Objectives: This systematic review (SR) highlights principles for nutrient clinical trials and explore the diverse physiological functions of vitamin D beyond its traditional role in the musculoskeletal system related to clinical study designs. Background: Thousands of published research articles have investigated the benefits of vitamin D (a nutrient example taken in this SR) beyond the musculoskeletal system, including the immune, pulmonary, and cardiovascular systems; pregnancy; autoimmune disorders; and cancer. They illustrated vitamin D's molecular mechanisms, interactions, and genomic and nongenomic actions. Methods: This SR was designed to identify shortcomings in clinical study designs, statistical methods, and data interpretation that led to inconsistent findings in vitamin D-related publications. SR also highlights examples and insights into avoiding study design errors in future clinical studies, including randomized controlled clinical trials (RCTs). The SR adheres to the latest PRISMA statement, guidelines, and the PICOS process. Results: Inappropriate or flawed study designs were frequent in clinical trials. Major failures discussed here include too short clinical study duration, inadequate or infrequent doses, insufficient statistical power, failure to measure baseline and achieved levels, and recruiting vitamin D-sufficient participants. These design errors have led to misleading interpretations. Thus, conclusions from such studies should not be generalized or used in guidelines, recommendations, or policymaking. Conclusion: Adequately powered epidemiological studies and RCTs with sufficient vitamin D and duration in individuals with vitamin D deficiency reported favorable clinical outcomes, enriching the literature, enabling to understand its physiology and mechanisms. Proper study designs with rigorous methodologies and cautious interpretation of outcomes are crucial in advancing the nutrient field. The principles discussed apply not only to vitamin D, but also other micro-nutrients and nutraceutical research. Adhering to them enhances the credibility and reliability of clinical trials, SRs, and meta-analysis outcomes. The study emphasizes the importance of focused, hypothesis-driven, well-designed, statistically powered RCTs to explore the diverse benefits of nutrients, conducted in index nutrient deficient participants, and avoidance of study design errors. Findings from such studies should be incorporated into clinical practice, policymaking, and public health guidelines, improving the health of the nation and reducing healthcare costs.

To explore the current state of research on off-label drug use in children and identify the existing research gaps in this topic. Six literature databases were searched to identify studies focusing exclusively on off-label drug use in children (aged < 18 years) published in Chinese or English between 2016 and 2021. We also searched clinicaltrials.gov for pediatric clinical trials conducted in the same period and compared the numbers of studies on off-label use and clinical trials for the most commonly reported drugs and drug types. Our search revealed 568 studies on off-label drug use. Almost half of the studies (n = 240) were cross-sectional. A total of 212 specific drugs or drug types were addressed in 361 studies, the most frequent being antipsychotic agents (n = 12), dexmedetomidine (n = 10), and rituximab (n = 8). Antipsychotic agents were also the most common type of drug examined in clinical trials in children. We identified a total of 435 different types of off-label use, the top three being unapproved indication (n = 157), population (n = 96), or age (n = 36). Only about one-third of the studies reported collecting informed consent (n = 195) or having ethics committee approval (n = 166). Conclusions: Off-label use of antipsychotics in children is widely reported in the literature. We suggest pediatric researchers to consider the number of studies on off-label use and existing clinical trials on different drugs when selecting target drugs for new studies and systematic reviews. What is Known: center dot There exist a large number of studies on off-label drug use in children. What is New: center dot This is the first scoping review of studies on off-label drug use in children. center dot Off-label use of antipsychotic agents is widely reported.

Objective: To describe the characteristics of Covid-19 randomized clinical trials (RCTs) and examine the association between trial characteristics and the likelihood of finding a significant effect. Study design: We conducted a systematic review to identify RCTs (up to October 21, 2020) evaluating drugs or blood products to treat or prevent Covid-19. We extracted trial characteristics (number of centers, funding sources, and sample size) and assessed risk of bias (RoB) using the Cochrane RoB 2.0 tool. We performed logistic regressions to evaluate the association between RoB due to randomization, single vs. multicentre, funding source, and sample size, and finding a statistically significant effect. Results: We included 91 RCTs (n = 46,802); 40 (44%) were single-center, 23 (25.3%) enrolled < 50 patients, 28 (30.8%) received industry funding, and 75 (82.4%) had high or probably high RoB. Thirty-eight trials (41.8%) reported a statistically significant effect. RoB due to randomization and being a single-center trial were associated with increased odds of finding a statistically significant effect. Conclusions: There is high variability in RoB among Covid-19 trials. Researchers, funders, and knowledge-users should be cognizant of the impact of RoB due to randomization and single-center trial status in designing, evaluating, and interpreting the results of RCTs. (C) 2021 Elsevier Inc. All rights reserved.