ADO09, a co-formulation of pramlintide and insulin A21G, lowers body weight versus insulin lispro in type 1 diabetes.

AIM: To study safety, efficacy and weight loss with ADO09, a co-formulation of insulin A21G and pramlintide, in type 1 diabetes. MATERIALS AND METHODS: A randomized, two-arm ambulatory 16-week study compared ADO09 with insulin lispro in 80 participants with type 1 diabetes. We compared changes of weight, glycated haemoglobin, glycaemic patterns during continuous glucose monitoring, and insulin doses at baseline and at the end of treatment. RESULTS: A significant and continuing weight loss, the primary endpoint, was observed with ADO09 compared with lispro as prandial insulin. In the whole group, the weight loss with ADO09 relative to lispro was 2.1 kg. Glycaemic control was relatively good (7.7% mean glycated haemoglobin) in both groups and did not change during treatment. Prandial insulin doses were reduced by 21% in the ADO09 group, whereas basal insulin dosage was not modified. Gastrointestinal symptoms were more frequent with ADO09, but no clear difference in hypoglycaemia was observed. CONCLUSIONS: These results extend previous observations on the efficacy and safety of this insulin/pramlintide co-formulation. They show a beneficial effect on weight, using less mealtime insulin and without increased hypoglycaemia.

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.

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.

Comments on "sensitivity of estimands in clinical trials with imperfect compliance" by Chen and Heitjan.

Chen and Heitjan (Sensitivity of estimands in clinical trials with imperfect compliance. Int J Biostat. 2023) used linear extrapolation to estimate the population average causal effect (PACE) from the complier average causal effect (CACE) in multiple randomized trials with all-or-none compliance. For extrapolating from CACE to PACE in this setting and in the paired availability design involving different availabilities of treatment among before-and-after studies, we recommend the sensitivity analysis in Baker and Lindeman (J Causal Inference, 2013) because it is not restricted to a linear model, as it involves various random effect and trend models.

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.

Resilience and distress among adolescents and young adults receiving hematopoietic cell transplantation: The Promoting Resilience in Stress Management randomized trial.

BACKGROUND: Adolescents and young adults (AYAs) receiving hematopoietic cell transplantation (HCT) are at high risk of poor psychosocial health. This study aimed to determine whether the Promoting Resilience in Stress Management (PRISM) intervention mitigated these risks during the first 6 months posttransplant. METHODS: This multisite, parallel, randomized trial was conducted from April 2019 to March 2023. Eligible AYAs were aged 12-24 years, English speaking, and within 1 month of HCT for cancer or cancer predisposition syndrome. They were assigned 1:1 to PRISM (a brief, skills-based intervention targeting "resilience resources" [stress management, goal setting, cognitive reframing, and meaning making]) or usual care (UC). Outcomes included total symptoms of depression and anxiety (Hospital Anxiety and Depression Scale; primary outcome), hope (Snyder Hope Scale), resilience (10-item Connor-Davidson Resilience Scale), and health-related quality of life (HRQOL; Pediatric Quality of Life Inventory Cancer Module). Analyses leveraged multivariable linear regressions; exploratory analyses assessed the influence of baseline depression or anxiety. RESULTS: Of 94 enrolled and randomized AYAs, the mean age was 16.7 years (SD, 4.2); 43 (46%) were female, 56 (60%) were non-Hispanic White, 22 (23%) were Hispanic, and nine (10%) were Black. Most (77%) had leukemia. Of n = 50 randomized to PRISM and n = 44 to UC, 37 (74%) and 33 (73%) completed all study procedures, respectively. In intention-to-treat analyses, PRISM did not affect 6-month depression and anxiety (ß = -1.1; 95% CI, -3.7 to 1.5), hope (ß = 0.83; 95% CI, -3.3 to 4.9), resilience (ß = -0.01; 95% CI, -3.0 to 3.0), or HRQOL (ß = 1.5; 95% CI, -4.7 to 7.9). Among AYAs with preexisting anxiety or depression, PRISM recipients reported greater 6-month improvements in hope (score change, +3.71; SD, 6.9) versus UC recipients (score change, -2.76; SD, 6.5) (p = .04). CONCLUSIONS: Resilience coaching did not influence outcomes in this sample. Exploratory findings suggest it may be more effective when directed toward those with concurrent distress.

Changes in risk behaviour following a network peer education intervention for HIV prevention among male Tajik migrants who inject drugs in Moscow: a cluster-randomized controlled trial.

INTRODUCTION: The "Migrants' Approached Self-Learning Intervention in HIV/AIDS for Tajiks" (MASLIHAT) recruits and trains Tajik labour migrants who inject drugs as peer educators (PEs) in delivering HIV prevention information and encouragement to adopt risk-reduction norms and practices within their diaspora social networks while reducing their own HIV risk. METHODS: The MASLIHAT intervention was tested in Moscow in a cluster-randomized controlled trial with 12 recruitment sites assigned to either the MASLIHAT intervention or an equal-time peer-educator training focused on other health conditions (TANSIHAT). From October 2021 to April 2022, 140 male Tajik migrants who inject drugs were recruited as PEs to attend the 5-session MASLIHAT training or the TANSIHAT non-HIV comparison condition. Each participant in both groups recruited two network members (NMs) who inject drugs with the intent to share with them the information and positive strategies for change they had learned (n = 280). All PEs and NMs (n = 420) participated in baseline and follow-up interviews at 3-month intervals for 1 year. All received HIV counselling and testing. Modified mixed effects Poisson regressions tested for group differences in injection practices, sexual risk behaviours and heavy alcohol use over time. RESULTS: At baseline, across both groups, 75% of participants reported receptive syringe sharing (RSS), 42% reported condomless sex and 20% reported binge drinking at least once a month. In contrast to TANSIHAT where HIV risk behaviours remained the same, significant intervention effects that were sustained over the 12 months were observed for receptive syringe and ancillary equipment sharing among both MASLIHAT PEs and NMs (p < 0.0001). Significant declines in the prevalence of sexual risk behaviours were also associated with the MASLIHAT intervention (p < 0.01), but not the comparison condition. Binge alcohol use was not affected in either condition; the MASLIHAT intervention had a transitory effect on drinking frequency that dissipated after 9 months. CONCLUSIONS: The MASLIHAT peer-education intervention proved highly effective in reducing HIV-related injection risk behaviour, and moderately effective in reducing sexual risk behaviour among both PEs and NMs. Network-based peer education is an important tool for HIV prevention among people who inject drugs, especially in environments that are not amenable to community-based harm reduction.

Comparison of the Impact of a 6 French GlideSheath Slender® and a Conventional Sheath on Distal Radial Artery Occlusion: A Randomized Controlled Trial.

BACKGROUND: There is a lack of randomized clinical trials investigating whether the 6-Fr Glidesheath Slender (GSS) is superior to the 6-Fr conventional radial sheath (CS) with respect to the early-term incidence of distal radial artery occlusion (dRAO) in patients undergoing coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) via distal transradial access (dTRA). METHODS: This was a prospective, single-centre trial of patients who were randomized to undergo CAG and/or PCI with either a 6-Fr GSS or a 6-Fr CS. The primary endpoint was the incidence of dRAO at 24 h postoperatively, as evaluated by Doppler ultrasound. RESULTS: A total of 620 patients were included in the study. The baseline patient and procedural characteristics were similar between the two groups. For the primary endpoint, the incidence of dRAO at 24 h after the procedure was 1.0% (3/314) in the GSS group and 3.6% (11/306) in the CS group (RR= 0.266, 95% CI= 0.075-0.943, P= 0.027) according to the intention-to-treat (ITT) analysis. For the secondary endpoints, the incidence of proximal RAO was 0.3% (1/314) in the GSS group and 2.3% (7/306) in the CS group (P= 0.029). Other secondary endpoints, including the puncture success rate, procedural outcomes, other puncture-related outcomes and access-related complications, were not significantly different between the two groups. CONCLUSION: The use of a thin-walled and hydrophilic coating sheath can reduce the incidence of early-term dRAO in patients who undergo CAG and/or PCI via the dTRA.

A sequential multiple assignment randomized trial of symptom management for cancer survivors during treatment and their informal caregivers.

CONTEXT: Many cancer survivors and their informal caregivers experience multiple symptoms during the survivor's treatment. OBJECTIVE: Test relative effectiveness and optimal sequencing of two evidence-based interventions for symptom management. METHODS: In this sequential multiple assignment randomized trial (SMART), survivors of solid tumors with elevated depression or anxiety and their caregivers as dyads were initially randomized after baseline assessment in a 3:1 ratio to the Symptom Management and Survivorship Handbook (SMSH, N = 277 dyads) intervention or SMSH plus 8 weeks of telephone interpersonal counseling (TIPC, N = 97 dyads). After 4 weeks, survivors who were not responding (no improvement or worsening score on depression and/or anxiety item) to SMSH only and their caregivers were re-randomized to continue with SMSH alone (N = 44 dyads) to give it more time or to SMSH + TIPC (N = 44 dyads). Mixed effects and generalized linear models compared severity of depression, anxiety, and a summed index of 16 other symptoms over weeks 1-13 and week 17 between randomized groups and among three dynamic treatment regimes (DTRs). Dyads received SMSH only for 12 weeks (DTR1); SMSH for 12 weeks with 8 weeks of TIPC added from week 1 (DTR2); and SMSH for 4 weeks followed by the combined SMSH + TIPC for 8 weeks if no response at 4 weeks (DTR3). RESULTS: Survivors randomized initially to SMSH alone had significantly lower anxiety over weeks 1-13 compared to those randomized to the combined SMSH + TIPC. In comparing DTRs, survivor's anxiety was significantly lower at week 13 for DTR1 compared to DTR2 with no other main effects for survivors or caregivers. Exploratory moderation analyses indicated a potential benefit of adding TIPC for caregivers of non-responders with elevated baseline symptoms. CONCLUSION: SMSH + TIPC did not result in better symptom outcomes at week 17 than SMSH alone. Lower intensity SMSH may improve depression and anxiety symptoms for most survivors and their caregivers. TRIAL REGISTRATION: Clinicaltrails.gov ID number, NCT03743415; approved and posted on 11/16/2018.

Estimating causal effects for binary outcomes using per-decision inverse probability weighting.

Micro-randomized trials are commonly conducted for optimizing mobile health interventions such as push notifications for behavior change. In analyzing such trials, causal excursion effects are often of primary interest, and their estimation typically involves inverse probability weighting (IPW). However, in a micro-randomized trial, additional treatments can often occur during the time window over which an outcome is defined, and this can greatly inflate the variance of the causal effect estimator because IPW would involve a product of numerous weights. To reduce variance and improve estimation efficiency, we propose two new estimators using a modified version of IPW, which we call "per-decision IPW." The second estimator further improves efficiency using the projection idea from the semiparametric efficiency theory. These estimators are applicable when the outcome is binary and can be expressed as the maximum of a series of sub-outcomes defined over sub-intervals of time. We establish the estimators' consistency and asymptotic normality. Through simulation studies and real data applications, we demonstrate substantial efficiency improvement of the proposed estimator over existing estimators. The new estimators can be used to improve the precision of primary and secondary analyses for micro-randomized trials with binary outcomes.

Seeing the Truth About Double Blinding.

Randomized clinical trials provide reassurances that confounding factors are balanced at baseline whereas blinding is essential to assure the balance of extraneous factors thereafter. This article provides a three-part taxonomy of pitfalls that can arise because of inadequate blinding in clinical trials. We introduce a cautionary framework for readers interpreting a blinded randomized trial for evidence-based medicine. Each pitfall is illustrated with a relevant example of a potential bias resulting from knowledge of group assignment. Several pitfalls occur during the conduct of the study including inadequate blinding of the intervention group, control group, or responsible clinicians. Additional pitfalls relate to data analysis including unsubstantiated assertions of blinding and subverted tests for blinding. Further pitfalls arise due to surrounding oversight including unblinding of research ethics boards and scientific reviewers. These caveats are sources of misunderstanding when observing the apparent connection between a clinical intervention and patient outcomes. An awareness of specific pitfalls might help advance the interpretation and application of blinded randomized clinical trials to inform evidence-based medical care.

A randomized cross-over trial of prebiotics and probiotics in multiple sclerosis: Trial feasibility, supplement tolerability and symptom abatement.

BACKGROUND: Dietary supplements can modulate the gut microbial ecosystem and affect the immune system. This has potential implications for autoimmune diseases, including multiple sclerosis (MS). Prior studies explored tolerability, symptomatic improvement, and immunologic effects of probiotics in people with MS (pwMS), but no study has examined prebiotics in this population or compared prebiotics with probiotics. METHODS: This is a randomized, open-label trial of participants with relapsing-remitting MS on B-cell depletion therapy from two MS centers. 22 participants enrolled in the original cross-over study in which probiotic (Visbiome, containing Lactobacillus, Bifidobacterium and Streptococcus species) or prebiotic (Prebiotin, containing oligofructose enriched inulin) supplementation for 6 weeks was randomized, each followed by a washout period. Due to pandemic-related interruptions and expiration of the study supply of probiotics, another 15 participants enrolled in a single-arm study to receive prebiotic supplementation for 6 weeks followed by a washout period. We assessed supplement tolerability and patient-reported outcomes (PRO) relevant to MS (disability, fatigue, mood, and bowel symptoms) before and after each supplement administration period and each washout period. We bio-archived plasma, serum, peripheral blood mononuclear cells and stool samples at each timepoint for future multi-omic assessment. RESULTS: Prebiotics and probiotics had comparable adherence rates and both supplements were well tolerated in pwMS. Participants on either supplement reported minor adverse events, most of which were mild and self-limited. There was a subjective preference for prebiotics over probiotics. Comparing supplement-associated changes in PRO scores from baseline to 6 weeks post-supplementation, there were significant difference between prebiotics and probiotics for the change in patient-reported global symptom burden (MSRS-R Total) and bowel control (BWCS), but only probiotics statistically improved bowel control from baseline to post-supplementation. CONCLUSION: Supplementation with either prebiotics or probiotics is reasonably well-tolerated and safe. Probiotics improved bowel control, but did not improve other PROs in a 6-week time frame. These data regarding feasibility, tolerability, adherence, and adverse events of supplements will inform future clinical trial designs to definitively compare the efficacy and safety of prebiotics and probiotics. The biological data that will be generated from this study in the future will provide mechanistic insights into the effects of these dietary supplements on MS pathophysiology.

Linking Invasive and Noninvasive Brain Stimulation in Parkinson's Disease: A Randomized Trial.

BACKGROUND: Recent imaging studies identified a brain network associated with clinical improvement following deep brain stimulation (DBS) in Parkinson's disease (PD), the PD response network. OBJECTIVES: This study aimed to assess the impact of neuromodulation on PD motor symptoms by targeting this network noninvasively using multifocal transcranial direct current stimulation (tDCS). METHODS: In a prospective, randomized, double-blinded, crossover trial, 21 PD patients (mean age 59.7 years, mean Hoehn & Yahr [H&Y] 2.4) received multifocal tDCS targeting the a-priori network. Twenty-minute sessions of tDCS and sham were administered on 2 days in randomized order. Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) scores were assessed. RESULTS: Before intervention, MDS-UPDRS-III scores were comparable in both conditions (stimulation days: 37.38 (standard deviation [SD] = 12.50, confidence interval [CI] = 32.04, 42.73) vs. sham days: 36.95 (SD = 13.94, CI = 30.99, 42.91), P = 0.63). Active stimulation resulted in a reduction by 3.6 points (9.7%) to 33.76 (SD = 11.19, CI = 28.98, 38.55) points, whereas no relevant change was observed after sham stimulation (36.43 [SD = 14.15, CI = 30.38, 42.48], average improvement: 0.5 [1.4%]). Repeated-measures analysis of variance (ANOVA) confirmed significance (main effect of time: F(1,20)=4.35, P < 0.05). Tukey's post hoc tests indicated MDS-UPDRS-III improvement after active stimulation (t [20] = 2.9, P = 0.03) but not after sham (t [20] = 0.42, P > 0.05). In a subset of patients that underwent DBS surgery later, their DBS response correlated with tDCS effects (R = 0.55, P(1) = 0.04). CONCLUSION: Noninvasive, multifocal tDCS targeting a DBS-derived network significantly improved PD motor symptoms. Despite a small effect size, this study provides proof of principle for the successful noninvasive neuromodulation of an invasively identified network. Future studies should investigate repeated tDCS sessions and their utility for screening before DBS surgery. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An overview of the CANVAS Program and CREDENCE trial: The primary outcomes and key clinical implications for those managing patients with type 2 diabetes.

AIMS: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event-driven, double-blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD). METHODS AND RESULTS: The CANVAS programme (CANVAS and CANVAS-R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings. CONCLUSION: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium-glucose cotransporter-2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide.

Visceral fat mass dynamics in a 2-year randomized STrength versus ENdurance training trial in people with obesity.

AIM: To compare the effectiveness of strength versus endurance training on reducing visceral fat in individuals with obesity. MATERIALS AND METHODS: For the STrength versus ENdurance (STEN) 24-month randomized clinical trial, we assigned 239 participants with abdominal obesity to either strength or endurance training (two to three times a week, 60 min/training session) in addition to standard nutritional counselling to promote a healthy diet. Changes in abdominal visceral adipose tissue (VAT) area quantified by magnetic resonance imaging after 12 months were defined as a primary endpoint. RESULTS: Participants (aged 44 years, 74% women, body mass index: 37 kg/m2, mean VAT volume: 4050 cm3) had an approximately 50% retention rate and a 30% good training programme adherence at 12 months. There was no difference between strength and endurance training in VAT volume dynamics after 12 and 24 months (p = .13). Only in the good adherence group did we find a trend for reduced VAT volume in both training regimens. Independently of the exercise programme, there was a continuous trend for moderate loss of abdominal subcutaneous AT volume, body fat mass, body mass index and improved parameters of insulin sensitivity. Although parameters of physical fitness improved upon both exercise interventions, the dynamics of resting energy expenditure, glucose and lipid metabolism parameters were not different between the intervention groups and did not significantly improve during the 2-year trial (p > .05). CONCLUSIONS: Despite heterogeneous individual training responses, strength and endurance training neither affected VAT volume nor key secondary endpoints differently.

The implementation of online and offline hybrid weight management approach for pregnant women based on the Fogg behavior model in Hainan, China: a pilot randomized controlled trial.

OBJECTIVE: This study aimed at evaluating the effects of online and offline hybrid weight management approach based on the Fogg behavior model on total gestational weight gain and perinatal outcomes. METHODS: Pregnant women in Hainan, the southernmost province of China, were recruited into a randomized controlled trial, which was designed to develop a WeChat platform for pregnancy weight management, and implement individualized and continuous pregnancy weight management services for pregnant women under the guidance of the Fogg behavior model. All pregnant women participating in the study were included in the full analysis set (FAS) for analysis. The pregnant women who completed the intervention and provided all outcome indicators were included in the per protocol set (PPS) for outcome evaluation. RESULTS: Fifty-eight pregnant women were included in FAS analysis, and 52 pregnant women were finally included in PPS analysis. There was no statistically significant difference (P > 0.05) between the two groups at baseline. The gestational weight gain of the intervention group was significantly lower than that of the control group (P < 0.05). In the control group, the rate of appropriate weight gain during pregnancy was 48.26%, the rate of appropriate weight gain during pregnancy was 93.30% in the intervention group, with a statistically significant difference (P < 0.05). In the delivery outcomes, the cesarean section rate in the intervention group was significantly lower than that in the control group, and the differences were statistically significant (P < 0.05). The incidence of gestational diabetes mellitus and gestational hypertension in the intervention group was lower than those in the control group, and the differences were statistically significant (P < 0.05). The neonatal weight and incidence of macrosomia of the intervention group were lower than that of the control group, and the difference was statistically significant (P < 0.05). CONCLUSIONS: This study combined the individualized and continuous pregnancy weight management of the online WeChat platform and offline consultation based on the Fogg behavior model, showing great potential in improving maternal and infant outcomes. TRIAL REGISTRATION: The study was registered with www.chictr.org.cn/index.aspx , Chinese Clinical Trial Registry (ChiCTR2200066707, 2022-12-14, retrospectively registered).

Increasing goals of care conversations in primary care: Study protocol for a cluster randomized, pragmatic, sequential multiple assignment randomized trial.

BACKGROUND: Goals of care conversations explore seriously ill patients' values to guide medical decision making and often inform decisions about life sustaining treatments. Ideally, conversations occur before a health crisis between patients and clinicians in the outpatient setting. In the United States Veterans Affairs (VA) healthcare system, most conversations still occur in the inpatient setting. Strategies are needed to improve implementation of outpatient, primary care goals of care conversations. METHODS: We plan a cluster randomized (clinician-level) sequential, multiple assignment randomized trial to evaluate the effectiveness of patient implementation strategies on the outcome of goals of care conversation documentation when delivered in combination with clinician implementation strategies. Across three VA healthcare system sites, we will enroll primary care clinicians with low rates of goals of care conversations and their patients with serious medical illness in the top 10th percentile of risk of hospitalization or death. We will compare the effectiveness of sequences of implementation strategies and explore how patient and site factors modify implementation strategy effects. Finally, we will conduct a mixed-methods evaluation to understand implementation strategy success or failure. The design includes two key innovations: (1) strategies that target both clinicians and patients and (2) sequential strategies with increased intensity for non-responders. CONCLUSION: This study aims to determine the effect of different sequences and combinations of implementation strategies on primary care documentation of goals of care conversations. Study partners, including the VA National Center for Ethics in Health Care and Office of Primary Care, can consider policies based on study findings.

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.

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.