Impact of tranexamic acid use in total hip replacement patients: A systematic review and meta-analysis.

Purpose: Tranexamic acid (TXA) dose in the context of primary complete hip replacements (THA) is still a hot debate about the best way to administer TXA. The need to select the most efficient and secure TXA dosing regimen, taking into account elements like perioperative bleeding, postoperative complications, and patient outcomes, has been emphasized by numerous studies. Improving clinical procedures and the general efficacy and safety of employing TXA in THA surgeries requires addressing this ongoing debate. Methods: For this systematic review, We looked at the safety and efficacy of administering TXA intravenously (iTXA) and topically (tTXA) during THA. A thorough search turned up ten randomized controlled trials with 1295 individuals. Parameters evaluated included blood loss, Hb level on the day following surgery, transfusion rates, and drainage volume. Results: Strategies had comparable impacts on deep vein thrombosis occurrences and wound complications. iTXA produced considerably less intraoperative blood loss (WMD = -12.687), concealed blood loss (WMD = 14.276), and the greatest hemoglobin drop (WMD = -0.400) when compared to tTXA. Conclusion: Both administration techniques were secure and efficient in primary THA, although iTXA showed superior results in lowering blood loss and Hb decline.

Epidemiological Study in Antiviral Innate Immunity.

This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

The effectiveness of psychotherapies in reducing further suicide attempts: a systematic review with meta-analysis of randomized controlled trials

There is little evidence on the effectiveness of psychotherapeutic interventions in reducing new suicide attempts. This article aims to evaluate the effectiveness of psychotherapeutic interventions in reducing suicide attempts among patients with a history of previous attempts. We selected 17 articles from four databases: PubMed, Cochrane, APA PsycInfo and LILACS, in 2023. Six studies showed statistical differences that favored psychotherapeutic intervention at some point during the follow-up period. These psychotherapies addressed: problem-solving, hope induction, skills training. When comparing psychotherapy with usual care, a meta-analysis revealed an odds ratio of 0.41 (95 % CI, 0.17-0.99, p = .05) in the analysis up to 12 months of follow-up, and an odds ratio of 0.48 (95 % CI, 0.30-0.78, p < .001) after 12 months of follow-up. The results indicate the efficacy of these interventions in reducing additional suicide attempts, but they should be analyzed with caution, given the heterogeneity of the sample, treatments, and comparators. This review supports the development of prevention strategies indicated for patients who have attempted suicide.

Hay poca evidencia sobre la eficacia de las psicoterapias para reducir los nuevos intentos de suicidio. Este artículo tiene como objetivo evaluar la efectividad de las intervenciones psicoterapéuticas en la reducción de los intentos de suicidio entre pacientes con intentos previos. Se seleccionaron 17 artículos de cuatro bases de datos: PubMed, Cochrane, APA PsycInfo y LILACS. Seis estudios mostraron diferencias estadísticas que favorecieron la intervención psicoterapéutica en algún momento durante el período de seguimiento. Estas psicoterapias abordaron: resolución de problemas, inducción de esperanza y entrenamiento de habilidades. Al comparar la psicoterapia con el tratamiento habitual, el metanálisis reveló un odds ratio de 0.41 (IC del 95 %, 0.17 a 0.99, p = .05) en el análisis hasta los 12 meses de seguimiento, y un odds ratio de 0.48 (IC del 95 %, 0.30 a 0.78, p < .001) después de 12 meses de seguimiento. Los resultados apuntan a la eficacia de estas intervenciones para reducir los intentos de suicidio adicionales, pero deben analizarse con cautela, dada la heterogeneidad de la muestra, los tratamientos y los comparadores. Esta revisión apoya el desarrollo de estrategias de prevención indicadas para pacientes que han intentado suicidarse.

The Platform trial In COVID-19 vaccine priming and BOOsting (PICOBOO) booster vaccination substudy protocol.

BACKGROUND: Coronavirus-2019 (COVID-19) vaccination in Australia commenced in February 2021. The first vaccines recommended for use were AZD1222 and BNT162b2, both delivered as a two-dose primary schedule. In the absence of sustained immunity following immunisation, recommendations for booster vaccination have followed. It is likely that periodic boosting will be necessary for at least some Australians, but it is unknown what the optimal booster vaccines and schedules are or for whom vaccination should be recommended. METHODS: The Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, randomised, Bayesian adaptive platform trial evaluating different booster vaccine interventions in immunocompetent children and adults, stratified by their primary vaccination schedule and age. Participants are randomised to receive one of three licensed COVID-19 booster vaccines available for use in Australia. PICOBOO aims to generate evidence about the immunogenicity, reactogenicity, and cross-protection of different booster vaccine strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants/subvariants. The protocol structure specifying PICOBOO is modular and hierarchical. We have previously published the PICOBOO core (master) protocol. Here, we detail the substudy protocol which outlines the study processes which are specific to PICOBOO participants enrolled in the booster vaccination substudy. DISCUSSION: PICOBOO is an adaptive platform trial evaluating different COVID-19 booster vaccination strategies to generate evidence to inform immunisation practice and policy. The modular and flexible protocol structure is intended to enable investigators to respond with agility to new research questions as they arise, such as immunogenicity targeting emergent virus variants, and the immunogenicity and reactogenicity of new vaccines as they become available for use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register ACTRN12622000238774; registered on 10/02/2022. Protocol V8.0_23112023.

Citrus supplementation in subjective cognitive decline: results of a 36-week, randomized, placebo-controlled trial.

BACKGROUND: Developing interventions for older adults with subjective cognitive decline (SCD) has the potential to prevent dementia in this at-risk group. Preclinical models indicate that Citrus-derived phytochemicals could benefit cognition and inflammatory processes, but results from clinical trials are still preliminary. The aim of this study is to determine the effects of long-term supplementation with Citrus peel extract on cognitive performance and inflammation in individuals with SCD. METHODS: Eighty participants were randomly assigned to active treatment (400 mg of Citrus peel extract containing 3.0 mg of naringenin and 0.1 mg of auraptene) or placebo at 1:1 ratio for 36 weeks. The primary endpoint was the change in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score across the 36-week trial period. Other cognitive outcomes included tests and scales evaluating verbal memory, attention, executive and visuospatial functions, and memory concerns. The secondary endpoint was the change of interleukin-8 (IL-8) levels over the 36-week trial period in a subsample of 60 consecutive participants. An Intention-to-treat approach with generalized linear mixed models was used for data analysis. RESULTS: The RBANS total score showed significant improvement in both Citrus peel extract and placebo groups at 36 weeks (p for time < .001, d = 0.36, p time x treatment = .910). Significant time effects were also found in cognitive domains of short- and long-term verbal memory (p < .001) and scales of subjective memory (p < .01), with no significant time x treatment interaction. The largest effect sizes were observed in verbal memory in the placebo group (d = 0.69 in short-term, and d = 0.78 in long-term verbal memory). Increased IL-8 levels were found at 36-week follow-up in both Citrus peel extract and placebo groups (p for time = .010, d = 0.21, p time x treatment = .772). Adverse events were balanced between groups. CONCLUSIONS: In this randomized clinical trial, long-term Citrus peel extract supplementation did not show cognitive benefits over placebo in participants with SCD, possibly due to high placebo response. These findings might have specific implications for designing future nutraceutical trials in individuals experiencing SCD. TRIAL REGISTRATION: The trial has been registered at the United States National Library of Medicine at the National Institutes of Health Registry of Clinical Trials under the code NCT04744922 on February 9th, 2021 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT04744922 ).

Cost-utility analysis of provision of e-cigarette starter kits for smoking cessation in emergency departments: An economic evaluation of a randomized controlled trial.

AIMS: To assess the cost-effectiveness of the Cessation of Smoking Trial in Emergency Department (COSTED) intervention compared with signposting to local stop smoking service (SSS) from the National Health Service (NHS) and personal social services (PSS) perspective. DESIGN, SETTING AND PARTICIPANTS: This was a two-group, multi-centre, pragmatic, individually randomized controlled trial set in six Emergency Departments (EDs) in urban and rural areas in the United Kingdom. Adult (≥ 18 years) daily smokers (at least one cigarette or equivalent per day) but not daily e-cigarette users, with carbon monoxide reading ≥ 8 parts per million, attending the ED (n = 972) were included. The intervention consisted of provision of an e-cigarette starter kit plus brief smoking cessation advice and referral to a local SSS. Control was an information card on how to access local SSS. MEASUREMENTS: Intervention costs included costs of training and delivery. Control costs included costs of printing information cards. Costs of smoking cessation and health-care services were estimated based on quantities reported by participants and unit costs extracted from secondary sources. The effects were measured by quality-adjusted life years (QALYs) derived from EQ-5D-5L. Other outcomes were smoking cessation measures. The primary outcome was incremental cost-effectiveness ratio (ICER), which was calculated by dividing the difference in costs by the difference in QALYs between groups. FINDINGS: The mean intervention costs were £48 [standard error (SE) = £0] per participant and the mean control costs were £0.2 (SE = £0) per participant. Using regression estimates, total costs were £31 [95% confidence interval (CI) = -£341 to £283] higher and 6-month QALYs were 0.004 (95% CI = -0.004 to 0.014) higher in the intervention group than in the control group. The ICER was calculated at £7750 (probability of cost-effective at range £20 000-30 000: 72.2-76.5%). CONCLUSIONS: The UK Cessation of Smoking Trial in Emergency Department (COSTED) intervention (provision of an e-cigarette starter kit plus brief smoking cessation advice) was cost-effective compared with signposting to local stop smoking services under the current recommendations of the maximum acceptable thresholds.

The Efficacy of Two Triple Therapy Regimens and One Quadruple Regimen [Omeprazole, Amoxicillin, Metronidazole with Bismuth] in Eradicating Helicobacter Pylori in Patients with Peptic Ulcer: A Randomized Clinical Trial.

BACKGROUND: Helicobacter pylori [H. pylori] infection is the main cause of most PUD; therefore, the eradication of H. pylori is extremely important in the treatment of PUD. There are several recommended treatment regimens suggested to eradicate this organism. AIM: This study compared the efficacy of three anti-Helicobacter pylori regimens in patients with dyspepsia or peptic ulcer disease [PUD]. OBJECTIVE: The objective of this study was to assess the efficacy of three anti-H Pylori treatments in patients based on C14 urease breath test [C-UBT] results, drug compliance, and adverse effects. METHODS: This randomized, open-label clinical trial included 136 H. Pylori-infected patients without prior treatment. Patients were randomly divided into three groups. The OAC group received 20 mg Omeprazole capsules twice a day, two 500 mg Amoxicillin capsules twice a day, and 500 mg Clarithromycin capsules twice a day for 14 days. The OAL group received 20 mg Omeprazole capsules twice a day, two 500 mg Amoxicillin capsules twice a day, and Levofloxacin 500 mg capsules twice a day for 14 days. The OAMB group received 20 mg Omeprazole capsules twice a day, two 500 mg Amoxicillin capsules twice a day, Metronidazole 500mg three times a day, and Bismuth 240 mg twice a day for 14 days. Evaluation for compliance and drug-related adverse effects were assessed at the end of two weeks. H. Pylori eradication was evaluated eight weeks after treatment using the C-UBT. RESULTS: A total of 136 patients participated in this study, and their groups were matched based on age and sex. The results of the C-UBT test showed that the eradication rate of H. Pylori was 82.2%, 91.3%, and 97.3% for the three-drug OAC, OAMB, and OAL treatment regimens, respectively. Moreover, all the regimens showed high compliance among the patients. Only OAC and OAL showed a significant difference in the H. Pylori eradication rate, and no superiority was found between OAMB and OAL or OAC therapies. CONCLUSION: The regime of OAL achieved a satisfactory rate of H. pylori infection eradication with good tolerance in patients with PUD, without any acute side effects. CLINICAL TRIAL REGISTRATION NUMBER: IRCT201605189014N100.

Trial Waste in Hyaluronic Acid-Related Randomised Controlled Trials.

BACKGROUND: A notable obstacle in applying the findings of hyaluronic acid (HA)-related randomised controlled trials (RCTs) to real-world patient treatment is trial waste (TW). To date, the extent of TW in RCTs for HA is not clear. OBJECTIVES: To analyse the extents of TW within HA-RCTs and identify protective factors against TW. METHODS: In July 2024, we searched the ClinicalTrials database using the 'hyaluronic acid' as keyword. We documented the data available and then explored PubMed and Scopus for the publication status. Reporting adequacy was evaluated using the CONSORT checklist. Design limitations were analysed based on bias risk and whether the article referenced a relevant systematic review. Subsequently, we evaluated extent of TW (unpublished studies, insufficient reporting and design flaws). RESULTS: One hundred and eighty-four RCTs met the inclusion criteria. The analysis of TW excluded 53 RCTs completed after June 2020 that remained unpublished. Among the remaining 131 RCTs, 72 were published, 47 had adequate reporting and 19 had design limitations. Taken together, 96 RCTs (73.3%) exhibited at least one characteristic of TW. Characteristics of these RCTs included early registration (p < 0.001) and the absence of a multi-blind approach (p = 0.007). Registration prior to 2014 (p < 0.001) and the open-label or single-blinding design (p = 0.003) emerged as independent risk factor for TW. CONCLUSION: We delineated the features of 184 HA-related RCTs. 73.3% of the RCTs included in TW analysis exhibited TW. The diverse traits of the different TW indicators identified could serve as valuable insights for conducting future HA-RCTs more rationally and efficiently.

Short-term outcomes of oropharyngeal administration of colostrum in preterm neonates: a double-blind placebo-controlled randomized trial.

Background: The oropharyngeal administration of colostrum (OAC) in neonates has several benefits. Purpose: To investigate the short-term outcomes of OAC in preterm neonates. Methods: We performed this two-arm, double-blind, placebo-controlled randomized trial at a tertiary neonatal center in Iran in 2021-2023. The intervention and control arms received 0.2 mL of their mother's colostrum or distilled water via oropharyngeal administration every 6 h for 3 days starting from birth until 72 h of age. The main study outcomes were neonatal death, the incidence of necrotizing enterocolitis (NEC), sepsis, retinopathy of prematurity (ROP), length of hospital stay, and period to full enteral feeding. A regression analysis was used to adjust for possible confounders. Results: A total of 126 neonates (mean gestational age, 30.05 weeks) were randomized to the intervention and placebo groups (n=63 each) and had a mean ± SD weight of 1247 ± 193 vs 1156 ± 215 g (P=0.013) and 1- and 5-min Apgar scores of 6.35 vs 5.38 (P=0.003) and 7.84 vs 7.13 (P=0.001), respectively. The mortality rate was 12.7% in the intervention group versus 14.3% in the placebo group (P=0.794). The NEC rate was significantly lower in the intervention versus placebo arm (11.1% vs. 28.6%, respectively; P=0.010), as was the clinically suspected sepsis rate (15.9% vs. 39.7%, respectively; P=0.004). The ROP and bronchopulmonary dysplasia rates did not differ significantly between groups after the adjustment for confounders. The mean length of hospital stay was shorter in the intervention group (26.1 vs. 37.32; P=0.023). Moreover, the mean duration of antibiotic therapy and period to full feeding were significantly shorter in the intervention group. Conclusion: OAC could effectively decrease the incidence of complications in preterm infants and facilitate earlier patient discharge.

Comparison of postoperative complications and outcomes following primary versus revision discectomy: A national database analysis.

Background: Lumbar microdiscectomy is a surgical procedure that is frequently used in the treatment of symptomatic lumbar herniation. Differences in outcomes following primary and revision lumbar microdiscectomy have been previously studied, with reports of comparably satisfactory results from the Spine Patient Outcomes Research Trial. In this study, we further investigate these outcomes, including length of stay, bleeding events, and durotomy. We hypothesized that length of stay, incidence of bleeding events, and dural tear would be greater in the revision cohort. Methods: The ACS-National Surgical Quality Improvement Program database was queried for patients undergoing single-level primary and revision lumbar microdiscectomy between 2019 and 2022. Eligibility for inclusion was determined by age >18 years and current procedural terminology codes 63030 and 63042. Patients with preoperative sepsis or cancer were excluded. Length of stay, wound infection, bleeding events requiring transfusion, cerebrospinal fluid leak, dural tear, and neurological injury were compared between the cohorts. Multivariable Poisson regression adjusted for demographics and comorbidities, including age, sex, race, body mass index, diabetes, smoking, and hypertension, was used to determine if revision was predictive of complications. Results: A total of 37,669 patients were included, of whom 3,635 (9.6%) required revision surgery. Patients in the revision cohort were older (54.25 ± 15.7 vs. 50.85 ± 16.0 years, P < 0.001) and had higher proportions of male (59.0% vs. 55.7%, P < 0.001) and non-Hispanic White patients (82.0% vs. 77.4%, P < 0.001). Length of stay (1.11 ± 2.5 vs. 1.58 ± 2.7, P < 0.001) and rates of wound infection (2.1% vs. 1.4%, P = 0.002) and bleeding events requiring transfusion (1.3% vs. 0.7%, P < 0.001) were greater in the revision cohort compared to primary patients. Differences in cerebrospinal fluid leak (0.2% vs. 0.1%, P = 0.116), dural tear complication (0.01% vs. 0.01%, P = 0.092), and neurological injury (0.008% vs. 0.006%, P = 0.691) between the revision and primary cohorts were nonsignificant. Poisson log-linear regression adjusted for demographics and comorbidities demonstrated revision as a significant predictor for length of stay (χ 2 = 462.95, P < 0.001), wound infection (χ 2 = 9.22, P = 0.002), and bleeding events (χ 2 = 9.74, P = 0.002), while it was a nonsignificant predictor of cerebrospinal fluid leak (χ 2 = 2.61, P = 0.106), dural tear (χ 2 = 2.37, P = 0.123), and neurological injury (χ 2 = 0.229, P = 0.632). Conclusion: Revision surgery was a significant predictor of increased length of stay, wound infection, and bleeding events requiring transfusion. Surgeons and patients alike should be aware of increased risk for complications following revision lumbar microdiscectomy compared to primary discectomy.

Examining the Efficacy of Control Groups in Achieving Statistical Control: A Critical Look at Randomized Controlled Trials.

The randomized controlled trial (RCT) is widely esteemed as the gold standard of experimental research methodologies, purportedly due to its rigorous approach to achieving statistical control. By systematically assigning participants to either a control group or an experimental group through randomization, RCTs claim to isolate the effects of the intervention from confounding variables. This methodological rigor is believed to be instrumental in ensuring that observed outcomes can be attributed with a high degree of confidence to the experimental treatment rather than to extraneous factors. Random assignment in RCTs is believed to mitigate selection bias and enhance generalizability. However, they necessitate a large sample size and are often constrained by ethical considerations. The repeated measures design represents a sophisticated alternative that provides nuanced statistical control by allowing each participant to serve as their own control. Repeated measures analyses commonly include the paired t-test, Wilcoxen Signed Rank Test, and the Repeated Measures Analysis of Variance (ANOVA). These approaches are particularly advantageous in mitigating the impact of individual variability, an inherent noise source in many research settings. By employing repeated measures, researchers can achieve heightened precision in estimating treatment effects, as each subject's baseline characteristics and responses to experimental conditions are held constant across the various stages of the study. This nuanced control contrasts with the traditional claim within medical science on the "rigorously controlled" nature of RCTs. While RCTs are celebrated for their methodological robustness and capacity to minimize bias through randomization, their application is not always the most efficient or practical for all research questions. Although significant, the methodological strengths of RCTs may be overshadowed by the inherent limitations of their design, including the inability to "control for" an infinite number of confounding variables, ethical considerations, and the challenge of achieving generalizability across varied real-world contexts. In contrast, the often-underutilized repeated measures design offers a valuable alternative by harnessing within-subject comparisons to enhance statistical sensitivity. This design is particularly effective when longitudinal data is paramount or focuses on assessing dynamic changes over time as the result of treatment. It is imperative, however, to acknowledge that repeated measures designs have challenges. Potential issues such as carryover effects, order effects, and the complexity of statistical analysis necessitate careful consideration and robust methodological strategies to ensure valid interpretations of the data. While RCTs remain the gold standard for their claimed methodological rigor and ability to establish causal relationships with high confidence, repeated measures designs offer a complementarily more progressive approach that enhances precision by controlling for individual differences. Both methodologies hold significant merit within the research landscape, and their application should be thoughtfully considered based on the specific research objectives, practical constraints, and the nature of the phenomena under investigation.

Efficacy and safety of traditional Chinese medicine combined with azithromycin sequential therapy for mycoplasma pneumonia among children: a meta-analysis of randomized controlled trials.

Background: Traditional Chinese medicine (TCM) is used to treat mycoplasma pneumonia (MP) in children with favorable treatment outcome in China. In the present study, we evaluated the clinical efficacy of TCM combined with azithromycin (AZM) for the treatment of MP among children, providing high evidence-based reference for clinical treatment. Method: We retrieved eligible randomized controlled trials (RCTs) from CQVIP, CNKI, WanFang, NSTL, PubMed, Embase, and Embase databases from January 2000 to November 2023. Data extraction and quality assessment of the enrolled studies were independently by two reviewers. Review Manager 5.3 was used for meta-analysis. Result: A total of 51 RCTs involving 5,799 children aged 1-14 enrolled. Meta-analysis demonstrated that TCM combined with AZM improved the cure rate (odds ratio [OR] = 2.34, 95% CI: 2.06 to 2.64) and the effective rate (OR = 5.21, 95% CI: 4.22 to 6.43), shorted the disappearance duration of cough (WMD = -1.62, 95% CI: -1.90 to -1.34), the duration of fever (WMD = -1.62, 95% CI: -1.96 to -1.29), and the disappearance time of lung rales (WMD = -1.15, 95% CI: -1.32 to -0.98), improved CRP levels (WMD = -2.06, 95% CI: -2.57 to -1.55), IL-6 levels (WMD = -1.92,95% CI: -2.51 to -1.34), and TNF-α levels (WMD = -1.59, 95% CI: -2.14 to -1.04), and reduced adverse reactions (OR = 0.37, 95% CI: 0.32 to 0.44). Conclusion: TCM combined with AZM in the treatment of MP among children has favorable clinical efficacy and safety.

Improvement in Patient-reported Symptoms and Satisfaction with Tildrakizumab in a Real-world Study in Patients with Moderate-to-severe Plaque Psoriasis.

Objective: Tildrakizumab, an anti-interleukin-23 p19 monoclonal antibody, is approved for the treatment of adults with moderate-to-severe plaque psoriasis. Limited evidence is available regarding the effects of tildrakizumab on patient-reported symptoms and satisfaction. This report describes the secondary endpoints of patient-reported symptoms and treatment satisfaction over 64 weeks in patients with moderate-to-severe plaque psoriasis treated with tildrakizumab in a Phase IV, real-world study. Methods: In this uncontrolled, open-label study (NCT03718299), patients received tildrakizumab 100 mg at baseline, Week (W)4, and every 12 weeks thereafter to W52, with the final assessment at W64. Patient-reported secondary endpoints included numerical rating scale (NRS) scores for itch, pain, and scaling, and treatment satisfaction measured by 3 rating scales (Treatment Satisfaction Questionnaire for Medication [TSQM], Tildrakizumab Overall Satisfaction, and Patient Happiness with Psoriasis Control instrument) through W64. Results: Of the 55 patients enrolled, 45 were assessed at W64. Mean NRS scores for itch, pain, and scaling all decreased from baseline beginning as early as W4 with maintenance through W64 (P≤0.001). Treatment satisfaction was positive throughout treatment based on all 3 measures. Mean±SD TSQM domain scores increased from 59.5±17.0 at W4 to 79.5±20.1 at W64 for Effectiveness and from 72.7±18.6 to 81.9±20.5 for Global Satisfaction. Limitations: The study is small and lacks a comparator arm. Conclusion: Tildrakizumab treatment improved patient-reported symptoms in patients with moderate-to-severe plaque psoriasis in a real-world setting and was associated with high levels of treatment satisfaction over 64 weeks.

Causal inference in multi-cohort studies using the target trial framework to identify and minimize sources of bias.

Longitudinal cohort studies, which follow a group of individuals over time, provide the opportunity to examine causal effects of complex exposures on long-term health outcomes. Utilizing data from multiple cohorts has the potential to add further benefit by improving precision of estimates through data pooling and by allowing examination of effect heterogeneity through replication of analyses across cohorts. However, the interpretation of findings can be complicated by biases that may be compounded when pooling data, or, contribute to discrepant findings when analyses are replicated. The "target trial" is a powerful tool for guiding causal inference in single-cohort studies. Here we extend this conceptual framework to address the specific challenges that can arise in the multi-cohort setting. By representing a clear definition of the target estimand, the target trial provides a central point of reference against which biases arising in each cohort and from data pooling can be systematically assessed. Consequently, analyses can be designed to reduce these biases and the resulting findings appropriately interpreted in light of potential remaining biases. We use a case study to demonstrate the framework and its potential to strengthen causal inference in multi-cohort studies through improved analysis design and clarity in the interpretation of findings. Special Collection: N/A.

Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US.

INTRODUCTION: Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. METHODS: We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. RESULTS: Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. DISCUSSION: These findings support further studies to assess semaglutide's potential in preventing AD. HIGHLIGHTS: Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

Diacerein reduces inflammasome activation and SARS-CoV-2 virus replication: a proof-of-concept translational study.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection. Methods: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12 h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D). Results: In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1ß secretion caused by SARS-CoV-2 infection in human PBMCs (p < 0.05), and suppressed viral replication when administered either before or after the virus incubation (p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CLpro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PLpro) virus and in the phosphorylation of proteins related cytoskeleton network (p < 0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo (p < 0.05). Conclusion: The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials.

Impact of the VTE-PREDICT calculator on clinicians' decision making in fictional patients with venous thromboembolism: a randomized controlled trial.

Background: After 3 months of anticoagulation for venous thromboembolism (VTE), the decision needs to be made whether to stop anticoagulation or extend treatment indefinitely. The VTE-PREDICT calculator can be used to estimate individual risks of VTE recurrence and bleeding to guide this decision. Objectives: To evaluate the impact of predicted individual risks of recurrence and bleeding on clinicians' decisions on anticoagulation duration and to assess usefulness of the VTE-PREDICT calculator. Methods: A randomized controlled trial and within-subject study was conducted among clinicians treating VTE patients. The clinicians were asked to complete an online survey containing 6 fictional case vignettes. Group A proposed anticoagulant duration for each case without additional information first and subsequently after seeing calculator-predicted risks (within-subject analysis). Group B was directly provided with calculator risks and proposed treatment duration for each case vignette (for comparison with group A results in a randomized controlled trial analysis). Then, group B received questions on usefulness and credibility of the calculator. Results: Forty-five clinicians were assigned to group A and 48 to B. Overall, group A did not propose different anticoagulation durations than group B. However, individual clinicians in group A changed proposed duration in 35% of the cases after seeing the calculator risks. The calculator was considered useful and credible by most clinicians. Conclusion: Overall, use of the VTE-PREDICT calculator did not affect proposed anticoagulation duration. However, individual clinicians frequently changed their proposed duration after using the calculator, especially for patients with high bleeding risk.

A self-help mobile messaging intervention to improve subthreshold depressive symptoms among older adults in a socioeconomically deprived region of Brazil (PRODIGITAL): a pragmatic, two-arm randomised controlled trial.

Background: Subthreshold depression is a risk factor for major depression and is associated with increased morbidity and mortality, especially in older adults. There is emerging evidence that digital interventions, including self-help interventions, may reduce depressive symptoms. We aimed to evaluate the effectiveness of a mobile messaging intervention at reducing subthreshold depressive symptoms among older adults in Brazil. Methods: PRODIGITAL was a single blind, two-arm, individually randomised controlled trial conducted in 46 primary care clinics in the city of Guarulhos, Brazil. Individuals aged 60+ years were contacted by phone following a randomly ordered list for a screening assessment. Those who presented with anhedonia and/or depressed mood (Patient Health Questionnaire (PHQ)-2≥1), and who subsequently scored between 5 and 9 on the PHQ-9 were invited to participate. The intervention arm received the 'Viva Vida' digital self-help intervention consisting of automated multi-media messages sent via WhatsApp. Forty-eight audio and visual messages based on psychoeducation and behavioural activation were automatically delivered over six weeks. The control arm received a single message containing information about depression. The primary outcome was the difference in mean PHQ-9 scores between treatment arms at the three-month follow-up. All primary analyses were performed according to allocated arm with imputed data. The trial is registered with ReBEC, RBR-6c7ghfd. Findings: Participants were recruited between 8 September 2021 and 19 August 2022. Of the 454 participants enrolled, 223 were randomised to the intervention arm, 231 to the control arm. Participants' mean age was 65.3 years (SD 5.0) and 64.0% (n = 292) were female. A total of 385 (84.8%) completed the three-month follow-up assessment; no difference in mean PHQ-9 scores between the treatment arms was observed (adjusted difference: -0.61; 95% CI: -1.75, 0.53; p = 0.29). Interpretation: These results demonstrate that the Viva Vida digital self-help intervention did not help to improve subthreshold depressive symptoms amongst older adults. Further research is needed to understand why this self-help intervention was not effective in this population, and to explore how it might be adapted to achieve this goal. Funding: São Paulo Research Foundation and UK Joint Global Health Trials.