On exact randomization-based covariate-adjusted confidence intervals.

Randomization-based inference using the Fisher randomization test allows for the computation of Fisher-exact P-values, making it an attractive option for the analysis of small, randomized experiments with non-normal outcomes. Two common test statistics used to perform Fisher randomization tests are the difference-in-means between the treatment and control groups and the covariate-adjusted version of the difference-in-means using analysis of covariance. Modern computing allows for fast computation of the Fisher-exact P-value, but confidence intervals have typically been obtained by inverting the Fisher randomization test over a range of possible effect sizes. The test inversion procedure is computationally expensive, limiting the usage of randomization-based inference in applied work. A recent paper by Zhu and Liu developed a closed form expression for the randomization-based confidence interval using the difference-in-means statistic. We develop an important extension of Zhu and Liu to obtain a closed form expression for the randomization-based covariate-adjusted confidence interval and give practitioners a sufficiency condition that can be checked using observed data and that guarantees that these confidence intervals have correct coverage. Simulations show that our procedure generates randomization-based covariate-adjusted confidence intervals that are robust to non-normality and that can be calculated in nearly the same time as it takes to calculate the Fisher-exact P-value, thus removing the computational barrier to performing randomization-based inference when adjusting for covariates. We also demonstrate our method on a re-analysis of phase I clinical trial data.

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.

Effective dosage and mode of exercise for enhancing cognitive function in Alzheimer's disease and dementia: a systematic review and Bayesian Model-Based Network Meta-analysis of RCTs.

OBJECTIVE: Research the dose-response relationship between overall and certain types of exercise and cognitive function in older adults with Alzheimer's disease and dementia. DESIGN: Systemic and Bayesian Model-Based Network Meta-Analysis. METHODS: In our study, we analyzed data from randomized controlled trials investigating the effects of different exercises on cognitive outcomes in older adults with AD. We searched the Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and Embase up to November 2023. Using the Cochrane Risk of Bias tool (Rob2) for quality assessment and R software with the MBNMA package for data analysis, we determined standard mean differences (SMDs) and 95% confidence intervals (95%CrI) to evaluate exercise's impact on cognitive function in AD. RESULTS: Twenty-seven studies with 2,242 AD patients revealed a nonlinear relationship between exercise and cognitive improvement in AD patients. We observed significant cognitive enhancements at an effective exercise dose of up to 1000 METs-min/week (SMDs: 0.535, SD: 0.269, 95% CrI: 0.023 to 1.092). The optimal dose was found to be 650 METs-min/week (SMDs: 0.691, SD: 0.169, 95% CrI: 0.373 to 1.039), with AE (Aerobic exercise) being particularly effective. For AE, the optimal cognitive enhancement dose was determined to be 660 METs-min/week (SMDs: 0.909, SD: 0.219, 95% CrI: 0.495 to 1.362). CONCLUSION: Nonlinear dose-response relationship between exercise and cognitive improvement in Alzheimer's disease, with the optimal AE dose identified at 660 METs-min/week for enhancing cognitive function in AD.

Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics.

BACKGROUND: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s). This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design. METHODS: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit. RESULTS: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level. CONCLUSIONS: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics.

Approaches and experiences implementing remote, electronic consent at the Leeds Clinical Trials Research Unit.

BACKGROUND: Use of electronic methods to support informed consent ('eConsent') is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK. MAIN TEXT: We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system's generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system. We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake. CONCLUSIONS: We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach.

Remote ischemic conditioning may improve graft function following kidney transplantation: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Remote ischemic conditioning (RIC) has the potential to benefit graft function following kidney transplantation by reducing ischemia-reperfusion injury; however, the current clinical evidence is inconclusive. This meta-analysis with trial sequential analysis (TSA) aimed to determine whether RIC improves graft function after kidney transplantation. METHODS: A comprehensive search was conducted on PubMed, Cochrane Library, and EMBASE databases until June 20, 2023, to identify all randomized controlled trials that examined the impact of RIC on graft function after kidney transplantation. The primary outcome was the incidence of delayed graft function (DGF) post-kidney transplantation. The secondary outcomes included the incidence of acute rejection, graft loss, 3- and 12-month estimated glomerular filtration rates (eGFR), and the length of hospital stay. Subgroup analyses were conducted based on RIC procedures (preconditioning, perconditioning, or postconditioning), implementation sites (upper or lower extremity), and graft source (living or deceased donor). RESULTS: Our meta-analysis included eight trials involving 1038 patients. Compared with the control, RIC did not significantly reduce the incidence of DGF (8.8% vs. 15.3%; risk ratio = 0.76, 95% confidence interval [CI], 0.48-1.21, P = 0.25, I2 = 16%), and TSA results showed that the required information size was not reached. However, the RIC group had a significantly increased eGFR at 3 months after transplantation (mean difference = 2.74 ml/min/1.73 m2, 95% CI: 1.44-4.05 ml/min/1.73 m2, P < 0.0001, I2 = 0%), with a sufficient evidence suggested by TSA. The secondary outcomes were comparable between the other secondary outcomes. The treatment effect of RIC did not differ between the subgroup analyses. CONCLUSION: In this meta-analysis with trial sequential analysis, RIC did not lead to a significant reduction in the incidence of DGF after kidney transplantation. Nonetheless, RIC demonstrated a positive correlation with 3-month eGFR. Given the limited number of patients included in this study, well-designed clinical trials with large sample sizes are required to validate the renoprotective benefits of RIC. TRIAL REGISTRATION: This systematic review and meta-analysis was registered at the International Prospective Register of Systematic Reviews (Number CRD42023464447).

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

BACKGROUND: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. RESULTS: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. CONCLUSION: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Sequential covariate-adjusted randomization via hierarchically minimizing Mahalanobis distance and marginal imbalance.

In comparative studies, covariate balance and sequential allocation schemes have attracted growing academic interest. Although many theoretically justified adaptive randomization methods achieve the covariate balance, they often allocate patients in pairs or groups. To better meet the practical requirements where the clinicians cannot wait for other participants to assign the current patient for some economic or ethical reasons, we propose a method that randomizes patients individually and sequentially. The proposed method conceptually separates the covariate imbalance, measured by the newly proposed modified Mahalanobis distance, and the marginal imbalance, that is the sample size difference between the 2 groups, and it minimizes them with an explicit priority order. Compared with the existing sequential randomization methods, the proposed method achieves the best possible covariate balance while maintaining the marginal balance directly, offering us more control of the randomization process. We demonstrate the superior performance of the proposed method through a wide range of simulation studies and real data analysis, and also establish theoretical guarantees for the proposed method in terms of both the convergence of the imbalance measure and the subsequent treatment effect estimation.

Fidelity, pragmatism and the "grey line" in between-exploring the delivery of a pragmatic physical activity randomised controlled trial-a secondary analysis.

BACKGROUND: Intervention fidelity in health services research has been poor with a reported lack of understanding about what constitutes pragmatic adaptation of interventions and what constitutes failure to maintain intervention fidelity. However, the challenges facing those delivering such interventions have not been thoroughly explored. The aims of this study were to critically explore the challenges in maintaining fidelity experienced by physiotherapy staff and support workers when delivering a complex intervention for older people living with frailty. METHODS: This study is a secondary analysis of data from a process evaluation of a large randomised controlled trial (RCT). The process evaluation employed qualitative methodologies with mixed methods including a variety of data collection methods, including participant observation, semi-structured interviews and documentary analysis. Thematic analysis was used to make sense of the data. RESULTS: Many therapy staff felt ongoing confusion about what was acceptable to adapt and what needed to follow the protocol exactly. We found that some therapy staff were able to embrace the challenges of pragmatically adapting interventions while maintaining intervention fidelity, others stuck rigidly to the protocol and failed to adapt interventions where it was necessary. CONCLUSION: It was clear that the understanding of fidelity and pragmatism was poor. While pragmatic trials are vital to replicate real world clinical practice, further guidance may need to be developed in order to guide the level of adaptation that is acceptable before fidelity is undermined.

Effectiveness of vestibular rehabilitation on postural balance in Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Postural balance impairment can affect the quality of life of patients with Parkinson's disease. Previous studies have described connections of the vestibular system with postural functions, suggesting a potential participation of the basal ganglia in receiving vestibular stimuli. This systematic review aims to summarize the evidence on the effectiveness of vestibular rehabilitation on postural balance in patients with Parkinson's disease. METHODS: A systematic review was conducted using the electronic databases: PubMed, Embase, Scopus and PEDro. The study selection was independently conducted by two reviewers, and disagreements were evaluated by a third reviewer. The included studies had no restrictions on publication dates or languages and the last update occurred in July 2023. RESULTS: From the 485 studies found in the searches, only 3 studies were deemed eligible for the systematic review involving a total of 130 participants. The Berg Balance Scale was described as the tool for evaluation of postural balance in all studies. The meta-analysis showed statistically significant results in favor of vestibular rehabilitation (MD = 5.35; 95% CI = 2.39, 8.31; P < 0.001), regardless of the stage of Parkinson's disease. Although the effect size was suggested as a useful functional gain, the analysis was done with caution, as it only included 3 randomized controlled trials. The risk of bias using the RoB-2 was considered as being of "some concern" in all studies. Furthermore, the quality of the evidence based on the Grading of Recommendations Assessment Development and Evaluation system, produced by pooling the included studies was considered very low. CONCLUSION: Compared to other interventions, vestibular rehabilitation has potential to assist the postural balance of patients with Parkinson's disease. However, the very low quality of the evidence demonstrates uncertainty about the impact of this clinical practice. More robust studies are needed to confirm the benefits of this therapy in patients with Parkinson's disease. This study was prospectively registered in PROSPERO: CRD42020210185.

Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review.

BACKGROUND: The use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes. METHODS: A systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included. RESULTS: 8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2-3). Trials using a COM recruited fewer participants (409 (198.8-851.5) vs 584 (300-1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important. CONCLUSIONS: COM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.

Technology-based interventions on burden of older adults' informal caregivers: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: An increasing number of technologies are provided to reduce the burden of older adults' informal caregivers. However, less is known about the effects and the mechanism of technology to work on burden. This review is to evaluate the effectiveness of technology-based interventions (TBI) in alleviating the burden of older adults' informal caregivers and to distinguish its effective mechanism via group disparities. METHODS: A systematic review and meta-analysis of randomized controlled trials studies (RCTs) has been conducted. Web of Science, PubMed, EMBASE, Scopus, CINAHL, PsycINFO, WANFANG, CNKI, CQVIP databases, Cochrane Library Trials, and ClinicalTrials.gov were searched for trial studies and registry in both English and Chinese published from January 1990 to October 2022. Reviewers independently screened the articles and trials, conducted quality assessments, and extracted the data. All processes were guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias of the studies was evaluated by the Cochrane Systematic Review Handbook. The meta-analysis was conducted by RevMan 5.13. Subgroup analyses, sensitivity analyses, publication bias were also conducted. RESULTS: A total of 11,095 RCTs were initially screened, and 14 trials representing 1010 informal caregivers were included finally. This review proved TBI effective in reducing caregiving burden older adults. Subgroup analysis showed effects of TBI differed by interventions on control group and medical conditions of care recipients. CONCLUSION: TBI is an effective way to alleviate the burden on informal caregivers of aging people. Interventions for control groups and medical conditions of care-recipients are significant factors in effective interventions. Future researches could include more trials with high-quality or to explore more targeted aging groups, modalities of TBI, or caregiver outcomes. TRIAL REGISTRATION: The review protocol was registered on PROSPERO [CRD42021277865].

Effect of vitamin D, calcium, or combined supplementation on fall prevention: a systematic review and updated network meta-analysis.

BACKGROUND: The association between vitamin D supplementation and the risk of falls in older adults has been controversial. This systematic review and network meta-analysis aims to assess the efficacy of vitamin D, calcium, and combined supplementation in the prevention of falls. METHODS: Randomized controlled trials (RCTs) on the efficacy of vitamin D in fall prevention were systematically searched in PubMed, Embase, Cochrane Library, and Web of Science from inception to May 9, 2023. The network meta-analysis was performed using a random effects model in R4.1.3 and Stata15.0. Heterogeneity was evaluated by the I2 statistic, and publication bias was assessed using funnel plots, Begg's test, and Egger's tests. Data were pooled and expressed as relative risk (RR) and 95% confidence interval (CI). RESULTS: A total of 35 RCTs involving 58,937 participants were included in this study, among which 11 RCTs (31.4%) applied calcium combined with vitamin D. There was low heterogeneity (I2 = 11%) among the included studies. Vitamin D supplementation at 800-1000 International Unit (IU)/d resulted in a lower risk of falls than placebo or no treatment (RR = 0.85, 95%CI: 0.74-0.95). In addition, 800-1000 IU/d of vitamin D with or without calcium were more effective in preventing falls than calcium alone. High-dose vitamin D (> 1000 IU/day) increased the risk of falls compared with 800-1000 IU/d of vitamin D. According to the subgroup analysis, daily administration of 800-1000 IU/d vitamin D was associated with a 22% reduction in the risk of falls (RR = 0.78, 95%CI:0.64-0.92), whereas intermittent vitamin D administration had no preventive effect. Furthermore, 800-1000 IU/d of vitamin D also significantly decreased the risk of falls in old adults with ≤ 50 nmol/L 25-hydroxyvitamin D [25(OH)D] (RR = 0.69, 95%CI:0.52-0.86) but not in individuals with > 50 nmol/L 25(OH)D. CONCLUSION: Vitamin D supplementation at 800-1000 IU/d is associated with a lower risk of falls among older adults. 800-1000IU/d of vitamin D has a benefit on prevention of falls in population received daily dose regimens and in population with vitamin D deficiency.

Dexmedetomidine versus remifentanil in nasal surgery: a systematic review and meta-analysis.

BACKGROUND: Nasal surgeries, addressing anatomical variations for form and function, require careful anesthesia administration, including dexmedetomidine and remifentanil. This meta-analysis evaluates their safety and efficacy variations in nasal surgeries, emphasizing patient comfort and optimal outcomes. METHODS: Four electronic databases (PubMed, Scopus, Web of Science, and CINAHL Complete) were searched for records in English. Studies that measure the effect of dexmedetomidine versus remifentanil on patients underwent nasal surgery were included. The Cochrane Collaboration's tool was used to assess the quality of the included studies. A random-effect model was preferred and statistical analysis was performed by Stata software version 17. RESULTS: Out of an initial pool of 63 articles, five studies were selected for this analysis. All of these chosen studies were Randomized Controlled Trials (RCTs). The meta-analysis involved a total of 302 participants, with 152 in the remifentanil group and 150 in the dexmedetomidine group. The analysis aimed to compare the effects of Dexmedetomidine and Remifentanil on heart rate (HR) and mean arterial pressure (MAP) during surgery. Both groups exhibited similar MAP and HR, with the exception of a slightly lower HR in the remifentanil group at the 15th minute of surgery (Standardized Mean Difference: -0.24 [-0.83, 0.34]). Furthermore, when evaluating the impact of these medications on post-surgery outcomes, including pain levels, the use of pain relief medications, patient-surgeon satisfaction, agitation scores, and recovery time, no significant differences were observed between the two medications in any of these aspects. CONCLUSION: In summary, the study compared Dexmedetomidine and Remifentanil in nasal surgeries anesthesia. No significant differences were found in heart rate, blood pressure, satisfaction, pain, agitation, or recovery time. The study had limitations, and future research should establish standardized protocols and consider various surgical factors.

Modifications of the readiness assessment for pragmatic trials tool for appropriate use with Indigenous populations.

BACKGROUND: Inequities in health access and outcomes exist between Indigenous and non-Indigenous populations. Embedded pragmatic randomized, controlled trials (ePCTs) can test the real-world effectiveness of health care interventions. Assessing readiness for ePCT, with tools such as the Readiness Assessment for Pragmatic Trials (RAPT) model, is an important component. Although equity must be explicitly incorporated in the design, testing, and widespread implementation of any health care intervention to achieve equity, RAPT does not explicitly consider equity. This study aimed to identify adaptions necessary for the application of the 'Readiness Assessment for Pragmatic Trials' (RAPT) tool in embedded pragmatic randomized, controlled trials (ePCTs) with Indigenous communities. METHODS: We surveyed and interviewed participants (researchers with experience in research involving Indigenous communities) over three phases (July-December 2022) in this mixed-methods study to explore the appropriateness and recommended adaptions of current RAPT domains and to identify new domains that would be appropriate to include. We thematically analyzed responses and used an iterative process to modify RAPT. RESULTS: The 21 participants identified that RAPT needed to be modified to strengthen readiness assessment in Indigenous research. In addition, five new domains were proposed to support Indigenous communities' power within the research processes: Indigenous Data Sovereignty; Acceptability - Indigenous Communities; Risk of Research; Research Team Experience; Established Partnership). We propose a modified tool, RAPT-Indigenous (RAPT-I) for use in research with Indigenous communities to increase the robustness and cultural appropriateness of readiness assessment for ePCT. In addition to producing a tool for use, it outlines a methodological approach to adopting research tools for use in and with Indigenous communities by drawing on the experience of researchers who are part of, and/or working with, Indigenous communities to undertake interventional research, as well as those with expertise in health equity, implementation science, and public health. CONCLUSION: RAPT-I has the potential to provide a useful framework for readiness assessment prior to ePCT in Indigenous communities. RAPT-I also has potential use by bodies charged with critically reviewing proposed pragmatic research including funding and ethics review boards.

Effectiveness of Gerontechnology Empowerment Program on Awareness and Use of Mobile Apps Among Older Adults for Instrumental Activities of Daily Living: Protocol for a Cluster Randomized Controlled Trial.

BACKGROUND: Instrumental activities of daily living (iADLs) are crucial for older adults to live independently. Health care and technological advancements will increase the older adult population and life expectancy globally. Difficulties with iADLs impact older adults' quality of life. Mobile apps can assist older adults, but many require help due to limited awareness. Lack of awareness is a barrier to app use. Existing literature mainly covers health care and app design, needing more focus on iADL apps for older adults. OBJECTIVE: The study objectives encompass 2 main aspects: first, to evaluate the awareness, use, and factors influencing the use of apps among older adults for iADLs; and second, to create and assess the effectiveness of a gerontechnology empowerment program (GEP) for older adults on the awareness and use of apps for iADLs. METHODS: This research uses a quantitative approach divided into 2 distinct phases. In phase 1, we conduct a descriptive survey to assess the level of awareness and use of mobile apps for iADLs and identify the factors that influence the use of such apps among older adults. To ensure clarity and comprehension among participants, we provide them with a subject information sheet in both Kannada and English. The data collected during this phase enable us to gain insights into awareness levels, use patterns, and factors that shape older adults' use of apps for iADLs. The results serve as the foundation for designing the GEP. In phase 2, a cluster randomization method will be used to select older adults aged 60 to 75 years in Udupi district, Karnataka, India, who are active smartphone users. These participants will be divided into 2 groups: the experimental and the control groups. The experimental group will join the GEP. The sample size for phase 1 is 554, and phase 2 is 50. To assess the effectiveness of this program, we will measure the outcomes before and after its implementation using the same assessment tools used in phase 1. RESULTS: This study is funded by the Indian Council of Medical Research (Adhoc/193/2022/SBHSR on November 18, 2022). Phase 1 data collection is expected to be completed by November 2023, and phase 2 is scheduled to commence in the upcoming months. Phase 1 and 2 findings will be analyzed and discussed in the main paper, which we intend to submit to a high-quality peer-reviewed journal for publication. The research protocol, informed consent forms, and associated documentation received approval from institutional ethics committees (214/2020). CONCLUSIONS: Upon the successful testing of the GEP, it can be recommended that welfare departments encourage older adults to use mobile apps for iADLs and establish training programs to provide support to older adults in using these apps. TRIAL REGISTRATION: Clinical Trials Registry - India CTRI/2020/09/027977; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NDUxMzM=&Enc=&userName=027977. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53587.

Rates of bronchopulmonary dysplasia in very low birth weight neonates: a systematic review and meta-analysis.

IMPORTANCE: Large-scale estimates of bronchopulmonary dysplasia (BPD) are warranted for adequate prevention and treatment. However, systematic approaches to ascertain rates of BPD are lacking. OBJECTIVE: To conduct a systematic review and meta-analysis to assess the prevalence of BPD in very low birth weight (≤ 1,500 g) or very low gestational age (< 32 weeks) neonates. DATA SOURCES: A search of MEDLINE from January 1990 until September 2019 using search terms related to BPD and prevalence was performed. STUDY SELECTION: Randomized controlled trials and observational studies evaluating rates of BPD in very low birth weight or very low gestational age infants were eligible. Included studies defined BPD as positive pressure ventilation or oxygen requirement at 28 days (BPD28) or at 36 weeks postmenstrual age (BPD36). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently conducted all stages of the review. Random-effects meta-analysis was used to calculate the pooled prevalence. Subgroup analyses included gestational age group, birth weight group, setting, study period, continent, and gross domestic product. Sensitivity analyses were performed to reduce study heterogeneity. MAIN OUTCOMES AND MEASURES: Prevalence of BPD defined as BPD28, BPD36, and by subgroups. RESULTS: A total of 105 articles or databases and 780,936 patients were included in this review. The pooled prevalence was 35% (95% CI, 28-42%) for BPD28 (n = 26 datasets, 132,247 neonates), and 21% (95% CI, 19-24%) for BPD36 (n = 70 studies, 672,769 neonates). In subgroup meta-analyses, birth weight category, gestational age category, and continent were strong drivers of the pooled prevalence of BPD. CONCLUSIONS AND RELEVANCE: This study provides a global estimation of BPD prevalence in very low birth weight/low gestation neonates.

Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus.

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.