Reporting of Harms in Randomized Controlled Trials Published in Urology Journals: An Updated Analysis.

PURPOSE: Harms are often overlooked, but important, outcomes of randomized controlled trial reporting. Our goal was to determine if harms reporting has improved in high-impact urology journals. MATERIALS AND METHODS: Randomized controlled trials published in The Journal of Urology®, Urology, European Urology, and BJU International in 2012 and 2020 were analyzed. Each randomized controlled trial was evaluated by 2 authors in a masked-duplicate fashion to evaluate for adherence to harms reporting guidelines recommended by the Consolidated Standards of Reporting Trials (CONSORT) group. RESULTS: One hundred and thirty-two published studies met inclusion criteria. Between 2012 and 2020, there was a statistically significant increase in the median number of harms criteria reported between 2012 and 2020 (5.3 vs 7.2; P = .01). Methods criteria demonstrating the greatest improvements included item #3 "which harms were assessed," item #4a "when harm information was collected," and item #4b "methods to attribute harm to intervention." Results sections with the most improvement in reporting include item #6 "reasons for patient withdrawal," item #8a "effect size for harms," and item #8b "stratified serious + minor harms." CONCLUSIONS: Reporting of adverse events in randomized trials published in several top urology journals has demonstrated marked improvement. Studies published in 2020 reported approximately 70% of CONSORT-Harms criteria-an increase of nearly 40% since 2004. While these improvements mark significant change, deficits remain present and should be addressed to provide clinicians with the most complete perspective possible.

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

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

Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

Background: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision, and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. In the previous update of this review, we found moderate-quality evidence that, at 12 months, aflibercept was slightly more effective than ranibizumab and bevacizumab for improving vision in people with DMO, although the difference may have been clinically insignificant (less than 0.1 logarithm of the minimum angle of resolution (logMAR), or five Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or one ETDRS line). Objectives: The objective of this updated review was to compare the effectiveness and safety of the different anti-VEGF drugs in RCTs at longer followup (24 months). Search methods: We searched various electronic databases on 8 July 2022. Selection criteria: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham, or no treatment in people with DMO. Data collection and analysis: We used standard Cochrane methods for pairwise meta-analysis and we augmented this evidence using network meta-analysis (NMA) methods. We used the Stata 'network' meta-analysis package for all analyses. We used the CINeMA (Confidence in Network Meta-Analysis) web application to grade the certainty of the evidence. Main results: We included 23 studies (13 with industry funding) that enrolled 3513 people with DMO (median central retinal thickness (CRT) 460 microns, interquartile range (IQR) 424 to 482) and moderate vision loss (median best-corrected visual acuity (BCVA) 0.48 logMAR, IQR 0.42 to 0.55. One study that investigated ranibizumab versus sham and one study that mainly enrolled people with subclinical DMO and normal BCVA were not suitable for inclusion in the efficacy NMA. Consistent with the previous update of this review, we used ranibizumab as the reference drug for efficacy, and control (including laser, observation, and sham) as the reference for systemic safety. Eight trials provided data on the primary outcome (change in BCVA at 24 months, in logMAR: lower is better). We found no evidence of a difference between the following interventions and ranibizumab alone: aflibercept (mean difference (MD) -0.05 logMAR, 95% confidence interval (CI) -0.12 to 0.02; moderate certainty); bevacizumab (MD -0.01 logMAR, 95% CI -0.13 to 0.10; low certainty), brolucizumab (MD 0.00 logMAR, 95% CI -0.08 to 0.07; low certainty), ranibizumab plus deferred laser (MD 0.00 logMAR, 95% CI -0.11 to 0.10; low certainty), and ranibizumab plus prompt laser (MD 0.03 logMAR, 95% CI -0.04 to 0.09; very low certainty). We also analysed BCVA change at 12 months, finding moderate-certainty evidence of increased efficacy with brolucizumab (MD -0.07 logMAR, 95%CI -0.10 to -0.03 logMAR), faricimab (MD -0.08 logMAR, 95% CI -0.12 to -0.05), and aflibercept (MD -0.07 logMAR, 95 % CI -0.10 to -0.04) compared to ranibizumab alone, but the difference could be clinically insignificant. Compared to ranibizumab alone, NMA of six trials showed no evidence of a difference with aflibercept (moderate certainty), bevacizumab (low certainty), or ranibizumab with prompt (very low certainty) or deferred laser (low certainty) regarding improvement by three or more ETDRS lines at 24 months. There was moderate-certainty evidence of greater CRT reduction at 24 months with brolucizumab (MD -23 microns, 95% CI -65 to -1 9) and aflibercept (MD -26 microns, 95% CI -53 to 0.9) compared to ranibizumab. There was moderate-certainty evidence of lesser CRT reduction with bevacizumab (MD 28 microns, 95% CI 0 to 56), ranibizumab plus deferred laser (MD 63 microns, 95% CI 18 to 109), and ranibizumab plus prompt laser (MD 72 microns, 95% CI 25 to 119) compared with ranibizumab alone. Regarding all-cause mortality at the longest available follow-up (20 trials), we found no evidence of increased risk of death for any drug compared to control, although effects were in the direction of an increase, and clinically relevant increases could not be ruled out. The certainty of this evidence was low for bevacizumab (risk ratio (RR) 2.10, 95% CI 0.75 to 5.88), brolucizumab (RR 2.92, 95% CI 0.68 to 12.58), faricimab (RR 1.91, 95% CI 0.45 to 8.00), ranibizumab (RR 1.26, 95% CI 0.68 to 2.34), and very low for conbercept (RR 0.33, 95% CI 0.01 to 8.81) and aflibercept (RR 1.48, 95% CI 0.79 to 2.77). Estimates for Antiplatelet Trialists Collaboration arterial thromboembolic events at 24 months did not suggest an increase with any drug compared to control, but the NMA was overall incoherent and the evidence was of low or very low certainty. Ocular adverse events were rare and poorly reported and could not be assessed in NMAs. Authors' conclusions: There is limited evidence of the comparative efficacy and safety of anti-VEGF drugs beyond one year of follow-up. We found no clinically important differences in visual outcomes at 24 months in people with DMO, although there were differences in CRT change. We found no evidence that any drug increases all-cause mortality compared to control, but estimates were very imprecise. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated, and the individuals exposed to these drugs may be less healthy than trial participants.

Pregnancy stressors and postpartum symptoms of depression and anxiety: the moderating role of a cognitive-behavioural therapy (CBT) intervention.

Background: Little is known about the association between stressors (especially positive stressors) during pregnancy and postpartum depression and anxiety. Aims: We investigated the association between positive and negative stress events during different stages of pregnancy and postpartum mental health outcomes among low-income pregnant women with symptoms of anxiety in Pakistan and evaluated whether an intervention based on cognitive-behavioural therapy (CBT) had a regulatory effect. Methods: Participants were 621 pregnant Pakistani women with mild anxiety. Using the Pregnancy Experience Scale-Brief Version, six scores were created to assess positive and negative stressors. We performed a multivariate linear regression to examine whether these six scores, measured both at baseline and in the third trimester, were associated with postpartum anxiety and depressive symptoms. The effect of the intervention on this relationship was examined by adding an interaction term to the regression model. Results: Hassles frequency measured in the third trimester was positively associated with depression (B=0.22, 95% confidence interval (CI): 0.09 to 0.36) and anxiety (B=0.19, 95% CI: 0.08to 0.30). At the same timepoint, uplifts intensity was negatively associated with symptoms of depression (B=-0.82, 95% CI: -1.46 to -0.18) and anxiety (B=-0.70, 95% CI: -1.25 to -0.15), whereas hassles intensity was positively related to symptoms of depression (B=1.02, 95% CI: 0.36 to 1.67) and anxiety (B=0.90, 95% CI: 0.34 to 1.47). The intensity ratio of hassles to uplifts reported in the third trimester was positively related to both depression (B=1.40, 95% CI: 0.59 to 2.20) and anxiety (B=1.26, 95% CI: 0.57 to 1.96). The intervention strengthened the overall positive effects of uplifts and the negative effects of hassles. Pregnancy experiences at baseline during early pregnancy to mid-pregnancy were not associated with mental health outcomes. Conclusions: Stressors in the third trimester but not earlier in pregnancy were associated with postpartum symptoms of anxiety and depression. The CBT intervention modified the association between pregnancy stressors and postpartum mental health outcomes. Programmes that promote positive experiences and reduce negative experiences, especially in late pregnancy, may mitigate postpartum mental health consequences. Trial registration number: NCT03880032.

Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial (PRISM-RCT) in Chinese patients with young-onset diabetes: design, methods and baseline characteristics.

INTRODUCTION: We designed and implemented a patient-centered, data-driven, holistic care model with evaluation of its impacts on clinical outcomes in patients with young-onset type 2 diabetes (T2D) for which there is a lack of evidence-based practice guidelines. RESEARCH DESIGN AND METHODS: In this 3-year Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomized Controlled Trial, we evaluate the effects of a multicomponent care model integrating use of information and communication technology (Joint Asia Diabetes Evaluation (JADE) platform), biogenetic markers and patient-reported outcome measures in patients with T2D diagnosed at ≤40 years of age and aged ≤50 years. The JADE-PRISM group received 1 year of specialist-led team-based management using treatment algorithms guided by biogenetic markers (genome-wide single-nucleotide polymorphism arrays, exome-sequencing of 34 monogenic diabetes genes, C-peptide, autoantibodies) to achieve multiple treatment goals (glycated hemoglobin (HbA1c) <6.2%, blood pressure <120/75 mm Hg, low-density lipoprotein-cholesterol <1.2 mmol/L, waist circumference <80 cm (women) or <85 cm (men)) in a diabetes center setting versus usual care (JADE-only). The primary outcome is incidence of all diabetes-related complications. RESULTS: In 2020-2021, 884 patients (56.6% men, median (IQR) diabetes duration: 7 (3-12) years, current/ex-smokers: 32.5%, body mass index: 28.40±5.77 kg/m2, HbA1c: 7.52%±1.66%, insulin-treated: 27.7%) were assigned to JADE-only (n=443) or JADE-PRISM group (n=441). The profiles of the whole group included positive family history (74.7%), general obesity (51.4%), central obesity (79.2%), hypertension (66.7%), dyslipidemia (76.4%), albuminuria (35.4%), estimated glomerular filtration rate <60 mL/min/1.73 m2 (4.0%), retinopathy (13.8%), atherosclerotic cardiovascular disease (5.2%), cancer (3.1%), emotional distress (26%-38%) and suboptimal adherence (54%) with 5-item EuroQol for Quality of Life index of 0.88 (0.87-0.96). Overall, 13.7% attained ≥3 metabolic targets defined in secondary outcomes. In the JADE-PRISM group, 4.5% had pathogenic/likely pathogenic variants of monogenic diabetes genes; 5% had autoantibodies and 8.4% had fasting C-peptide <0.2 nmol/L. Other significant events included low/large birth weight (33.4%), childhood obesity (50.7%), mental illness (10.3%) and previous suicide attempts (3.6%). Among the women, 17.3% had polycystic ovary syndrome, 44.8% required insulin treatment during pregnancy and 17.3% experienced adverse pregnancy outcomes. CONCLUSIONS: Young-onset diabetes is characterized by complex etiologies with comorbidities including mental illness and lifecourse events. TRIAL REGISTRATION NUMBER: NCT04049149.

Virtual reality-based cognitive-behavioural therapy for the treatment of anxiety in patients with acute myocardial infarction: a randomised clinical trial.

Background: The presence of mental health conditions is pervasive in patients who experienced acute myocardial infarction (AMI), significantly disrupting their recovery. Providing timely and easily accessible psychological interventions using virtual reality-based cognitive-behavioural therapy (VR-CBT) could potentially improve both acute and long-term symptoms affecting their mental health. Aims: We aim to examine the effectiveness of VR-CBT on anxiety symptoms in patients with AMI who were admitted to the intensive care unit (ICU) during the acute stage of their illness. Methods: In this single-blind randomised clinical trial, participants with anxiety symptoms who were admitted to the ICU due to AMI were continuously recruited from December 2022 to February 2023. Patients who were Han Chinese aged 18-75 years were randomly assigned (1:1) via block randomisation to either the VR-CBT group to receive VR-CBT in addition to standard mental health support, or the control group to receive standard mental health support only. VR-CBT consisted of four modules and was delivered at the bedside over a 1-week period. Assessments were done at baseline, immediately after treatment and at 3-month follow-up. The intention-to-treat analysis began in June 2023. The primary outcome measure was the changes in anxiety symptoms as assessed by the Hamilton Anxiety Rating Scale (HAM-A). Results: Among 148 randomised participants, 70 were assigned to the VR-CBT group and 78 to the control group. The 1-week VR-CBT intervention plus standard mental health support significantly reduced the anxiety symptoms compared with standard mental health support alone in terms of HAM-A scores at both post intervention (Cohen's d=-1.27 (95% confidence interval (CI): -1.64 to -0.90, p<0.001) and 3-month follow-up (Cohen's d=-0.37 (95% CI: -0.72 to -0.01, p=0.024). Of the 70 participants who received VR-CBT, 62 (88.6%) completed the entire intervention. Cybersickness was the main reported adverse event (n=5). Conclusions: Our results indicate that VR-CBT can significantly reduce post-AMI anxiety at the acute stage of the illness; the improvement was maintained at the 3-month follow-up. Trial registration number: The trial was registered at www.chictr.org.cn with the identifier: ChiCTR2200066435.

Evaluation of the impact of "speak out" and "human libraries" educational methodologies on nursing students' attitudes toward immigration.

Introduction: Measuring and understanding attitudes toward migrants is crucial in Health Sciences professionals. Nursing students, as future professionals in the healthcare system, must be comprehensively trained and prepared from the undergraduate level to effectively face the challenges of caring for health and disease processes in an increasingly globalized world. Our study aims to determine the level of attitudinal change in nursing students for immigrants, based on a training intervention with sessions of coexistence with immigrants in Spain. Methods: Quasi-experimental controlled and non-randomized study, carried out in 2019 in Nursing School La Fe, Valencia (Spain), with 201 participants (74 intervention group, 127 control group). Instrument: Attitudes toward Immigration Instrument (IAHI) questionnaire. Educational techniques of the training intervention: Speak outs and Human Libraries. Descriptive statistical analysis and comparison of results between groups was performed. Results: The participants in the intervention group showed significant changes in attitude modification, both in the total score of the questionnaire and in 4 of the 5 dimensions (pre-post intervention medition). When comparing the differences between the intervention group and the control group, we observed significant differences in 3 of the 5 dimensions: equality principles and policies, positive favorability, and negative favorability. Conclussion: Sessions involving coexistence, discussion, and reflection with immigrants, as educational intervention methods for nursing students (Speak outs and Human Libraries), are useful and effective tools to promote positive attitudinal changes toward immigrants within the healthcar context in nursing students.

Effect of transcranial direct current stimulation on postoperative sleep disturbance in older patients undergoing lower limb major arthroplasty: a prospective, double-blind, pilot, randomised controlled trial.

Background: Postoperative sleep disturbance (PSD) is a common and serious postoperative complication and is associated with poor postoperative outcomes. Aims: This study aimed to investigate the effect of transcranial direct current stimulation (tDCS) on PSD in older patients undergoing lower limb major arthroplasty. Methods: In this prospective, double-blind, pilot, randomised, sham-controlled trial, patients 65 years and over undergoing lower limb major arthroplasty were randomly assigned to receive active tDCS (a-tDCS) or sham tDCS (s-tDCS). The primary outcomes were the objective sleep measures on postoperative nights (N) 1 and N2. Results: 116 inpatients were assessed for eligibility, and a total of 92 patients were enrolled; 47 received a-tDCS and 45 received s-tDCS. tDCS improved PSD by altering the following sleep measures in the a-tDCS and s-tDCS groups; the respective comparisons were as follows: the promotion of rapid eye movement (REM) sleep time on N1 (64.5 (33.5-105.5) vs 19.0 (0.0, 45.0) min, F=20.10, p<0.001) and N2 (75.0 (36.0-120.8) vs 30.0 (1.3-59.3) min, F=12.55, p<0.001); the total sleep time on N1 (506.0 (408.0-561.0) vs 392.0 (243.0-483.5) min, F=14.13, p<0.001) and N2 (488.5 (455.5-548.5) vs 346.0 (286.5-517.5) min, F=7.36, p=0.007); the deep sleep time on N1 (130.0 (103.3-177.0) vs 42.5 (9.8-100.8) min, F=24.4, p<0.001) and N2 (103.5 (46.0-154.8) vs 57.5 (23.3-106.5) min, F=8.4, p=0.004); and the percentages of light sleep and REM sleep on N1 and N2 (p<0.05 for each). The postoperative depression and anxiety scores did not differ significantly between the two groups. No significant adverse events were reported. Conclusion: In older patients undergoing lower limb major arthroplasty, a single session of anodal tDCS over the left dorsolateral prefrontal cortex showed a potentially prophylactic effect in improving postoperative short-term objective sleep measures. However, this benefit was temporary and was not maintained over time.

Outcomes of Mulligan Concept Applications in Obese Individuals with Chronic Mechanical Low Back Pain: A Randomized Controlled Trial.

BACKGROUND: Various treatment modalities have been employed for mechanical low back pain (MLBP), but evidence of their efficacy varies greatly. Objective: This randomized controlled trial aimed to assess the outcomes of Mulligan concept applications, including sustained natural apophyseal glides (SNAGS) and natural apophyseal glides (NAGS), in obese patients with MLBP. METHODS: The study, conducted between January 2021 and June 2022 at a tertiary hospital, involved randomizing patients into two groups. Both groups underwent six sessions of stretching and strengthening exercises every other day. The Mulligan group received additional intervention with SNAG and NAGS techniques. Measurements were made regarding the Visual Analog Scale (VAS) score, Oswestry Disability Index (ODI) score and range of motion (ROM) for the patients' MLBP level. RESULTS: Post-interventions, both groups exhibited positive changes in flexion ROM, extension ROM, right and left rotation ROM, right and left lateral flexion ROM, VAS score, and ODI score compared to pre-intervention (p < 0.001 for both groups and variables). The Mulligan group showed a higher increase in ROM and a more significant decrease in VAS and ODI scores. Conclusions: Mulligan mobilization techniques prove significantly beneficial for enhancing ROM in all directions, reducing pain levels, and alleviating disability in obese individuals with MLBP.

If Art Were a Drug: Implications for Parkinson's Disease.

Parkinson's disease (PD) is a chronic and complex neurodegenerative disorder. Conventional pharmacological or surgical therapies alone are often insufficient at adequately alleviating disability. Moreover, there is an increasing shift toward person-centered care, emphasizing the concept of "living well". In this context, arts-based interventions offer great promise, functioning as platforms for creative expression that could provide novel mechanisms to promote quality of life. Here we present a qualitative review of arts-based interventions for PD, including music, dance, drama, visual arts, and creative writing. For each, we discuss their applications to PD, proposed mechanisms, evidence from prior studies, and upcoming research. We also provide examples of community-based projects. Studies to date have had relatively small sample sizes, but their findings suggest that arts-based interventions have the potential to reduce motor and non-motor symptoms. They may also empower people with PD and thereby address issues of self-esteem, foster personal problem-solving, and augment holistic well-being. However, there is a paucity of research determining optimal dosage and symptom-specific benefits of these therapies. If art were a drug, we would have to perform appropriately powered studies to provide these data before incorporating it into routine patient care. We therefore call for further research with properly designed studies to offer more rigorous and evidence-based support for what we intuitively think is a highly promising approach to support individuals living with PD. Given the possible positive impact on people's lives, arts-based approaches merit further development and, if proven to be effective, systematic inclusion within integrated management plans.

Comparison of the Functional Outcomes of Arthroscopic Anterior Cruciate Ligament Reconstruction through the All-inside and Outside-in Techniques: A Double-Blinded Randomized Controlled Trial.

Objective To compare the functional outcomes of anterior cruciate ligament (ACL) reconstruction with hamstring autograft (HA) through the all-inside (AI) technique with adjustable-loop cortical Endobutton (Smith & Nephew, Watford, Hertfordshire, England) on the sides of the femur and tibia and through the outside-in (OI) technique using an interference screw on the tibial side and a cortical Endobutton on the femoral side. Materials and Methods The present is a double-blinded randomized controlled trial (RCT) of 44 patients undergoing arthroscopic ACL reconstruction from February 2019 to February 2022 in a tertiary care hospital. As per computer-based randomization, the patients were distributed into two groups: the AI and OI groups. Both groups were evaluated for 12 months using the Visual Analog Scale (VAS), the Lysholm Knee Scoring Scale, and part I (pain score) and part II (function score) of the Knee Society Score (KSS). Results On postoperative day 2, the VAS score was significantly higher in the OI group ( p = 0.0001), but insignificant ( p = 0.807) at 6 weeks. At 3, 6, and 12 months of follow-up, the score on the Lysholm Knee Scoring Scale was significantly higher ( p = 0.001) in the AI group. At 6 months, both parts of the KSS showed a significant difference, with the AI group presenting a better outcome ( p = 0.04). However, at 12 months, the AI group presented a better score on part I of the KSS, but no differences were observed regarding part II. Conclusion In a follow-up of 12 months, the patients submitted to the AI technique presented better outcome scores and pain relief than those submitted to the OI technique.

Effectiveness of pharmacogenomics on the response and remission of treatment-resistant depression: a meta-analysis of randomised controlled trials.

Background: Pharmacogenomics (PGx) is a promising tool to realise tailored drug therapy for depression. Aims: To investigate the treatment efficacy of PGx for treatment-resistant depression (TRD) compared with treatment as usual. Methods: A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science and PsycINFO to identify relevant studies published from inception to 15 April 2023. Two-arm randomised controlled trials (RCTs) exploring the efficacy of PGx-guided versus unguided treatment for TRD were included. The risk of bias in the included studies was evaluated using the Cochrane risk of bias assessment tool. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results: Seven RCTs (n=3003) comparing PGx-guided (n=1492) and unguided (n=1511) groups were identified and analysed. PGx-guided treatment was superior to treatment as usual in response (relative risk (RR)=1.31; 95% confidence interval (95% CI): 1.15 to 1.49; p<0.001) and remission (RR=1.40; 95% CI: 1.09 to 1.80; p=0.009) improvements. Effect sizes for acceptability (RR=0.90; 95% CI: 0.80 to 1.02; p=0.100) and side effect burden (RR=0.58; 95% CI: 0.29 to 1.15; p=0.120) between the two groups were not statistically different. The overall quality of evidence was rated from 'very low' (25%) to 'low' (75%) based on the GRADE criteria. Conclusions: PGx-guided treatment has shown a small overall effect in improving the response and remission rates for patients with TRD. However, these results should be interpreted cautiously because of the few included studies and the low quality of evidence. Further high-quality clinical trials are warranted to confirm the findings. PROSPERO registration number: CRD42022340182.

What is an "ongoing" clinical trial? An analysis of different sources revealed heterogeneous definitions of when a clinical trial starts and ends: a meta-research study

ABSTRACT BACKGROUND: Although the concept of an "ongoing study" seems self-explanatory, it is difficult to determine whether a trial is underway. OBJECTIVE: To analyze the definitions of "ongoing clinical trial" across different clinical trial registries, methodological guidelines, and other sources. DESIGN AND SETTING: This meta-research study was conducted at the Universidade Federal de São Paulo (UNIFESP), Brazil. METHODS: We performed a cross-sectional analysis of relevant clinical trial registry databases, methodological guidelines for conducting systematic reviews, and other sources that would define or regulate clinical trials. RESULTS: We identified various heterogeneous definitions used by eligible sources at both the start and end of a clinical trial. The starting criteria used were as follows: when the team is planning the protocol, when permission is given to conduct the study, or when the first participant is enrolled. Some sources used the time at which the last outcome data was collected as a criterion to determine the end of the trial. The International Committee of Medical Journal Editors stated that a study is still "ongoing" during the analysis process. Several sources use a vague definition or present no clear criteria for defining the start or end of a study. CONCLUSION: The concept of "ongoing clinical trials" lacks a transparent and homogeneous definition across relevant sources. A consensus on this concept is important to facilitate the evaluation of available evidence and conduct research synthesis. Further efforts are necessary to determine the best definition for the start and end of a clinical trial.

¿Ensayos clínicos de superioridad, equivalencia o no inferioridad? / ¿Clinical trials of superiority, non-inferiority or equivalence?

La eficacia de una nueva intervención se establece generalmente a través de ensayos clínicos (EC) con asignación aleatoria (AA). Sin embargo, entre otros tantos desafíos metodológicos, el especificar la hipótesis de un EC con AA, sigue siendo un problema complejo de resolver para los investigadores clínicos. En este manuscrito discutimos las características de tres variantes de los EC con AA: EC de superioridad (ECS), EC de no-inferioridad (ECNI), y EC de equivalencia (ECE). Estos tres tipos de EC tienen supuestos diferentes sobre los efectos de una intervención, por lo que plantear hipótesis y definir objetivos requiere conocer algunos supuestos subyacentes a estos EC, incluso hasta elementos relacionados con la estimación del tamaño de muestra para cada cual. El objetivo de este manuscrito fue describir las diferencias metodológicas entre ECS, ECNI y ECE.

Efficacy and effectivity of new interventions are generally established through randomized clinical trials (RCTs). However, among many other methodological challenges, specifying the hypothesis of a RCT remains complex problem for clinical researchers. In this manuscript we discuss the characteristics of three variants of RCTs: superiority RCT (SRCT), non-inferiority RCT (NIRCT), and equivalence RCT (ERCT). These three types of RCT have different assumptions about the effects of an intervention, so setting hypotheses and defining objectives requires knowing some assumptions underlying these RCTs, including elements related to the estimation of the sample size for each one. The aim of this manuscript was to describe methodological differences between SRCT, NIRCT and ERCT.

Fixed and on-demand regimens of acetaminophen in periodontal surgery: randomized clinical trial

Aim: to evaluate the clinical efficacy of an acetaminophen analgesic by comparing its prescription in fixed versus ondemand schedules after periodontal surgery. The hypothesis of the study was that the fixed regimen would be more effective than the on-demand regimen for postoperative analgesics following periodontal surgery. Methods: An open randomized clinical trial was conducted. The 68 patients who needed total flap surgery to restore supracrestal tissue attachment or surgical treatment of periodontitis were randomized". Visual Analogue Scale was used to assess pain. The fixed group (n = 34) received 500 mg of acetaminophen every 4 hours for 2 days. The on-demand group (n = 34) was instructed to use the acetaminophen "as needed," at intervals of no less than 4 hours between doses. Ibuprofen was the rescue medication for both groups. Pain scores and medication use were recorded 2, 6, 12, 24 and 48 hours after the surgical procedure. The study was registered at the Brazilian Registry of Clinical Trials under RBR-7wv259. Results: The two groups did not differ in relation to the frequency or the intensity of pain in a 48-hour period (n=20 in the fixed group, and n=22 in the on-demand group), or even in the intention-to-treat (n=34 in each group). Individuals who experienced moderate to severe pain used rescue medication more frequently in both groups. No adverse events were reported. Conclusion: Both regimens were effective in controlling postoperative pain after periodontal surgery

Low-intensity extracorporeal shockwave therapy in the treatment of erectile dysfunction - a narrative review

ABSTRACT Objectives: To provide an overview of low-intensity extracorporeal shockwave therapy (LIEST) for erectile dysfunction (ED), pointing out which concepts are already consolidated and which paths we still need to advance. Materials and Methods: We performed a narrative review of the literature on the role of shockwave therapies in erectile dysfunction, selecting publications in PUBMED, including only relevant clinical trials, systematic reviews and meta-analyses. Results: We found 11 studies (7 clinical trials, 3 systematic review and 1 meta-analysis) that evaluated the use of LIEST for the treatment of erectile dysfunction. One clinical trial evaluated the applicability in Peyronie's Disease and one other clinical trial evaluated the applicability after radical prostatectomy. Conclusions: The literature presents little scientific evidence but suggests good results with the use of LIEST for ED. Despite a real optimism since it is a treatment modality capable of acting on the pathophysiology of ED, we must remain cautious, until a larger volume of higher quality studies allows us to establish which patient profile, type of energy and application protocol will achieve clinically satisfactory results.

Hidroxicloroquina para Pacientes com COVID-19 não Hospitalizados: Uma Revisão Sistemática e Metanálise de Ensaios Clínicos Randomizados / Hydroxychloroquine for Non-Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Resumo Fundamento: Revisões sistemáticas anteriores não identificaram benefício do uso da hidroxicloroquina ou da cloroquina em pacientes com COVID-19 não hospitalizados. Após a publicação dessas revisões, os resultados do COPE, o maior ensaio clínico randomizado até hoje, tornaram-se disponíveis. Objetivos: Conduzir uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) para sintetizar as evidências sobre a eficácia e a segurança da hidroxicloroquina e da cloroquina em pacientes com COVID-19 não hospitalizados em comparação a controle ou tratamento padrão. Métodos: As buscas foram conduzidas nos bancos de dados PubMed, Embase, The Cochrane Library e ClinicalTrials.gov, e complementadas por busca manual. Foram realizadas metanálises diretas e avaliações de risco de viés e certeza da evidência, incluindo análise do tamanho ótimo da informação (OIS, optimal information size). Um nível de significância de 0,05 foi adotado na metanálise. PROSPERO: CRD42021265427. Resultados: Oito ECRs com 3219 participantes foram incluídos. As taxas de internação por COVID-19 e de eventos adversos não foram significativamente diferentes entre hidroxicloroquina (5,6% e 5,1%) e controle (7,4% e 20,4%) [risco relativo (RR) 0,77, intervalo de confiança 95% (IC95%), 0,57-1,04, I2: 0%; RR 1,78, IC95% 0,90; 3,52, I2: 93%, respectivamente)]. O OIS (7880) não foi alcançado para hospitalização por COVID-19, independentemente da simulação para a taxa de evento e redução do RR estimados. Conclusão: A evidência de muito baixa qualidade indicou falta de benefício com hidroxicloroquina em prevenir internações por COVID-19. Apesar de ser a revisão sistemática com o maior número de participantes incluídos, o OIS, considerando a resposta à infecção anterior à vacinação, não foi atingido.

Abstract Background: Previous systematic reviews have identified no benefit of hydroxychloroquine and chloroquine in non-hospitalized COVID-19 patients. After publication of these reviews, the results of COPE, the largest randomized trial conducted to date, became available. Objectives: To conduct a systematic review and meta-analyses of randomized clinical trials (RCTs) to synthesize the evidence on the efficacy and safety of hydroxychloroquine and chloroquine for non-hospitalized COVID-19 patients compared to placebo or standard of care. Methods: Searches were conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov complemented by manual search. Pairwise meta-analyses, risk of bias, and evidence certainty assessments were conducted, including optimal information size analysis (OIS). A level of significance of 0.05 was adopted in the meta-analysis. PROSPERO: CRD42021265427. Results: Eight RCTs with 3,219 participants were included. COVID-19 hospitalization and any adverse events rates were not significantly different between hydroxychloroquine (5.6% and 35.1%) and control (7.4% and 20.4%) (risk ratio, RR, 0.77, 95% confidence interval, CI, 0.57-1.04, I2: 0%; RR 1.78, 95%-CI 0.90; 3.52, I2: 93%, respectively). The OIS (7,880) was not reached for COVID-19 hospitalization, independently of the simulation for anticipated event rate and RR reduction estimate. Conclusion: Evidence of very low certainty showed lack of benefit with hydroxychloroquine in preventing COVID-19 hospitalizations. Despite being the systematic review with the largest number of participants included, the OIS, considering pre-vaccination response to infection, has not yet been reached.

Evaluation of outcomes in intervention randomized clinical trials - distal radius fractures / Avaliação dos desfechos em ensaios clínicos randomizados de intervenção - fraturas distais do rádio

ABSTRACT Objectives: Describe the frequency and types of outcomes in randomized clinical trials (RCT) of intervention for distal radius fractures, analyze how confusing outcome presentations can lead to misinterpretations, and suggest strategies to improve the reader's understanding of the decision-making process. Methods: A retrospective study was conducted through a systematized search on the PubMed® database in the last 10 years, in which only intervention RCT was included for distal radius fractures, and outcomes were analyzed. Results: Of the primary outcomes analyzed in the 75 selected articles, 46.6% were classified as clinical outcomes, 20% as surrogate, 30.6% as composite, 1.3% as complex scales, and 1.3% as safety outcomes. 34.7% of the articles did not report adverse events. Conclusion: The presentation of outcomes with little clinical relevance represented more than half of the sample (53.4%) - such studies can harm the reader since they confuse the interpretation of scientific evidence; the Core Outcome Measures in Effectiveness Trials (COMET) initiative could help health professionals in understanding and selecting the most appropriate therapeutic interventions for patients. Level of Evidence III; Retrospective comparative study .

RESUMO Objetivos: Descrever a frequência e os tipos de desfechos em ensaios clínicos randomizados (RCT) de intervenção para fraturas distais do rádio, analisar como apresentações confusas de desfechos podem levar a interpretações equivocadas e sugerir estratégias para melhorar a compreensão do leitor sobre o processo de tomada de decisão. Métodos: Foi realizado estudo retrospectivo mediante busca sistematizada na base de dados PubMed® nos últimos 10 anos, na qual foram incluídos apenas RCT de intervenção para fraturas do segmento distal do rádio, cujos desfechos foram analisados. Resultados: Dos desfechos primários analisados nos 75 artigos selecionados, 46,6% foram classificados como desfechos clínicos, 20% como substitutos, 30,6% como compostos, 1,3% como escalas complexas e em 1,3% como desfechos de segurança. 34,7% dos artigos não reportaram eventos adversos. Conclusão: A apresentação de desfechos com pouca relevância clínica representou mais da metade da amostra (53,4%) - tais estudos podem prejudicar o leitor, uma vez que confundem a interpretação das evidências científicas; a iniciativa Core Outcome Measures in Effectiveness Trials (COMET) auxilia os profissionais de saúde na compreensão e seleção das intervenções terapêuticas mais adequadas para os pacientes. Nível de Evidência III; Estudo retrospectivo comparativo .

Group physiotherapy and quality of life in parkinsonism: quasi-experimental study

According to systematic reviews, a short-term treatment of aquatic physiotherapy, mind-body therapies and exergame improve quality of life of people with parkinsonism. But few studies examined the group physiotherapy effects on quality of life of people with parkinsonism. Objective: We aimed to investigate the short-term effects of group physiotherapy protocols on the quality of life of people with Parkinson's disease or secondary parkinsonism. Methods: This is a quasi-experimental study, a controlled, non-randomized, unmasked trial, with consecutive arms for one group and parallel to another, with 15 participants with parkinsonism. They were organized in 3 groups: OG-E1wI (n = 9), observed group treated with group physiotherapy once a week; EG-C (n = 6), in the control phase without treatment, concomitant with OG-E1wI; EG-2wI (n = 6), the same subjects as EG-C, they were treated with group physiotherapy twice a week, in a posterior consecutive phase. The PDQ-39 scale was used to assess Quality of Life. Results: The mean differences between OG-E1wI and EG-C and between EG-2wI and EG-C in the various domains of PDQ-39 were not statistically significant. Conclusion: A group physiotherapy protocols performed once or twice a week may not be enough to improve quality of life for people with parkinsonism. The literature suggests that group physiotherapy protocols performed three to five times a week improve quality of life in a short period

Contexto: Revisões sistemáticas sugerem que fisioterapia aquática, terapias corporais complementares e exergame aumentam a qualidade de vida da pessoa com parkinsonismo em tratamento de curto prazo. Porém, os efeitos da fisioterapia em grupo na qualidade de vida da pessoa com parkinsonismo são pouco estudados. Objetivo: Investigar os efeitos em curto prazo de protocolos de fisioterapia grupal sobre a Qualidade de Vida de pessoas com doença de Parkinson e parkinsonismo secundário. Métodos: Estudo quasi-experimental, ensaio controlado não randomizado, sem mascaramento, com braços consecutivos para um grupo e paralelo para outro, com 15 participantes com parkinsonismo. Os participantes foram organizados em 3 grupos: OG-E1wI (n= 9), intervenção de fisioterapia em grupo uma vez por semana; EG-C (n= 6), em fase controle sem tratamento, concomitante ao OG-E1wI; EG-2wI (n=6), os mesmos sujeitos do EG-C, em fase consecutiva com intervenção de fisioterapia em grupo, duas vezes por semana. A escala PDQ-39 foi utilizada para avaliar a Qualidade de Vida. Resultados: As diferenças médias entre OG-E1wI e EG-C e entre EG-2wI e EG-C nos vários domínios da PDQ-39 não são estatisticamente significativas. Conclusão: Protocolos de fisioterapia em grupo com frequência de uma ou duas vezes por semana podem não ser suficiente para promover ganhos na qualidade de vida de pessoas com parkinsonismo. A literatura sugere que protocolos de fisioterapia em grupo feitos três a cinco vezes por semana obtêm ganho de qualidade de vida em um período de curto prazo

Anti-inflammatory treatment after selective laser trabeculoplasty: a systematic review of the literature and meta-analysis of randomized control trials / Tratamento anti-inflamatório após trabeculoplastia seletiva a laser: revisão sistemática da literatura e meta-análise de ensaios clínicos randomizados controlados

ABSTRACT We assessed the effects of anti-inflammatory treatment after selective laser trabeculoplasty through a systematic search of the MEDLINE, COCHRANE, and ClinicalTrials.gov. The outcome measures were intraocular pressure, anterior chamber inflammation, and discomfort. Evidence synthesis was performed using fixed effects or random-effects model according to the heterogeneity of the included studies. Heterogeneity was assessed using Q-statistic and I2. For an overall estimate of continuous outcomes, the mean differences and their 95% confidence intervals were applied, while odds ratios and their 95% confidence intervals were applied for dichotomous outcomes. Six studies were included in all. No significant difference was noted in the patients for intraocular pressure and discomfort when treated with anti-inflammatory drops. However, the patients showed benefit from reduced anterior chamber inflammation in the first postoperative week [FE OR=0.43, 95% CI=(0.19, 0.95), PQ=0.97, I2=0%], with no significant difference between the outcomes of non-steroidal anti-inflammatory drugs and steroids [FE OR=0.75, 95% CI=(0.20, 2.82), PQ=0.37, I2=0%]. Anti-inflammatory drops reduce anterior chamber inflammation after selective laser trabeculoplasty but showed no effect on the intraocular pressure.

RESUMO O objetivo deste estudo é avaliar os efeitos do tratamento anti-inflamatório após a trabeculoplastia seletiva a laser. Uma busca sistemática foi feita no MEDLINE, COCHRANE e ClinicalTrials.gov. As medidas de resultado foram pressão intraocular, inflamação da câmara anterior e desconforto. A síntese de evidência foi realizada utilizando-se modelo de efeitos fixos ou efeitos aleatórios, de acordo com a heterogeneidade dos estudos incluídos. A heterogeneidade foi avaliada utilizando-se Q-statistic e I². Para uma estimativa global dos resultados contínuos, foram usadas diferenças médias e seus intervalos de confiança de 95% enquanto para resultados dicótomos, usou-se odds ratios e seus intervalos de confiança de 95%. Seis estudos foram incluídos. Nenhuma diferença significativa foi encontrada em pacientes tratados com gotas anti-inflamatórias em termos de pressão intraocular e desconforto. No entanto, eles se beneficiaram da redução da inflamação da câmara anterior na primeira semana pós-operatória [FE OR=0,43, IC 95% = (0,19, 0,95), PQ=0,97, I2=0%], sem diferença significativa entre anti-inflamatórios não esteroidais e esteroidais [FE OR=0,75, IC 95% = (0,20, 2,82), PQ=0,37, I2=0%]. Gotas anti-inflamatórias reduzem a inflamação da câmara anterior após trabeculoplastia seletiva a laser, não afetando a pressão intraocular.