proteins (NLRP3, Caspase-1, ASC) in aortic tissues to systematically assess the effects of SphK1 deficiency and Pue intervention on the SphK1/S1P/S1PR1/NLRP3 signaling pathway. Results Both SphK1 deficiency and Pue treatment significantly attenuated AS progression, as evidenced by improved lipid profiles, reduced systemic inflammation, decreased atherosclerotic plaque formation, and improved vascular structure. Mechanistic analysis indicated that SphK1 deficiency or Pue intervention reduced serum S1P levels and downregulated the expression of S1PR1 and NLRP3 inflammasome-related proteins in aortic tissues, suggesting that the effect is likely mediated through inhibition of the S1P/S1PR1/NLRP3 signaling axis. Conclusion Genetic ablation of SphK1 or Pue intervention mitigates AS through suppression of the S1P/S1PR1/NLRP3 inflammasome pathway. This study provides novel mechanistic insights into the role of SphK1/S1P/S1PR1 signaling in vascular inflammation and highlights Pue as a potential therapeutic strategy for AS.

Importance:Externally controlled trials (ECTs) can serve as an alternative in settings where randomized clinical trials (RCTs) are unfeasible. However, the methodological rigor of ECTs, particularly with regard to bias control, is often inadequately assessed, which can compromise the validity of studies and lead to incorrect decisions. Objective:To examine the design, conduct, and analysis characteristics of current ECTs and to assess whether appropriate methods were used to control bias. Design, Setting, and Participants:This cross-sectional study searched PubMed for ECTs published between January 1, 2010, and December 31, 2023. Eligible ECTs included single-arm trials with an external control or that used a treatment group from an RCT compared with an external control and evaluated the efficacy and/or safety of a drug or medical device. Data analysis was conducted from March 5 to 20, 2025. Main Outcomes and Measures:Extracted information included design characteristics, external control data sources, transparency in covariate selection, statistical methods, and the use of sensitivity and quantitative bias analyses. The characteristics of included ECTs were compared between journals in the top 25% in their Journal Citation Reports category (Q1) and non-Q1. Results:This study included 180 ECTs, of which 85 (47.2%) focused on oncology. Only 64 (35.6%) provided reasons for using external controls, and 29 (16.1%) were prespecified to use external controls. The main sources of external controls were clinical (also termed real-world) data (98 [54.4%]) and trial-derived controls (67 [37.2%]), while concurrent data collection with the treatment arm was relatively infrequent (18 [10.0%]). Only 14 studies (7.8%) conducted feasibility assessments to evaluate the adequacy of data sources, and 13 (7.2%) specified how to handle missing data in external control datasets. Covariate selection procedures were described in 37 of the 164 studies (22.6%) that reported important covariates. Sixty studies (33.3%) used statistical methods to adjust for important covariates when generating the external control, with the propensity score method being the most common (35 of 60 [58.3%]). Among 120 ECTs that generated external controls without statistical methods, 91 (75.8%) used univariate analysis to estimate treatment effects, and only 18 (15.0%) used multivariable regression analysis. Sensitivity analyses for primary outcomes were performed in 32 studies (17.8%), and quantitative bias analyses (2 [1.1%]) were nearly absent. ECTs in Q1 journals were more likely to prespecify the use of external controls (χ21 = 9.86; P = .002) and provided rationales for using external controls (χ21 =  4.33; P = .04). Thirteen recommendations for the careful practice of ECTs are proposed. Conclusions and Relevance:In this cross-sectional study of ECTs, current practices in the design, conduct, and analysis were suboptimal, limiting their reliability and credibility. The study identified several critical methodological issues, such as the lack of justification for using external controls, failure to prespecify external controls in the protocol, insufficient use of confounding adjustment techniques, inadequate sensitivity analyses, and almost complete absence of quantitative bias analyses. Therefore, actionable suggestions for future ECT practices are proposed.

INTRODUCTION:Dry Eye Disease (DED) is a prevalent and significant condition that affects a large number of people. Artificial tears can alleviate the symptoms in patients with mild to moderate dry eyes, but they do not have a long-term effect. Micro-needle is a novel type of acupuncture, with needle tips arrayed on a silicon chip attached to medical plaster, without penetrating the skin. Its effectiveness and efficacy need to be proven clinically. METHODS AND ANALYSIS:This is a single-center, randomized, sham-controlled trial. In total, 129 DED patients will be recruited and randomized into three groups: micro-needle, sham, and artificial tears. They will receive four weeks of treatment and undergo follow-up at six and ten weeks. The primary outcome is measured by the Objective Symptoms Scoring Sheet (OSSS). Secondary outcomes include the China Dry Eye Questionnaire (CDEQ), Ocular Surface Disease Index (OSDI), non-invasive tear film break-up time (NIBUT), Schirmer Test I (SIT), Tear Meniscus Height (TMH), and Corneal Fluorescein Staining (CFS). Questionnaires, including OSSS, CDEQ, and OSDI, will be administered at screening, at the end of week two, and at the conclusion of week four, when treatment is completed. They will also be conducted at follow-up in week six and week ten; OSSS will be taken additionally on day two of the treatment. Tests of Intraocular Pressure (IOP), Best Corrected Visual Acuity (BCVA), NIBUT, SIT 1, TMH, and CFS are conducted at screening and upon completion of treatment. At week two, NIBUT, SIT 1, TMH, and CFS tests are taken as intermittent measurements. ETHICS AND DISSEMINATION:The trial protocol and informed consent document were reviewed and approved by the Ethics Committee of the Shanghai Municipal Hospital of Traditional Chinese Medicine (Approval Number: 2023SHL-KY-101-01). Prior to enrollment, each potential participant undergoes a structured informed consent process conducted by a trained research coordinator, which includes explaining the trial purpose, design, interventions, benefits, risks, and time commitments; providing sufficient time for participants to review the plain-language written informed consent document; addressing all questions to ensure comprehension; and obtaining signed written consent, with a copy provided to the participant and the original stored in the trial file. To safeguard participant confidentiality, all data are labeled with a unique study ID instead of personal identifiers; paper records are stored in locked cabinets in a restricted-access office, and electronic data are stored on password-protected, encrypted servers accessible only to authorized team members via unique logins; de-identified data are used solely for analysis and reporting, with personal identifiers accessible only to the trial coordinator for enrollment and follow-up and never shared with other parties; and study findings in publications and presentations will be aggregated to prevent individual identification. The findings of this investigation will be disseminated through peer-reviewed publications, and any protocol amendments will be submitted to the ethics committee for re-approval and updated in the trial registry. TRIAL REGISTRATION NUMBER:ChiCTR2300078187 TRIAL REGISTRATION DATE: 2023.11.30 TRIAL REGISTRY: China Clinical Trial Registration Center https://www.chictr.org.cn.

Promoting the international acceptance of clinical studies about traditional Chinese medicine (TCM) interventions is a key strategy for internationalization of TCM. However, the complexities of TCM interventions—in terms of the theories, practice patterns, and components—pose challenges to the design and implementation of clinical studies that are well accepted by the international community. This article summarized the current status of clinical studies about TCM interventions that were published in international journals, explored underlying barriers hindering the international acceptance, and discussed potential strategies for future development.

BACKGROUND:The use of inserted sham acupuncture as a placebo in randomized controlled trials (RCTs) is controversial, because it may produce specific effects that cause an underestimation of the effect of acupuncture treatment. OBJECTIVE:This systematic survey investigates the magnitude of insert-specific effects of sham acupuncture and whether they affect the estimation of acupuncture treatment effects. SEARCH STRATEGY:PubMed, Embase and Cochrane Central Register of Controlled Trials were searched to identify acupuncture RCTs from their inception until December 2022. INCLUSION CRITERIA:RCTs that evaluated the effects of acupuncture compared to sham acupuncture and no treatment. DATA EXTRACTION AND ANALYSIS:The total effect measured for an acupuncture treatment group in RCTs were divided into three components, including the natural history and/or regression to the mean effect (controlled for no-treatment group), the placebo effect, and the specific effect of acupuncture. The first two constituted the contextual effect of acupuncture, which is mimicked by a sham acupuncture treatment group. The proportion of acupuncture total effect size was considered to be 1. The proportion of natural history and/or regression to the mean effect (PNE) and proportional contextual effect (PCE) of included RCTs were pooled using meta-analyses with a random-effect model. The proportion of acupuncture placebo effect was the difference between PCE and PNE in RCTs with non-inserted sham acupuncture. The proportion of insert-specific effect of sham acupuncture (PIES) was obtained by subtracting the proportion of acupuncture placebo effect and PNE from PCE in RCTs with inserted sham acupuncture. The impact of PIES on the estimation of acupuncture's treatment effect was evaluated by quantifying the percentage of RCTs that the effect of outcome changed from no statistical difference to statistical difference after removing PIES in the included studies, and the impact of PIES was externally validated in other acupuncture RCTs with an inserted sham acupuncture group that were not used to calculate PIES. RESULTS:This analysis included 32 studies with 5492 patients. The overall PNE was 0.335 (95% confidence interval [CI], 0.255-0.415) and the PCE of acupuncture was 0.639 (95% CI, 0.567-0.710) of acupuncture's total effect. The proportional contribution of the placebo effect to acupuncture's total effect was 0.191, and the PIES was 0.189. When we modeled the exclusion of the insert-specific effect of sham acupuncture, the acupuncture treatment effect changed from no difference to a significant difference in 45.45% of the included RCTs, and in 40.91% of the external validated RCTs. CONCLUSION:The insert-specific effect of sham acupuncture in RCTs represents 18.90% of acupuncture's total effect and significantly affects the evaluation of the acupuncture treatment effect. More than 40% of RCTs that used inserted sham acupuncture would draw different conclusions if the PIES had been controlled for. Considering the impact of the insert-specific effect of sham acupuncture, caution should be taken when using inserted sham acupuncture placebos in RCTs. Please cite this article as: Luo XC, Liu JL, Yao MH, Chen YM, Fan AY, Liang FR, Zhao JP, Zhao L, Zhou X, Zhong XY, Yang JH, Li B, Zhang Y, Sun X, Li L. Specific effect of inserted sham acupuncture and its impact on the estimation of acupuncture treatment effect in randomized controlled trials: A systematic survey. J Integr Med. 2025; 23(6):630-640.

Machine learning (ML) models have been developed to identify randomised controlled trials (RCTs) to accelerate systematic reviews (SRs). However, their use has been limited due to concerns about their performance and practical benefits. We developed a high-recall ensemble learning model using Cochrane RCT data to enhance the identification of RCTs for rapid title and abstract screening in SRs and evaluated the model externally with our annotated RCT datasets. Additionally, we assessed the practical impact in terms of labour time savings and recall improvement under two scenarios: ML-assisted double screening (where ML and one reviewer screened all citations in parallel) and ML-assisted stepwise screening (where ML flagged all potential RCTs, and at least two reviewers subsequently filtered the flagged citations). Our model achieved twice the precision compared to the existing SVM model while maintaining a recall of 0.99 in both internal and external tests. In a practical evaluation with ML-assisted double screening, our model led to significant labour time savings (average 45.4%) and improved recall (average 0.998 compared to 0.919 for a single reviewer). In ML-assisted stepwise screening, the model performed similarly to standard manual screening but with average labour time savings of 74.4%. In conclusion, compared with existing methods, the proposed model can reduce workload while maintaining comparable recall when identifying RCTs during the title and abstract screening stages, thereby accelerating SRs. We propose practical recommendations to effectively apply ML-assisted manual screening when conducting SRs, depending on reviewer availability (ML-assisted double screening) or time constraints (ML-assisted stepwise screening).

IntroductionAlthough various sham acupuncture techniques have been employed to ensure blinding in randomised controlled trials (RCTs) of acupuncture, the effectiveness of blinding in these trials and its influence on trial effect size estimates remain unclear. The objectives of this study are the following: (1) to investigate the proportion and study characteristics of sham-controlled trials reporting on blinding assessment, (2) to assess the blinding effectiveness of different types of sham acupuncture, (3) to investigate the relationship between blinding effectiveness and effect sizes in acupuncture RCTs.Methods and analysisWe will search PubMed and EMBASE from inception to 1 January 2025 to identify RCTs that compared acupuncture with sham acupuncture in humans with any disease or symptom, with no restrictions on language. Paired investigators will independently determine eligibility and use pilot-tested standardised forms for data extraction. We will calculate the proportion of sham-controlled trials that assessed and reported blinding success and conduct descriptive analyses of general study characteristics, acupuncture treatment details, sham acupuncture details and blinding assessments for included trials. We will assess the effectiveness of blinding success using the James blinding index (BI) and Bang BI, and pool data from included trials using random-effects models. We will use Hedges’ g, a standardised mean difference, with its 95% CI, to calculate treatment effects. We will use Pearson’s r correlation coefficient to assess the relationship between blinding effectiveness and trial effect sizes when variable distributions meet the assumptions of normality and linearity; otherwise, we will consider employing non-parametric tests. When sufficient data are available, we will also use random-effects meta-regression to explore the relationship.Ethics and disseminationEthical approval is not required. The findings of this study will be disseminated through peer-reviewed publications, conference presentations and condensed summaries for clinicians, health policymakers and guideline developers regarding the design, conduct, analysis and interpretation of blinded assessment of sham acupuncture RCTs.Study registrationOpen Science Framework (https://doi.org/10.17605/OSF.IO/B3U7K).

Osteoporosis and cardiovascular disease are prevalent health concerns, particularly among the elderly. Recent studies have increasingly demonstrated that osteoporosis is consistently associated with vascular calcification, drawing attention to the interactions between bones and blood vessels, and giving rise to the concept of the bone-vascular axis. The bone vascular axis involves several factors, including osteokines such as FABP3, PDGF-BB, MYGDF, and Aging Bone-Derived Extracellular Vesicles (AB-EVs), which influence vascular calcification. Simultaneously, calcified blood vessels secrete sclerostin, Dickkopf1 (Dkk-1), Activin-A, and frizzled-related protein (SFRP), further affecting bone metabolism. The bone-vascular axis is characterized by reciprocal regulation and influence between the skeletal and vascular systems, and is crucial for maintaining bone metabolic homeostasis and preventing cardiovascular disease. However, the causal relationship between these two systems, as well as the specific regulatory mechanisms and targets, remains unclear. Therefore, this review aims to explore the mechanisms underlying the crosstalk between bone and blood vessels from both the skeletal and vascular perspectives, as well as their common pathways, and to provide an overview of current therapeutic agents, with the goal of enhancing understanding of the bone-vascular association and offering new insights and approaches for clinical treatment.

BACKGROUND:Although acupuncture is widely used to treat ischemic stroke, its effects remain uncertain. This systematic review aims to synthesize current evidence on the effects of acupuncture for ischemic stroke and assess whether current randomized controlled trials (RCTs) have sufficient power to detect its effects. METHODS:Seven databases and two registry platforms were searched systematically from inception to June 13, 2023, to identify RCTs comparing the effects of acupuncture on ischemic stroke with control groups (placebo/blank). The Cochrane Risk of Bias 2 (RoB 2) tool was used to evaluate the risk of bias in the included trials. Random effects models through restricted maximum likelihood estimation were further used to estimate the pooled mean differences (MDs) and the corresponding 95 % confidence intervals (CIs). The primary outcome was neurological function (National Institutes of Health Stroke Scale, NIHSS), while secondary outcomes included global disability (modified Rankin Scale, mRS) and activities of daily living (ADLs) (Barthel Index, BI or Modified Barthel Index, MBI). The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system was used to evaluate the certainty of the evidence. Trial sequential analysis (TSA) was further applied to control random errors and calculate the required information size (RIS). RESULTS:Forty RCTs involving 4485 patients were included. Acupuncture was found to significantly improve NIHSS (18 trials, 2658 patients; MD = -1.61, 95 % CI [-2.12, -1.09], low certainty evidence), mRS (3 trials, 298 patients; MD = -0.34, 95 % CI [-0.50, -0.19], moderate certainty evidence), and BI/MBI (26 trials, 2562 patients; MD = 8.98, 95 % CI [6.18, 11.77], low certainty evidence). Further, graphs of TSA indicated that the sample size of the trials was sufficient, and the results are robust. CONCLUSION:Current evidence suggests that acupuncture can significantly improve neurological function, global disability, and ADLs in patients with ischemic stroke. The results were robust, as confirmed by TSA. However, the certainty of the evidence is moderate to low and should be further verified by more high-quality RCTs.

The effectiveness and safety of acupuncture therapy to delay lung function decline in chronic obstructive pulmonary disease (COPD) remain unclear. This study aimed to determine whether acupuncture, as an adjunctive therapy to COPD-guided medication, could prevent lung function decline. This randomised, two-centre study was conducted between February 2022 and July 2023. Men and women aged 40–80 years with COPD were recruited. Participants received active or sham acupuncture three times a week (36 sessions total). The primary outcome was the change in the percentage of forced expiratory volume for 1 s to the predicted value (FEV1

Alteplase is the current standard of care for acute ischemic stroke. Tenecteplase is a newer fibrinolytic agent with preferable administration and lower costs; however, its comparative effectiveness to alteplase remains uncertain. We set out to perform a systematic review and meta-analysis to establish the benefits and harms of tenecteplase versus alteplase for acute ischemic stroke. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov from inception to April 2023 for randomized and non-randomized studies that compared tenecteplase versus alteplase for acute ischemic stroke. Paired reviewers independently assessed risk of bias and extracted data. We performed both conventional meta-analyses and Bayesian network meta-analyses (NMA) with random-effects models and used the GRADE approach to evaluate the certainty of evidence. Our primary efficacy outcome was excellent functional outcome at 3 months, defined as a score of 0–1 on the modified Rankin Scale. Our primary safety outcomes were symptomatic intracranial hemorrhage and all-cause mortality. Thirty-six studies were eligible for review, including 12 randomized (n = 5533) and 24 non-randomized studies (n = 44,956). Moderate certainty evidence showed that there was no difference between tenecteplase and alteplase in increasing the proportion of patients achieving excellent functional outcome at 3 months (odds ratio [OR], 1.10; 95

Background:Surgical interventions for spontaneous supratentorial intracerebral haemorrhage (ICH) include conventional craniotomy (CC), decompressive craniectomy (DC), and minimally invasive surgery (MIS), with the latter encompassing endoscopic surgery (ES) and minimally invasive puncture surgery (MIPS). However, the superiority of surgery over conservative medical treatment (CMT) and the comparative benefits of different surgical procedures remain unclear. We aimed to evaluate the efficacy and safety of various surgical interventions for treating ICH. Methods:In this systematic review and network meta-analysis, we searched PubMed, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov from inception to June 16, 2024. Eligible studies were randomised controlled trials (RCTs) comparing surgery (i.e., CC, ES, MIPS, or DC) with CMT or comparing different types of surgeries in patients with spontaneous supratentorial ICH. Paired reviewers independently screened citations, assessed the risk of bias of included trials, and extracted data. Primary outcomes were good functional outcome and mortality at 6 months. Secondary outcomes were good functional outcome and mortality at different follow-up times, complications (rebleeding, brain infection, pulmonary infection), and hematoma evacuation rate. The frequentist pairwise and network meta-analysis (NMA) were performed. The GRADE approach was used to evaluate the certainty of evidence. This study is registered with PROSPERO, CRD42024518961. Findings:Of the 8573 total records identified by our searches, 31 studies (6448 patients) were eligible for the systematic review and network analysis. Compared with CMT, moderate certainty evidence showed that surgery improved good functional outcome (risk ratio [RR] 1.31, 95% CI 1.13-1.52; risk difference [RD] 9.1%, 95% CI 3.8 to 15.3; I 2  = 36%) and reduced mortality (RR 0.82, 95% CI 0.71-0.95; RD -5.1%, 95% CI -8.2 to -1.4; I 2  = 14%). Moderate certainty evidence from NMA suggested that compared with CMT, both ES (RR 1.51, 95% CI 1.18-1.93; RD 9.4%, 95% CI 3.3-17.1) and MIPS (RR 1.48, 95% CI 1.24-1.76; RD 15.7%, 95% CI 7.9-24.9) improved good functional outcome at 6 months, and both ES (RR 0.66, 95% CI 0.52-0.85; RD -17.0%, 95% CI -24.0 to -7.5) and CC (RR 0.75, 95% CI 0.60-0.94; RD -6.3%, 95% CI -10.1 to -1.5) reduced mortality at 6 months, whereas MIPS and DC showed a trend, although not statistically significant, towards a reduction in mortality. ES and MIPS also reduced pulmonary infection risk (ES RR 0.39, 95% CI 0.23-0.69; MIPS RR 0.35, 95% CI 0.20-0.60; RD -5.3%, 95% CI -6.6 to -3.3). ES showed higher hematoma evacuation than CC (MD: 7.03, 95% CI: 3.42-10.65; I 2  = 94%). No difference in rebleeding or brain infection was found between CC and MIS. Interpretation:Current moderate certainty evidence suggested that surgical intervention of spontaneous supratentorial ICH, may be associated with improved functional outcomes and a reduced risk of death at 6 months. The advantages of surgical haematoma removal are particularly pronounced when MIS including ES and MIPS are employed. ES could improve functional outcomes, reduce the risk of mortality and pulmonary infection, and have a high hematoma evacuation rate, suggesting that it might be an optimal surgical treatment. Funding:National Natural Science Foundation of China, National Science Fund for Distinguished Young Scholars, Fundamental Research Funds for the Central Public Welfare Research Institutes, and 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University.

Abstract Background Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. Results Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated β = 0.14, p < 0.01) and the multicenter trials (estimated β = 2.22, p < 0.01) were associated with better reporting. Conclusion Adaptive design has shown an increasing use over the years, and was primarily applied to early phase drug trials. However, the reporting quality of adaptive trials is suboptimal, and substantial efforts are needed to improve the reporting.

OBJECTIVES:To investigate the design, conduct, and analysis of adaptive trials through a systematic survey and provide recommendations for future adaptive trials. STUDY DESIGN AND SETTING:We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases up to January 2020. We included trials that were self-described as adaptive trials or applied adaptive designs. We identified three frequently used adaptive designs and summarized their methodological details in terms of design, conduct, and analysis. Lastly, we provided recommendations for future adaptive trials. RESULTS:We included a total of 128 trials in this study. The primary motivations for using adaptive design were to speed up the trials and facilitate decision-making (n = 29, 31.5%). The three most frequently used methods were group sequential design (GSD) (n = 71, 55.5%), adaptive dose-finding design (ADFD) (n = 35, 27.3%), and adaptive randomization design (ARD) (n = 26, 20.3%). The timing and frequency of interim analysis were detailed in three-fourths of the GSD trials (n = 55, 77.5%) and in half of the ADFD trials (n = 19, 54.3%); however, more than half of the ARD trials (n = 15, 57.7%) did not provide this information. Some trials selected a different outcome than the primary outcome for interim analysis (GSD: n = 7, 12.7%; ADFD: n = 8, 27.6%; ARD: n = 7, 50.0%), but the majority of these trials did not provide explicit reasons for this choice (GSD: n = 7, 100.0%; ADFD: n = 7, 87.5%; ARD: n = 5, 71.4%). More than half (n = 76, 59.4%) of trials did not mention the accessibility of supporting documents, and two-thirds (n = 86, 67.2%) did not state the establishment of independent data monitoring committees (IDMCs). Moreover, unplanned adjustments were observed during the conduct of one-sixth adaptive trials (n = 22, 17.2%). Based on our findings, we provide 14 recommendations for improving adaptive trials in the future. CONCLUSION:Substantial improvements were needed in methods of adaptive trials, particularly in the areas of interim analysis, the establishment of independent data monitoring committees, and unplanned adjustments. In this study, we offer recommendations from both general and specific aspects for researchers to carefully design, conduct, and analyze adaptive trials.

Is acupuncture effective in treating knee osteoarthritis (KOA)?

Rapid recommendation is a novel methodological framework for developing clinical practice guidelines and this framework shares the basic features of classical guidelines but differs from classical clinical practice guidelines in its `rapid’ development process (typically within 90 days) with an aim of translating practice-changing studies to recommendations. A recent global innovation of guideline development methodology is the proposal of a rapid recommendation framework for Traditional Chinese Medicine (TCM), which has the potential to add value to the translation of evidence to practice for TCM interventions. Up to now, more than 180 rapid recommendations have been published, but none of them is pertaining to TCM interventions. Due to the nature of multi-dimensional evidence sources for TCM interventions, including classical randomized controlled trials and real world evidence, a more sophisticated methodological approach to synthesize and evaluate the totality of evidence about effects of TCM interventions is required. Therefore, appropriate modification to the rapid recommendation framework is necessary. In the efforts to respond to these needs, we have proposed a specific approach to developing rapid recommendations for TCM interventions the Multi-dimensional Evidence Synthesis, Evaluation and Recommendations for TCM interventions (MESERT).

OBJECTIVES:To examine whether appropriate statistical methods were used in acupuncture randomized controlled trials (RCTs). STUDY DESIGN AND SETTING:We searched PubMed to identify acupuncture RCTs with continuous outcome as primary outcome published in the core clinical journals and complementary and alternative medicine (CAM) journals between January 2010 and December 2019 (10 years). We compared statistical characteristics of included trials published in core clinical journals and CAM journals. RESULTS:We included 262 RCTs, including 46 published in core clinical journals and 216 in CAM journals. Of included RCTs, only 132 (50.4%) clearly predefined the primary outcome, 72 (27.5%) specified the use of intention to treat or modified intention to treat population for primary analysis. In the 167 trials reported missing participant data (MPD), 118 (70.7%) used suboptimal methods (e.g., complete case analysis) for dealing with MPD; 11 (6.6%) conducted sensitivity analysis regarding MPD. Among the 161 trials with repeated measures design, only 21 (13.0%) used advanced statistical models (e.g., mixed-effects models) for handling repeated-measure data in the primary analysis. In the 72 trials involving multiple acupuncturists, only 4 (5.6%) adjusted acupuncturist variable or considered the clustering by acupuncturist in analysis. Trials in core clinical journals were more likely to predefine primary outcome (78.3% vs. 44.4%, P < 0.001), use multiple imputations for handling MPD (40% vs. 1.5%, P < 0.001), and use statistically advanced methods for assessing treatment effect at a single time point (26.1% vs. 2%, P = 0.001). CONCLUSION:The use of statistical methods among acupuncture RCTs is far from satisfactory. Our findings highlighted the need for researchers to carefully use the optimal statistical methods and for journal editors to strengthen the use of statistical methods.