FIRE Stones: impact of forced diuresis on the residual fragment rate after flexible ureteroscopy for destruction of kidney stones with laser-protocol for a randomized controlled two-parallel group multicenter trial with blinding evaluation.

BACKGROUND: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical. OBJECTIVE: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser. METHODS/DESIGN: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist. DISCUSSION: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00.

Single-Center Randomized Trial Comparing Feeding Jejunostomy with Nasojejunal Tube Placement in Patients Undergoing Transhiatal Esophagectomy Post-Neoadjuvant Therapy for Esophageal Cancer.

BACKGROUND: Enteral nutrition is the preferred mode of nutrition following esophagectomy. However, the preferred mode of enteral nutrition (feeding jejunostomy (FJ) vs. nasojejunal (NJ) tube) remains contentious. In this randomized controlled trial (RCT), we compared FJ with NJ tube feeding in terms of safety, feasibility, efficacy, and quality-of-life (QOL) parameters in Indian patients undergoing trans-hiatal esophagectomy (THE) for carcinoma esophagus. MATERIALS AND METHODS: This single-center, two-armed (FJ and NJ tube), non-inferiority RCT was conducted from March 2020 to January 2024. Forty-eight patients underwent THE with posterior-mediastinal-gastric pull-up and were randomized to NJ and FJ arms (24 in each group). The postoperative complications, catheter efficacy, and QOL parameters were compared between the two groups till the 6-week follow-up. RESULTS: In this RCT, we found no significant difference in the occurrence of catheter-related complications, postoperative complication rate, catheter efficacy, and visual analog pain scores between patients with NJ tube and FJ, following THE for esophageal cancer. There was a significantly better self-reported physical domain QOL score noted in the NJ group, both at the time of discharge (44.7 ± 6.2 vs 39.8 + 5.6; p value, 0.005) and at the 6-week follow-up (55.4 ± 5.2 vs 48.6 ± 4.5; p value, < 0.001). CONCLUSION: Based on the findings of our RCT, we conclude that both enteral access methods (NJ vs. FJ) exhibit comparable incidences of catheter-related complications. The use of NJ tube is a viable alternative to a surgical FJ, has the benefit of early removal, and saves the distress associated with a tube per abdomen.

Sample Size Calculation for an Individual Stepped-Wedge Randomized Trial.

In the individual stepped-wedge randomized trial (ISW-RT), subjects are allocated to sequences, each sequence being defined by a control period followed by an experimental period. The total follow-up time is the same for all sequences, but the duration of the control and experimental periods varies among sequences. To our knowledge, there is no validated sample size calculation formula for ISW-RTs unlike stepped-wedge cluster randomized trials (SW-CRTs). The objective of this study was to adapt the formula used for SW-CRTs to the case of individual randomization and to validate this adaptation using a Monte Carlo simulation study. The proposed sample size calculation formula for an ISW-RT design yielded satisfactory empirical power for most scenarios except scenarios with operating characteristic values near the boundary (i.e., smallest possible number of periods, very high or very low autocorrelation coefficient). Overall, the results provide useful insights into the sample size calculation for ISW-RTs.

Effectiveness of the transitional care model in total knee arthroplasty patients: A randomized controlled trial.

AIM: This study has aimed to assess the effectiveness of the transitional care model (TCM) on functional status, perceived self-efficacy and healthcare utilization in patients undergoing total knee arthroplasty (TKA). METHOD: This randomized controlled study was conducted between February and November 2021 in a public hospital. The study randomly assigned patients to either a 6-week 'TCM' program or usual care. The sample size was n = 70, with each group comprising 35 individuals. Patient outcomes, including self-efficacy, functional status and healthcare service readmission rates, were monitored for TKA patients. RESULTS: Nursing care based on the 'TCM' was found to enhance functional status and increase the level of self-efficacy among TKA patients, leading to a decrease in healthcare service readmissions. CONCLUSIONS: The study recommends preparing patients and their families for the preoperative and postoperative processes. It emphasizes the importance of providing necessary training and consultancy services under the leadership of orthopaedic nurses responsible for TKA patient care, guided by the principles of TCM.

Offering nurse care management for opioid use disorder in primary care: Impact on emergency and hospital utilization in a cluster-randomized implementation trial.

BACKGROUND: Patients with opioid use disorder (OUD) have increased emergency and hospital utilization. The PROUD trial showed that implementation of office-based addiction treatment (OBAT) increased OUD medication treatment compared to usual care, but did not decrease acute care utilization in patients with OUD documented pre-randomization (clinicaltrials.gov/study/NCT03407638). This paper reports secondary emergency and hospital utilization outcomes in patients with documented OUD in the PROUD trial. METHODS: This cluster-randomized implementation trial was conducted in 12 clinics from 6 diverse health systems (March 2015-February 2020). Patients who visited trial clinics and had an OUD diagnosis within 3 years pre-randomization were included in primary analyses; secondary analyses added patients with OUD who were new to the clinic or with newly-documented OUD post-randomization. Outcomes included days of emergency care and hospital utilization over 2 years post-randomization. Explanatory outcomes included measures of OUD treatment. Patient-level analyses used mixed-effect regression with clinic-specific random intercepts. RESULTS: Among 1988 patients with documented OUD seen pre-randomization (mean age 49, 53 % female), days of emergency care or hospitalization did not differ between intervention and usual care; OUD treatment also did not differ. In secondary analyses among 1347 patients with OUD post-randomization, there remained no difference in emergency or hospital utilization despite intervention patients receiving 32.2 (95 % CI 4.7, 59.7) more days of OUD treatment relative to usual care. CONCLUSIONS: Implementation of OBAT did not reduce emergency or hospital utilization among patients with OUD, even in the sample with OUD first documented post-randomization in whom the intervention increased treatment.

Factors Predicting Completion of Four or More Antenatal Care Visits in Sarlahi District, Nepal.

Background: A significant number of women die from pregnancy and childbirth complications globally, particularly in low- and middle-income countries (LMICs). Receiving at least four antenatal care (ANC) visits may be important in reducing maternal and perinatal deaths. This study investigates factors associated with attending ≥ 4 ANC visits in Sarlahi district of southern Nepal. Methods: A secondary analysis was conducted on data from the Nepal Oil Massage Study (NOMS), a cluster-randomized, community-based longitudinal pregnancy cohort study encompassing 34 Village Development Committees. We quantified the association between receipt/attendance of ≥ 4 ANC visits and socioeconomic, demographic, morbidity, and pregnancy history factors using logistic regression; Generalized Estimating Equations were used to account for multiple pregnancies per woman. Results: All pregnancies resulting in a live birth (n=31,867) were included in the model and 31.4% of those pregnancies received 4+ ANC visits. Significant positive associations include socioeconomic factors such as participation in non-farming occupations for women (OR=1.52, 95% CI: 1.19, 1.93), higher education (OR=1.79, 95% CI: 1.66, 1.93) and wealth quintile OR=1.44, 95% CI: 1.31, 1.59), nutritional status such as non-short stature (OR=1.17, 95% CI: 1.07, 1.27), obstetric history such as adequate interpregnancy interval (OR=1.31, 95% CI: 1.19, 1.45) and prior pregnancy but no live birth (OR=2.14, 95% CI: 1.57, 2.92), symptoms such as vaginal bleeding (OR=1.35, 95% CI:1.11, 1.65) and awareness of the government's conditional cash transfer ANC program (OR=2.26, 95% CI: 2.01, 2.54). Conversely, belonging to the lower Shudra caste (OR=0.56, 95% CI: 0.47, 0.67), maternal age below 18 or above 35 (OR=0.81, 95% CI:0.74, 0.88; OR=0.77, 95% CI: 0.62, 0.96)), preterm birth (OR=0.41, 95% CI: 0.35, 0.49), parity ≥ 1 (OR=0.66, 95% CI: 0.61, 0.72), and the presence of hypertension during pregnancy (OR=0.79, 95% CI: 0.69, 0.90) were associated with decreased likelihood of attending ≥ 4 ANC visits. Conclusions: These findings underscore the importance of continuing and promoting the government's program and increasing awareness among women. Moreover, understanding these factors can guide interventions aimed at encouraging ANC uptake in the most vulnerable groups, subsequently reducing maternal-related adverse outcomes in LMICs. Trial registration: The clinicaltrial.gov trial registration number for NOMS was #NCT01177111. Registration date was August 6th, 2010.

Impact of cannabidiol on myocardial recovery in patients with acute myocarditis: Rationale & design of the ARCHER trial.

AIMS: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF). METHODS AND RESULTS: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper. CONCLUSIONS: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.

Nurse-led sequential multiple assignment randomized trial of nudging intervention for early antiretroviral therapy initiation among patients with HIV/AIDS: Implementation study protocol.

AIMS: In China, more than 30% of patients have not initiated treatment within 30 days of HIV diagnosis. Delayed initiation has a detrimental influence on disease outcomes and increases HIV transmission. The study aims to evaluate the effectiveness of a nurse-led antiretroviral therapy initiation nudging intervention for people newly diagnosed with HIV in China to find the optimal intervention implementation strategy. METHODS: A Hybrid Type II sequential multiple assignment randomized trial will be conducted at four Centers for Disease Control and Prevention in Hunan, China. This study will recruit 447 people newly diagnosed with HIV aged ≥18 years and randomly assign them into two intervention groups and one control group. On top of the regular counselling services and referrals, intervention groups will receive a 4-week, 2-phase intervention based on the dual-system theory and the nudge theory. The control group will follow the currently recommended referral procedures. The primary outcomes are whether treatment is initiated, as well as the length of time it takes. The study outcomes will be measured at the baseline, day 15, day 30, week 12, week 24 and week 48. Generalized estimating equations and survival analysis will be used to compare effectiveness and explore factors associated with antiretroviral therapy initiation. Both qualitative and quantitative information will be collected to assess implementation outcomes. DISCUSSION: Existing strategies mostly target institutional-level factors, with little consideration given to patients' decision-making. To close this gap, we aim to develop an effective theory-driven nudging strategy to improve early ART initiation. IMPACT: This nurse-led study will help to prevent delayed initiation by employing implementation science strategies for people newly diagnosed with HIV. This study contributes to the United Nations' objective of ending the AIDS pandemic by 2030. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300070140. The trial was prospectively registered before the first participant was recruited. PATIENT AND PUBLIC INVOLVEMENT: The nudging intervention was finalized through the Nominal Group Technique where we invited five experts in the related field and five people living with HIV to participate.

Psychological processes and alcohol reduction in patients with chronic hepatitis C: Results from the HepART trial.

BACKGROUND: There is a lack of randomized controlled trials of behavioral interventions and process-level research related to alcohol reduction among patients with chronic liver disease (e.g., hepatitis C viral (HCV) infection). We conducted a process-level, secondary analysis of the Hepatitis C-Alcohol Reduction Treatment (HepART) trial to investigate the association between change in psychological processes posited by the Integrated Behavioral Model (IBM) and change in World Health Organization (WHO) drinking risk levels. METHODS: Patients with HCV who consume alcohol were recruited from hepatology clinics and received provider-delivered SBIRT (Screening, Brief Intervention, Referral to Treatment) or SBIRT+ 6 months of co-located alcohol counseling. Treatment arms were combined for this analysis because no between-group differences were found. At baseline and 6 months, the timeline followback method was used to determine alcohol risk levels according to the 2000 WHO risk categories (based on average grams of alcohol per day). Changes in alcohol consumption and WHO risk levels were quantified and regressed on change in individual psychological processes (e.g., readiness, self-efficacy, motives, attitudes, and strategies) from baseline to 6 months. RESULTS: At the baseline assessment, 162 participants were classified as abstinent (5%), low (47%), moderate (16%), high (19%), or very high (13%) WHO risk levels. At 6 months, 38% remained at the same risk level and 48% decreased by at least one level. In univariate analyses, changes in 7 of 12 psychological processes were associated with change in risk levels. Adjusted multivariate analyses demonstrated that change in four processes were significantly associated with change in risk levels, including SOCRATES Taking Steps, Ambivalence, and Recognition scores and alcohol reduction strategies. CONCLUSIONS: These findings demonstrate significant reductions in quantitative indices of alcohol consumption following opportunistic alcohol interventions in patients with HCV. However, results provided mixed support for associations between change in IBM psychological processes and alcohol consumption.

Integrated pulmonary index during procedural sedation and analgesia: A cluster-randomized trial.

AIM: To evaluate the effectiveness of utilizing the integrated pulmonary index for capnography implementation during sedation administered by nurses. DESIGN: Cluster-randomized trial. METHODS: Participants were enrolled from the interventional radiology department at an academic hospital in Canada. Nurses were randomized to either enable or disable the Integrated Pulmonary Index feature of the capnography monitor. Procedures were observed by a research assistant to collect information about alarm performance characteristics. The primary outcome was the number of seconds in an alert condition state without an intervention being applied. RESULTS: The number of seconds in an alarm state without intervention was higher in the group that enabled the integrated pulmonary index compared to the group that disabled this feature, but this difference did not reach statistical significance. Likewise, the difference between groups for the total alarm duration, total number of alarms and the total number of appropriate alarms was not statistically significant. The number of inappropriate alarms was higher in the group that enabled the Integrated Pulmonary Index, but this estimate was highly imprecise. There was no difference in the odds of an adverse event (measured by the Tracking and Reporting Outcomes of Procedural Sedation tool) occurring between groups. Desaturation events were uncommon and brief in both groups but the area under the SpO2 90% desaturation curve scores were lower for the group that enabled the integrated pulmonary index. CONCLUSION: Enabling the integrated pulmonary index during nurse-administered procedural sedation did not reduce nurses' response times to alarms. Therefore, integrating multiple physiological parameters related to respiratory assessment into a single index did not lower the threshold for intervention by nurses. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The time it takes to respond to capnography monitor alarms will not be reduced if the integrated pulmonary Iindex feature of capnography monitors is enabled during nurse-administered procedural sedation. IMPACT: Results do not support the routine enabling of the integrated pulmonary index when nurses use capnography to monitor patients during procedural sedation as a strategy to reduce the time it takes to initiate responses to alarms. REPORTING METHOD: CONSORT. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution. TRIAL REGISTRATION: This study was prospectively registered at ClinicalTrials.gov (ID: NCT05068700).

Benefits of Quercetin on Glycated Hemoglobin, Blood Pressure, PiKo-6 Readings, Night-Time Sleep, Anxiety, and Quality of Life in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial.

Background: Diabetes is a rapidly growing global morbidity issue with high prevalence, and the associated dysglycemia leads to complications. Patients with type 2 diabetes mellitus (T2DM) often experience elevated anxiety levels, affecting their quality of life and diabetes management. This study investigated quercetin, a nutraceutical and potential senolytic with antioxidant activity, to detect its possible positive effect on the bio-clinical measurements and routine health of patients with T2DM. Methods: This prospective randomized controlled trial (RCT) investigated the clinical usefulness of quercetin in patients with T2DM receiving non-insulin medications. One hundred participants were stratified by age and sex (1:1) and randomized to control (n = 50) or intervention (n = 50) groups. The control received standard care only, while the intervention received 500 mg quercetin daily for 12 weeks, followed by an 8-week washout and a final consecutive 12-week supplementation period (total: 32 weeks), as adjunct to their usual care. Comprehensive health assessments, including blood analyses, were conducted at baseline and study termination. Quality of life and anxiety were assessed using the 36-item Short Form Health Survey (SF-36) and Short Anxiety Screening Test (SAST-10). Results: Eighty-eight patients with T2DM concluded the trial. Compared with the control, glycated hemoglobin (HbA1c) levels showed a significant decrease (Δ%-change: -4.0% vs. 0.1%, p = 0.011). Quercetin also significantly improved PiKo-6 readings (FEV1: 5.6% vs. -1.5%, p = 0.002), systolic blood pressure (-5.0% vs. -0.2%, p = 0.029), night-time sleep (11.6% vs. -7.3%, p < 0.001), anxiety levels (SAST-10) (-26.2% vs. 3.3%, p < 0.001), and quality of life (SF-36) (both physical and mental components, p < 0.001). Conclusions: Based on the current open-label study, quercetin appears to be a promising supplement for T2DM, providing lifestyle and care support. Further research is warranted to shift this potential from clinical usefulness and feasibility to multidisciplinary evidence.

Optimizing accrual to a large-scale, clinically integrated randomized trial in anesthesiology: A 2-year analysis of recruitment.

BACKGROUND: Performing large randomized trials in anesthesiology is often challenging and costly. The clinically integrated randomized trial is characterized by simplified logistics embedded into routine clinical practice, enabling ease and efficiency of recruitment, offering an opportunity for clinicians to conduct large, high-quality randomized trials under low cost. Our aims were to (1) demonstrate the feasibility of the clinically integrated trial design in a high-volume anesthesiology practice and (2) assess whether trial quality improvement interventions led to more balanced accrual among study arms and improved trial compliance over time. METHODS: This is an interim analysis of recruitment to a cluster-randomized trial investigating three nerve block approaches for mastectomy with immediate implant-based reconstruction: paravertebral block (arm 1), paravertebral plus interpectoral plane blocks (arm 2), and serratus anterior plane plus interpectoral plane blocks (arm 3). We monitored accrual and consent rates, clinician compliance with the randomized treatment, and availability of outcome data. Assessment after the initial year of implementation showed a slight imbalance in study arms suggesting areas for improvement in trial compliance. Specific improvement interventions included increasing the frequency of communication with the consenting staff and providing direct feedback to clinician investigators about their individual recruitment patterns. We assessed overall accrual rates and tested for differences in accrual, consent, and compliance rates pre- and post-improvement interventions. RESULTS: Overall recruitment was extremely high, accruing close to 90% of the eligible population. In the pre-intervention period, there was evidence of bias in the proportion of patients being accrued and receiving the monthly block, with higher rates in arm 3 (90%) compared to arms 1 (81%) and 2 (79%, p = 0.021). In contrast, in the post-intervention period, there was no statistically significant difference between groups (p = 0.8). Eligible for randomization rate increased from 89% in the pre-intervention period to 95% in the post-intervention period (difference 5.7%; 95% confidence interval = 2.2%-9.4%, p = 0.002). Consent rate increased from 95% to 98% (difference of 3.7%; 95% confidence interval = 1.1%-6.3%; p = 0.004). Compliance with the randomized nerve block approach was maintained at close to 100% and availability of primary outcome data was 100%. CONCLUSION: The clinically integrated randomized trial design enables rapid trial accrual with a high participant compliance rate in a high-volume anesthesiology practice. Continuous monitoring of accrual, consent, and compliance rates is necessary to maintain and improve trial conduct and reduce potential biases. This trial methodology serves as a template for the implementation of other large, low-cost randomized trials in anesthesiology.

Tuberculosis Treatment Compliance Under Smartphone-Based Video-Observed Therapy Versus Community-Based Directly Observed Therapy: Cluster Randomized Controlled Trial.

BACKGROUND: There are no recent studies comparing the compliance rates of both patients and observers in tuberculosis treatment between the video-observed therapy (VOT) and directly observed therapy (DOT) programs. OBJECTIVE: This study aims to compare the average number of days that patients with pulmonary tuberculosis and their observers were compliant under VOT and DOT. In addition, this study aims to compare the sputum conversion rate of patients under VOT with that of patients under DOT. METHODS: Patient and observer compliance with tuberculosis treatment between the VOT and DOT programs were compared based on the average number of VOT and DOT compliance days and sputum conversion rates in a 60-day cluster randomized controlled trial with patients with pulmonary tuberculosis (VOT: n=63 and DOT: n=65) with positive sputum acid-fast bacilli smears and 38 observers equally randomized into the VOT and DOT groups (19 observers per group and n=1-5 patients per observer). The VOT group submitted videos to observers via smartphones; the DOT group followed standard procedures. An intention-to-treat analysis assessed the compliance of both the patients and the observers. RESULTS: The VOT group had higher average compliance than the DOT group (patients: mean difference 15.2 days, 95% CI 4.8-25.6; P=.005 and observers: mean difference 21.2 days, 95% CI 13.5-28.9; P<.001). The sputum conversion rates in the VOT and DOT groups were 73% and 61.5%, respectively (P=.17). CONCLUSIONS: Smartphone-based VOT significantly outperformed community-based DOT in ensuring compliance with tuberculosis treatment among observers. However, the study was underpowered to confirm improved compliance among patients with pulmonary tuberculosis and to detect differences in sputum conversion rates. TRIAL REGISTRATION: Thai Clinical Trials Registry (TCTR) TCTR20210624002; https://tinyurl.com/3bc2ycrh. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/38796.

Intravenous Tocilizumab versus Standard of Care in the Treatment of Severe and Critical COVID-19-related Pneumonia: A Single-center, Double-blind, Placebo-controlled, Phase 3 Trial.

Background: Severe and critical COVID-19 disease is characterized by hyperinflammation involving pro-inflammatory cytokines, particularly IL-6. Tocilizumab is a monoclonal antibody that blocks IL-6 receptors. Objectives: This study evaluated the efficacy of tocilizumab in Filipino patients with severe to critical COVID-19 disease. Methods: This phase 3 randomized double-blind trial, included patients hospitalized for severe or critical COVID-19 in a 1:1 ratio to receive either tocilizumab plus local standard of care or placebo plus standard of care. Patients were eligible for a repeat IV infusion within 24-48 hours if they deteriorated or did not improve. Treatment success or clinical improvement was defined as at least two categories of improvement from baseline in the WHO 7-point Ordinal Scale of patient status, in an intention-to-treat manner. Results: Forty-nine (49) patients were randomized in the tocilizumab arm and 49 in the placebo arm. There was no significant difference in age, comorbidities, COVID-19 severity, need for mechanical ventilation, presence of acute respiratory distress syndrome, or biomarker levels between groups. Use of adjunctive therapy was similar between groups, with corticosteroid used in 91.8% in tocilizumab group and 81.6% in the placebo group, while remdesivir was used in 98% of participants in both groups.There was no significant difference between groups in terms of treatment success in both the intention-to-treat analysis (relative risk=1.05, 95% CI: 0.85-1.30) and per-protocol analysis (relative risk=0.98, 95% CI: 0.80 to 1.21). There was no significant difference in time to improvement of at least two categories relative to baseline on the 7-point Ordinal Scale of clinical status. Conclusion: The use of tocilizumab on top of standard of care in the management of patients with severe to critical COVID-19 did not result in significant improvement as defined by the WHO 7-point Ordinal Scale of patient status, nor in significant improvement in incidence of mechanical ventilation, incidence of ICU admission, length of ICU stay, and mortality rate.

Interaction analysis of subgroup effects in randomized trials: the essential methodological points.

Subgroup analysis aims to identify subgroups (usually defined by baseline/demographic characteristics), who would (or not) benefit from an intervention under specific conditions. Often performed post hoc (not pre-specified in the protocol), subgroup analyses are prone to elevated type I error due to multiple testing, inadequate power, and inappropriate statistical interpretation. Aside from the well-known Bonferroni correction, subgroup treatment interaction tests can provide useful information to support the hypothesis. Using data from a previously published randomized trial where a p value of 0.015 was found for the comparison between standard and Hemopatch® groups in (the subgroup of) 135 patients who had hand-sewn pancreatic stump closure we first sought to determine whether there was interaction between the number and proportion of the dependent event of interest (POPF) among the subgroup population (patients with hand-sewn stump closure and use of Hemopatch®), Next, we calculated the relative excess risk due to interaction (RERI) and the "attributable proportion" (AP). The p value of the interaction was p = 0.034, the RERI was - 0.77 (p = 0.0204) (the probability of POPF was 0.77 because of the interaction), the RERI was 13% (patients are 13% less likely to sustain POPF because of the interaction), and the AP was - 0.616 (61.6% of patients who did not develop POPF did so because of the interaction). Although no causality can be implied, Hemopatch® may potentially decrease the POPF after distal pancreatectomy when the stump is closed hand-sewn. The hypothesis generated by our subgroup analysis requires confirmation by a specific, randomized trial, including only patients undergoing hand-sewn closure of the pancreatic stump after distal pancreatectomy.Trial registration: INS-621000-0760.

Psychological safety perception in community pharmacies: A randomized controlled trial of agile interventions.

Background: Agile coaching, recognized as a more advanced methodology compared to education, is hypothesized to yield superior outcomes in enhancing psychological safety perception. Objective: Investigating the effectiveness of agile interventions versus no intervention on psychological safety perception, this randomized controlled trial aimed to clarify outcomes. Methods: The survey sample consisted of 54 licensed pharmacists, with each group comprising 18 participants: E1 underwent Agile Coaching, E2 underwent Agile Education, and C served as the control. After six weeks, psychological safety perception was measured using a validated scale, and statistical analyses, including the Kruskal-Wallis test and Mann-Whitney U test, were conducted. Results: The group undergoing agile coaching showed the most substantial enhancements in psychological safety perception compared to others. Mann-Whitney U test revealed no significant difference in psychological safety perception between E1 and E2 groups before (Z = -0.938, p = 0.348) and after intervention (Z = -1.269, p = 0.204). Significant differences were observed between E1 and C both before (Z = -2.693, p = 0.007) and after intervention (Z = -1.414, p = 0.157). Significant differences were found between E2 and C before (p = 0.038) but not after intervention (p = 0.962). Conclusions: The findings suggest that agile coaching could be an effective intervention for enhancing psychological safety in organizational settings, particularly in community pharmacies. Further research is warranted to explore long-term effects and generalize findings to broader contexts.

Randomized Laboratory Study of Single-Dose Cannabis, Dronabinol, and Placebo in Patients With Schizophrenia and Cannabis Use Disorder.

BACKGROUND AND HYPOTHESIS: Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total n = 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis. STUDY DESIGN: Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed. STUDY RESULTS: Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (B = -9.89; 95% CI: -16.06, -3.18; P = .004) and attention (B = -0.61; 95% CI: -1.00, -0.23; P = .002). Every 10-point increment in serum THC + THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; P = .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory. CONCLUSIONS: In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.

Incorporating nonparametric methods for estimating causal excursion effects in mobile health with zero-inflated count outcomes.

In mobile health, tailoring interventions for real-time delivery is of paramount importance. Micro-randomized trials have emerged as the "gold-standard" methodology for developing such interventions. Analyzing data from these trials provides insights into the efficacy of interventions and the potential moderation by specific covariates. The "causal excursion effect," a novel class of causal estimand, addresses these inquiries. Yet, existing research mainly focuses on continuous or binary data, leaving count data largely unexplored. The current work is motivated by the Drink Less micro-randomized trial from the UK, which focuses on a zero-inflated proximal outcome, i.e., the number of screen views in the subsequent hour following the intervention decision point. To be specific, we revisit the concept of causal excursion effect, specifically for zero-inflated count outcomes, and introduce novel estimation approaches that incorporate nonparametric techniques. Bidirectional asymptotics are established for the proposed estimators. Simulation studies are conducted to evaluate the performance of the proposed methods. As an illustration, we also implement these methods to the Drink Less trial data.

Lower incidence of vaginal cancer after cervical human papillomavirus screening - long-term follow-up of Finnish randomized screening trial.

OBJECTIVE: Around 70% of vaginal cancers and 40-50% of vulvar cancers are attributable to human papillomavirus (HPV). Globally the burden of these diseases is estimated to grow due to the increasing HPV prevalence and rapidly aging global population. We aimed to examine if HPV screening for cervical cancer has an additional beneficial effect in preventing vaginal and vulvar cancers. To assess this, we used long-term follow-up data from the Finnish randomized HPV screening trial. METHODS: Between 2003 and 2008, over 236,000 women were individually randomized (1:1) to primary HPV or cytology screening in Southern Finland. We followed this cohort up to the year 2020. To compare the study arms, we calculated site-specific and pooled incidence rate ratios (IRRs) and mortality rate ratios (MRRs) for vaginal and vulvar cancers using Poisson regression. RESULTS: During 3,5 million person-years of follow-up, the IRR for vaginal cancer in the HPV arm compared to the cytology arm was 0.40 (95% CI 0.17-0.88) and the corresponding MRR was 0.74 (95% 0.21-2.24). The corresponding IRR for vulvar cancer was 0.73 (95% 0.50-1.08) and the MRR was 0.64 (95% 0.23-1.62). The pooled IRR was 0.67 (95% 0.47 ̶ 0.95) and MRR 0.67 (95% 0.31 ̶ 1.37). CONCLUSION: We found lower incidence of vaginal cancers with HPV screening compared to cytology screening. To validate our results, we recommend analyzing data on vaginal and vulvar cancers also from other HPV screening studies.

Rationale and design of the KP ENRICH trial: A food is medicine intervention in low-income high-risk adults with diabetes within Kaiser Permanente.

BACKGROUND: Food insecurity is associated with poor glycemic control and increased risk for diabetes-related complications. The clinical benefit of addressing these challenges through a medically supportive grocery prescription (GRx) program in patients with type 2 diabetes mellitus (T2D) remains unclear. We report the aims and design of a randomized clinical trial to evaluate the effectiveness of a 6-month GRx intervention on hemoglobin A1c (HbA1c) levels among low-income adults with T2D. METHODS: The Kaiser Permanente Evaluating Nutritional Interventions in Food-Insecure High-Risk Adults (KP ENRICH) Study is a pragmatic randomized trial enrolling 1100 participants within Kaiser Permanente Northern California and Southern California, two integrated health care delivery systems serving >9 million members. Medicaid-insured adults with T2D and baseline HbA1c ≥7.5% will be randomized at a 1:1 ratio to either GRx, delivered as $100 per month for select items from among a curated list of healthful food groups in an online grocery ordering and home-delivery platform along with biweekly digital nutrition educational materials, or control, consisting of free membership and deliveries from the online grocery platform but without curated food groups or purchasing dollars. The primary outcome is 6-month change in HbA1c. Secondary outcomes include 12-month change in HbA1c, and 6- and 12-month change in medical resource utilization, food security, nutrition security, dietary habits, diabetes-related quality of life, and dietary self-efficacy. CONCLUSIONS: The results of this large randomized clinical trial of GRx will help inform future policy and health system-based initiatives to improve food and nutrition security, disease management, and health equity among patients with T2D.