Adaptive designs were primarily used but inadequately reported in early phase drug trials.

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 ß = 0.14, p < 0.01) and the multicenter trials (estimated ß = 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.

Acupuncture versus sham acupuncture for simple obesity: a systematic review and meta-analysis.

Obesity is a growing chronic health problem worldwide. Studies about acupuncture for obesity treatment are many. But there are some doubts about the effectiveness of acupuncture versus sham acupuncture in treating obesity due to its lack of medical evidence. Therefore, the aim of this study is to assess the efficacy of acupuncture for obesity treatment and provide clinic evidence. Four English databases (PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials) and four Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Database, Chinese Scientific Journal Database and Wan-Fang Data) were searched from their receptions to August 2019. Randomized controlled trials (RCTs) using the comparison between acupuncture and sham acupuncture to treat simple obesity were included. The primary outcome of body mass index (BMI) would be used to measure the effect of acupuncture on obesity. According to the trial data extraction form based on the Cochrane Handbook, two reviewers separately extracted the data. Risk of bias of the RCTs was assessed by the Cochrane Risk of Bias Tool. The study included 8 RCTs with 403 patients. When compared with sham acupuncture, acupuncture showed obviously effect in BMI reduction (MD=1.0kg/m2, 95% CI=0.6 to 1.4, P<0.001). There was also significant reduction in body weight (MD=1.85kg, 95%CI=0.82 to 2.88, p<0.001), WC (MD=0.97cm, 95%CI=0.24 to 1.71, p=0.01) and body fat mass percentage (MD=1.01, 95%CI=0.25 to 1.77, p<0.05). However, WHR (MD=0.01, 95%CI=0 to 0.03, p>0.05) was not statistically and significantly different between the acupuncture and control groups. Adverse effects were reported in 3 studies. The review suggests that acupuncture is an effective therapy for simple obesity rather than a placebo effect. This potential benefit needs to be further evaluated by longer-term and more rigorous RCTs.

Effects of acupuncture on ischemic stroke: A systematic review with meta-analyses and trial sequential analyses.

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.

Risk of angioedema and thrombolytic therapy among stroke patients: An analysis of data from the FDA Adverse Event Reporting System database.

The angioedema risk may vary among stroke patients receiving different thrombolytic agents. This study aimed to investigate the angioedema risk associated with different thrombolytic agents and to identify associated risk factors. We conducted a large-scale retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Stroke patients receiving thrombolytic therapy (i.e., alteplase or tenecteplase) were identified, and the associations with angioedema were explored using disproportionality analysis and time-to-onset analysis. Additionally, we used adapted Bradford Hill criteria to confirm these associations. Risk factors for angioedema were explored using stepwise logistic regression. A total of 17,776 stroke patients were included, with 2973 receiving alteplase and 278 receiving tenecteplase. Disproportionality analysis revealed that angioedema might be associated with alteplase (adjusted ROR [aROR] 5.13 [95 â€‹% CI, 4.55-5.79]) or tenecteplase (aROR 2.72 [95 â€‹% CI, 1.98-3.67]). The adapted Bradford Hill criteria suggested a probable causal relationship between alteplase and angioedema, whereas there was insufficient evidence of a probable causal relationship with tenecteplase. Multivariate analysis revealed that ACE-inhibitors use (aROR 9.73 [95 â€‹% CI, 7.29-12.98]), female sex (aROR 1.38 [95 â€‹% CI, 1.13-1.67]) and hypertension (aROR 2.11 [95 â€‹% CI, 1.52-2.92]) were significant risk factors for angioedema among alteplase-treated stroke patients. Our study suggested that alteplase is associated with a greater risk of angioedema among stroke patients, but there is insufficient evidence to support an association between tenecteplase and angioedema. Clinicians should be vigilant for this potentially life-threatening complication, particularly in patients with identified risk factors. It is also prudent to consider tenecteplase as an alternative, if available.

A systematic survey of adaptive trials shows substantial improvement in methods is needed.

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.

Tenecteplase versus alteplase for acute ischemic stroke: a systematic review and meta-analysis of randomized and non-randomized studies.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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% CI 0.98-1.23; risk difference [RD] 2.4%, 95% CI - 0.5 to 5.2), while moderate certainty evidence from NMA suggested that 0.25 mg/kg tenecteplase significantly improved excellent functional outcome at 3 months (OR, 1.16; 95% credible interval 1.02-1.32). Moderate certainty evidence showed that, compared to alteplase, tenecteplase may make little to no difference in the prevalence of symptomatic intracranial hemorrhage (OR, 1.12; 95% CI 0.79-1.59; RD 0.3%, 95% CI - 0.5 to 1.4), and probably reduces all-cause mortality (adjusted odds ratio [aOR], 0.44; 95% CI 0.30-0.64; RD - 4.6%; 95% CI - 5.8 to - 2.9). CONCLUSIONS: Moderate certainty evidence suggested that there was little to no difference between tenecteplase and alteplase in increasing the proportion of patients achieving excellent functional outcome at 3 months and the risk of symptomatic intracranial hemorrhage, while compared to alteplase, tenecteplase probably reduce all-cause mortality. Administration of 0.25 mg/kg tenecteplase after acute ischemic stroke is suggestive of increasing the proportion of patients that achieve excellent functional outcome at 3 months.

Efficacy of acupuncture as an adjunctive treatment to patients with stable COPD: a multicenter, randomized, sham-controlled trial protocol.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common respiratory disease and the third leading cause of death worldwide. Previous evidence has shown that acupuncture may be an effective complementary alternative therapy for stable COPD. However, large-sample, rigorously designed long-term follow-up studies still need to be completed. Notably, the relationship between the frequency of acupuncture and clinical efficacy in studies on acupuncture for stable COPD still needs further validation. This study aims to evaluate the efficacy and safety of acupuncture for stable COPD and further investigate the dose-effect relationship of acupuncture. METHODS/DESIGN: This is a multicenter, randomized, controlled trial that uses central randomization to randomly allocate 550 participants in a 1:1:1:1:1 ratio to once a week acupuncture group, twice a week acupuncture group, three times a week acupuncture group, sham acupuncture group and waiting-list control group. The sham acupuncture group will receive placebo acupuncture treatments three times per week, and the waiting-list control group will not receive any form of acupuncture intervention. The study consists of a 2-week baseline, 12-week of treatment, and 52-week of follow-up. Patients with COPD between 40 to 80 years old who have received stable Western medication within the previous 3 months and have had at least 1 moderate or severe acute exacerbation within the past 1 year will be included in the study. Basic treatment will remain the same for all participants. The primary outcome is the proportion of responders at week 12. Secondary outcomes include the proportion of responders at week 64, change in the St. George's Respiratory Questionnaire (SGRQ) Scale, change in the Modified-Medical Research Council (mMRC) Scale, change in the COPD Assessment Test (CAT) Scale, change in the Lung Function Screening Indicators (LFSI), change in the 6-min walk distance (6-MWD), change in Short-Form 36 Health Survey (SF-36) Scale, the number of moderate and severe acute exacerbations and adverse event rate during the follow-up period. DISCUSSION: This study will provide robust evidence on whether acupuncture is safe and effective for treating stable COPD. Meanwhile, comparing the differences in efficacy between different acupuncture frequencies will further promote the optimization of acupuncture for stable COPD. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (ChiCTR2200058757), on April 16, 2022.

Effects of Tai Chi Yunshou on upper-limb function and balance in stroke survivors: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Physical rehabilitation plays an important role in the recovery of motor function after a stroke. This study aimed to evaluate the effects of Tai Chi Yunshou (TCY), a form of physical therapy, on upper-limb function and balance in stroke survivors. METHODS: MEDLINE, Embase, CENTRAL and five Chinese databases were retrieved from inception to July 1, 2020 (updated on March 31, 2022). Randomized controlled trials of TCY versus no-treatment for stroke were included. The RoB-2 was used to evaluate the quality of included studies. Upper-limb motor impairment, balance, and activities of daily living (ADLs) were measured by Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE), Berg Balance Scale (BBS), and Barthel Index (BI), respectively. Data synthesis was performed using RevMan (v5.3), and expressed as mean difference (MD) with 95% confidence intervals (CI). RESULTS: Seven studies with 529 participants were included. Compared with no-treatment, TCY improved FMA-UE (MD = 7.31, 95% CI: 5.86-8.77, minimal clinically important difference [MCID]: 9-10), BBS (MD = 4.68, 95% CI: 0.28-9.07, MCID: 4), and BI (MD = 4.12, 95% CI: 3.28-4.96, MCID: 1.85) in stroke survivors. CONCLUSION: TCY may benefit balance and ADLs in rehabilitation after a stroke, but it may not improve upper-limb function clinically.

Acupuncture for treatment of knee osteoarthritis: A clinical practice guideline.

CLINICAL QUESTION: Is acupuncture effective in treating knee osteoarthritis (KOA)? CURRENT PRACTICE: Although increasingly used in the clinical setting, acupuncture is not mentioned or weakly recommended in guidelines for the treatment of KOA. RECOMMENDATIONS: We suggest acupuncture rather than no treatment in adult KOA (weak recommendation, moderate certainty evidence), and acupuncture combined with nonsteroidal anti-inflammatory drugs (NSAIDs) rather than acupuncture alone when KOA symptoms are severe (weak recommendation, moderate certainty evidence), with duration of acupuncture for 4-8 weeks depending on KOA severity and treatment response (weak recommendation, moderate certainty evidence), and discussing with patients in shared decision-making. HOW THIS GUIDELINE WAS CREATED: This rapid recommendation was developed following the Making GRADE the Irresistible Choice (MAGIC) methodological framework. First, the clinical specialist identified the topic of recommendation and demand for evidence. Then the independent evidence synthesis group performed a systematic review to summarize available evidence and evaluate the evidence using the GRADE approach. Finally, the clinical specialist group produced recommendations for practice through a consensus procedure. THE EVIDENCE: The linked systematic review and meta-analysis included 9422 KOA patients, 61.1% of whom were women. The median mean age was 61.8 years. Compared with no treatment, acupuncture had beneficial effect on KOA in improving the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (moderate certainty evidence), and WOMAC pain (very low certainty evidence), WOMAC stiffness (low certainty evidence), and WOMAC function (low certainty evidence) subscale scores. Compared with usual care, acupuncture improved WOMAC stiffness subscale score (moderate certainty evidence). Subgroup analyses showed different effects in the improvement of WOMAC total scores by different durations of acupuncture and whether acupuncture combined with NSAIDs, but no difference between manual acupuncture and electroacupuncture was found. UNDERSTANDING THE RECOMMENDATIONS: Compared with no treatment, acupuncture is suggested to reduce pain, stiffness, and disfunction in KOA patients, ultimately improving the patient's health status. Acupuncture can be used as an alternative therapy when usual care is ineffective or there are adverse reactions so that patients can no longer continue the treatment. Manual acupuncture or electroacupuncture is suggested for 4-8 weeks to improve the health status of KOA. The patient's values and preferences should be considered when selecting acupuncture for KOA treatment.

Shenlingcao oral liquid for patients with non-small cell lung cancer receiving adjuvant chemotherapy after radical resection: A multicenter randomized controlled trial.

BACKGROUND: Low quality of life (QoL) in patients with non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy after radical resection is a major global health issue. High-quality evidence for the effectiveness of Shenlingcao oral liquid (SOL) as a complementary treatment in this patients is lacking at present. PURPOSE: To determine whether complementary SOL treatment in NSCLC patients receiving adjuvant chemotherapy would yield greater improvements in QoL than chemotherapy alone. STUDY DESIGN: We conducted a multicenter, randomized controlled trial of stages IIA-IIIA NSCLC patients undergoing adjuvant chemotherapy in seven hospitals. METHODS: Using stratified blocks, participants were randomized in a 1:1 ratio to receive SOL combined with conventional chemotherapy or conventional chemotherapy alone. The primary outcome was the change in global QoL from baseline to the fourth chemotherapy cycle, and intention-to-treat analysis was applied with a mixed-effect model. Secondary outcomes were functional QoL, symptoms, and performance status scores at the 6-month follow-up. Missing data were handled with multiple imputation and a pattern-mixture model. RESULTS: Among 516 randomized patients, 446 (86.43%) completed the study. After the fourth chemotherapy cycle, in comparison with the control group, patients receiving SOL showed a lower reduction in mean global QoL (-2.76 vs. -14.11; mean difference [MD], 11.34; 95% confidence interval [CI], 8.28 to 14.41), greater improvement in physical function (MD, 11.61; 95% CI, 8.57 to 14.65), role function (MD, 10.15; 95% CI, 5.75 to 14.54), and emotional function (MD, 4.71; 95% CI, 1.85 to 7.57), and greater improvements in lung cancer-related symptoms (e.g., fatigue, nausea/vomiting, and appetite loss) and performance status during the 6-month follow-up period (treatment main effect, p < 0.05). CONCLUSION: SOL treatment for NSCLC patients receiving adjuvant chemotherapy can significantly improve QoL and performance status within 6 months after radical resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03712969.

Use of statistical methods among acupuncture randomized controlled trials was far from satisfactory.

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.

Specification of interventions and selection of controls in randomized controlled trials of acupuncture: a cross-sectional survey.

OBJECTIVE: Specification of interventions and selection of controls are two methodological determinants for a successful acupuncture trial. However, current practice with respect to these two determinants is not fully understood. Thus, we conducted a cross-sectional survey to examine the specification of interventions and selection of controls among published randomized controlled trials (RCTs) of acupuncture. STUDY DESIGN AND SETTING: We searched PubMed for acupuncture RCTs published in core clinical journals and complementary and alternative medicine (CAM) journals from January 2010 to December 2019 (10 years) and included RCTs that assessed treatment effects of acupuncture versus any type of control. We used network meta-analyses to explore whether there were differential treatment effects in patients with chronic pain when using sham acupuncture as a control versus using waiting list or no treatment. RESULTS: Most of the 319 eligible RCTs specified well the style of acupuncture (86.8%), traditional acupuncture point locations (96.2%), type of needle stimulation (90.3%) and needle retention time (85.6%). However, other acupuncture details were less-frequently specified, including response sought (65.5%), needle manipulation (50.5%), number of needle insertions (21.9%), angle and direction of insertion (31.3%), patient posture (32.3%) and co-interventions (22.9%). Sham acupuncture (41.4%) was the most frequently used control, followed by waiting list or no treatment (32.9%). There was no differential treatment effect when using sham acupuncture versus waiting list/no treatment as a control (standardized mean difference = -0.15, 95% confidence interval: -0.91 to 0.62). CONCLUSION: Over a decade of research practice, important gaps have remained in the specification of acupuncture interventions, including response sought, needle manipulation, and co-interventions. While sham acupuncture has been widely used, waiting list or no treatment may also be considered as an appropriate control.

The add-on effects of Danhong injection among patients with ischemic stroke receiving Western medicines: A systematic review and meta-analysis.

Background: Danhong injection is widely used for treating ischemic stroke in China. However, its effects on ischemic stroke patients when given along with Western medicines (i.e., the add-on effect) were not well-established. Methods: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases from inception to 20 July 2020 to identify randomized controlled trials (RCTs) that assessed the effects of Danhong injection as add-on therapy in patients with ischemic stroke. Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted the data. The outcomes were the National Institutes of Health Stroke Scale Score (NIHSS), Barthel index, activities of daily living (ADL), total cholesterol, and homocysteine (Hcy). Results: Sixty-seven RCTs of 6594 patients with varying risk of bias were included. Compared with Western medicine alone, the addition of Danhong injection to Western medicine significantly lowered the NIHSS score (45 RCTs with 4565 patients; MD -4.21, 95% CI -4.96 to -3.46), total cholesterol (10 trials with 1019 patients; MD -1.14 mmol/L, 95% CI -1.57 to -0.72), and Hcy (four trials with 392 patients; MD -3.54 µmol/L, 95% CI -4.38 to -2.07). The addition of Danhong also increased the Barthel index (14 trials with 1270 patients; MD 8.71, 95% CI 3.68-13.74) and ADL (12 trials with 1114 patients; MD 14.48, 95% CI 9.04-19.92) scores. Subgroup analyses showed differential effects in the average cerebral blood flow rate by mean age of patients (<60 years: MD 0.74 cm/s, 95% CI 0.29-1.19; ≥60 years: MD 4.09 cm/s, 95% CI 2.02-6.16; interaction p = 0.002) and the NIHSS score by type of baseline Western medicines (interaction p < 0.00001). Conclusion: The addition of Danhong injection to Western medicine may improve neurological function, self-care ability, and blood lipid level of ischemic stroke patients. However, given most included trials with unclear risk of bias, current evidence is not definitive, and more carefully designed and conducted trials are warranted to confirm our findings. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022298628].

A methodological framework for tackling confounding by indication when assessing the treatment effects of Chinese herbal injections in the real world.

AIM: In the context of integrative medicine, whether Chinese herbal injections are effective in routine practice has become a question of broad interest. However, confounding by indication (i.e., indication bias) is a prevalent and highly challenging methodological issue when using routinely collected health care data to assess the real-world effectiveness of Chinese herbal injections. METHODS AND RESULTS: We proposed a methodological approach to tackling confounding by indication in assessing the real-world effectiveness of Chinese herbal injections, incorporating empirical experiences, a literature review and interactive discussions, and a panel of external experts to finally achieve a consensus. This approach consisted of three cohesive steps, including a full understanding of treatment patterns, construction of fair comparisons by identifying appropriate combination treatments and comparators, and using statistical methods to further control for confounding. In the investigation of treatment patterns, we proposed five domains to identify treatment patterns with Chinese herbal injections, and we offered five patterns of combination treatments to characterize how Chinese herbal injections are used in conjunction with other treatments. In constructing fair comparisons, we suggested the use of both nonuse and active comparators; given the diverse combination treatments, we developed six scenarios that may form fair comparisons. In the statistical analysis, we discussed five statistical models for controlling confounding by indication, including their pros and cons. We also included a practical example to illustrate the usefulness of the methodological approach. CONCLUSION: The proposed approach may serve as an effective tool to guide researchers to reliably assess the effectiveness of Chinese herbal injections in the context of integrative medicine.

Effects of acupuncture at acupoints with lower versus higher pain threshold for knee osteoarthritis: a multicenter randomized controlled trial.

BACKGROUND: The acupoint selections impact the effects of acupuncture, and preliminary evidence showed potential connection between pain threshold (PT) and acupuncture response. This study examined whether acupuncture at acupoints with lower PT versus higher PT would yield different effects in patients with knee osteoarthritis (KOA). METHODS: In this multicenter randomized clinical trial, patients were randomly assigned (1:1:1) to receive acupuncture at acupoints with lower PT (LPT group), acupuncture at acupoints with higher PT (HPT group), and no acupuncture (waiting-list group). PT was measured with electronic von Frey detector. The primary outcome was the change in WOMAC total score from baseline to 16 weeks, and the secondary outcomes were SF-12 score, and active knee range of motion (ROM). Intention-to-treat analysis was conducted with linear mixed-effect model. RESULTS: Among 666 randomized patients, 625 (93.84%) completed the study. From baseline to 16 weeks, patients in the LPT group versus HPT group had similar effects in reducing WOMAC total score (adjusted mean difference (MD) 2.21, 95% confidence interval (CI) -2.51 to 6.92, P = 0.36), while a greater reduction in WOMAC total score was observed in LPT group (-9.77, 95% CI -14.47 to -5.07, P < 0.001) and HPT group (-11.97, 95% CI -16.71 to -7.24, P < 0.001) compared with waiting-list group. There were no differences in SF-12 score and knee ROM between LPT versus HPT groups. CONCLUSION: Our findings found that the effects of acupuncture at acupoints with lower versus higher PT were similar, both were effective for patients with KOA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03299439. Registered 3 October 2017, https://clinicaltrials.gov/ct2/show/NCT03299439.

Effects of Motherwort Injection Versus Intramuscular Oxytocin for Preventing Postpartum Hemorrhage Among Women Who Underwent Cesarean Section.

Objectives: Subject to ethical constraints, real-world data are an important resource for evaluating treatment effects of medication use during pregnancy and the postpartum period. This study investigated whether motherwort injection, a traditional Chinese medicine preparation, was more effective than intramuscular (IM) oxytocin for preventing postpartum hemorrhage (PPH) in a real-world setting when intravenous (IV) oxytocin is administered. Methods: We conducted an active-controlled, propensity-score matched cohort study using an established pregnancy registry database. Women who underwent cesarean section and received IV oxytocin at the third stage of labor were included. We used an active-comparator design to minimize indication bias, in which we compared IM motherwort injection in the uterus versus IM oxytocin, both on top of IV oxytocin use. We applied 1:1 propensity-score matching (PSM) to balance patient baseline characteristics and used a logistic regression model to estimate treatment effect (i.e., risk difference (RD) and odds ratio (OR)) by using the counterfactual framework. The outcomes of interest were blood loss over 500 ml within 2 h after delivery (PPH, primary) and blood loss over 1,000 ml (severe PPH, secondary). We conducted four sensitivity analyses to examine the robustness of the results. Results: A total of 22,519 pregnant women underwent cesarean sections, among which 4,081 (18.12%) PPH and 480 (2.13%) severe PPH occurred. Among included women, 586 (2.60%) were administrated with IM motherwort injection, and 21,933 (97.40%) used IM oxytocin. After PSM, patient baseline characteristics were well balanced. Compared with IM oxytocin, the use of IM motherwort injection was associated with significantly lower risk of PPH (RD -25.26%, 95% CI -30.04% to -20.47%, p < 0.001; OR 0.25, 95% CI 0.18 to 0.32, p < 0.001) and severe PPH (RD -3.58%, 95% CI -5.87% to -1.30%, p < 0.001; OR 0.39, 95% CI 0.20 to 0.71, p < 0.002). Sensitivity analyses showed that the results were similar. Conclusion: With the use of data from a real-world setting, the findings consistently showed that among women undergoing cesarean section who had received IV oxytocin, the additional use of IM motherwort injection could achieve a lower risk of PPH as compared to the additional use of IM oxytocin. Our study suggested a paradigm for investigating the treatment effect of Chinese herbal medicine in the real-world practice setting.

Effects of Tai Chi Yunshou on upper limb function and balance in stroke survivors: A protocol for systematic review and meta analysis.

BACKGROUND: Functional disability is the most common disorder that occurs after stroke and seriously affects the quality of life of stroke survivors. Tai Chi Yunshou (TCY), a fundamental form of Tai Chi, is a simple, convenient, and economical exercise therapy from ancient China. Some clinical trials have reported that it improves upper limb function and balance during stroke rehabilitation. Thus, we plan to conduct a systematic review to investigate the effects of TCY in stroke survivors. METHODS: This review will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. We will search English and Chinese databases for randomized controlled trials on TCY for stroke survivors from the dates when the databases were established to 1 July 2020. The English databases will include MEDLINE (PubMed), EMBASE (embase.com), and the Cochrane Central Register of Controlled Trials (Cochrane Library). In addition, the Chinese databases will include the Chinese National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the Chinese Science and Technology Periodical Database, the Wanfang database, and the Chinese Dissertation Database. The primary outcomes will include upper limb function and balance function, as measured by the Fugl-Meyer assessment and Berg balance scale, respectively. Two reviewers will independently screen the studies on the basis of the inclusion criteria and extract data. Review Manager (v5.3) will be used for data synthesis, and Cochrane Collaboration's tool will be used to assess the risk of bias. A fixed effects model or a random effects model will be selected based on the level of heterogeneity. The grading of recommendations assessment, development, and evaluation system will be used to evaluate the quality of the outcomes. RESULTS: This systematic review results will be carried out after the completion of the protocol. CONCLUSIONS: This protocol aims to guide a systematic review and meta-analysis investigating the effects of JCY on upper limb function and body balance in stroke survivors, which will provide evidence for post-stroke rehabilitation training. PROSPERO REGISTRATION NUMBER: CRD42020169549.

[Mechanism on moxibustion for rheumatoid arthritis based on PD-1/PD-L1 signaling pathway].

OBJECTIVE: To explore the mechanism of moxibustion on the treatment of rheumatoid arthritis (RA) in the perspective of programmed cell death-1 and its ligand 1 (PD-1/PD-L1). METHODS: A total of 30 Japanese big ear white rabbits were randomly divided into a control group, a model group and a moxibustion group, 10 rabbits in each one. In the model group and the moxibustion group, RA model was prepared by the injection of Freund's complete adjuvant (FCA) into the hind knee joint cavities of each rabbit. In the control group, 0.9% sodium chloride solution of the same dose was injected. On the 8th day of experiment, in the moxibustion group, moxibustion was applied to "Shenshu" (BL 23) and "Zusanli" (ST 36), 5 cones at each acupoint, on the bilateral sides alternatively, once a day, 6 treatments as one course, with an interval of 1 days between the treatment courses. Totally, 3 courses of treatment were required. On the 1st, 7th, 14th, 21st and 28th days of experiment, successively, the circumference of the bilateral knee joints was measured with the tape. On the 28th day of experiment, H.E. staining was adopted to observe the histopathological morphology and to evaluate the score of knee synovial tissue. ELISA was used to determined the concentrations of soluble PD-1 (sPD-1) and its ligand 1 (sPD-L1), the interleukin 2 (IL-2) and IL-17 in knee synovial fluid and the concentrations of sPD-1 and sPD-L1 in serum. The histochemistry method was used to determine the expressions of membrane PD-1 (mPD-1) and its ligand 1 (mPD-L1) in spleen tissue. RESULTS: On the 14th, 21st and 28th days of experiment, the circumference of both knee joints was increased in each of the rabbits in the model group as compared with the control group (P<0.01), and it was reduced significantly in the moxibustion group as compared with the model group (P<0.01). Compared with the control group, the hyperplasia of synovial tissue and fibrous tissue, as well as inflammatory cell infiltration were increased obviously in the model group (P<0.01), and they were reduced significantly in the moxibustion group as compared with the model group (P<0.01, P<0.05). Compared with the control group, the concentrations of IL-2 and IL-17 in knee synovial fluid were increased in the rabbits of the model group (P<0.01). Compared with the model group, after the intervention with moxibustion, the concentrations of IL-2 and IL-17 in knee synovial fluid were reduced in the rabbits of the moxibustion group (P<0.05). Compared with the control group, the concentrations of sPD-1 and sPD-L1 in knee synovial fluid and serum in the rabbits of the model group were all increased (P<0.05). Compared with the model group, the concentration of sPD-1 in the knee synovial fluid and serum were reduced in the rabbits of moxibustion group (P<0.05). Compared with the control group, the expressions of mPD-1 and mPD-L1 in spleen tissue were increased obviously in the rabbits of the model group (P<0.05). Compared with the model group, the expression of mPD-L1 in spleen tissue was up-regulated in the rabbits of the moxibustion group (P<0.05). CONCLUSION: Moxibustion could inhibit the over-activation of T cells by enhancing the negative regulation of PD-1/PD-L1 signaling pathway so as to play its effect in treatment of RA.

[Effects of moxibustion on serum cytokines in experimental animals with rheumatoid arthritis: a systematic review and meta-analysis].

OBJECTIVE: To systematically review the effects of moxibustion on serum cytokines in experimental animals with rheumatoid arthritis. METHODS: PubMed, Embase, Web of Science, The Cochrane Library, CNKI, VIP, Wanfang Data, and CBM were searched for animal experiments on moxibustion intervention for rheumatoid arthritis. Related data were extracted, and RevMan 5.3 was used to perform a meta-analysis of outcome measures, including serum tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interleukin-17 (IL-17), interleukin-2 (IL-2), interferon-γ (IFN-γ), receptor activator of nuclear factor-kappa B ligand (RANKL), transforming growth factor-ß (TGF-ß), and degree of swelling of diseased joint. RESULTS: A total of 18 studies were included. The detection methods included radioimmunoassay and ELISA and the experimental animal species included rats and rabbits. The studies on serum TNF-α and degree of swelling of diseased joint had publication bias. Meta-analysis showed that the moxibustion group had significant reductions in the serum levels of TNF-α, IL-1, IL-2, IL-6, VEGF, IL-17, and RANKL, significant increases in the serum levels of TGF-ß and IFN-γ, and a significant reduction in the degree of swelling of diseased joints in model animals. CONCLUSION: Moxibustion can effectively regulate levels of the serum cytokines in experimental animals of rheumatoid arthritis and thus reduce inflammatory response and alleviate the swelling of diseased joints.

Effect of Tai Chi Chuan in Breast Cancer Patients: A Systematic Review and Meta-Analysis.

Background: Tai Chi Chuan(TCC), as a mind-body exercise, may have a positive impact on physical function and psychological well-being in breast cancer patients. The latest systematic review and meta-analysis of TCC for breast cancer was made 4 years ago and some new clinical trials about it were published. We remade a systematic review and meta-analysis to evaluate the effect of TCC in breast cancer patients. Methods: In this systematic review and meta-analysis, we searched MEDLINE (via PubMed), EMBASE (via embase.com), CENTRAL, CNKI, COVIP, Wanfang, Chaoxing, CiNii, J-SSTAGE, DBpia, and ThaiJO with no language restrictions from inception to December 31, 2018 (updated on February 16, 2020), for randomized clinical trials comparing TCC with non-exercised therapy in breast cancer patients. The primary outcome was quality of life in patients with breast cancer and data pooled by a random-effects model. Subgroup analyses were conducted to estimate the effect of different durations of TCC for breast cancer patients. This study was registered in PROSPERO, number CRD 4201810326. Results: Fifteen articles involving a total of 885 breast cancer participants were included in this review. Compared with non-exercised therapy, TCC had a significant effect on quality of life in breast cancer patients (SMD = 0.37, 95% CI 0.15-0.59, p = 0.001), and subgroup analysis found that TCC showed beneficial effect in 12 weeks and 25 weeks (12 weeks: SMD = 0.40, 95% CI 0.19-0.62, p = 0.0003; 25 weeks: SMD = 0.38, 95% CI 0.15-0.62, p = 0.002). Meta-analyses of secondary outcomes showed that 3 weeks TCC increased shoulder function (SMD = 1.08, 95% CI 0.28-1.87, p = 0.008), 12 weeks TCC improved pain (SMD = 0.30, 95% CI 0.08-0.51, p = 0.007), shoulder function (SMD = 1.34, 95% CI 0.43-2.25, p = 0.004), strength of arm (SMD = 0.44, 95% CI 0.20-0.68, p = 0.0004), and anxiety (MD = -4.90, 95% CI -7.83 to -1.98, p = 0.001) in breast cancer patients compared with the control group. Conclusions: TCC appears to be effective on some physical and psychological symptoms and improves the quality of life in patients with breast cancer. Additional randomized controlled trials with a rigorous methodology and low risk of bias are needed to provide more reliable evidence.