UNASSIGNED: Global inequality in clinical research capacity and service delivery can be indicated simply by the proportion of clinical trials that a country or region has registered in clinical trial registry databases. The proportion of clinical trials registered in Africa is very low at 0.02%, even though the region accounts for approximately 15% of the world\'s population. Despite the economic challenges in most African countries, they have shown potential for growth and change in recent years.
UNASSIGNED: We conducted desk reviews on the interventional clinical trials done in Kenya, Ethiopia, and Nigeria between 2015 to May 2023. The search was done in clinical trials repositories, and journal repositories. The search focused on intervention clinical trials. Data was extracted by screening through the publications and clinical trial platforms. The data extracted from the publications included the type of clinical trial, clinical trial phase, diseases, etc. The data extracted from the reports included: challenges in conducting clinical trials, capacity-building efforts, and the impact of the clinical trial.
UNASSIGNED: The number of clinical trial studies identified in Kenya was 113 (28 were on infant clinical trials). The study identified 97 clinical trials in Nigeria, of which 11 studies were on infant clinical trials. In Ethiopia, there were 28 clinical trials and only five were on infant clinical trials. The landscape review also expanded to capacity and gaps in clinical trials in the three countries. The largest proportion of clinical trials carried out in Kenya was on injury, occupational disease, and poisoning, 30.5% (n = 18) and the smallest proportion was on kidney disease, neonatal disease, obstetrics, and gynecology. Most Infant clinical trials were carried out in the area of infections and infestations 33.3% (n = 7). Most of the challenges faced by clinical trials in the three countries include a lack of infrastructure, a lack of human resources, and a lack of financial resources.
UNASSIGNED: There is a need to map clinical trials done by African researchers based in Africa to exclude the trials done by non-African researchers based in Africa. Opportunities for clinical trials should be supported and challenges addressed.

UNASSIGNED: We aimed to perform a meta-analysis of randomized trials comparing long-term outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) for severe aortic stenosis. The short-term efficacy and safety of TAVR are proven, but long-term outcomes are unclear.
UNASSIGNED: We included randomized controlled trials comparing TAVR vs SAVR at the longest available follow-up. The primary end point was death or disabling stroke. Secondary end points were all-cause mortality, cardiac mortality, stroke, pacemaker implantation, valve thrombosis, valve gradients, and moderate-to-severe paravalvular leaks. The study is registered with PROSPERO (CRD42023481856).
UNASSIGNED: Seven trials (N = 7785 patients) were included. Weighted mean trial follow-up was 5.76 ± 0.073 years. Overall, no significant difference in death or disabling stroke was observed with TAVR vs SAVR (HR, 1.02; 95% CI, 0.93-1.11; P = .70). Mortality risks were similar. TAVR resulted in higher pacemaker implantation and moderate-to-severe paravalvular leaks compared to SAVR. Results were consistent across different surgical risk profiles. As compared to SAVR, self-expanding TAVR had lower death or stroke risk (P interaction = .06), valve thrombosis (P interaction = .06), and valve gradients (P interaction < .01) but higher pacemaker implantation rates than balloon-expandable TAVR (P interaction < .01).
UNASSIGNED: In severe aortic stenosis, the long-term mortality or disabling stroke risk of TAVR is similar to SAVR, but with higher risk of pacemaker implantation, especially with self-expanding valves. As compared with SAVR, the relative reduction in death or stroke risk and valve thrombosis was greater with self-expanding than with balloon-expandable valves.

UNASSIGNED: Noninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin.
UNASSIGNED: This study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials.
UNASSIGNED: We reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included.
UNASSIGNED: We analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001).
UNASSIGNED: Recalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.

In \"Explanatory and Pragmatic Attitudes in Therapeutic Trials\", Schwatrz and Lelouch describe two approaches to the design of trials, \"… the first \"explanatory\", the second \"pragmatic\". They explained \"… the biologist may be interested to know whether the drugs differ in their effects … the explanatory approach\". Biologically endpoints might determine whether it was better to give androgen deprivation therapy (ADT) before or after external beam radiation (EBRT) (i.e., does the sequence of treatments matter). Alternatively, if the arms focus on a clinical endpoint, this is considered … \"the pragmatic approach\". An example of a clinically relevant endpoint is overall survival (OS). A real-world example of this are the two randomized controlled trials (RCTs) evaluating the role of prophylactic whole pelvic radiotherapy (WPRT) conducted by the Radiation Therapy Oncology Group (RTOG). RTOG 9413 evaluated possible interactions between the sequence of drugs and volume irradiated, while RTOG/NRG 0924 focuses on OS. There appears to be a common pattern of \"what not to do\", or \"design errors\" made by a number of investigators, that I call the \"three sins\". I posit that the prospects for a well-designed pragmatic RCT are likely to be high if these \"three sins\" are avoided/minimized. The \"three sins\" alluded to are: 1. You can\'t prove something doesn\'t work by treating people who don\'t need the treatment. 2. You can\'t prove something does not work if the treatment is not done properly. 3. You can\'t prove something does not work with an underpowered study.

The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative was established in 2016 to assess the quality and standardization of patient-reported outcomes (PRO) data analysis in randomized controlled trials (RCTs) on advanced breast cancer. The initiative identified deficiencies in PRO data reporting, including nonstandardized methods for handling missing data. This study evaluated the reporting of health-related quality of life (HRQOL) in Japanese cancer RCTs to provide insights into the state of PRO reporting in Japan. The study reviewed PubMed articles published from 2010 to 2018. Eligible studies included Japanese cancer RCTs with ≥50 adult patients (≥50% were Japanese) with solid tumors receiving anticancer treatments. The evaluation criteria included clarity of the HRQOL hypotheses, multiplicity testing, primary analysis methods, and reporting of clinically meaningful differences. Twenty-seven HRQOL trials were identified. Only 15% provided a clear HRQOL hypothesis, and 63% examined multiple HRQOL domains without adjusting for multiplicity. Model-based methods were the most common statistical methods for the primary HRQOL analysis. Only 22% of the trials explicitly reported clinically meaningful differences in HRQOL. Baseline assessments were reported in most trials, but only 26% reported comparisons between the treatment groups. HRQOL analysis was based on the intention-to-treat population in 19% of the trials, and 74% reported compliance at follow-up; however, 41% did not specify how missing values were handled. Although the rates of reporting clinical hypotheses and clinically meaningful differences were relatively low, the current state of HRQOL evaluation in the Japanese cancer RCT appears comparable to that of previous studies.

Equity and health equity are fundamental pillars in fostering a just and inclusive society. While equity underscores fairness in resource allocation and opportunity, health equity aims to eradicate avoidable health disparities among social groups. The concept of harms in interventions-undesirable consequences associated with the use of interventions-often varies across populations due to biological and social factors, necessitating a nuanced understanding. An equity lens reveals disparities in harm distribution, urging researchers and policymakers to address these differences in their decision-making processes. Furthermore, interventions, even well-intentioned ones, can inadvertently exacerbate disparities, emphasizing the need for comprehensive harm assessment. Integrating equity considerations in research practices and trial methodologies, through study design or through practices such as inclusive participant recruitment, is pivotal in advancing health equity. By prioritizing interventions that address disparities and ensuring inclusivity in research, we can foster a more equitable healthcare system.

OBJECTIVE: There is uncertainty about the optimum dose of omega-3 fatty acids for anxiety symptoms. We aimed to find the dose-dependent effect of omega-3 supplementation on anxiety symptoms.
METHODS: We systematically reviewed PubMed, Scopus, and Web of Science until December 2022 to find randomized trials that assessed the effects of omega-3 fatty acids supplementation on anxiety symptoms in adults. Investigators performed the literature search and screened the titles/abstracts and full-texts and between-reviewer agreement was assessed as Cohen\'s kappa coefficient. We conducted a random-effects dose-response meta-analysis to estimate standardized mean differences (SMD) and 95% confidence intervals (CIs) and assessed the certainty of evidence using the GRADE framework.
RESULTS: A total of 23 trials with 2189 participants were included. Each 1 gram per day supplementation with omega-3 fatty acids resulted in a moderate decrease in anxiety symptoms (SMD: -0.70, 95%CI: -1.17, -0.22; GRADE = low). The non-linear dose-response analysis indicated the greatest improvement at 2 g/d (SMD: -0.93, 95%CI: -1.85, -0.01), and that supplementation in a dose lower than 2 g/d did not affect anxiety symptoms. Omega-3 fatty acids did not increase adverse events (odds ratio: 1.20, 95%CI: 0.89, 1.61; GRADE = moderate).
CONCLUSIONS: The present dose-response meta-analysis suggested evidence of very low certainty that supplementation with omega-3 fatty acids may significantly improve anxiety symptoms, with the greatest improvements at 2 g/d. More trials with better methodological quality are needed to reach more robust evidence.
BACKGROUND: PROSPERO (CRD42022309636).

UNASSIGNED: Women are underrepresented in the leadership of and participation in randomized controlled trials (RCTs). We conducted a bibliometric review of nephrology RCTs to examine trial leadership by women and participation of women in nephrology RCTs.
UNASSIGNED: A bibliometric review of RCTs published in top medical, surgical, or nephrology journals was conducted using MEDLINE and EMBASE from January 2011 to December 2021. Leadership by women as corresponding authors, women trial participation, and trial characteristics were examined with duplicate independent data extraction. Logistic regression was used to examine associations between trial characteristics and women leadership and trial participation.
UNASSIGNED: A total of 1770 studies were screened and 395 RCTs met eligibility criteria. The number (%) of women in corresponding, first, and last authorship positions were as follows: 89 (22%), 109 (28%), and 74 (19%), respectively, without change over time (P = 0.94). The median percentage (interquartile range [IQR]) of women trial participants was 39.0% (13.5%) with no difference between women or men lead authors (P = 0.15). Men lead authors were statistically less likely to enroll women in RCTs. Women lead authors were less likely to be funded by industry (odds ratio [OR]: 0.30; 95% confidence interval [CI]: 0.14-0.63; P = 0.002) or lead international trials (OR: 0.11; 95% CI: 0.01-0.83; P = 0.03). Trials with sex-specific eligibility criteria were more likely to have women leaders (OR: 2.56; 95% CI: 1.19-5.49; P = 0.02) than those without.
UNASSIGNED: Gender inequalities in RCT leadership and RCT participation exist in nephrology and did not improve over time. Strategies to improve inequalities need to be implemented and evaluated.

UNASSIGNED: The optimal first-line immunotherapy regimen for patients with PD-L1 expression ≥50% in squamous non-small cell lung cancer (Sq-NSCLC) remains uncertain. This study utilized net-work meta-analysis (NMA) to indirectly compare the efficacy of various first-line immuno-therapy regimens in this patient subset.
UNASSIGNED: Systematic searches were conducted across PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials reporting overall survival (OS) and progression-free survival (PFS) outcomes. The search spanned from database inception to November 3, 2023. Bayesian network meta-analysis was employed for a comprehen-sive analysis. To ensure scientific rigor and transparency, this study is registered in the Interna-tional Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022349712.
UNASSIGNED: The NMA encompassed 9 randomized controlled trials (RCTs), involving 2170 patients and investigating 9 distinct immunotherapy regimens. For OS, the combination of camrelizumab and chemotherapy demonstrated the highest probability (36.68%) of efficacy, fol-lowed by cemiplimab (33.86%) and atezolizumab plus chemotherapy (23.87%). Regarding PFS, the camrelizumab and chemotherapy combination had the highest probability (39.70%) of efficacy, followed by pembrolizumab (22.88%) and pembrolizumab plus chemotherapy (17.69%). Compared to chemotherapy, first-line treatment with immune checkpoint inhibitors (ICIs) in Sq-NSCLC pa-tients exhibited significant improvements in OS (HR 0.59, 95% CI 0.47-0.75) and PFS (HR 0.44, 95% CI 0.37-0.52).
UNASSIGNED: This study suggests that, for Sq-NSCLC patients with PD-L1 expression ≥50%, the first-line immunotherapy regimen of camrelizumab plus chemotherapy provides superior OS and PFS outcomes. Furthermore, ICIs demonstrate enhanced efficacy compared to chemotherapy in this patient population.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier: CRD 42022349712.

Prospective benchmarking of an observational analysis against a randomized trial increases confidence in the benchmarking process as it relies exclusively on aligning the protocol of the trial and the observational analysis, while the trials findings are unavailable. The Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction (REDUCE-AMI, ClinicalTrials.gov ID: NCT03278509) trial started recruitment in September 2017 and results are expected in 2024. REDUCE-AMI aimed to estimate the effect of long-term use of beta blockers on the risk of death and myocardial following a myocardial infarction with preserved left ventricular systolic ejection fraction. We specified the protocol of a target trial as similar as possible to that of REDUCE-AMI, then emulated the target trial using observational data from Swedish healthcare registries. Had everyone followed the treatment strategy as specified in the target trial protocol, the observational analysis estimated a reduction in the 5-year risk of death or myocardial infarction of 0.8 percentage points for beta blockers compared with no beta blockers; effects ranging from an absolute reduction of 4.5 percentage points to an increase of 2.8 percentage points in the risk of death or myocardial infarction were compatible with our data under conventional statistical criteria. Once results of REDUCE-AMI are published, we will compare the results of our observational analysis against those from the trial. If this prospective benchmarking is successful, it supports the credibility of additional analyses using these observational data, which can rapidly deliver answers to questions that could not be answered by the initial trial. If benchmarking proves unsuccessful, we will conduct a \"postmortem\" analysis to identify the reasons for the discrepancy. Prospective benchmarking shifts the investigator focus away from an endeavour to use observational data to obtain similar results as a completed randomized trial, to a systematic attempt to align the design and analysis of the trial and the observational analysis.