Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is involved in pathophysiologic cascade of a notable number of rheumatic diseases. The development of JAK inhibitors has expanded treatment choices in rheumatoid arthritis (RA) with a sustained class-effect efficacy. Filgotinib is a novel selective inhibitor of JAK1 isoform licensed for use in RA and ulcerative colitis. In this review we aim to present an analysis of filgotinib\'s efficacy and drug-specific safety warnings. Patients with RA with or without concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) (naïve or experienced) and those who have failed biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) were examined in randomised clinical trials. Filgotinib was also tested against placebo, methotrexate, or adalimumab. Long-term extension trials provide insights for up to four years of continuous filgotinib administration. Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with a longitudinal efficacy. In head-to-head comparison with adalimumab, filgotinib 200 mg was non-inferior. Adverse effects alerts are marked by the elevated risk of infectious adverse effects with the exception of herpes zoster infection, which has a low incidence.

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OBJECTIVE: To estimate the difference in serum chloride levels between children receiving 5% Dextrose in Ringer\'s Lactate (RLD5) vs. 5% Dextrose Normal Saline (DNS) and to estimate the incidence of dyselectrolytemia, hyperchloremic metabolic acidosis (HCMA), acute kidney injury (AKI) and all-cause mortality in both groups.
METHODS: A randomised controlled trial was conducted in non-critically ill children aged 6 mo to 14 y, admitted between August 2021 and July 2022, requiring intravenous fluids. A sample size of 140 was estimated and randomised, with controls receiving 5% DNS and the intervention group receiving RLD5. Kidney function tests and blood gas analysis were done at admission, 24 h and 48 h after starting the maintenance IV fluid, and outcomes were analysed at 24 h and 48 h. Data was collected using a pre-designed data collection form that included demographic and clinical profile details, and outcomes were analysed using SPSS Version 20 software.
RESULTS: Seventy-one children per group were enrolled. The mean chloride difference between the two groups at 24 and 48 h were 1.67 (p-value 0.03) and 2.78 (p-value 0.01), respectively. The incidence of AKI at 24 h and 48 h was 1.4% and 2.8% in the RLD5 group and 0% and 1.4% in the DNS group, respectively. At 24 h and 48 h, 2.8% and 2.8% of children had HCMA in the RLD5 group, and 14% and 4.2% had HCMA in the DNS group, respectively. There was no mortality in either group.
CONCLUSIONS: Though clinically insignificant, there was a statistically significant difference in the serum chloride levels between the groups.

Preventing dropout (attrition) from clinical trials is vital for improving study validity. Dropout is particularly important in justice-involved populations as they can be very challenging to engage and recruit in the first instance. This study identifies factors associated with dropout in a double-blind, placebo-controlled randomised control trial of a selective serotonin reuptake inhibitor (SSRI) aimed at reducing reoffending in highly impulsive men with histories of violent offending. Age, education, social support, psychiatric history, and length of previous incarceration were identified as factors that predict attrition. These findings are consistent with previous research examining variables associated with attrition in clinical trials for community and offender populations. We also explored referral source and treatment allocation as attrition predictors. Although neither significantly predicted attrition, we identified that there are discernible differences in the median time to attrition among the referral source subgroups. Understanding factors that predict treatment completion and attrition will allow researchers to identify participants for whom additional provisions may optimise retention and inform development of targeted interventions.

BACKGROUND: The advertisement and adoption of untested orthodontic products is common. This study aimed to provide an update regarding the prevalence of clinical trials in orthodontics evaluating commercially marketed products. Associations between marketed/non-marketed products and study characteristics such as direction of effect, declaration of conflict of interest and industry sponsorship were evaluated. In addition, within the marketed products associations between direction of effect and study characteristics were explored.
METHODS: Electronic searching of a single database (Medline via PubMed) was undertaken to identify Randomized controlled trials (RCTs) published over a 5-year period (1st January 2017 to 31st December 2021). Descriptive statistics and associations between trial characteristics were explored.
RESULTS: 196 RCTs were analysed. RCTs were frequently published in Angle Orthodontist (18.4%), American Journal of Orthodontics and Dentofacial Orthopedics (14.8%) and European Journal of Orthodontics (13.3%). 65.3% (128/196) of trials assessed marketed products after their introduction. The majority of trials assessed interventions to improve treatment efficiency (33.7%). Growth modification appliances were typically analysed in non-marketed compared to marketed products. An association between the type of product (marketed vs non-marketed) and both the declaration of conflict of interest and industry sponsorship was detected. For individual RCTs assessing marketed products either a positive effect (45.3%) or equivalence between interventions or between intervention and untreated control (47.7%) was evident. In 27% of these trials either no conflict of interest or industry funding was not clearly declared. Within the marketed products, no association between the direction of the effect and conflict of interest or funding was detected.
CONCLUSIONS: The analysis of marketed orthodontic products after their introduction is still common practice. To reduce research waste, collaboration prior to the licensing and marketing of orthodontic products between researchers, industry and manufacturers is recommended.

UNASSIGNED: Sex and gender differences in chronic kidney disease (CKD), including epidemiology and response to treatment, remain poorly understood. This study aimed to investigate how women are represented in CKD clinical trials and whether sex- and gender-disaggregated outcomes were reported.
UNASSIGNED: Clinical trials on CKD were identified from ClinicalTrials.gov. Randomised, phase 3/4 trials with ≥100 participants were selected to quantify women\'s representation among participants by computing the participation:prevalence ratio (PPR) and investigating whether sex-disaggregated analyses had been performed.
UNASSIGNED: In total, 192 CKD trials registered on ClinicalTrials.gov and published between 1995 and 2022 were included. Overall, women accounted for 66 875 (45%) of the 147 136 participants. Women\'s participation in clinical trials was lower than their representation in the underlying CKD population globally (55%). The PPR was 0.75 (95% confidence interval 0.72-0.78), with no significant variation irrespective of mean age, CKD stage, dialysis, location, type of intervention or funding agency. A total of 39 (20%) trials reported sex-disaggregated efficacy outcomes and none reported sex-disaggregated safety outcomes.
UNASSIGNED: Women\'s participation in CKD clinical trials was lower than their representation in the underlying CKD population. Sex-disaggregated efficacy and safety outcomes were rarely reported. Improving women\'s enrolment into clinical trials is crucial to enable sex- and gender-disaggregated analysis and thus identify potential differences in treatment response between women and men.

BACKGROUND: Clinical equipoise, also defined as the uncertainty principle, is considered essential when recruiting subjects to a clinical trial. However, equipoise is threatened when clinicians are influenced by their own preferences. Little research has investigated equipoise in the context of trial recruitment.
METHODS: This cross-sectional survey sought clinicians\' views (operationalised as 11 statements relating to treatments offered in a trial of a psychological intervention for young people) about equipoise and individual treatment preferences in the context of moral justification for recruiting young people at risk of self-harm or suicide to a randomised controlled trial (RCT) to evaluate the Youth Culturally Adapted Manual Assisted Psychological Intervention (Y-CMAP) in Pakistan. We compared the views of clinicians involved in Y-CMAP RCT recruitment to those of a sample of clinicians not involved in trial recruitment but treating similar patients, comparing their sociodemographic characteristics and the proportions of those in each group agreeing with each statement.
RESULTS: There was a response rate of 96% (75/78). Findings showed that, during trial recruitment and before the RCT results were known, the majority of all responding clinicians (73.3%) considered Y-CMAP to be an effective treatment for young people at risk of self-harm or suicide. Although there was an acknowledgement of individual preferences for the intervention, there was near consensus (90%) on the need to conduct an RCT for reaching an evidence-based decision. However, there were no significant differences in the proportion of recruiting clinicians reporting a treatment preference for Y-CMAP than non-recruiting clinicians (31 (88.6%) versus 36 (90%), p = 0.566). A significantly higher proportion of non-recruiting clinicians (87.5%) as compared to (48.5%) in the trial (p = 0.000) stated that there may be other treatments that may be equally good for the patients, seemingly undermining a preference for the intervention. Those reporting a treatment preference also acknowledged that there was nothing on which this preference was based, however confident they felt about them, thus accepting clinical equipoise as ethical justification for conducting the RCT. There was a significant group difference in views that treatment overall is better as a result of young patients\' participation in the Y-CMAP trial (p = 0.015) (i.e. more clinicians not involved in the trial agreed with this statement). Similarly, more clinicians not involved in the trial agreed on the perceived availability of other treatment options that were good for young people at risk of self-harm (p < 0.05).
CONCLUSIONS: The paper highlights that clinicians in Pakistan accept the notion of clinical equipoise as an ethical justification for patient participation in RCTs. The need for conducting RCTs to generate evidence base and to reduce bias was considered important by the clinical community.

Sleep disturbances are seen even in individuals on opioid agonist treatment (OAT). Established pharmacotherapy for sleep disturbances such as benzodiazepines have misuse potential and increased mortality risk in patients with OAT. No study has explored the role of trazodone on sleep disturbance in individuals maintained on buprenorphine. We aimed to assess the efficacy of trazodone in improving sleep disturbance among individuals maintained on buprenorphine.
The study was a double-blind, placebo-controlled, parallel, randomised trial. Adult males (18-60 years) stabilised on buprenorphine with Pittsburgh Sleep Quality Index (PSQI) score of above five, without other psychiatric comorbidity were randomised to receive either trazodone (50-150mg per day) or placebo. Sleep-50 questionnaire, Epworth Sleepiness Scale (ESS), Brief Pain Inventory (BPI), Clinical Opiate Withdrawal Scale (COWS), Depression, Anxiety and Stress Scale (DASS)-21, Visual Analogue Scale (VAS) for opioid craving, and PSQI were assessed at baseline and at the end of six weeks.
Fifty-one patients were allocated to trazodone arm and 49 to placebo arm. Side-effects of trazodone were minimal and well-tolerated with comparable discontiuation rates between both groups. Significantly greater proportion of patients on trazodone (82%, mean dose 101.9 mg) had PSQI scores five or less than those on placebo (16%) at the end of six weeks. Sleep improvement was in various components like sleep quality, latency, efficiency, and duration of sleep.
Trazodone is well-tolerated and effective in improving sleep disturbances in individuals with opioid dependence maintained on buprenorphine over a six-week period.

Adequate reporting of limitations is crucial to enable clinicians to accurately interpret the clinical trial findings. This meta-epidemiological study aimed to evaluate whether study limitations are reported in full-text articles of randomized controlled trials (RCTs) published in the leading dental journals. Associations between the trial characteristics and the reporting of limitations were also explored.
RCTs published between 1st January and 31st December in the years 2011, 2016 and 2021 were identified from the 12 high impact factor dental journals (general and specialty). RCT characteristics were extracted, and reporting of limitations was recorded for the selected studies. Descriptive statistics were calculated for trial and limitations related characteristics. Univariable ordinal logistic regression models were fit to explore univariable associations between trial characteristics and reporting of limitations.
Two hundred and sixty-seven trials were included and analyzed. Most RCTs were published in 2021 (40.8%), had authors based in Europe (50.2%), did not have a statistician involved (88.8%) and assessed a procedure/method intervention type (40.5%). The reporting of trial limitations was generally sub-optimal. More recent trials and studies with a published protocol were associated with better reporting of limitations. The type of journal was a significant predictor for limitation reporting.
Within this study, the clear reporting of study limitations in the manuscripts of dental RCTs is sub-optimal and requires improvement.
The reporting of limitations should not be viewed as a weakness of a trial but due diligence, so clinicians can fully interpret the impact of these limitations on both the validity and generalisability of the results.

OBJECTIVE: The aim of this study was to describe the methodological features of the randomized controlled trials (RCTs) cited in American and European clinical practice guidelines (CPGs) for ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS).
RESULTS: Out of 2128 non-duplicated references cited in the 2013 and 2014 American College of Cardiology/American Heart Association and 2017 and 2020 European Society of Cardiology CPGs for STEMI and NSTE-ACS, we extracted data for 407 RCTs (19.1% of total references). The majority were multicenter studies (81.8%), evaluated pharmacological interventions (63.1%), had a 2-arm (82.6%), and superiority (90.4%) design. Most RCTs (60.2%) had an active comparator, and 46.2% were funded by industry. The median observed sample size was 1001 patients (84.2% of RCTs achieved ≥80% of the intended sample size). Most RCTs had a single primary outcome (90.9%), which was a composite in just over half (51.9%). Among the RCTs testing for superiority, 44.0% reported a P-value of ≥0.05 for the primary outcome and 61.9% observed a risk reduction of >15%. The observed treatment effect was lower-than-expected in 67.6% of RCTs, with 34.4% having at least a 20% lower-than-expected treatment effect. The calculated post hoc statistical power was ≥80% for 33.9% of cited RCTs.
CONCLUSIONS: This analysis demonstrates that RCTs cited by CPGs can still have significant methodological issues and limitations, highlighting that a better understanding of the methodological aspects of RCTs is crucial in order to formulate recommendations relevant to clinical practice.