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Data Availability: All relevant data from this study will be made available upon study completion. The authors would like to thank Joanne Mcphie, an academic liaison librarian, Brunel University London, for technical assistance with the search strategy development. Copyright: © 2023 Imiuwa et al. Background: The environmental prevalence of widely prescribed human pharmaceuticals that target key evolutionary conserved biomolecules present across phyla is concerning. Antidepressants, one of the most widely consumed pharmaceuticals globally, have been developed to target biomolecules modulating monoaminergic neurotransmission, thus interfering with the endogenous regulation of multiple key neurophysiological processes. Furthermore, rising prescription and consumption rates of antidepressants caused by the burgeoning incidence of depression is consistent with increasing reports of antidepressant detection in aquatic environments worldwide. Consequently, there are growing concerns that long-term exposure to environmental levels of antidepressants may cause adverse drug target-specific effects on non-target aquatic organisms. While these concerns have resulted in a considerable body of research addressing a range of toxicological endpoints, drug target-specific effects of environmental levels of different classes of antidepressants in non-target aquatic organisms remain to be understood. Interestingly, evidence suggests that molluscs may be more vulnerable to the effects of antidepressants than any other animal phylum, making them invaluable in understanding the effects of antidepressants on wildlife. Here, a protocol for the systematic review of literature to understand drug target-specific effects of environmental levels of different classes of antidepressants on aquatic molluscs is described. The study will provide critical insight needed to understand and characterize effects of antidepressants relevant to regulatory risk assessment decision-making, and/or direct future research efforts. Methods: The systematic review will be conducted in line with the guidelines by the Collaboration for Environmental Evidence (CEE). A literature search on Scopus, Web of Science, PubMed, as well as grey literature databases, will be carried out. Using predefined criteria, study selection, critical appraisal and data extraction will be done by multiple reviewers with a web-based evidence synthesis platform. A narrative synthesis of outcomes of selected studies will be presented. The protocol has been registered in the Open Science Framework (OSF) registry with the registration DOI: 10.17605/OSF.IO/P4H8W. MEI received funding from Tertiary Education Trust Fund (TETFund), Nigeria (https://tetfund.gov.ng/).

ObjectiveTo appraise the currency, completeness and quality of evidence from systematic reviews (SRs) of acute management of moderate to severe traumatic brain injury (TBI).MethodsWe conducted comprehensive searches to March 2016 for published, English-language SRs and RCTs of acute management of moderate to severe TBI. Systematic reviews and RCTs were grouped under 12 broad intervention categories. For each review, we mapped the included and non-included RCTs, noting the reasons why RCTs were omitted. An SR was judged as 'current' when it included the most recently published RCT we found on their topic, and 'complete' when it included every RCT we found that met its inclusion criteria, taking account of when the review was conducted. Quality was assessed using the AMSTAR checklist (trichotomised into low, moderate and high quality).FindingsWe included 85 SRs and 213 RCTs examining the effectiveness of treatments for acute management of moderate to severe TBI. The most frequently reviewed interventions were hypothermia (n = 17, 14.2%), hypertonic saline and/or mannitol (n = 9, 7.5%) and surgery (n = 8, 6.7%). Of the 80 single-intervention SRs, approximately half (n = 44, 55%) were judged as current and two-thirds (n = 52, 65.0%) as complete. When considering only the most recently published review on each intervention (n = 25), currency increased to 72.0% (n = 18). Less than half of the 85 SRs were judged as high quality (n = 38, 44.7%), and nearly 20% were low quality (n = 16, 18.8%). Only 16 (20.0%) of the single-intervention reviews (and none of the five multi-intervention reviews) were judged as current, complete and high-quality. These included reviews of red blood cell transfusion, hypothermia, management guided by intracranial pressure, pharmacological agents (various) and prehospital intubation. Over three-quarters (n = 167, 78.4%) of the 213 RCTs were included in one or more SR. Of the remainder, 17 (8.0%) RCTs post-dated or were out of scope of existing SRs, and 29 (13.6%) were on interventions that have not been assessed in SRs.ConclusionA substantial number of SRs in acute management of moderate to severe TBI lack currency, completeness and quality. We have identified both potential evidence gaps and also substantial research waste. Novel review methods, such as Living Systematic Reviews, may ameliorate these shortcomings and enhance utility and reliability of the evidence underpinning clinical care.

Background\ud \ud Falls are a major cause of morbidity among older people. A multifaceted podiatry intervention may reduce the risk of falling. This study evaluated such an intervention.\ud \ud Design\ud \ud Pragmatic cohort randomised controlled trial in England and Ireland. 1010 participants were randomised (493 to the Intervention group and 517 to Usual Care) to either: a podiatry intervention, including foot and ankle exercises, foot orthoses and, if required, new footwear, and a falls prevention leaflet or usual podiatry treatment plus a falls prevention leaflet. The primary outcome was the incidence rate of self-reported falls per participant in the 12 months following randomisation. Secondary outcomes included: proportion of fallers and those reporting multiple falls, time to first fall, fear of falling, Frenchay Activities Index, Geriatric Depression Scale, foot pain, health related quality of life, and cost-effectiveness.\ud \ud Results\ud \ud In the primary analysis were 484 (98.2%) intervention and 507 (98.1%) control participants. There was a small, non statistically significant reduction in the incidence rate of falls in the intervention group (adjusted incidence rate ratio 0.88, 95% CI 0.73 to 1.05, p = 0.16). The proportion of participants experiencing a fall was lower (49.7 vs 54.9%, adjusted odds ratio 0.78, 95% CI 0.60 to 1.00, p = 0.05) as was the proportion experiencing two or more falls (27.6% vs 34.6%, adjusted odds ratio 0.69, 95% CI 0.52 to 0.90, p = 0.01). There was an increase (p = 0.02) in foot pain for the intervention group. There were no statistically significant differences in other outcomes. The intervention was more costly but marginally more beneficial in terms of health-related quality of life (mean quality adjusted life year (QALY) difference 0.0129, 95% CI -0.0050 to 0.0314) and had a 65% probability of being cost-effective at a threshold of £30,000 per QALY gained.\ud \ud Conclusion\ud \ud There was a small reduction in falls. The intervention may be cost-effective.\ud \ud Trial Registration\ud \ud ISRCTN ISRCTN68240461

Dipender Gill and Stephen Burgess discuss the accompanying study by James Yarmolinsky and colleagues investigating the associations between genetically-proxied inhibition of antihypertensive drug targets and risk of common cancer subtypes using Mendelian randomization.

We conducted a scoping systematic review with respect to how consumer engagement with interactive advertising is evaluated and if interactive features influence consumer recall, awareness, or comprehension of product claims and risk disclosures for informing regulatory science. MEDLINE, PsycINFO, Business Source Corporate, and SCOPUS were searched for original research published from 1997 through February 2021. Two reviewers independently screened titles/abstracts and full-text articles for inclusion. Outcomes were abstracted into a structured abstraction form. We included 32 studies overall. The types of interactive ads evaluated included website banner and pop up ads, search engine ads, interactive TV ads, advergames, product websites, digital magazine ads, and ads on social network sites. Twenty-three studies reported objective measures of engagement using observational analyses or laboratory-based experiments. In nine studies evaluating the association between different interactivity features and outcomes, the evidence was mixed on whether more interactivity improves or worsens recall and comprehension. Studies vary with respect to populations, designs, ads evaluated, and outcomes assessed.

Mayookha Mitra-Majumdar and Aaron Kesselheim reflect on steps taken to combat reporting bias in clinical trials over the last two decades.

The parasitic trypanosomatids cause lethal and debilitating diseases, the leishmaniases, Chagas disease, and the African trypanosomiases, with major impacts on human and animal health. Sustained research has borne fruit by assisting efforts to reduce the burden of disease and by improving our understanding of fundamental molecular and cell biology. But where has the research primarily been conducted, and which research areas have received the most attention? These questions are addressed below using publication and citation data from the past few decades.

Background Financial incentives and audit/feedback are widely used in primary care to influence clinician behaviour and increase quality of care. While observational data suggest a decline in quality when these interventions are stopped, their removal has not been evaluated in a randomised controlled trial (RCT), to our knowledge. This trial aimed to determine whether chlamydia testing in general practice is sustained when financial incentives and/or audit/feedback are removed. Methods and findings We undertook a 2 × 2 factorial cluster RCT in 60 general practices in 4 Australian states targeting 49,525 patients aged 16–29 years for annual chlamydia testing. Clinics were recruited between July 2014 and September 2015 and were followed for up to 2 years or until 31 December 2016. Clinics were eligible if they were in the intervention group of a previous cluster RCT where general practitioners (GPs) received financial incentives (AU$5–AU$8) for each chlamydia test and quarterly audit/feedback reports of their chlamydia testing rates. Clinics were randomised into 1 of 4 groups: incentives removed but audit/feedback retained (group A), audit/feedback removed but incentives retained (group B), both removed (group C), or both retained (group D). The primary outcome was the annual chlamydia testing rate among 16- to 29-year-old patients, where the numerator was the number who had at least 1 chlamydia test within 12 months and the denominator was the number who had at least 1 consultation during the same 12 months. We undertook a factorial analysis in which we investigated the effects of removal versus retention of incentives (groups A + C versus groups B + D) and the effects of removal versus retention of audit/feedback (group B + C versus groups A + D) separately. Of 60 clinics, 59 were randomised and 55 (91.7%) provided data (group A: 15 clinics, 11,196 patients; group B: 14, 11,944; group C: 13, 11,566; group D: 13, 14,819). Annual testing decreased from 20.2% to 11.7% (difference −8.8%; 95% CI −10.5% to −7.0%) in clinics with incentives removed and decreased from 20.6% to 14.3% (difference −7.1%; 95% CI −9.6% to −4.7%) where incentives were retained. The adjusted absolute difference in treatment effect was −0.9% (95% CI −3.5% to 1.7%; p = 0.2267). Annual testing decreased from 21.0% to 11.6% (difference −9.5%; 95% CI −11.7% to −7.4%) in clinics where audit/feedback was removed and decreased from 19.9% to 14.5% (difference −6.4%; 95% CI −8.6% to −4.2%) where audit/feedback was retained. The adjusted absolute difference in treatment effect was −2.6% (95% CI −5.4% to −0.1%; p = 0.0336). Study limitations included an unexpected reduction in testing across all groups impacting statistical power, loss of 4 clinics after randomisation, and inclusion of rural clinics only. Conclusions Audit/feedback is more effective than financial incentives of AU$5–AU$8 per chlamydia test at sustaining GP chlamydia testing practices over time in Australian general practice. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12614000595617, In a cluster randomized trial, Jane S Hocking and colleagues investigate the impact of removing financial incentives and/or audit and feedback on chlamydia testing in general practice in Australia., Author summary Why was this study done? Financial incentives and audit/feedback are widely used in primary care to influence clinician behaviour and increase quality of care. As healthcare costs continue to increase, governments and funding agencies are reassessing funding models for primary care, with widespread cuts to financial incentives. While observational data suggest a decline in quality when these interventions are stopped, their removal has not been evaluated in a randomised controlled trial (RCT). What did the researchers do and find? We conducted a 2 × 2 factorial cluster RCT in Australian general practices that aimed to determine the impact on chlamydia testing in general practice when incentive payments per activity and/or audit/feedback on activity performance were removed. Clinics were randomised into 1 of 4 groups: incentives removed but audit/feedback retained, audit/feedback removed but incentives retained, both removed, and both retained. The primary outcome was the annual chlamydia testing rate among 16- to 29-year-old patients. We found that removal of incentive payments had little impact on general practice chlamydia testing, but the removal of audit and feedback reduced testing. What do these results mean? Our payments were consistent with other incentives general practitioners (GPs) received at the time, suggesting that in the Australian general practice setting, incentive payments of this amount do not have a substantial impact on influencing GP preventive healthcare activities such as chlamydia testing. The removal of quarterly audit and feedback for GPs had a greater impact on testing rates, reflecting the importance of this strategy in influencing GP preventive healthcare activities. The provision of audit and feedback was costlier than the provision of financial incentives. However, using online video conferencing and fully automating the audit and feedback reports would reduce costs. Our results suggest that, in Australia at least, audit and feedback is more effective than incentive payments of AU$5 to AU$8 per activity at influencing GP behaviour.

Introduction Early rehabilitation is indicated in critically ill adults to counter functional complications. However, the physiological response to rehabilitation is poorly understood. This study aimed to determine the cardiorespiratory response to rehabilitation and to investigate the effect of explanatory variables on physiological changes during rehabilitation and recovery. Methods In a prospectively planned, secondary analysis of a randomised controlled trial conducted in a tertiary, mixed intensive care unit (ICU), we analysed the 716 physiotherapy-led, pragmatic rehabilitation sessions (including exercise, cycling and mobilisation). Participants were previously functionally independent, mechanically ventilated, critically ill adults (n = 108). Physiological data (2-minute medians) were collected with standard ICU monitoring and indirect calorimetry, and their medians calculated for baseline (30min before), training (during physiotherapy) and recovery (15min after). We visualised physiological trajectories and investigated explanatory variables on their estimated effect with mixed-effects models. Results This study found a large range of variation within and across participants’ sessions with clinically relevant variations (>10%) occurring in more than 1 out of 4 sessions in mean arterial pressure, minute ventilation (MV) and oxygen consumption (VO2), although early rehabilitation did not generally affect physiological values from baseline to training or recovery. Active patient participation increased MV (mean difference 0.7l/min [0.4–1.0, p2 (23ml/min [95%CI: 13–34, p Conclusions A large range of variation during rehabilitation and recovery mirrors the heterogenous interventions and patient reactions. This warrants close monitoring and individual tailoring, whereby the best option to stimulate a cardiorespiratory response seems to be active patient participation, shorter session durations and mobilisation. Trial registration German Clinical Trials Register (DRKS) identification number: DRKS00004347, registered on 10 September 2012.

BackgroundThe prevailing view is that ablation does not reduce the incidence of stroke and deaths in atrial fibrillation (AF), and guidelines suggest that long-term anticoagulation is required after ablation, regardless of the success of the procedure. We performed a meta-analysis of recent randomized, controlled trials (RCTs) to verify whether ablation compared with drugs reduced the incidence of stroke and deaths.MethodsWe systematically searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials databases for RCTs of AF catheter ablation (CA) compared to medical therapy (MT). The risk ratio (RR) and weighted mean difference (WMD) with 95% CIs were calculated using a random-effects model. A trial sequential analysis (TSA) was used to further validate the reliability of the primary outcomes.ResultsSeventeen RCTs were included, comprising 5,258 patients (CA, n = 2760; MT, n = 2498). Compared with medical therapy, CA was associated with a reduction in stroke/transient ischaemic attacks (TIAs) (p = 0.035; RR = 0.61 [95% CI, 0.386 to 0.965]; I2= 0.0%) and deaths (p = 0.004; RR = 0.7 [95% CI, 0.55 to 0.89]; I2= 0.0%). CA was associated with improvement in left ventricular ejection fraction (LVEF) (p = 0.000; WMD = 5.39 [95% CI, 2.45 to 8.32]; I2= 84.4%) and the rate of maintenance of sinus rhythm (SR) (p = 0.000; RR = 3.55 [95% CI, 2.34 to 5.40]; I2= 76.7%).ConclusionsCA for AF had more favourable outcomes in terms of stroke/TIAs, deaths, change in LVEF, and the maintenance of SR at the end of follow-up compared to MT. Besides, the TSA results supported this conclusion.

Background Oxygen (O2) is a mainstay of treatment in acute severe asthma but how it is administered varies widely. The objectives were to examine whether a trial comparing humidified O2 to standard O2 in children is feasible, and specifically to obtain data on recruitment, tolerability and outcome measure stability. Methods Heated humidified, cold humidified and standard O2 treatments were compared for children (2–16 years) with acute severe asthma in a multi-centre, open, parallel, pilot randomised controlled trial (RCT). Multiple outcomes were assessed. Results Of 258 children screened, 66 were randomised (heated humidified O2 n = 25; cold humidified O2 n = 21; standard O2 n = 20). Median (IQR) length of stay (hours) in hospital was 37.9 (29.1), 52 (35.4) and 49.1 (29.7) for standard, heated humidified and cold humidified respectively and time (hours) on O2 was 15.9 (9.4), 13.6 (14.9) and 13.1 (14.9) for the three groups respectively. The mean (standard deviation) time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3), 35.1 (28.2) and 32.7 (20.1). Asthma Severity Score decreased in all three groups similarly, although missing data prevented complete analysis. Humidified O2 was least well tolerated with eight participants discontinuing their randomised treatment early. An important barrier to recruitment was research nurse availability. Conclusion Although, the results of this pilot study should not be extrapolated beyond the study sample and inferential conclusions should not be drawn from the results, this is the first RCT to compare humidified and standard O2 therapy in acute severe asthmatics of any age. These findings and accompanying screening data show that a large RCT of O2 therapy is feasible. However, challenges associated with randomisation and data collection should be addressed in any future trial design.

Introduction By measuring patients’ satisfaction, providers can gain insight into several elements of health care services, including the effectiveness of their care and the level of empathy they exhibit. The aim of this study was to assess patient satisfaction with pharmaceutical services and associated factors in public hospitals located in Northwestern Ethiopia. Methods An institution-based quantitative cross-sectional study was used. The study was carried out in an outpatient pharmacy from January 1–June 30, 2021. Participants were selected by a systematic sampling technique. The IBM SPSS statistical package (version 23) was used to enter and analyze the collected data. The findings were presented using descriptive statistical methods. To find factors linked to satisfaction, binary logistic regression was used. Results The final analysis included a total of 401 samples. More than half of the participants (229, or 55.1%) were female. The overall mean score of satisfaction was 30.6 out of a maximum of 100 scores. By taking this mean score as a cut-off point, 204 (50.9%) of the study participants had satisfaction with the outpatient pharmacists’ service. Participants’ responses scored on the uncomfortable and inconvenient waiting areas [AOR = 0.31; 95%CI, (0.13, 0.49)] were found to be negatively associated with the level of patients’ satisfaction. Also, the unavailability of medications [AOR = 0.12; 95%CI, (0.02, 0.37)] was negatively associated with the respondent satisfaction. Uncomfortable and inconvenient private counseling areas [AOR = 1.37; 95%CI, (0.79, 4.42)] showed a negative association with their satisfaction. Conclusion Patients’ satisfaction levels with pharmacy service were found to be greater than 50%. The socio-demographic characteristics of patients have no association with their level of satisfaction, but their perception of uncomfortable private counseling areas and waiting areas was negatively associated with their satisfaction.

Researchers, policy makers and science communicators have become increasingly been interested in factors that affect public’s trust in science. Recently, one such potentially important driving factor has emerged, the COVID-19 pandemic. Have trust in science and other science-related beliefs changed in Germany from before to during the pandemic? To investigate this, we re-analyzed data from a set of representative surveys conducted in April, May, and November 2020, which were obtained as part of the German survey Science Barometer, and compared it to data from the last annual Science Barometer survey that took place before the pandemic, (in September 2019). Results indicate that German’s trust in science increased substantially after the pandemic began and slightly declined in the months thereafter, still being higher in November 2020 than in September 2019. Moreover, trust was closely related to expectations about how politics should handle the pandemic. We also find that increases of trust were most pronounced among the higher-educated. But as the pandemic unfolded, decreases of trust were more likely among supporters of the populist right-wing party AfD. We discuss the sustainability of these dynamics as well as implications for science communication.

Aim The current research aims to systematically review the rates of adherence reported in randomised controlled clinical trials of acamprosate. It also sought to determine the reliability of the adherence monitoring and measurement methods used in these trials. Methods The protocol for this review was pre-registered (PROSPERO: CRD42021230011). A search of the literature was conducted using OVID MEDLINE, Embase and PsycINFO from database inception to January 2021. Randomised controlled trials with a minimum sample size of 10 per treatment arm that compared the efficacy of acamprosate with placebo or other active medication in adults with a diagnosis of alcohol dependence were included. Data on rates of adherence, methods of measurement and monitoring of adherence was extracted from eligible studies independently in duplicate by two reviewers. A weighted mean adherence rate was calculated. The reliability of adherence monitoring methods was determined by calculating an adherence-assurance score based on the adherence monitoring method used. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Results Fifteen studies met the eligibility criteria involving 4,450 participants (2,480 participants in the placebo arms). A mean adherence rate of 88% (54.2–95.0%) was reported across studies that reported the percentage of medication taken. A mean adherence rate of 84.9% (56.4–91.3%) was reported for trials that reported the percentage of participants taking more than 80% of medication prescribed. There is low confidence in the methods used to monitor adherence with all clinical trials having a low adherence-assurance rating. Risk of bias was judged to be high for all included studies. Conclusions Adherence to acamprosate in clinical trials can be poor with low confidence in the methods used to measure it. Adherence rates therefore might not be accurate, which has implications for determining the efficacy of acamprosate.

Background Peripheral venous cannulation is one of the most common procedures in medicine. It is associated with noticeable pain and apprehension, although in most cases it is performed without any anesthesia due to lack of a painless, cost-effective option, which would provide rapid local anesthesia with subsequent significant reduction in the experienced pain. We conducted an open-label placebo-controlled clinical trial to evaluate the efficacy and safety of a 2% lidocaine injection using the commercially available microneedle device MinronJet600 (NanoPass Technologies Ltd, Israel) to achieve rapid local anesthesia prior to peripheral venous cannulation. Methods One hundred and two subjects were randomly allocated into two groups. In the first group, 100μL of lidocaine hydrochloride (2%) was injected intradermally to subjects using the MicronJet600 device in the left arm (MJ-Lido) and 100μL of saline was injected intradermally using the device in the right arm (MJ-Saline). In the second group, 100μL of lidocaine hydrochloride (2%) was injected using the MicronJet600 device into the left arm (MJ-Lido), with no injection into the right arm of subjects (No pretreatment). In both groups the intradermal injection was performed at the cannulation site prior to insertion of a 18G cannula into a median cubital vein in both arms. As a primary variable, a score of cannulation-induced pain was indicated by subjects using a 100-point visual analog scale immediately after cannulation. As a secondary variable, subjects in Group 2 also indicated their preference to receive the anaesthetic injection with MicronJet600 in the future by using the 5-point Likert scale. Also, as a secondary variable, the duration of skin numbness after lidocaine injection was indicated by performing a superficial pin-prick with a 27G needle at 15, 30 and 45 minutes, at distances of 1, 2 and 3 centimeters from the injection site. Results A significant pain reduction (11.0-fold) was achieved due to the lidocaine injection compared to the cannulation without any pretreatment (p< 0.005). After the lidocaine injection the anesthesia was effective up to 2 centimeters from the injection site and remained for up to 30 minutes. Eighty percent of subjects from the second group preferred cannulation after the lidocaine injection over cannulation without any pretreatment. No significant side effects were identified. Conclusion Intradermal injection of anaesthetic with Micronjet600 was found to be a safe and effective option for providing rapid local anesthesia for peripheral intravenous cannulation. Trial regiatration The clinical trial was registered, before the patient enrollment began, in the Research Registry publicly accessible database (registration identifier: researchregistry4662). Also, the trial was registered in ClinicalTrials.gov (registration identifier: NCT05108714) after its completion.

Background The evidence for rehabilitation interventions poststroke lack sufficient robustness. However, variation in treatment effects across countries have been given little attention. Objective To compare two identically protocolized trials conducted in different western countries in order to identify factors that may have caused variation in secondary trial outcomes. Methods Comparative study based on individual patient data (N = 129) from two randomized controlled trials, conducted in hospitals and rehabilitation facilities in the Netherlands (N = 66) and Australia (N = 63). Patients with stroke and their caregivers were randomly allocated to an 8-week caregiver-mediated exercises intervention (N = 63; 31 Australian and 32 Dutch) or to a control group (N = 66; 32 Australian and 34 Dutch). Patient characteristics, compliance, usual care and process measures were compared across countries. We examined if study setting significantly moderated the trial outcomes: Hospital Anxiety and Depression Scale, Fatigue Severity Scale and General Self-Efficacy Scale, measured at 8- and 12 weeks follow-up. In addition, we explored if factors that were significantly different across countries caused variation in these trial outcomes. Results Most patients suffered an ischemic stroke, were in the subacute phase and participated with their partner. Dutch patients were younger (P = 0.005) and had a lower functional status (P = 0.001). Australian patients were recruited earlier poststroke (PPPP = 0.040) among Dutch controls. No effect modification was observed and trial outcomes did not change after controlling for cross-country differences. Conclusions The present study highlighted important clinical differences across countries whilst using an identical study protocol. The observed differences could result in a different potential for recovery and variation in treatment effects across trials. We argue that we can proceed faster to evaluating interventions within international pragmatic trials.

Background The uptake of Self-Management Support (SMS) among clinicians is suboptimal. To date, few studies have tested knowledge translation (KT) interventions to increase the application of SMS in chiropractic teaching clinics. Study objective Evaluate the feasibility of implementing a KT intervention to promote the use of a SMS strategy among chiropractic interns, their supervisors, and individuals with spine pain compared to controls. Methods Mixed methods pilot clustered-clinical trial. Clusters of 16 Patient Management Teams were allocated to a complex KT intervention (online and workshop training). Primary feasibility outcomes for clinicians, interns and patients were rates of recruitment, retention, and adherence to protocol. A nominal group technique and interviews were used to seek end-users’ views on the implementation process, and generate possible solutions. Results In total, 16 (84%) clinicians, 65 (26%) interns and 42 patients agreed to participate. All clinicians in the intervention group completed all KT intervention components, 23 interns (85%) completed the online training and 14 interns (51.8%) attended the workshop training. All clinicians in the intervention and seven (78%) in the control group completed all outcome measures at baseline and 6-month follow-up, while 15 (55.6%) and 23 (60.5%) interns in the intervention and control groups completed the questionnaires at baseline and 6-month follow-up, respectively. Among patients, 10 (52.6%) and 12 (52.2%) in the intervention and control groups respectively completed the questionnaires at the end of the study. Based on interview findings, solutions to improve the feasibility of conducting a full trial include: making SMS a part of the internship, changing the time of introducing the study to the interns, and having more training on SMS. Conclusion Recruitment and retention of chiropractic interns and patients for a larger implementation trial in a single outpatient teaching clinic may be challenging.

Background Facilitating the childbirth process is a global issue. Many strategies have been developed to cope with labor pain and improve the delivery experience and satisfaction of pregnant women. The results of different types of medical intervention on women’s expectant pain have been varied. Therefore, this systematic review was aimed at summarizing the body of evidence regarding the effects of various non-pharmacological coping strategies for reducing labor pain. Methods The review was conducted according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched the articles published between 1989 and 2020 in six electronic databases: PubMed, MEDLINE, CINAHL, WOS, PsycARTICLES, and Airiti Library, and the reference lists of the Clinical Trial Registry. Twenty studies were identified, with eight eligible studies included in the Bayesian network meta-analysis. Results Eight studies with 713 participants were included in the meta-analysis with nine different non-pharmacological strategies for reducing labor pain. The traditional meta-analysis demonstrated that the non-pharmacological coping strategies were effective in reducing labor pain. Of these interventional strategies, the ranking probabilities analysis of the network meta-analysis suggested that the Bonapace Method may be the most effective strategy in reducing labor pain, followed by acupressure. Conclusions Non-pharmacological coping strategies can reduce labor pain while maintaining an effective and satisfactory delivery experience. This systematic review, by synthesizing the body of evidence, demonstrated that non-pharmacological coping strategies are effective in reducing labor pain. Furthermore, as demonstrated in the network meta-analysis, the Bonapace Method, modulating birth pain by involving the father, is the most effective non-pharmacological intervention for reducing labor pain.

The present study is aimed at enhancing the solubility of rosuvastatin (RST) by designing betacyclodextrin/polyvinypyrrolidone-co-poly (2-acrylamide-2-methylpropane sulphonic acid) crosslinked hydrophilic nanogels in the presence of crosslinker methylene bisacrylamide through free-radical polymerization method. Various formulations were fabricated by blending different amounts of betacyclodextrin, polyvinylpyrrolidone, 2-acrylamide-2-methylpropane sulphonic acid, and methylene bisacrylamide. The developed chemically crosslinked nanogels were characterized by FTIR, SEM, PXRD, TGA, DSC, sol-gel analysis, zeta size, micromeritics properties, drug loading percentage, swelling, solubility, and release studies. The FTIR spectrum depicts the leading peaks of resultant functional groups of blended constituents while a fluffy and porous structure was observed through SEM images. Remarkable reduction in crystallinity of RST in developed nanogels revealed by PXRD. TGA and DSC demonstrate the good thermal stability of nanogels. The size analysis depicts the particle size of the developed nanogels in the range of 178.5 ±3.14 nm. Drug loading percentage, swelling, solubility, and release studies revealed high drug loading, solubilization, swelling, and drug release patterns at 6.8 pH paralleled to 1.2 pH. In vivo experiments on developed nanogels in comparison to marketed brands were examined and better results regarding pharmacokinetic parameters were observed. The compatibility and non-toxicity of fabricated nanogels to biological systems was supported by a toxicity study that was conducted on rabbits. Efficient fabrication, excellent physicochemical properties, improved dissolution, high solubilization, and nontoxic nanogels might be a capable approach for the oral administration of poorly water-soluble drugs.

Funder: nihr oxford biomedical research centre; funder-id: http://dx.doi.org/10.13039/501100013373, Funder: national institute for health research; funder-id: http://dx.doi.org/10.13039/501100000272, OBJECTIVES: The aim was to investigate the impact of a group-based weight management programme on symptoms of depression and anxiety compared with self-help in a randomised controlled trial (RCT). METHOD: People with overweight (Body Mass Index [BMI]���28kg/m2) were randomly allocated self-help (n = 211) or a group-based weight management programme for 12 weeks (n = 528) or 52 weeks (n = 528) between 18/10/2012 and 10/02/2014. Symptoms were assessed using the Hospital Anxiety and Depression Scale, at baseline, 3, 12 and 24 months. Linear regression modelling examined changes in Hospital Anxiety and Depression Scale between trial arms. RESULTS: At 3 months, there was a -0.6 point difference (95% confidence interval [CI], -1.1, -0.1) in depression score and -0.1 difference (95% CI, -0.7, 0.4) in anxiety score between group-based weight management programme and self-help. At subsequent time points there was no consistent evidence of a difference in depression or anxiety scores between trial arms. There was no evidence that depression or anxiety worsened at any time point. CONCLUSIONS: There was no evidence of harm to depression or anxiety symptoms as a result of attending a group-based weight loss programme. There was a transient reduction in symptoms of depression, but not anxiety, compared to self-help. This effect equates to less than 1 point out of 21 on the Hospital Anxiety and Depression Scale and is not clinically significant.

Introduction The objective of this study was to use a prospective error analysis method to examine the process of dispensing medication in community pharmacy settings and identify remedial solutions to avoid potential errors, categorising them as strong, intermediate, or weak based on an established patient safety action hierarchy tool. Method Focus group discussions and non-participant observations were undertaken to develop a Hierarchical Task Analysis (HTA), and subsequent focus group discussions applied the Systematic Human Error Reduction and Prediction Approach (SHERPA) focusing on the task of dispensing medication in community pharmacies. Remedial measures identified through the SHERPA analysis were then categorised as strong, intermediate, or weak based on the Veteran Affairs National Centre for Patient Safety action hierarchy. Non-participant observations were conducted at 3 pharmacies, totalling 12 hours, based in England. Additionally, 7 community pharmacists, with experience ranging from 8 to 38 years, participated in a total of 4 focus groups, each lasting between 57 to 85 minutes, with one focus group discussing the HTA and three applying SHERPA. A HTA was produced consisting of 10 sub-tasks, with further levels of sub-tasks within each of them. Results Overall, 88 potential errors were identified, with a total of 35 remedial solutions proposed to avoid these errors in practice. Sixteen (46%) of these remedial measures were categorised as weak, 14 (40%) as intermediate and 5 (14%) as strong according to the Veteran Affairs National Centre for Patient Safety action hierarchy. Sub-tasks with the most potential errors were identified, which included ‘producing medication labels’ and ‘final checking of medicines’. The most common type of error determined from the SHERPA analysis related to omitting a check during the dispensing process which accounted for 19 potential errors. Discussion This work applies both HTA and SHERPA for the first time to the task of dispensing medication in community pharmacies, detailing the complexity of the task and highlighting potential errors and remedial measures specific to this task. Future research should examine the effectiveness of the proposed remedial solutions to improve patient safety.

The heme oxygenase/biliverdin reductase (HO/BVR) system is involved in heme metabolism. The inducible isoform of HO (HO-1) and BVR both exert cytoprotective effects by enhancing cell stress response. In this context, some xenobiotics, which target HO-1, including herbal products, behave as neuroprotectants in several experimental models of neurodegeneration. Despite this, no drug having either HO-1 or BVR as a main target is currently available.After a description of the brain HO/BVR system, the paper analyzes the main classes of drugs acting on the nervous system, with HO as second-level target, and their neuroprotective potential. Finally, the difficulties that exist for the development of drugs acting on HO/BVR and the possible ways to overcome these hurdles are examined.Although the limited clinical evidence has restricted the translational research on the HO/BVR system, mainly because of the dual nature of its by-products, there has been growing interest in the therapeutic potential of these enzymes. Scientists should boost the translational research on the HO/BVR system which could be supported by the significant evidence provided by preclinical studies.

Background Only one recommendation currently exists for the treatment of Lassa fever (LF), which is ribavirin administered in conjunction with supportive care. This recommendation is primarily based on evidence generated from a single clinical trial that was conducted more than 30 years ago–the methodology and results of which have recently come under scrutiny. The requirement for novel therapeutics and reassessment of ribavirin is therefore urgent. However, a significant amount of work now needs to be undertaken to ensure that future trials for LF can be conducted consistently and reliably to facilitate the efficient generation of evidence. Methodology We convened a consultation group to establish the position of clinicians and researchers on the core components of future trials. A Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV) were developed through the process of a multi-stakeholder consultation that took place using a modified-Delphi methodology. Results A consensus position was achieved for each aspect of the framework, which accounts for the inclusion of pregnant women and children in future LF clinical trials. The framework consists of 8 core criteria, as well as additional considerations for trial protocols. Conclusions This project represents the first step towards delineating the clinical development pathway for new Lassa fever therapeutics, following a period of 40 years without advancement. Future planned projects will bolster the work initiated here to continue the advancement of LF clinical research through a regionally-centred, collaborative methodology, with the aim of delineating a clear pathway through which LF clinical trials can progress efficiently and ensure sustainable investments are made in research capacity at a regional level., Author summary Lassa fever (LF) is an acute viral haemorrhagic fever endemic to West Africa, causing an estimated 500,000 new infections and 10,000 deaths per year. At present, no treatment has been developed to specifically treat LF and only one prospective clinical trial has been conducted to evaluate the current treatment recommendation. Before a new era of LF clinical trials can begin, it is important to develop standardised methods and tools to ensure that trials are conducted in a consistent way and can generate reliable, comparable data. The aim of this project was initiate the first step to improve the comparability of LF studies by developing a standardised Phase III clinical trial methodology for LF therapeutics that could be applied in low-resource settings. Through multi-stakeholder consultation, we established a consensus position of clinicians and researchers on the core components of future Phase III clinical trials: Core Eligibility Criteria (CEC), Core Case Definition (CCD), Core Outcome Set (COS) and Core Data Variables (CDV).

Funder: Public Health England, Funder: Public Health Wales, Funder: Bristol City Council, BACKGROUND: Teachers are at heightened risk of poor mental health and well-being, which is likely to impact on the support they provide to students, and student outcomes. We conducted a cluster randomised controlled trial, to test whether an intervention to improve mental health support and training for high school teachers led to improved mental health and well-being for teachers and students, compared to usual practice. We also conducted a cost evaluation of the intervention. METHODS AND FINDINGS: The intervention comprised (i) Mental Health First Aid training for teachers to support students; (ii) a mental health awareness session; and (iii) a confidential staff peer support service. In total 25 mainstream, non-fee-paying secondary schools stratified by geographical area and free school meal entitlement were randomly allocated to intervention (n = 12) or control group (n = 13) after collection of baseline measures. We analysed data using mixed-effects repeated measures models in the intention-to-treat population, adjusted for stratification variables, sex, and years of experience. The primary outcome was teacher well-being (Warwick-Edinburgh Mental Well-being Scale). Secondary outcomes were teacher depression, absence, and presenteeism, and student well-being, mental health difficulties, attendance, and attainment. Follow-up was at months 12 (T1) and 24 (T2). We collected process data to test the logic model underpinning the intervention, to aid interpretation of the findings. A total of 1,722 teachers were included in the primary analysis. Teacher well-being did not differ between groups at T2 (intervention mean well-being score 47.5, control group mean well-being score 48.4, adjusted mean difference -0.90, 95% CI -2.07 to 0.27, p = 0.130). The only effect on secondary outcomes was higher teacher-reported absence among the intervention group at T2 (intervention group median number of days absent 0, control group median number of days absent 0, ratio of geometric means 1.04, 95% CI 1.00 to 1.09, p = 0.042). Process measures indicated little change in perceived mental health support, quality of relationships, and work-related stress. The average cost of the intervention was ��9,103 per school. The study's main limitations were a lack of blinding of research participants and the self-report nature of the outcome measures. CONCLUSIONS: In this study, we observed no improvements to teacher or student mental health following the intervention, possibly due to a lack of impact on key drivers of poor mental health within the school environment. Future research should focus on structural and cultural changes to the school environment, which may be more effective at improving teacher and student mental health and well-being. TRIAL REGISTRATION: www.isrctn.com ISRCTN95909211.

Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.

Background Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes. Methods A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity. Results Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p2 [95% CI -5.69 to -0.29; p = 0.03]). Intervention also preserved battery longevity by approximately 5 months (+0.38 years [95% CI 0.14 to 0.62; p Conclusions Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients. Trial registration ClinicalTrials.gov identifier: NCT03627585.

Purpose The present study aimed to evaluate the clinical characteristics of exudative age-related macular degeneration (AMD) in Japanese patients over a 10-year period and to compare the past our report. Methods We retrospectively reviewed 1,600 treatment-naïve patients (1,777 eyes) with exudative AMD. The 10 years were divided into 2-year phases I to V. Results Of the 1,600 patients, 720 (45.0%), 733 (45.8%), 98 (6.1%), and 49 (3.1%) were diagnosed with typical AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation, and combined subtypes, respectively. The prevalence of PCV decreased from 54.7% in phase I to 46.0% at phase V. Of the 1,777 eyes, the mean baseline logarithm of the minimum angle of resolution best-corrected visual acuities (BCVAs) in phases I, II, III, IV, and V were 0.70, 0.66, 0.55, 0.50, and 0.48, respectively. Phases III, IV, and V had significantly (P = 0.0012, P Conclusions Although the prevalence of PCV decreased from 54.7% in phase I to 46.0% at phase V, PCV has nevertheless been highly prevalent in Japanese patients with AMD compared with Caucasian patients. The annual better baseline VAs and smaller lesion sizes over time might be related to development of treatment and better concerns about AMD.

The design of efficient combination therapies is a difficult key challenge in the treatment of complex diseases such as cancers. The large heterogeneity of cancers and the large number of available drugs renders exhaustive in vivo or even in vitro investigation of possible treatments impractical. In recent years, sophisticated mechanistic, ordinary differential equation-based pathways models that can predict treatment responses at a molecular level have been developed. However, surprisingly little effort has been put into leveraging these models to find novel therapies. In this paper we use for the first time, to our knowledge, a large-scale state-of-the-art pan-cancer signaling pathway model to identify candidates for novel combination therapies to treat individual cancer cell lines from various tissues (e.g., minimizing proliferation while keeping dosage low to avoid adverse side effects) and populations of heterogeneous cancer cell lines (e.g., minimizing the maximum or average proliferation across the cell lines while keeping dosage low). We also show how our method can be used to optimize the drug combinations used in sequential treatment plans—that is, optimized sequences of potentially different drug combinations—providing additional benefits. In order to solve the treatment optimization problems, we combine the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) algorithm with a significantly more scalable sampling scheme for truncated Gaussian distributions, based on a Hamiltonian Monte-Carlo method. These optimization techniques are independent of the signaling pathway model, and can thus be adapted to find treatment candidates for other complex diseases than cancers as well, as long as a suitable predictive model is available., Author summary Combination therapies are a promising approach to counter complex diseases such as cancers. Two key difficulties in the design of effective cancer combination therapies are the large number of available drugs and the heterogeneity of cancers which render exhaustive laboratory studies impractical. In recent years, sophisticated signaling pathway models that can predict responses to combination treatments at a molecular level have been developed. This motivates the question of how one can leverage mechanistic models to identify candidates for novel combination treatments. In this paper we propose a combination treatment optimization framework which employs a large-scale pan-cancer pathway model. We formulate treatment optimization problems for single cell lines and heterogeneous populations of cancer cells. We further investigate sequential treatment plans and combine an existing evolutionary algorithm with an efficient Hamiltonian Monte-Carlo based sampling scheme. During extensive simulation studies our approach identified combination therapies which are predicted to be more effective than conventional treatments. We hope that one day in silico experiments will be used to identify a small set of promising treatment candidates which can then form a starting point for laboratory studies, allowing for an efficient use of limited resources and accelerated discovery of effective therapies.

Introduction Poverty is a key contributor to delayed diagnosis and limited access to early intervention and rehabilitation for children with cerebral palsy (CP) in rural Bangladesh. 97% of families of children with CP live below the poverty line in Bangladesh. Therefore, in low-and middle-income countries (LMICs), efforts to improve outcomes for children with CP (including health-related quality of life, motor function, communication, and nutritional attainments) should also include measures to improve family economic and social capital. We propose a randomised controlled trial (RCT) to evaluate the effectiveness of an integrated microfinance/livelihood and community-based rehabilitation (IMCBR) program for ultra-poor families of children with CP in rural Bangladesh. Material and methods This will be a cluster RCT comparing three arms: (a) integrated microfinance/livelihood and community-based rehabilitation (IMCBR); (b) community-based rehabilitation (CBR) alone; and (c) care-as-usual (i.e. no intervention). Seven clusters will be recruited within each arm. Each cluster will consist of 10 child-caregiver dyads totalling 21 clusters with 210 dyads. Parents recruited in the IMCBR arm will take part in a microfinance/livelihood program and Parent Training Module (PTM), their children with CP will take part in a Goal Directed Training (GDT) program. The programs will be facilitated by specially trained Community Rehabilitation Officers. The CBR arm includes the same PTM and GDT interventions excluding the microfinance/livelihood program. The care-as-usual arm will be provided with information about early intervention and rehabilitation. The assessors will be blinded to group allocation. The duration of the intervention will be 12 months; outcomes will be measured at baseline, 6 months, 12 months, and 18 months. Conclusion This will be the first RCT of an integrated microfinance/livelihood and CBR program for children with CP in LMIC settings. Evidence from the study could transform approaches to improving wellbeing of children with CP and their ultra-poor families.

Advances in genome-scale metabolic models (GEMs) and computational drug discovery have caused the identification of drug targets at the system-level and inhibitors to combat bacterial infection and drug resistance. Here we report a structural systems pharmacology framework that integrates the GEM and structure-based virtual screening (SBVS) method to identify drugs effective for Escherichia coli infection. The most complete genome-scale metabolic reconstruction integrated with protein structures (GEM-PRO) of E. coli, iML1515_GP, and FDA-approved drugs have been used. FBA was performed to predict drug targets in silico. The 195 essential genes were predicted in the rich medium. The subsystems in which a significant number of these genes are involved are cofactor, lipopolysaccharide (LPS) biosynthesis that are necessary for cell growth. Therefore, some proteins encoded by these genes are responsible for the biosynthesis and transport of LPS which is the first line of defense against threats. So, these proteins can be potential drug targets. The enzymes with experimental structure and cognate ligands were selected as final drug targets for performing the SBVS method. Finally, we have suggested those drugs that have good interaction with the selected proteins as drug repositioning cases. Also, the suggested molecules could be promising lead compounds. This framework may be helpful to fill the gap between genomics and drug discovery. Results show this framework suggests novel antibacterials that can be subjected to experimental testing soon and it can be suitable for other pathogens.

Increasing oncological treatment costs are a major global concern with the risk of entailing two-tiered health care. Among cost determining factors is the price of individual drugs. In recognition of the central role of this factor, we present a comprehensive overview of the development of monthly prices of oncological drugs introduced over the last 15 years in Switzerland. We identified all oncological drugs newly reimbursed by mandatory health insurance in 2005–2019, and searched public repositories for their package prices, indications with approval dates, and treatment regimens for the calculation of (indication-specific) monthly prices. We found 81 products covering 77 different substances (39.5% protein kinase inhibitors, 21.0% monoclonal antibodies). Most indications related to the topography “blood”, followed by “lung and thorax” and “digestive tract”. From 2005–2009 to 2015–2019, the median monthly product price over all distinct indications of all products decreased by 7.56% (CHF 5,699 [interquartile range 4,483–7,321] to CHF 5,268 [4,19–6,967]), whereas it increased by 73.7% for monoclonal antibodies. In December 2019, six products had monthly prices over CHF 10,000, all approved for hematological or dermatological cancers. Our analysis suggests that individual price developments of oncological drugs are presently not the major driver of rising cancer treatment costs. However, rising launch prices of some new, mostly hematological drugs are of concern and require continued monitoring.

Objective To evaluate different hypofractionated radiotherapy (HRT) regimens for newly diagnosed elderly glioblastoma (GBM) patients. Methods We performed a systematic review with network meta-analysis (NMA), including searches on CENTRAL, Medline, EMBASE, CINAHL, clinical trial databases and manual search. Only randomized clinical trials (RCTs) were included. Primary outcomes: overall survival (OS) and adverse events (AE). Secondary outcomes: progression-free-survival (PFS) and quality of life (QoL). We used the Cochrane Risk of Bias (RoB) table for assessing individual studies and CINeMA for evaluating the certainty of the final body of evidence. Results Four RCTs (499 patients) were included. For OS, the estimates from NMA did not provide strong evidence of a difference between the HRTs: 40 Gray (Gy) versus 45 Gy (HR: 0.89; CI 95%: 0.42, 1.91); 34 Gy versus 45 Gy (HR: 0.85; CI 95% 0.43, 1.70); 25 Gy versus 45 Gy (HR: 0.81; CI 95% 0.32, 2.02); 34 Gy versus 40 Gy (HR: 0.95; CI 95% 0.57, 1.61); and 25 Gy versus 34 Gy (HR: 0.95; CI 95% 0.46, 1.97). We performed qualitative synthesis for AE and QoL due to data scarcity and clinical heterogeneity among studies. The four studies reported a similar QoL (assessed by different methods) between arms. One RCT reported grade ≥ 3 AE, with no evidence of a difference between arms. PFS was reported in one study (25 Gy versus 40 Gy), with no evidence of a difference between arms. Conclusion This review found no evidence of a difference between the evaluated HRTs for efficacy and safety.

Background Intervention trials promoting physical activity among older people frequently report low and unrepresentative recruitment. Better understanding of reasons for participation can help improve recruitment. This study explored why participants enrolled in the Coaching for Healthy Ageing (CHAnGE) trial, including how their decision was influenced by recruitment strategies. CHAnGE was a cluster randomised controlled trial testing the effectiveness of a healthy ageing program targeting inactivity and falls. Seventy-two groups of people aged 60+ were recruited from community organisations via informal presentations by the health coaches. Methods We conducted a secondary thematic analysis of interview data from our wider qualitative evaluation in which 32 purposively sampled trial participants took part in semi-structured interviews about their experiences of CHAnGE. Data relating to recruitment and participation were analysed inductively to identify themes, then a coding framework comprising the core constructs from self-determination theory—autonomy, competence and relatedness—was used to explore if and how this theory fit with and helped to explain our data. Results Recruitment presentations promoted the CHAnGE intervention well in terms of addressing value expectations of structured support, different forms of accountability, credibility, achievability and, for some, a potential to enhance social relationships. Participation was motivated by the desire for improved health and decelerated ageing, altruism and curiosity. These factors related strongly to self-determination concepts of autonomy, competence and relatedness, but the intervention’s demonstrated potential to support self-determination needs could be conveyed more effectively. Conclusions Findings suggest that recruitment could have greater reach using: 1. Strengths-based messaging focusing on holistic gains, 2. Participant stories that highlight positive experiences, and 3. Peer support and information sharing to leverage altruism and curiosity. These theory-informed improvements will be used to increase participation in future trials, including people in hard-to-recruit groups. They may also inform other physical activity trials and community programs.

Background Fatigue is considered one of the most common symptoms of multiple sclerosis (MS) and lacks a current standardized treatment. Therefore, the aim of this study was to examine the feasibility and effectiveness of a cognition-targeted exercise versus symptom-targeted exercise for MS fatigue. Methods In this Pilot, parallel-group, randomized controlled trial, sixty participants with multiple sclerosis, were randomly assigned to either a Cognition-Targeted Exercise (CTE) (N = 30, mean age 41) or a Symptom-Targeted Exercise (STE) (N = 30, mean age 42). The participants in the experimental group received eight, 50-minute sessions of weekly Cognitive Behavior Therapy (CBT) in addition to a CTE Program; whereas, participants in the control group received eight, 50-minute sessions of weekly CBT in addition to the standardized physiotherapy program (STE Program). Feasibility was assessed through recruitment rate, participant retention, adherence and safety, in addition to clinical outcome measures, including: (1) Modified Fatigue Impact Scale (MFIS), (2) Work and Social Adjustment Scale (WSAS), (3) Hospital Anxiety and Depression Scale (HADS), and Perceived Stress Scale (PSS). All outcome measures were assessed at baseline (pretreatment), following completion of the eight visit intervention protocol, and at 3-months follow-up. Results The recruitment rate was 60% and 93% of participants completed the entire study. The recruited participants complied with 98% of the required visits. No adverse events were recorded. A Generalized Estimation Equation Model revealed a significant difference over time as an interaction term during the post and follow up visit for all clinical outcome measures (p < .001). Conclusion The addition of CTE to CBT exhibited positive and more lasting influence on MS fatigue outcomes compared to Symptom-Targeted Exercise (STE). Feasibility and efficacy data from this pilot study provide support for a full-scale RCT of CTE as an integral component of Multiple Sclerosis fatigue management.

Objective To systematically review the effects of eccentric training based on biceps femoris fascicle length using ultrasound assessment and extrapolation methods. Design Systematic review and meta-analysis of randomised controlled trials. Data sources CENTRAL, CINAHL Plus with full text, PubMed and OpenGrey databases were searched on 6 July 2021. Eligibility criteria for selecting studies Randomised controlled trials (RCTs) lasting at least four weeks and presenting data about biceps femoris (BF) fascicle length (FL) as an outcome. Method Searching databases, screening studies, performing risk of bias assessments and determining the level of evidence (LoE) for each meta-analysis were applied during the study. PRISMA 2020 statement and Cochrane Handbook for Systematic Reviews of Interventions were used as the guidelines of this systematic review. Results Eight randomised controlled trials included in meta-analyses. Based on the very low and low LoE, eccentric training has small (g = 0.29, 95% CI [-0.26, 0.85]), moderate (g = 0.72, 95% CI [0.17, 1.28]) and large (g = 2.20, 95% CI [0.99, 3.41]) effect sizes (ES) based on manual linear extrapolation (MLE), panoramic ultrasound scanning and trigonometric equation methods, respectively. Similarly, Nordic hamstring exercise (NHE) has small (g = 0.23 [-1.02, 1.47]), small (g = 0.38, 95% CI [-0.50, 1.27]) and large (g = 1.98, 95% CI [0.52, 3.44]) ES based on the MLE, panoramic ultrasound scanning and trigonometric equation methods, respectively. Conclusion ES of eccentric training, including NHE, vary between the MLE, panoramic ultrasound scanning, and equation methods. The relevant scientific community should have a consensus on measurement standards of the BF FL measurements. Further studies can be conducted to compare the effects of eccentric training based on the ultrasound assessment and extrapolation methods.

Background Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear. Methods and findings We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel–Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697). Conclusions Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring., Cini Bhanu and colleagues evaluate the extent to which different drug groups are associated with orthostatic hypertension in this systematic review and meta-analysis., Author summary Why was this study done? Orthostatic hypotension (OH) is a common side effect of drugs. It causes a reduction in blood pressure (BP) on standing, which results in reduced cerebral blood flow that is linked to falls, strokes, cognitive impairment, and increased mortality. Over 250 medications are associated with OH. However, there is conflicting evidence on the extent to which different drug groups are associated with OH as a side effect. To our knowledge, there are no systematic reviews providing an overview of which drugs are associated with OH. What did the researchers do and find? We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing a drug to placebo, including 69 trials comprising 27,079 participants, to address the extent to which specific medications are associated with OH. We found that drugs primarily inhibiting sympathetic activity were associated with significantly increased odds of OH, compared to placebo (beta-blockers, TCAs, antipsychotics, alpha-blockers). Drugs primarily causing vasodilation (CCBs, ACE inhibitors/ARBs, SSRIs, SGLT-2 inhibitors) were associated with smaller differences that were not statistically significant, compared to placebo. What do these findings mean? Drugs prescribed widely for common conditions including lower urinary tract symptoms, mental health conditions, pain, and insomnia are associated with significantly increased risk of OH; alternative prescribing, shorter treatment, and postural BP checks should be considered to manage this risk. The relationship between antihypertensives and antidiabetic drugs and OH is more complex. Drugs targeting multiple parts of the BP reflex pathway causing OH may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from routine postural BP monitoring.

Summary points: Efficient sharing and reuse of data from clinical trials are critical in advancing medical knowledge and developing improved treatments. We believe that the International Committee of Medical Journal Editors (ICMJE) clinical trial data sharing policy is currently inadequate. Although data sharing plans help increase transparency, they do not ensure that data are shared, and they are often inadequately implemented. We believe that the ICMJE should adapt a stronger policy on data sharing that is enforced rigorously in all ICMJE members and affiliated journals. The policy should include a strong evaluation component to ensure that all clinical trial data are shared, their value maximized, and data producers incentivized.

Introduction After stage 3 CKD, the risk of adverse cardiovascular events increased significantly. Therefore, we performed a meta-analysis to investigate the cardiovascular protective effect of SGLT2 inhibitors in patients with stage 3/4 CKD with different baseline kidney function or underlying diseases. Method To identify eligible trials, we systematically searched the Embase, PubMed, Web of Science, and Cochrane library databases from inception to April 15, 2021. The primary cardiovascular outcome was defined as a combination of cardiovascular mortality and hospitalization due to heart failure. Baseline kidney functions (stage 3a CKD: eGFR45-59mL/min per 1.73m2, stage 3b CKD: eGFR30-44mL/min per 1.73m2, stage 4 CKD: eGFR Results In the present study, a total of eleven trials were included that involved a total of 27,823 patients with stage 3/4 CKD. The treatment and control groups contained 14,451 and 13,372 patients, respectively. In individuals with stage 3/4 CKD, SGLT2 inhibitors reduced the risk of primary cardiovascular outcomes by 26% (HR 0.74, [95% CI 0.69–0.80], I2 = 0.00%), by 30% in patients with stage 3a CKD (HR 0.70, [95% CI 0.59–0.84], I2 = 18.70%), by 23% in patients with stage 3b CKD (HR 0.77, [95% CI 0.66–0.90], I2 = 2.12%), and by 29% in patients with stage 4 CKD (HR 0.71, [95% CI 0.53–0.96], I2 = 0.00%). The risk of primary outcomes was reduced by 29% (HR 0.71, [95% CI 0.63–0.80], I2 = 0.00%) in patients with type 2 diabetes, by 28% (HR 0.72, [95% CI 0.56–0.93], I2 = 37.23%) in patients with heart failure with preserved ejection fraction, by 21% (HR 0.79, [95% CI 0.70–0.89], I2 = 0.00%) in patients with heart failure with reduced ejection fraction, and by 25% (HR 0.75, [95% CI 0.64–0.88], I2 = 0.00%) in patients with atherosclerotic cardiovascular disease. Conclusions For stage 3/4 CKD, SGLT2 inhibitors significantly decreased the risk of primary cardiovascular outcomes, and these benefits were consistent throughout the spectrum of different kidney functions, even in stage 4 CKD. There was no evidence of increased adverse outcomes across different baseline clinical complications, such as type 2 diabetes, heart failure, or atherosclerotic cardiovascular disease.

Objective Heart failure (HF) and atrial fibrillation (AF) are often coexisting. They have common risk factors and pathophysiologic mechanisms. Sacubitril/valsartan has shown efficacy and tolerability in patients with HF. Thus, the study was performed to evaluate the impact of sacubitril/valsartan on AF occurrence in patients with HF. Methods The Embase and PubMed were searched from their inception date to June 2021 for all relevant randomized controlled trials (RCTs) evaluating the efficacy of sacubitril/valsartan in HF. The outcome of interest was the AF occurrence during the follow-up. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results Six trials involving a total of 15,512 patients were included (7,750 randomized to sacubitril/valsartan and 7,762 to control). All trials were randomized, double-blind, and active-control. There was no significant difference in the prevention of AF occurrence between the sacubitril/valsartan group and the control group (enalapril or valsartan) in patients with HF (RR 1.07, 95%CI 0.95 to 1.19; I2 4%). Conclusions Sacubitril/valsartan was similar to either enalapril or valsartan in preventing the occurrence of AF in patients with HF.

The Michaelis constant KM describes the affinity of an enzyme for a specific substrate and is a central parameter in studies of enzyme kinetics and cellular physiology. As measurements of KM are often difficult and time-consuming, experimental estimates exist for only a minority of enzyme–substrate combinations even in model organisms. Here, we build and train an organism-independent model that successfully predicts KM values for natural enzyme–substrate combinations using machine and deep learning methods. Predictions are based on a task-specific molecular fingerprint of the substrate, generated using a graph neural network, and on a deep numerical representation of the enzyme’s amino acid sequence. We provide genome-scale KM predictions for 47 model organisms, which can be used to approximately relate metabolite concentrations to cellular physiology and to aid in the parameterization of kinetic models of cellular metabolism., To understand the action of an enzyme, we need to know its affinity for its substrates, quantified by Michaelis constants, but these are difficult to measure experimentally. This study shows that a deep learning model that can predict them from structural features of the enzyme and substrate, providing KM predictions for all enzymes across 47 model organisms.

Background We previously described the association between rare ADAMTS13 single nucleotide variants (SNVs) and deep vein thrombosis (DVT). Moreover, DVT patients with at least one rare ADAMTS13 SNV had a lower ADAMTS13 activity than non-carriers. Aims To confirm ADAMTS13 variants association with DVT and reduced plasma ADAMTS13 activity levels in a larger population. To investigate the role of VWF and F8 variants. Methods ADAMTS13, VWF and F8 were sequenced using next-generation sequencing in 594 Italian DVT patients and 571 controls. Genetic association testing was performed using logistic regression and gene-based tests. The association between rare ADAMTS13 variants and the respective plasmatic activity, available for 365 cases and 292 controls, was determined using linear regression. All analyses were age-, sex- adjusted. Results We identified 48 low-frequency/common and 272 rare variants. Nine low-frequency/common variants had a PADAMTS13 (rs28641026, rs28503257, rs685523, rs3124768, rs3118667, rs739469, rs3124767; all protective) and 2 in VWF (rs1800382 [risk], rs7962217 [protective]). Rare ADAMTS13 variants were significantly associated with DVT using the burden, variable threshold (VT) and UNIQ (PVWF and F8 variants were not associated with DVT. Carriers of rare ADAMTS13 variants had lower ADAMTS13 activity than non-carriers (ß -6.2, 95%CI -11,-1.5). This association was stronger for DVT patients than controls (ß -7.5, 95%CI -13.5,-1.5 vs. ß -2.9, 95%CI -10.4,4.5). Conclusions ADAMTS13 and VWF low-frequency/common variants mainly showed a protective effect, although their association with DVT was not confirmed. DVT patients carrying a rare ADAMTS13 variants had slightly reduced ADAMTS13 activity levels, but a higher DVT risk. Rare VWF and FVIII variants were not associated with DVT suggesting that other mechanisms are responsible for the high VWF and FVIII levels measured in DVT patients.

Esclerosis múltiple; Reacciones adversas; Infecciones respiratorias Esclerosi múltiple; Reaccions adverses; Infeccions respiratòries Multiple sclerosis; Adverse reactions; Respiratory infections Objective To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. Methods An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. Results Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p

In mainland China, there remains a shortage of pediatric drugs. The Chinese government has recently launched policies and incentives to encourage pediatric drug development and clinical trials. However, data on the characteristics or development trends of these trials are limited. In this review, we extracted source data from the Chinese Clinical Trials Registry and Information Transparency Platform and systematically reviewed the pediatric clinical trials conducted in mainland China from 2009 to 2020, a comprehensive process evaluation of the pediatric drug clinical trials development in the past decade, providing data support to policy makers and industry stakeholders. We included 487 pediatric clinical trials. Over the past decade, the number of pediatric trials has increased, especially since 2016. The most common therapeutic areas were infectious diseases (n = 108, 22.2%), agents for preventive purpose (n = 99, 20.3%), and neurological and psychiatric diseases (n = 71, 14.6%). The number of clinical trials involving epilepsy (39, 10.1%), asthma (33, 8.5%), and influenza (24, 6.2%) were the highest. The distribution of leading institutions is unbalanced in mainland China, with most units in East China (34.0%) and few in Southwest China (6.9%). China has made progress in improving the research and development environment of pediatric drugs and increasing pediatric trials. However, a wide gap in pediatric drug development and clinical trials quality exists between China and the developed countries. The pharmaceutical industry in China has faced grim setbacks, including study duplication, lack of innovation, poor research design, and unbalanced resource allocation. Thus, we suggest that the Chinese government should adjust their policies to improve innovation and clinical design capacity, and optimize resource allocation between regions.

Communication of science through online media has become a primary means of disseminating and connecting science with a public audience. However, online media can come in many forms and stories of scientific discovery can be told by many individuals. We tested whether the relationship of a spokesperson to the science story being told (i.e., the narrative perspective) influences how people react and respond to online science media. We created five video stimuli that fell into three treatments: a scientist presenting their own research (male or female), a third-party summarizing research (male or female), and an infographic-like video with no on-screen presenter. Each of these videos presented the same fabricated science story about the discovery of a new ant species (Formicidae). We used Qualtrics to administer and obtain survey responses from 515 participants (~100 per video). Participants were randomly assigned to one of the videos and after viewing the stimulus answered questions assessing their perceptions of the video (trustworthiness and enjoyment), the spokesperson (trustworthiness and competence), scientists in general (competence and warmth), and attitudes towards the research topic and funding. Participants were also asked to recall what they had seen and heard. We determined that when participants watched a video in which a scientist presented their own research, participants perceived the spokesperson as having more expertise than a third-party presenter, and as more trustworthy and having more expertise than the no-spokesperson stimuli. Viewing a scientist presenting their own work also humanized the research, with participants more often including a person in their answer to the recall question. Overall, manipulating the narrative perspective of the source of a single online video communication effort is effective at impacting immediate objective outcomes related to spokesperson perceptions, but whether those objectives can positively influence long-term goals requires more investigation.

Objective To investigate the durability of the first integrase inhibitor-based regimen in a HIV geriatric multicentric prospective cohort and to explore the reasons of regimen discontinuation. Design This is an analysis conducted on the Geriatric Patients Living with HIV/AIDS (GEPPO) cohort, an Italian prospective observational multicentre cohort of people living with HIV with 65 years of age or more. Methods The analysis was performed using R (version 4.0.2). The tests performed were two sided assuming a 5% significance level (Kruskal-Wallis test, Chi-squared test, log-rank test and a Cox Proportional Hazard model). The proportion of participants discontinuing the three regimens was displayed using cumulative curves. Results Among 1531 patients enrolled between 2017 and 2019 in the GEPPO cohort, we included 822 participants in this analysis. At baseline, median age was 69.8, the immunovirological profile good, multimorbidity was present in 42.3% of participants, while 27.4% were on polypharmacy. Overall, 483, 243 and 96 participants received DTG, RAL and EVG/c respectively as first InSTI. At the end of the follow up 6.4%, 21.1% and 22.9% participants discontinued DTG, RAL and EVG/c respectively. Using a log-rank test, EVG showed a significantly lower durability than DTG (p Conclusions The three integrase inhibitors considered showed a good durability and no virological failures in geriatric patients such as those enrolled in the GEPPO cohort when used in a two or three drug regimen.

Background Gestational diabetes mellitus (GDM) in pregnancy leads to a range of perinatal complications. Although several randomized controlled trials (RCT) have tested the effect of non-pharmacological standard GDM care adjuncts on these outcomes, there is no agglomerated statistical evidence on how their occurrence risk varies across interventions and with placebo. Therefore, a systematic review and network meta-analysis (NMA) protocol is proposed here to address this evidence gap. Materials and methods A search for above RCTs published in the English language will transpire in PubMed, Embase, and Scopus databases irrespective of date and geographic boundary. The RCTs must test nutritional supplementation, digital intervention, structured exercise program, educational program, counseling service, or a combination of these prenatally in GDM patients. These should report ≥1 of the following outcomes- cesarean section, pre-eclampsia, polyhydramnios, preterm birth, macrosomia, prolonged labor, gestational hypertension, premature rupture of membranes, congenital anomaly, Apgar scores, birth weight, birth length, gestational age at birth, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal Corpulence Index. The risk of bias assessment of the recruited trials will transpire using the Revised Cochrane risk-of-bias tool. Determination of the comparative effectiveness between interventions will occur by the frequentist method NMA for respective outcomes. The categorical and continuous outcomes effect size will get calculated in risk ratio and weighted or standardized mean difference, respectively. For each NMA model, network maps and league tables will show the connections between interventions and effect sizes with their 95% confidence intervals for each intervention pair compared, respectively. The publication bias assessment will occur using comparison-adjusted funnel plots. Best intervention prediction for NMA models with statistically significant intervention effect will happen by determining the surface under the cumulative ranking curve values. Statistical analysis will ensue using Stata software (v16). The statistical significance estimation will happen at p Trial registration PROSPERO registration no: CRD42021271199; https://clinicaltrials.gov/.

Background Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. Methods Based on prespecified eligibility criteria, we created a cohort of Phase 1/2, Phase 2, Phase 2/3 and Phase 3 SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We excluded trials evaluating behavioural interventions and natural products, which are not regulated by the U.S. Food and Drug Administration (FDA). We evaluated trials on 3 criteria of informativeness: potential redundancy (comparing trial phase, type, patient-participant characteristics, treatment regimen, comparator arms and primary outcome), trials design (according to the recommendations set-out in the May 2020 FDA guidance document on SARS-CoV-2 treatment and prevention trials) and feasibility of patient-participant recruitment (based on timeliness and success of recruitment). Results We included all 500 eligible trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.9% (95% Confidence Interval 23.7–36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. Conclusions Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

A number of prior studies have demonstrated that research participants with limited English proficiency in the United States are routinely excluded from clinical trial participation. Systematic exclusion through study eligibility criteria that require trial participants to be able to speak, read, and/or understand English affects access to clinical trials and scientific generalizability. We sought to establish the frequency with which English language proficiency is required and, conversely, when non-English languages are affirmatively accommodated in US interventional clinical trials for adult populations.We used the advanced search function on ClinicalTrials.gov specifying interventional studies for adults with at least 1 site in the US. In addition, we used these search criteria to find studies with an available posted protocol. A computer program was written to search for evidence of English or Spanish language requirements, or the posted protocol, when available, was manually read for these language requirements. Of the 14,367 clinical trials registered on ClinicalTrials.gov between 1 January 2019 and 1 December 2020 that met baseline search criteria, 18.98% (95% CI 18.34%-19.62%; n = 2,727) required the ability to read, speak, and/or understand English, and 2.71% (95% CI 2.45%-2.98%; n = 390) specifically mentioned accommodation of translation to another language. The remaining trials in this analysis and the following sub-analyses did not mention English language requirements or accommodation of languages other than English. Of 2,585 federally funded clinical trials, 28.86% (95% CI 27.11%-30.61%; n = 746) required English language proficiency and 4.68% (95% CI 3.87%-5.50%; n = 121) specified accommodation of other languages; of the 5,286 industry-funded trials, 5.30% (95% CI 4.69%-5.90%; n = 280) required English and 0.49% (95% CI 0.30%-0.69%; n = 26) accommodated other languages. Trials related to infectious disease were less likely to specify an English requirement than all registered trials (10.07% versus 18.98%; relative risk [RR] = 0.53; 95% CI 0.44-0.64; p0.001). Trials related to COVID-19 were also less likely to specify an English requirement than all registered trials (8.18% versus 18.98%; RR = 0.43; 95% CI 0.33-0.56; p0.001). Trials with a posted protocol (n = 366) were more likely than all registered clinical trials to specify an English requirement (36.89% versus 18.98%; RR = 1.94, 95% CI 1.69-2.23; p0.001). A separate analysis of studies with posted protocols in 4 therapeutic areas (depression, diabetes, breast cancer, and prostate cancer) demonstrated that clinical trials related to depression were the most likely to require English (52.24%; 95% CI 40.28%-64.20%). One limitation of this study is that the computer program only searched for the terms "English" and "Spanish" and may have missed evidence of other language accommodations. Another limitation is that we did not differentiate between requirements to read English, speak English, understand English, and be a native English speaker; we grouped these requirements together in the category of English language requirements.A meaningful percentage of US interventional clinical trials for adults exclude individuals who cannot read, speak, and/or understand English, or are not native English speakers. To advance more inclusive and generalizable research, funders, sponsors, institutions, investigators, institutional review boards, and others should prioritize translating study materials and eliminate language requirements unless justified either scientifically or ethically.

Objective Airway inflammation in asthma involves not only the central airways but extends to peripheral airways. Lung deposition may be key for an appropriate treatment of asthma. We compared the clinical effects of extrafine hydrofluoroalkane (HFA)-beclomethasone-formoterol (BDP-F) versus equipotent doses of nonextrafine combination of an inhaled corticosteroid and a long acting β2-agonist (ICS-LABA) in asthma. Methods We identified eligible studies by a comprehensive literature search of PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Data analysis was performed with the Review Manager 5.3.5 software (Cochrane IMS, 2014). Results A total of 2326 patients with asthma from ten published randomized controlled trials (RCTs) were enrolled for analysis. Change from baseline in morning pre-dose peak expiratory flow (PEF), evening pre-dose PEF and forced expiratory volume in one second (FEV1) were detected no significant differences between extrafine HFA-BDP-F and nonextrafine ICS-LABAs (p = 0.23, p = 0.99 and p = 0.23, respectively). Extrafine HFA-BDP-F did not show any greater benefit in forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75%), the parameter concerning peripheral airways (MD 0.03L/s, p = 0.65; n = 877). There were no substantial differences between interventions in fractional exhaled nitric oxide (FeNO) levels or in its alveolar fraction. The overall analysis showed no significant benefit of extrafine HFA-BDP-F over nonextrafine ICS-LABA in improving Asthma Control Test (ACT) score (p = 0.30) or decreasing the number of puffs of rescue medication use (p = 0.16). Extrafine HFA-BDP-F did not lead to less exacerbations than nonextrafine ICS-LABA (RR 0.61, 95% CI: 0.31 to 1.20; I2 = 0; p = 0.15). Conclusion Enrolled RCTs of extrafine HFA-BDP-F have demonstrated no significant advantages over the equivalent combination of nonextrafine ICS-LABA in improving pulmonary function concerning central airways or peripheral airways, improving asthma symptom control or reducing exacerbation rate.