Adequate Allocation Concealment Research Articles

Compelling evidence from meta-epidemiological studies demonstrates overestimation of effects in randomized trials that fail to optimize randomization and blind patients and outcome assessors

ObjectivesTo investigate the impact of potential risk of bias elements on effect estimates in randomized trials. Study Design and SettingWe conducted a systematic survey of meta-epidemiological studies examining the influence of potential risk of bias elements on effect estimates in randomized trials. We included only meta-epidemiological studies that either preserved the clustering of trials within meta-analyses (compared effect estimates between trials with and without the potential risk of bias element within each meta-analysis, then combined across meta-analyses; between-trial comparisons), or preserved the clustering of substudies within trials (compared effect estimates between substudies with and without the element, then combined across trials; within-trial comparisons). Separately for studies based on between- and within-trial comparisons, we extracted ratios of odds ratios (RORs) from each study and combined them using a random-effects model. We made overall inferences and assessed certainty of evidence based on Grading of Recommendations, Assessment, development, and Evaluation and Instrument to assess the Credibility of Effect Modification Analyses. ResultsForty-one meta-epidemiological studies (34 of between-, 7 of within-trial comparisons) proved eligible. Inadequate random sequence generation (ROR 0.94, 95% confidence interval [CI] 0.90–0.97) and allocation concealment (ROR 0.92, 95% CI 0.88–0.97) probably lead to effect overestimation (moderate certainty). Lack of patients blinding probably overestimates effects for patient-reported outcomes (ROR 0.36, 95% CI 0.28–0.48; moderate certainty). Lack of blinding of outcome assessors results in effect overestimation for subjective outcomes (ROR 0.69, 95% CI 0.51–0.93; high certainty). The impact of patients or outcome assessors blinding on other outcomes, and the impact of blinding of health-care providers, data collectors, or data analysts, remain uncertain. Trials stopped early for benefit probably overestimate effects (moderate certainty). Trials with imbalanced cointerventions may overestimate effects, while trials with missing outcome data may underestimate effects (low certainty). Influence of baseline imbalance, compliance, selective reporting, and intention-to-treat analysis remain uncertain. ConclusionFailure to ensure random sequence generation or adequate allocation concealment probably results in modest overestimates of effects. Lack of patients blinding probably leads to substantial overestimates of effects for patient-reported outcomes. Lack of blinding of outcome assessors results in substantial effect overestimation for subjective outcomes. For other elements, though evidence for consistent systematic overestimate of effect remains limited, failure to implement these safeguards may still introduce important bias.

Allocation concealment appraisal of clinical therapy trials using the extended Composite Quality Score (CQS-2)-An empirically based update.

The objective of this study was to revise CQS-2/Criterion II concerning allocation concealment appraisal for prospective, controlled clinical therapy trials. Meta-analyses of trials with inadequate allocation concealment were tested for in-between trial heterogeneity (I2 > 0) due to imbalances in baseline variables. Meta-analyses with positive test results were used as a basis to deduce criteria for adequate allocation concealment. The CQS-2/Criterion II was reformulated in line with the findings. One suitable meta-analysis was identified. Two forest plots with data from five and four trials with inadequate/unclear allocation concealment were selected for testing. In addition, a total of five trials with adequate allocation concealment were identified. The meta-analysis test results were positive, and keywords for the judgment of adequate allocation concealment were extracted verbatim from the text of the meta-analysis. The extracted keywords indicated "central allocation" as the main criterion for adequate allocation concealment. Criterion II of the CQS-2 was revised accordingly. Criterion II of the CQS-2 trial appraisal tool was revised. The revised appraisal tool was specified as version CQS-2B.

Systematic review and pooled analysis of randomized controlled trials in countries of the Gulf Cooperation Council (GCC): Methods and quality assessment.

To describe variations in characteristics of randomized controlled trials conducted in the Gulf Cooperation Council (GCC) countries, and critically appraising the quality of design, conduct and analysis of the trials. We carried out a systematically comprehensive electronic search of articles published between 1990 and 2018 and indexed in several databases: i) MEDLINE/PubMed, ii) EMBASE, iii) Cochrane Central Register of Controlled Trials (CENTRAL), iv) ClinicalTrials.gov, and v) World Health Organization International Clinical Trials Registry Platform. We summarized the overall risk of bias present in all analyzed studies using the Cochrane Collaboration risk of bias tool (CCRBT). A remarkable shift in numbers of publications from 2006 onwards was found. The largest number of publications were from Saudi Arabia and consisted of hospitals/clinics based studies. Lack of randomization was found in the majority of reports, and nearly three-fourth of the studies involved the use of intention-to-treat (ITT) principle. However, the proportion of adequately generated random sequence methods has increased yearly, and this increase accounted for a relatively large proportion over the latter half of the studied period (p<0.001), in contrast to the proportion of allocation concealment and blinding. Journal impact factor was significantly correlated with the quality of random sequence generation (r=0.145; p=0.014). The randomization methods have gained more attention over the last 3 decades. Secondly, Journal impact factor can serve as an indicator of randomization quality. To mitigate the large rate of overall high risk of bias in GCC studies, high-quality trials must be considered by ensuring adequate allocation concealment and blinding methods. PROSPERO No. ID: CRD42022310331.

Abstract 12596: Comparison of the Efficacy and Safety of Direct Oral Anticoagulants With Vitamin K Antagonists in Patients With Thrombotic Antiphospholipid Syndrome: Systematic Review and Meta-analysis of Randomized Clinical Trials

Introduction: The efficacy and safety of direct oral anticoagulants (DOACs) as treatment alternatives for patients with thrombotic antiphospholipid syndrome (APS) remain controversial. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared the efficacy and safety of DOACs with vitamin-K antagonists (VKAs) in patients with thrombotic APS. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through April 9, 2022. Main efficacy outcomes were a composite of arterial thrombotic events, and a composite of venous thromboembolic events (VTE). The main safety outcome was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. A random effects model with inverse variance was used for the primary analysis. Risk of bias was assessed using the Cochrane Collaboration criteria. Results: Our search retrieved 253 studies. Four RCTs involving 474 patients were included (Figure). All four RCTs were open-label but had proper random sequence generation and adequate allocation concealment. The DOACs used were rivaroxaban (3 trials) and apixaban (1 trial). The mean percent time in therapeutic range in the warfarin arm among the four studies was 60%. Overall, use of DOACs compared with VKAs was associated with increased odds of composite of arterial thrombotic events (OR 5.64, 95% confidence interval [CI] 1.96-16.27, p =0.001, I 2 = 0%). The odds of subsequent VTE events (OR 1.19, 95% CI 0.31-4.53, p =0.80, I 2 = 0%), or major bleeding (OR 1.02, 95% CI 0.42-2.47, p =0.97, I 2 = 0%) were not significantly different between the two groups. Conclusions: Patients with thrombotic APS randomized to DOACs compared to VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized Trials

BackgroundThe efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial. ObjectivesThe authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs). MethodsWe searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used. ResultsOur search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I2 = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I2 = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I2 = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I2 = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups. ConclusionsPatients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

The effectiveness of ozone therapy for diabetic foot treatment: A systematic review

Introduction: Diabetic foot ulcer is a local wound in patients with diabetes. Ozone therapy is becoming a treatment option as it accelerates healing. Objective: To verify the effectiveness of ozone therapy for the treatment of diabetic foot ulcers. Methodology: We performed searches in PubMed, SciELO, LILACS, MEDLINE, Web of Science and CINAHL databases until October 2021. The search included article references and clinical trial registry websites without limitation of language or publication date. Randomized and non-randomized clinical trials addressing ozone therapy in patients with diabetic foot ulcers were included. The Risk of Bias assessment tool and the Review Manager software, version 5.4 were used. Results: Six randomized and non-randomized clinical trials met the inclusion criteria (608 patients). Only two studies were considered to be at low risk of bias, with adequate randomization, allocation concealment, and blinded evaluation of results. One study compared two IPC regimens where there was evidence of a statistically significant treatment effect in favor of the rapid IPC regimen (hazard ratio 0.74, 95% CI 0.56 to 0.90). Five trials evaluated CPI as adjunctive therapy to standard therapies and agreed that CPI increases the rate of ulcer healing and a higher cure rate. Two trials evaluated CPI alone compared to other therapies. Conclusion: Ozone therapy for diabetic foot ulcers has been shown to be effective as an adjunct to standard treatment, although the included studies were classified as having a high risk of bias.

A Systematic Review of Randomized Controlled Trials on Interventions Adopting Body-Mind-Spirit (BMS) Model on Holistic Well-Being.

BackgroundThis systematic review aims to examine existing randomized controlled trials on interventions adopting Body-Mind-Spirit (BMS) model and evaluated the effectiveness of holistic well-being outcomes. Following three key concepts of the BMS model, our review questions included (1) How was BMS defined? (2) What activities were included, and how were they related to BMS dimensions? (3) What were interventionists’ backgrounds, and whether they received BMS training? (4) What were holistic outcomes? and (5) What were the effectiveness and qualities of studies?MethodsSearches were performed using nine databases for the studies published through August 2020. The process follows PRISMA protocol, and the “risk of bias” tool from the Cochrane Handbook was utilized to determine the quality of included studies.ResultsAcross 20 included studies, 18 (90%) presented a BMS definition, but only seven (35%) included all three key concepts of the BMS model. Eight studies (40%) offered detailed descriptions of body, mind, and spirit sections, and 12 (60%) mentioned cultural factors. Only five (25%) specified the body, mind, and spirit activities, and only three (15%) reported the BMS training in detail. Seven studies (35%) showed effectiveness in holistic outcomes. Only three (15%) were considered as high quality.ConclusionA unified definition of the BMS model and the guideline to apply the BMS model to design and implement interventions are highly recommended to provide a standard framework for researchers to conduct future studies. The reason for low quality is because the lack of adequate allocation concealment and blindings.

Randomized controlled trials of Chinese herbal medicine published in English from 2010 to 2019: a bibliometrics study.

As the use of Chinese herbal medicine (CHM) in the international market increases, the number of clinical studies including randomized controlled trials (RCTs) of CHM which published in international journals has also increased. Using bibliometrics, we systematically and comprehensively analyzed the research status of CHM RCTs published in English during the period of 2010 to 2019. Electronic searches in MEDLINE, EMBASE, and Cochrane Library databases were undertaken. CHM RCTs published in English between January 2010 and December 2019 were included. We randomly selected 20% from the eligible articles. Descriptive statistical analysis was carried out by extracting information on general information, characteristics of the study participants, interventions, outcomes, and risk of bias assessment of included RCTs. Two hundred and twenty-seven CHM RCTs published in English were included in our study. Chinese Journal of Integrative Medicine was the journal which published most of the relevant papers (22.0%). A total of 45,774 participants were included, sample size ranged from 12 to 3,143 (median: 115). The most common disease was the circulatory diseases (n=36, 15.9%). Decoction was the most common dosage form (28.2%), and "CHM vs. placebo" was the most common type of control (36.1%). The median of the total number of outcomes was 4 (range, 1-14), 92 (40.5%) did not clearly specify any primary outcome, 56 (24.7%) did not report any adverse event, 41 (18.1%) and 68 (30.0%) reported traditional Chinese medicine (TCM)-specific outcomes and quality of life, respectively. Eighty-five (37.4%) did not report sufficient information about the random sequence generation process, 100 (44.1%) used the adequate allocation concealment, 92 (40.5%) blinded participants and key study personnel, and 24 (10.6%) blinded outcome assessors. Our results provided insight into the research status regarding CHM RCTs published in English during the past decade, this study may be helpful in understanding research trends in this field.

Intracorporeal versus extracorporeal anastomosis in laparoscopic right colectomy: updated meta-analysis of randomized controlled trials.

BackgroundSelection of intracorporeal anastomosis (IA) or extracorporeal anastomosis (EA) in laparoscopic right colectomy (LRC) remains controversial. This meta-analysis aimed to evaluate the effectiveness and safety of IA compared with EA in LRC patients.MethodsLiterature was searched systematically for randomized controlled trials (RCTs) that compared IA with EA in LRC patients until May 2021. The eligible studies for risk of bias were assessed using the Cochrane Risk of Bias Tool. Data were extracted and analysed for the following outcomes of interest: operative time, length of incision, nodal harvest, bowel function recovery, postoperative pain, postoperative complications (wound infection, anastomotic leak, ileus, obstruction, reoperation), death at 30 days, duration of hospital stay and 30-day readmission.ResultsFive RCTs, including a total of 559 patients, were eligible for meta-analysis. All of the trials reported adequate random sequence generation and allocation concealment. There were significantly better outcomes in the IA group than in the EA group in time to first flatus (mean difference (MD) −0.71 (95 per cent c.i. −1.12 to −0.31), P = 0.0005), time to first passage of stool (MD −0.53 (95 per cent c.i. −0.69 to −0.37), P < 0.00001), visual analogue scale of pain on postoperative day (POD) 3 (MD −0.76 (95 per cent c.i. −1.23 to −0.28), P = 0.002), POD 4 (MD −0.83 (95 per cent c.i. −1.46 to −0.20), P = 0.01), POD 5 (MD −0.60 (95 per cent c.i. −0.95 to −0.25), P = 0.0007), length of incision (MD −1.52 (95 per cent c.i. −2.30 to −0.74), P = 0.0001) and wound infection (relative risk 0.46 (95 per cent c.i. 0.23 to 0.91), P = 0.02). However, there were no statistically significant differences between the two groups in duration of hospital stay (P = 0.47), operative time (P = 0.07), number of lymph nodes harvested (P = 0.70), anastomotic leak (P = 0.88), postoperative ileus (P = 0.48), bleeding (P = 0.15), bowel obstruction (P = 0.24), reoperation (P = 0.34), readmission within 30 days (P = 0.26), and death (P = 0.70).ConclusionCompared with EA, IA shows a faster recovery of bowel function with fewer wound infections.

A comparative survival analysis of high viscosity glass ionomer restorations using conventional cavity preparation and atraumatic restorative treatment technique in primary molars: A randomized clinical trial.

Background:This randomized clinical trial (RCT) aimed to compare the 3-year survival rates of high viscosity glass ionomer restorations (HVGIC) using conventional cavity preparation and atraumatic restorative technique (ART) in primary molars.Materials and Methods:In this RCT, 139 schoolchildren aged 6–9 years with dentinal caries in primary molars were randomly allocated to groups, i.e. the ART group and the conventional group, utilizing a random number generator. Adequate allocation concealment was done. Intervention was delivered using standard procedure and GC Fuji IX ART HVGIC was used as restorations in both the groups. Analysis was carried in 92 participants, and survival rates in both the groups were compared at 12, 24, and 36-month intervals. IBM SPSS software was utilized to analyze the time taken for the procedure and the Kaplan–Meier estimate was used to assess the survival rates. P value of 0.05 was considered statistically significant.Results:The ART took longer to complete (16.48 ± 2.02 min) versus conventional rotary instrumentation (13.15 ± 1.32 min). The conventional method was slightly superior as compared to ART; excellent survival rates (i.e. >90%) were achieved in both groups at the end of 12-month follow-up with no significant differences at the end of 24 and 36 months as evident from Kaplan–Meier estimate (P = 0.255).Conclusion:Three-year follow-up showed that GIC restorations with ART and conventional method carried out using GC Fuji IX ART HVGIC were acceptably successful, substantiating the use of ART for the primary dentition in areas with high caries prevalence and limited access to dental care.

Maintenance agonist treatments for opiate-dependent pregnant women.

The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Just in the United States alone, among pregnant women with hospital delivery, a fourfold increase in opioid use is reported from 1999 to 2014 (Haight 2018). Heroin crosses the placenta, and pregnant, opiate-dependent women experience a six-fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro-behavioural problems, increased neonatal mortality and a 74-fold increase in sudden infant death syndrome. This is an updated version of the original Cochrane Review first published in 2008 and last updated in 2013. To assess the effectiveness of any maintenance treatment alone or in combination with a psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions alone for child health status, neonatal mortality, retaining pregnant women in treatment, and reducing the use of substances. We updated our searches of the following databases to February 2020: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). Randomised controlled trials which assessed the efficacy of any pharmacological maintenance treatment for opiate-dependent pregnant women. We used the standard methodological procedures expected by Cochrane. We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow-release morphine. Three out of four studies had adequate allocation concealment and were double-blind. The major flaw in the included studies was attrition bias: three out of four had a high dropout rate (30% to 40%), and this was unbalanced between groups. Methadone versus buprenorphine: There was probably no evidence of a difference in the dropout rate from treatment (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.37 to 1.20, three studies, 223 participants, moderate-quality evidence). There may be no evidence of a difference in the use of primary substances between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.68, two studies, 151 participants, low-quality evidence). Birth weight may be higher in the buprenorphine group in the two trials that reported data MD;-530.00 g, 95%CI -662.78 to -397.22 (one study, 19 particpants) and MD: -215.00 g, 95%CI -238.93 to -191.07 (one study, 131 participants) although the results could not be pooled due to very high heterogeneity (very low-quality of evidence). The third study reported that there was no evidence of a difference. We found there may be no evidence of a difference in the APGAR score (MD: 0.00, 95% CI -0.03 to 0.03, two studies,163 participants, low-quality evidence). Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, may not differ between groups (RR 1.19, 95% CI 0.87 to1.63, three studies, 166 participants, low-quality evidence). Only one study which compared methadone with buprenorphine reported side effects. We found there may be no evidence of a difference in the number of mothers with serious adverse events (AEs) (RR 1.69, 95% CI 0.75 to 3.83, 175 participants, low-quality evidence) and we found there may be no difference in the numbers of newborns with serious AEs (RR 4.77, 95% CI 0.59, 38.49,131 participants, low-quality evidence). Methadone versus slow-release morphine: There were no dropouts in either treatment group. Oral slow-release morphine may be superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants, low-quality evidence). In the comparison between methadone and slow-release morphine, no side effects were reported for the mother. In contrast, one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea (low-quality evidence). Methadone and buprenorphine may be similar in efficacy and safety for the treatment of opioid-dependent pregnant women and their babies. There is not enough evidence to make conclusions for the comparison between methadone and slow-release morphine. Overall, the body of evidence is too small to make firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.

Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials.

The immunomodulatory effects of denosumab have raised concerns for risk of malignancy. This meta-analysis of 25 randomized controlled trials (21,523 patients) shows similar risk of malignancy between denosumab (60mg every 6months, up to 48months) and any comparator. Post-marketing surveillance may detect rare or late-occurring drug effects. Possible increased risk of malignancy in patients treated with denosumab has been concerned due to inhibition of the immune modulator receptor activator of nuclear factor κ-Β ligand (RANKL). We aimed to assess the risk of malignancy associated with denosumab treatment. PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019 to include all randomized controlled trials of denosumab (60mg every 6months) versus any comparator. Trials using higher drug doses for prevention of skeletal-related events were excluded. Data were independently extracted by two reviewers and analyzed using a fixed-effect model to pool risk ratios (RRs) with 95% confidence intervals (CI). Twenty-five trials (21,523 patients) were included. The risk of malignancy was similar between denosumab and other comparators (absolute risk difference 0%, RR 1.08 [95% CI, 0.93-1.24], I2= 0%). Sensitivity analysis based on adequate allocation concealment showed similar results. The risk of malignancy did not differ between groups in any of the subgroup analyses, including stratification by race, individual comparators, indications for treatment, and longer drug exposure (≥ 24months, 9 studies). The risk ratio of malignancy-related death was similar between groups. Early concerns about a potential increased risk of malignancy resulting from an immunomodulatory effect of denosumab are not supported by evidence from this meta-analysis of 25 RCTs with drug exposure of up to 48months. Since RCTs with longer observation for safety outcomes are not expected, post-marketing surveillance will be the main means for detection of rare or late-occurring events.

The effect of cognitive behavioral therapy on the quality of life of breast cancer patients: a systematic review and meta-analysis of randomized controlled trials.

Several lines of clinical research support the efficacy of Cognitive behavioral therapy (CBT) with a large number of population and various disease conditions, however, the true effects of CBT interventions on Quality of Life of breast cancer patients remain unknown. The aim of the study was to evaluate the effect of Cognitive Behavioral Therapy on the Quality of Life of breast cancer patients. A systematic review of articles published using Web of Science (1950-January 2020); Medline via EBSCO (1992-January 2020); Science direct via ELSEVIER (1996-January 2020); SCOPUS (2004-January 2020); and PubMed (1946-January 2020 excluding Medline from 1992-January 2020) were included. Additional studies were included after checking reference lists of all relevant studies; searching ongoing trials and research registers and manual search. Data extraction was conducted by two independent authors and a third independent author checked the data extraction. The PRISMA statement was adopted. Eleven Randomized controlled trials (RCT) with 1690 breast cancer patients were included in this review. The overall effect size of cognitive behavioral therapy on QoL of breast cancer patients was medium 0.39 (95% CI 0.12-0.66, P < 0.00001, I2 = 83%). Five studies had shown statistically significant improvement in functional and symptoms scales in the treatment group than the control group. CBT is effective in improving the Quality of Life of breast cancer patients. In future research, further randomized controlled trials with adequate randomization, allocation concealment, and appropriate blinding may be needed.

Fragility of clinical trials across research fields: A synthesis of methodological reviews

BackgroundRandomized controlled trials (RCTs) are often used to inform clinical practice and it is desirable that their results be robust. A fragility index (FI), defined as the smallest number of participants in whom an outcome change from non-event to event would turn a statistically significant result to a non-significant result, can be computed to measure robustness. We sought to determine the distribution of fragility indices across various research areas and summarized the factors associated with fragility. MethodsWe searched PubMed between February 2014 and May 2019 and included reviews that reported on fragility indices and the associated factors. Two investigators independently screened articles for eligibility and extracted all relevant data from each review. Fragility indices were pooled using random effects meta-analysis. ResultsTwenty-four (24) reviews met the inclusion criteria. They contained a median of 41 trials (first quartile [Q1]-third quartile [Q3]: 17–120). The overall mean FI across different fields of research was 4 (95% confidence interval [CI] 3–5), indicating a high level of fragility. Higher journal impact factor, larger sample size, bigger effect size, more outcome events, a lower p-value, and adequate allocation concealment were reported to be associated with the higher FI. The ecological correlation between median FI and median sample size (22 studies) was 0.95 (95% CI 0.58–0.99). ConclusionTrials across various fields of research are frequently fragile. We also identified some factors associated with fragility. Researchers should consider strategies to enhance the robustness of studies and minimize fragility.

Can Myofascial Interventions Have a Remote Effect on ROM? A Systematic Review and Meta-Analysis.

Anatomical and in vivo studies suggest that muscles function synergistically as part of a myofascial chain. A related theory is that certain myofascial techniques have a remote and clinically important effect on range of motion (ROM). To determine if remote myofascial techniques can effectively increase the range of motion at a distant body segment. In November 2018, the authors searched 3 electronic databases (CENTRAL, MEDLINE, and PEDro) and hand-searched journals and conference proceedings. Inclusion criteria were randomized controlled trials comparing remote myofascial techniques with passive intervention (rest/sham) or local treatment intervention. The primary outcome of interest was ROM. Quality assessment was performed using the PEDro Scale. Three authors independently evaluated study quality and extracted data. RevMan software was used to pool data using a fixed-effect model. Eight randomized controlled trials, comprising N = 354 participants were included (mean age range 22-36y; 50% female). Study quality was low with PEDro scores ranging from 2 to 7 (median scores 4.5/10). None of the studies incorporated adequate allocation concealment and just 2 used blinded assessment of outcomes. In all studies, treatments and outcomes were developed around the same myofascial chain (superficial back line). Five studies included comparisons between remote interventions to sham or inactive controls; pooled results for ROM showed trends in favor of remote interventions (standard mean difference 0.23; 95% confidence intervals; -0.09 to 0.55; 4 studies) at immediate follow-ups. Effects sizes were small, corresponding to mean differences of 9% or 5° in cervical spine ROM, and 1 to 3cm in sit and reach distance. Four studies compared remote interventions to local treatments, but there were few differences between groups. Remote exercise interventions may increase ROM at distant body segments. However, effect sizes are small and the current evidence base is limited by selection and measurement bias.

Risk of bias assessments and reporting quality of systematic reviews and randomized controlled trials examining acupuncture for depression: An overview and meta-epidemiology study.

To assess the use of risk of bias (ROB) assessment tools and the reporting quality of ROB assessment results in systematic reviews (SRs) of acupuncture for depression, as well as to evaluate the ROB of depression-related randomized controlled trials (RCT). Embase, Medline, Chinese Journal Full-Text Database (CJFD), VIP Chinese Technology Periodical Database, and WanFang Data Resource System of Digital Periodicals were searched from their inception to 24 November 2017. SRs of RCTs concerning acupuncture on depression were included. General characteristics and the information related to risk of bias in SRs were extracted. A descriptive analysis was used. Thirty-nine SRs were included. Of these, two (5%) did not perform a ROB assessment, 18.9% did not report the ROB assessment results, and 62.2% did not report the assessment results of each ROB item. Text descriptions and tables were commonly used in reporting forms. Only 32.4% of SRs reported support for judgment. The reporting rate of ROB assessment results was low in all items (13.5%-35.1%). Regarding RCTs, 59.7% used adequate randomization methods, 13.1% performed adequate allocation concealment, 12.5% performed adequate blinding of participants and personnel, 27.3% performed adequate blinding of the assessment outcomes, and 41.5% and 49.3% had a low ROB in terms of incomplete outcome data and selective outcome reporting, respectively. For the SRs of acupuncture for depression, the selection of ROB assessment tools needs to be optimized. The reporting quality is poor, and the overall ROB of RCTs is high. Therefore, the results may not be reliable.

Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis

Denosumab inhibits the receptor activator of nuclear factor κ-Β ligand, an immune system modulator. Safety endpoints including risk for infections were assessed as secondary outcomes in randomized controlled trials (RCTs) of the drug. To assess the risk of serious adverse events of infections (SAEI) in denosumab-treated patients. PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019. All RCTs of denosumab (60 mg every 6 months) versus any comparator were included. We excluded trials in cancer patients for prevention of skeletal-related events. Two reviewers independently applied selection criteria and extracted the data. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a fixed effect model. Sensitivity analysis was based on risk of bias. Thirty-three studies (22 253 patients) were included. There was a higher incidence of SAEI during denosumab treatment versus any comparator (RR, 1.21; 95% CI, 1.04-1.40; I2 = 0%), mainly of ear, nose, and throat (RR, 2.66; 95% CI, 1.20-5.91) and gastrointestinal origin (RR, 1.43; 95% CI, 1.02-2.01). RR was similar in a sensitivity analysis based on adequate allocation concealment. The RR of any infection (RR, 1.03; 95% CI, 0.99-1.06) and infection-related mortality (RR, 0.50; 95% CI, 0.20-1.23) was comparable between groups. A higher incidence of SAEI is demonstrated during treatment with denosumab in an osteoporosis dose. Nevertheless, the overall risk for any infection or related mortality is similar to comparator groups. These findings merit consideration before therapy initiation.

Poor allocation concealment methods are associated with heterogeneity in age and statistical significance of the primary outcome: Review of recent trials published in four general medical journals.

To assess the association of the quality of allocation concealment with heterogeneity in age, the P value of the primary outcome and statistical significance of the primary outcome. We extracted data from articles published in four major medical journals in 2017 and 2018 that reported the results of randomized controlled trials. The outcome measures were the quality of allocation concealment used in the trial, the P value of the primary outcome, whether the P value of the primary outcome was statistically significant and the level of heterogeneity in age between the treatment groups (measured using the I2 statistic). The association between the quality of allocation concealment and the P value of the primary outcome was assessed using a kernel density plot, while the association between the quality of allocation concealment and whether the P value was statistically significant was assessed using logistic regression. Trials that used inadequate concealment methods were more likely to report statistically significant findings than trials that used good or adequate methods (OR 1.90; 95% CI: 0.91 to 3.95; P = .09). The values of I2 for trials that used good, adequate, inadequate and unclear concealment methods were 0%, 1.0%, 32.6%, and 93.8%, respectively. There is evidence of an association between poor allocation concealment methods and statistical significance of the primary outcome. Trials that use inadequate allocation concealment methods are more likely to have statistically significant P values compared with trials using good or adequate allocation concealment methods.

The safety of pulse corticosteroid therapy- Systematic review and meta-analysis

ObjectiveTo amass all available evidence from randomized controlled trials regarding the safety of pulse corticosteroids therapy, in order to establish its safety. Patients and MethodsAll electronic databases from 1/1966 up to 02/2019 were reviewed to find all randomized controlled trials comparing pulse corticosteroids to oral corticosteroids or to placebo/no treatment. Two reviewers independently extracted and recorded data regarding type of corticosteroid treatment, dosages, length of treatment and follow-up. Risk ratios (RR) with 95% (CI) for differences between pulse corticosteroids and comparator were pooled using a fixed effect meta-analysis. The primary outcome was occurrence of severe adverse events (SAEs). Secondary outcomes included any adverse events (AEs), AEs requiring discontinuation, AEs per system involved and all-cause mortality. ResultsA total of 64 trials were included: 18 trials which compared pulse corticosteroids to oral corticosteroids and 46 trials which compared pulse corticosteroids to placebo/no intervention. Pulse corticosteroids was not associated with increased risk for SAEs for both comparators: RR 0.77 (95% CI 0.52-1.14), and RR 0.99 (95% CI 0.93-1.06), respectively. Sensitivity analysis based on adequate allocation concealment and use of a valid AE grading did not alter the results. Subgroup analysis revealed no increased risk of specific SAEs or AEs with pulse corticosteroids compared to oral corticosteroids. ConclusionPulse corticosteroids was not associated with an increase risk of SAEs and should be regarded as safe.

Stapled versus handsewn methods for ileocolic anastomoses

This is the first systematic review specifically investigating ileocolic anastomosis. To compare outcomes of ileocolic anastomoses performed using stapling and handsewn techniques. The hypothesis tested was that the stapling technique is associated with fewer complications. MEDLINE, EMBASE, Cochrane Colorectal Cancer Group specialised register SR-COLOCA, and Cochrane Library were searched for randomised controlled trials comparing the use of a linear cutter stapler with any type of suturing technique for ileocolic anastomoses in adults from 1970 to 2005. Selection criteria were randomised controlled trials comparing the use of linear cutter stapler (isoperistaltic side to side or functional end to end) with any type of suturing technique in adults. Regarding data collection and analysis, eligible studies were selected and their methodological quality assessed. Sub-group analyses for cancer and inflammatory bowel disease as indication for ileocolic anastomoses were performed. Six trials (including one unpublished) with 955 ileocolic participants were included. The three largest trials had adequate allocation concealment. Stapled anastomosis was associated with significantly fewer anastomotic leaks compared with the handsewn technique (S = 5/357, HS = 36/598, OR 0.34 [0.14, 0.82] p = 0.02). For the sub-group of 825 cancer patients in four studies, stapled anastomosis led to significantly fewer anastomotic leaks (S = 4/300, HS = 35/525, OR 0.28 [0.10, 0.75] p = 0.01). There were very less Crohn's disease patients to perform a sub-group analysis. All other outcomes showed no significant difference. Stapled functional end-to-end ileocolic anastomosis is associated with fewer leaks than handsewn anastomosis.