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Purpose: To evaluate the influence of immediate loading on the osseointegration and bone density of implants placed in a healed alveolar bone crest and supporting single crowns. Materials and Methods: Two solid titanium transmucosal mini-implants were placed in the distal regions of the mandible in 14 patients. One mini-implant was immediately functionally loaded, whereas the other was left unloaded. After 2 months of healing, biopsy samples were retrieved and the levels of new bone, old bone, and total bone (new + old) were assessed. Results: Histologic examination was performed on biopsies from 12 patients (n = 12). The new bone-to-implant contact percentage (BIC%) was 40.3% ± 16.8% and 55.1% ± 19.1% (P = .043) at the unloaded and loaded sites, respectively; in addition, the total BIC% was 44.9% ± 17.0% and 59.5% ± 18.8%, respectively (P = .034). The new bone density was 45.9% ± 11.6% for the unloaded implants and 45.9% ± 16.7% for the loaded implants (P = .622). Conclusions: Immediate loading had a positive effect on bone apposition at the implant surface, but no effect on bone density was observed after 2 months of healing. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the clinical accuracy of a robotically assisted implant guidance system in partially edentulous patients without the use of postoperative CBCT. Materials and Methods: A total of 10 implants (7 patients) were placed in partially edentulous patients utilizing a robotically assisted implant guidance system. Following the implant placement, an intraoral scan was performed to register the implant position after attaching a scan body. The virtual plan and the postoperative intraoral scan with the scan bodies were exported as STL files and superimposed, and discrepancies were analyzed using Geomagic Control X software. Positional deviations were measured between the midpoint of the platform and apex of the planned and achieved implant positions. Results: Seven of the 10 implants in this study were defined as fully robotically guided, while 3 were partially robotically guided. For the fully robotic dynamically guided group, the mean deviation at the midpoint of the restorative platform of the implant, the apex of the implant, the top of the scan body, and the mean angular deviation were 1.31 ± 0.46 mm, 1.58 ± 0.61 mm, 1.11 ± 0.57 mm, and 2.34 ± 1.71 degrees, respectively. For the partially robotic dynamically guided cases, these values were 1.31 ± 0.49 mm, 1.45 ± 0.3 mm, 1.74 ± 0.47 mm, and 3.75 ± 2.53 degrees, respectively. Eight of the 10 implants (irrespective of full or partial guidance) showed a buccal displacement. Conclusions: Robotic surgery offers a level of accuracy similar to fully guided implant placement, without the need for a physical template, and allows for changes in the surgical plan at any time. The analytical method described in this study is an effective and radiation-free quality-control tool that can be used in implant dentistry as well as in other areas of dental research. [ABSTRACT FROM AUTHOR]

The Response Evaluation in Solid Tumors (RECIST) 1.1 provides key guidance for performing imaging response assessment and defines image-based outcome metrics in oncology clinical trials, including progression free survival. In this framework, tumors identified on imaging are designated as either target lesions, non-target disease or new lesions and a structured categorical response is assigned at each imaging time point. While RECIST provides definitions for these categories, it specifically and objectively defines only the target disease. Predefined thresholds of size change provide unbiased metrics for determining objective response and disease progression of the target lesions. However, worsening of non-target disease or emergence of new lesions is given the same importance in determining disease progression despite these being qualitatively assessed and less rigorously defined. The subjective assessment of non-target and new disease contributes to reader variability, which can impact the quality of image interpretation and even the determination of progression free survival. The RECIST Working Group has made significant efforts in developing RECIST 1.1 beyond its initial publication, particularly in its application to targeted agents and immunotherapy. A review of the literature highlights that the Working Group has occasionally employed or adopted objective measures for assessing non-target and new lesions in their evaluation of RECIST-based outcome measures. Perhaps a prospective evaluation of these more objective definitions for non-target and new lesions within the framework of RECIST 1.1 might improve reader interpretation. Ideally, these changes could also better align with clinically meaningful outcome measures of patient survival or quality of life.

INTRODUCTION: It remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial II (DETECT II), a multicentre, outcome-masked, randomised, placebo-controlled, clinical trial comparing DMEK to DSO with ripasudil (DSO-R) for this patient population. METHODS AND ANALYSIS: A total of 60 patients with endothelial dysfunction due to symptomatic FECD will be enrolled from seven participating sites in the USA. The patients will be randomly assigned in a 1:1 ratio to one of the following treatment groups: group 1-DMEK plus topical placebo and group 2-DSO plus topical ripasudil 0.4%. The enrolment period is 24 months. The primary outcome is best spectacle-corrected visual acuity at 12 months. Secondary outcomes include peripheral and central endothelial cell density, visual acuity, vision-related quality of life and Pentacam Scheimpflug tomography. Study outcomes will be analysed using mixed effects linear regression. Adverse events, including rebubble procedures, endothelial failure and graft rejection, will be documented and analysed using appropriate statistical methods. DETECT II aims to provide evidence on the comparative effectiveness of DMEK and DSO-R. The results of this trial will contribute to optimising the treatment of FECD, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee has been empanelled by the National Eye Institute. All study protocols will be subject to review and approval by WCG IRB as the single IRB of record. This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request. TRIAL REGISTRATION NUMBER: NCT05275972.

BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

BackgroundTo address the need for treatments for patients with coronavirus disease 2019 (COVID-19), 3 therapies have been given either full approval or Emergency Use Authorization. These were based on randomized data showing a reduction in deaths/hospitalization, but since then, circulating viral strains and population immunity have changed.MethodsWe searched PubMed, Web of Science, Embase, and ClinicalTrials.gov for clinical trials testing nirmatrelvir/ritonavir and molnupiravir for COVID-19. We identified all trials testing nirmatrelvir/ritonavir and molnupiravir in patients with COVID-19 and assessed the pooled efficacy in a meta-analysis. We calculated pooled estimates of hospitalization and death in patients with COVID-19 and the number of studies with published/reported data.ResultsOf the 23 studies found, 11 tested nirmatrelvir/ritonavir, 10 tested molnupiravir, and 2 tested both agents. The pooled estimate in reducing deaths and hospitalization for molnupiravir was 0.62 (95% confidence interval [CI], 0.15-2.53), and the pooled estimate for nirmatrelvir/ritonavir was 0.33 (95% CI, 0.03-3.35). The 1 nirmatrelvir/ritonavir trial that reported significant improvements tested people who were predominantly infected with earlier COVID-19 variants, whereas the 2 null trials were tested in people infected with more recent variants. The 2 positive molnupiravir trials included participants primarily with the Delta variant, whereas the null trials were tested later, against more recent variants.ConclusionsWhile early trial data show effectiveness of these therapies, the overall pooled effects are nonsignificant, suggesting that recommendations and use of approved oral COVID-19 treatment therapies need to be reevaluated in the context of current viral strains and population immunity.

INTRODUCTION: Poor communication about serious injury in older adults can lead to treatment that is inconsistent with patient preferences, create conflict and strain healthcare resources. We developed a communication intervention called Best Case/Worst Case-intensive care unit (ICU) that uses daily scenario planning, that is, a narrative description of plausible futures, to support prognostication and facilitate dialogue among patients, their families and the trauma ICU team. This article describes a protocol for a multisite, randomised, stepped-wedge study to test the effectiveness of the intervention on the quality of communication (QOC) in the ICU. METHODS AND ANALYSIS: We will follow all patients aged 50 and older admitted to the trauma ICU for 3 or more days after a serious injury at eight high-volume level 1 trauma centres. We aim to survey one family or like family member per eligible patient 5-7 days following their loved ones admission and clinicians providing care in the trauma ICU. Using a stepped-wedge design, we will use permuted block randomisation to assign the timing for each site to begin implementation of the intervention and routine use of the Best Case/Worst Case-ICU tool. We will use a linear mixed-effects model to test the effect of the tool on family-reported QOC (using the QOC scale) as compared with usual care. Secondary outcomes include the effect of the tool on reducing clinician moral distress (using the Measure of Moral Distress for Healthcare Professionals scale) and patients length of stay in the ICU. ETHICS AND DISSEMINATION: Institutional review board (IRB) approval was granted at the University of Wisconsin, and all study sites ceded review to the primary IRB. We plan to report results in peer-reviewed publications and national meetings. TRIAL REGISTRATION NUMBER: NCT05780918.

BACKGROUND: Amyloid beta protein (Aβ) is a treatment target in Alzheimers Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. METHODS: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. RESULTS: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. CONCLUSIONS: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. TRIAL REGISTRATION: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Purpose: The study evaluated the clinical performance of partial indirect resin composite (PIRC) restorations with "proximal box elevation" (PBE) placed in molars. Materials and Methods: Sixty-three patients received 80 posterior PIRC (SR Nexco, Ivoclar Vivadent) restorations. Large posterior defects with cuspal loss and deep cervical margins were included in the study. PBE was performed priorto preparation and impression making. Two independent observers evaluated the restorations using the FDI criteria (scores 1-5) foresthetic, functional, and biological properties. Patients were recalled at 6 months and 1, 2, and 3 years. Overall success rates were calculated (Kaplan-Meier analysis) and compared (log-rank tests) according to baseline variables. The impact of the baseline variables on the failure of the restorations was analyzed (multiple proportional Cox regression). Results: Seventy-nine (98.7%), 69 (88.4%), 66 (92.9%), 44 (86.2%) and 45 (91.8%) PIRCs completed their follow up at baseline, 6 months, and 1, 2 and 3 years, respectively. In total, 10 failures were observed: 5 with partial loss, 4 with material chipping, and one with secondary caries, yielding an overall success rate of 87.5% and a survival rate of 93.8%, with a mean observation timeof 26.5 ± 13.6 months. Conclusions: PIRCs with PBE demonstrated a high survival rate and satisfactory esthetic properties. Failure was less likelyfor PIRC restorations with partial cuspal coverage (onlay) compared to full cuspal coverage (overlay). [ABSTRACT FROM AUTHOR]

IntroductionAdverse sexual and reproductive health (SRH) outcomes, such as unplanned pregnancies and HIV infection, disproportionately affect adolescent girls and young women (AGYW; aged 15-24 years) in east Africa. Increasing uptake of preventive SRH services via innovative, youth-centred interventions is imperative to addressing disparities in SRH outcomes.Methods and analysisFrom 2018 to 2019, we used human-centred design to co-develop a theoretically driven HIV and pregnancy prevention intervention for AGYW at private drug shops called Accredited Drug Dispensing Outlets (ADDOs) in Tanzania. The result, Malkia Klabu (Queen Club), was a customer loyalty programme designed to strengthen ADDOs' role as SRH providers while encouraging uptake of critical SRH prevention products among AGYW. Malkia Klabu members had access to free contraceptives and oral HIV self-test (HIVST) kits and earned punches on a loyalty card for other shop purchases; punches were redeemable for small prizes. Our pilot among 40 shops showed that intervention ADDOs had higher AGYW patronage and distributed more HIVST kits and contraceptives to AGYW relative to business-as-usual (ie, client purchasing) comparison shops. We will conduct a cluster-randomised controlled trial (c-RCT) among 120-140 ADDOs in 40 health catchment areas in Shinyanga and Mwanza Regions (Lake Zone), Tanzania. ADDO shop recruitment includes a 1-month run-in with a tablet-based electronic inventory management system for tracking shop transactions, followed by enrolment, randomisation and a 24-month trial period. Our c-RCT evaluating the human-centred design-derived intervention will assess population impact on the primary outcomes of HIV diagnoses and antenatal care registrations, measured with routine health facility data. We will also assess secondary outcomes focusing on mechanisms of action, evaluate programme exposure and AGYW behaviour change in interviews with AGYW, and assess shop-level implementation strategies and fidelity.Ethics and disseminationEthical approval was granted from both the University of California, San Francisco and the Tanzanian National Institute for Medical Research. Study progress and final outcomes will be posted annually to the National Clinical Trials website; study dissemination will occur at conferences, peer-reviewed manuscripts and local convenings of stakeholders.Trial registration numberNCT05357144.

IntroductionGlobally, transgender ('trans') women experience extreme social and economic marginalisation due to intersectional stigma, defined as the confluence of stigma that results from the intersection of social identities and positions among those who are oppressed multiple times. Among trans women, gender-based stigma intersects with social positions such as engagement in sex work and substance use, as well as race-based stigma to generate a social context of vulnerability and increased risk of HIV acquisition. In Brazil, trans women are the 'most at-risk' group for HIV, with 55 times higher estimated odds of HIV infection than the general population; further, uptake of HIV testing and pre-exposure prophylaxis (PrEP) among trans women is significantly lower than other at-risk groups. Through extensive formative work, we developed Manas por Manas, a multilevel intervention using HIV prevention strategies with demonstrated feasibility and acceptability by trans women in Brazil, to address intersectional stigma and increase engagement in the HIV prevention continuum.Methods and analysisWe are conducting a two-arm randomised wait-list controlled trial of the intervention's efficacy in São Paulo, Brazil, to improve uptake of HIV testing and PrEP among transgender women (N=400). The primary outcomes are changes in HIV testing (self-testing and clinic based), changes in PrEP uptake and changes in PrEP persistence at baseline and follow-up assessment for 12 months at 3-month intervals.Ethics and disseminationThis study was approved by University of California, San Francisco Institutional Review Board (15-17910) and Comissão Nacional de Ética em Pesquisa (Research Ethics National Commission, CAAE: 25215219.8.0000.5479) in Brazil. Participants provided informed consent before enrolment. We are committed to collaboration with National Institutes of Health officials, other researchers, and health and social services communities for rapid dissemination of data and sharing of materials. The results will be published in peer-reviewed academic journals and scientific presentations.Trial registration numberNCT03081559.

INTRODUCTION: A three-pronged approach to acne treatment combining an antibiotic, antimicrobial, and retinoid may be more efficacious than single/double treatments while potentially reducing antibiotic resistance. This study evaluated the efficacy and safety of the first fixed-dose, triple-combination topical acne product, clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) using pooled phase 3 data. METHODS: In two identical phase 3 (N = 183; N = 180), double-blind, 12-week studies, participants aged ≥ 9 years with moderate-to-severe acne were randomized 2:1 to receive once-daily CAB or vehicle gel. Endpoints included ≥ 2-grade reduction from baseline in Evaluators Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in acne lesion counts. Treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were evaluated. RESULTS: At week 12, 50.0% of participants achieved treatment success with CAB versus 22.6% with vehicle gel (P  70% reductions in inflammatory and noninflammatory lesions at week 12 (77.9% and 73.0%, respectively), which were significantly greater than vehicle (57.9% and 48.2%; P

BACKGROUND: Observing medication ingestion through self-recorded videos (video directly observed therapy [VDOT]) has been shown to be a cost-effective alternative to in-person directly observed therapy (DOT) for monitoring adherence to treatment for tuberculosis disease. VDOT could be a useful tool to monitor short-course latent tuberculosis infection (LTBI) treatment. METHODS: We conducted a prospective randomized controlled trial comparing VDOT (intervention) and clinic-based DOT (control) among patients newly diagnosed with LTBI who agreed to a once-weekly 3-month treatment regimen of isoniazid and rifapentine. Study outcomes were treatment completion and patient satisfaction. We also assessed costs. Pre- and posttreatment interviews were conducted. RESULTS: Between March 2016 and December 2019, 130 participants were assigned to VDOT (n = 68) or DOT (n = 62). Treatment completion (73.5% vs 69.4%, P = .70) and satisfaction with treatment monitoring (92.1% vs 86.7%, P = .39) were slightly higher in the intervention group than the control group, but neither was statistically significant. VDOT cost less per patient (median, $230; range, $182-$393) vs DOT (median, $312; range, $246-$592) if participants used their own smartphone. CONCLUSIONS: While both groups reported high treatment satisfaction, VDOT was not associated with higher LTBI treatment completion. However, VDOT cost less than DOT. Volunteer bias might have reduced the observed effect since patients opposed to any treatment monitoring could have opted for alternative unobserved regimens. Given similar outcomes and lower cost, VDOT may be useful for treatment monitoring when in-person observation is prohibited or unavailable (eg, during a respiratory disease outbreak). The trial was registered at the National Institutes of Health (ClinicalTrials.gov NTC02641106). CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NTC02641106; registered 24 October 2016.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Purpose: To evaluate two pharmacologic antibiotic prophylaxis regimens and a control group of immunocompetent patients undergoing two-stage dental implant placement in a triple-blind randomized controlled clinical trial. Materials and Methods: From a group of 61 immunocompetent patients, 21 were randomly allocated into group 1 (G1) without antibiotic prophylaxis (control), 20 in group 2 (G2) with preoperative antibiotic prophylaxis (1 g amoxicillin 1 hour before the procedure), and 20 in group 3 (G3) with preoperative (1 g amoxicillin) and postoperative (500 mg every 8 hours for 5 days) antibiotic prophylaxis. Pain was assessed with the visual analog scale (VAS) and by considering the number of painkillers patients used. Infection was identified via the presence of pus and fistula. Patients were evaluated after 7, 14, 30, and 120 days. Implant failure (defined as mobility upon the application of manual torque) was evaluated after 120 days during the second surgical stage. Results: At the 7-day follow-up, pain intensity was less severe in the patients who had received antibiotics, with the G3 patients experiencing the least pain (P < .05). Infection was present in groups G1 (2 cases) and G3 (2 cases), but there was no statistically significant intergroup difference. Two implants failed, one in G1 and the other in G3. Conclusions: Based on the results of the present study, although the use of antibiotics reduced pain in the immediate postoperative period, it did not reduce infection rates and implant failure in immunocompetent patients. [ABSTRACT FROM AUTHOR]

INTRODUCTION: As malaria declines, low-density malaria infections (LMIs) represent an increasing proportion of infections and may have negative impacts on child health and cognition, necessitating development of targeted and effective solutions. This trial assesses the health, cognitive and socioeconomic impact of two strategies for detecting and treating LMI in a low transmission setting. METHODS AND ANALYSIS: The study is a 3-arm open-label individually randomised controlled trial enrolling 600 children aged 6 months to 10 years in Bagamoyo district, Tanzania. Children are randomised to one of three arms: active case detection with molecular (ACDm) testing by high volume quantitative PCR (qPCR), passive case detection also with molecular testing (PCDm) and a control of standard PCD using rapid diagnostics tests (RDTs). Over the 2-year trial, ACDm participants receive malaria testing using RDT and qPCR three times annually, and malaria testing by RDT only when presenting with fever. PCDm and PCD participants receive malaria testing by RDT and qPCR or RDT only, respectively, when presenting with fever. RDT or qPCR positive participants with uncomplicated malaria are treated with artemether lumefantrine. The primary outcome is cumulative incidence of all-cause sick visits. Secondary outcomes include fever episodes, clinical failure after fever episodes, adverse events, malaria, non-malarial infection, antibiotic use, anaemia, growth faltering, cognition and attention, school outcomes, immune responses, and socioeconomic effects. Outcomes are assessed through monthly clinical assessments and testing, and baseline and endline neurodevelopmental testing. The trial is expected to provide key evidence and inform policy on health, cognitive and socioeconomic impact of interventions targeting LMI in children. ETHICS AND DISSEMINATION: Study is approved by Tanzania NatHREC and institutional review boards at University of California San Francisco and Ifakara Health Institute. Findings will be reported on ClinicalTrials.gov, in peer-reviewed journals and through stakeholder meetings. TRIAL REGISTRATION NUMBER: NCT05567016.

BackgroundPeople living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated.ObjectiveThis study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase.MethodsDuring the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts.ResultsMS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians.ConclusionsCreated with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense-funded feasibility and efficacy trial, which is now underway.Trial registrationClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x.

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined brain frailty markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging brain frailty was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

INTRODUCTION: Depression occurs in over 50% of individuals living with multiple sclerosis (MS) and can be treated using many modalities. Yet, it remains: under-reported by patients, under-ascertained by clinicians and under-treated. To enhance these three behaviours likely to promote evidence-based depression care, we engaged multiple stakeholders to iteratively design a first-in-kind digital health tool. The tool, MS CATCH (Care technology to Ascertain, Treat, and engage the Community to Heal depression in patients with MS), closes the communication loop between patients and clinicians. Between clinical visits, the tool queries patients monthly about mood symptoms, supports patient self-management and alerts clinicians to worsening mood via their electronic health record in-basket. Clinicians can also access an MS CATCH dashboard displaying patients mood scores over the course of their disease, and providing comprehensive management tools (contributing factors, antidepressant pathway, resources in patients neighbourhood). The goal of the current trial is to evaluate the clinical effect and usability of MS CATCH in a real-world clinical setting. METHODS AND ANALYSIS: MS CATCH is a single-site, phase II randomised, delayed start, trial enrolling 125 adults with MS and mild to moderately severe depression. Arm 1 will receive MS CATCH for 12 months, and arm 2 will receive usual care for 6 months, then MS CATCH for 6 months. Clinicians will be randomised to avoid practice effects. The effectiveness analysis is superiority intent-to-treat comparing MS CATCH to usual care over 6 months (primary outcome: evidence of screening and treatment; secondary outcome: Hospital Anxiety Depression Scale-Depression scores). The usability of the intervention will also be evaluated (primary outcome: adoption; secondary outcomes: adherence, engagement, satisfaction). ETHICS AND DISSEMINATION: University of California, San Francisco Institutional Review Board (22-36620). The findings of the study are planned to be shared through conferences and publishments in a peer-reviewed journal. The deidentified dataset will be shared with qualified collaborators on request, provision of CITI and other certifications, and data sharing agreement. We will share the results, once the data are complete and analysed, with the scientific community and patient/clinician participants through abstracts, presentations and manuscripts. TRIAL REGISTRATION NUMBER: NCT05865405.

BACKGROUND: It remains uncertain which endothelial keratoplasty (EK) technique yields the best outcomes while maintaining safety, particularly in eyes with coexisting ocular conditions. Moreover, the impact of endothelial cell loss (ECL) on long-term graft survival requires further investigation. Adjuvant ripasudil, a rho kinase inhibitor, may address the challenge of ECL in corneal transplantation. This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial 1 (DETECT 1), a multicentre, outcome-masked, randomised, placebo-controlled, four-arm clinical trial. METHODS: A total of 160 eligible patients with endothelial dysfunction will be enrolled from five participating sites in the USA. The patients will be randomly assigned in a 2×2 factorial design to one of the following treatment groups: group 1-ultrathin Descemet stripping endothelial keratoplasty (UT-DSAEK) plus topical ripasudil 0.4%; group 2-UT-DSAEK plus topical placebo; group 3-Descemet membrane endothelial keratoplasty (DMEK) plus topical ripasudil 0.4% and group 4-DMEK plus topical placebo. Primary outcomes include the best spectacle-corrected visual acuity at 12 months and ECL at 12 months. Secondary outcomes include visual acuity at different time points, vision-related quality of life, endothelial cell morphology and cost-effectiveness. RESULTS: The study outcomes will be analysed using mixed effects linear regression models, taking into account the treatment arms and relevant covariates. Adverse events, including rebubble procedures, graft failure and graft rejection, will be documented and analysed using appropriate statistical methods. CONCLUSION: DETECT I aims to provide evidence on the comparative effectiveness of UT-DSAEK and DMEK, as well as the potential benefits of adjuvant topical ripasudil in reducing ECL. The results of this trial will contribute to optimising corneal transplantation techniques and improving long-term graft survival, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation. ETHICS AND DISSEMINATION: A data and safety monitoring committee (DSMC) has been empaneled by the NEI.All study protocols will be subject to review and approval by WCG IRB as the single IRB of record.This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Preclinical models are ubiquitous and essential for drug discovery, yet our understanding of how well they translate to clinical outcomes is limited. In this study, we investigate the translational success of treatments for Clostridium difficile infection from animal models to human patients. Our analysis shows that only 36% of the preclinical and clinical experiment pairs result in translation success. Univariate analysis shows that the sustained response endpoint is correlated with translation failure (SRC = -0.20, p-value = 1.53 × 10-54), and explainability analysis of multi-variate random forest models shows that both sustained response endpoint and subject age are negative predictors of translation success. We have developed a recommendation system to help plan the right preclinical study given factors such as drug dosage, bacterial dosage, and preclinical/clinical endpoint. With an accuracy of 0.76 (F1 score of 0.71) and by using only 7 features (out of 68 total), the proposed system boosts translational efficiency by 25%. The method presented can extend to any disease and can serve as a preclinical to clinical translation decision support system to accelerate drug discovery and de-risk clinical outcomes.

BackgroundThere are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder.MethodsThis is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18-65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles.DiscussionThis trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine.Trial registrationAustralian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.

Importance: The call for robust randomized clinical trials (RCTs) comparing Mohs micrographic surgery (MMS) with wide local excision for treatment of melanoma has stymied the development of guidelines for MMS despite growing evidence of benefit. This commentary explores the controversy by detailing opposing arguments, reviewing the relevant evidence supporting the use of MMS for early-stage melanoma, and discussing the role that RCTs may play in development of national guidelines for surgical treatment options for melanoma. Randomized clinical trials are considered the gold standard of clinical research, but there are no such trials currently to support MMS for melanoma. However, there is a growing literature base of retrospective and prospective cohorts and meta-analyses consistently demonstrating the efficacy and cost-effectiveness of MMS for melanoma. The dearth of clear consensus guidelines has contributed to confusion by referring specialties, controversy across specialties managing melanoma, and inequality in access. Recognizing that this is an ongoing area of discussion within dermatologic surgery, we explore opposing arguments with regard to the demand for RCT data to support dermatologic surgery practices.

BACKGROUND: Validating the National Institutes of Health NIH Stroke Scale (NIHSS) as a tool to assess deficit severity and prognosis in patients with acute intracerebral hemorrhage would harmonize the assessment of intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) patients, enable clinical use of a readily implementable and non-imaging dependent prognostic tool, and improve monitoring of ICH care quality in administrative datasets. METHODS: Among randomized trial ICH patients, the relation between NIHSS scores early after Emergency Department arrival and 3-month outcomes of dependency or death (modified Rankin Scale, mRS 3-6) and case fatality was examined. NIHSS predictive performance was compared to a current standard prognostic scale, the intracerebral hemorrhage score (ICH score). RESULTS: Among the 384 patients, the mean age was 65 (±13), with 66% being male. The median NIHSS score was 16 (interquartile range (IQR) 9-25), the mean initial hematoma volume was 29 mL (±38), and the ICH score median was 1 (IQR 0-2). At 3 months, the mRS had a median of 4 (IQR 2-6), with dependency or death occurring in 70% and case fatality in 26%. The NIHSS and ICH scores were strongly correlated (r = 0.73), and each was strongly correlated with the 90-day mRS (NIHSS, r = 0.61; ICH score, r = 0.62). The NIHSS performed comparably to the ICH score in predicting both dependency or death (c = 0.80 vs. 0.80, p = 0.83) and case fatality (c = 0.78 vs. 0.80, p = 0.29). At threshold values, the NIHSS predicted dependency or death with 74.1% accuracy (NIHSS 17.5) and case fatality with 75.0% accuracy (NIHSS 18.5). CONCLUSION: The NIHSS forecasts 3-month functional and case fatality outcomes with accuracy comparable to the ICH Score. Widely documented in routine clinical care and administrative data, the NIHSS can serve as a valuable measure for clinical prognostication, therapy development, and case-mix risk adjustment in ICH patients.Clinical trial registrationClinicaltrials.gov, NCT00059332.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p

PURPOSE: Although interventions can increase advance care planning (ACP) engagement, it remains unclear which interventions to choose in primary care settings. This study compares a passive intervention (mailed materials) to an interactive intervention (group visits) on participant ACP engagement and experiences. METHODS: We used mixed methods to examine ACP engagement at baseline and six months following two ACP interventions. Eligible patients were randomized to receive mailed materials or participate in two ACP group visits. We administered the 4-item ACP Engagement survey (n = 110) and conducted interviews (n = 23). We compared mean scores and percent change in ACP engagement, analyzed interviews with directed content analysis to understand participants ACP experiences, and integrated the findings based on mailed materials or group visits intervention. RESULTS: All participants demonstrated increased ACP engagement scores. At six months, group visit participants reported higher percent change in mean overall score compared with mailed materials participants (+8% vs +3%, P

BackgroundClinical trials using psilocybin therapy to treat anorexia nervosa (AN) are currently underway. The safety and tolerability of psilocybin is of utmost importance in individuals with AN who may present unique medical vulnerabilities. The purpose of this review is to describe how the common physiologic adverse effects of psilocybin may impact medical complications experienced by individuals with AN in clinical trials of psilocybin therapy.Main bodyThe physiologic underpinnings of common adverse effects following psilocybin administration are described, including tachycardia, hypertension, electrocardiogram changes, nausea, headache, and lightheadedness. These anticipated physiologic changes are described in relation to the common medical correlates seen in individuals with AN. Risk mitigation strategies for each adverse effect are proposed.ConclusionEarly evidence suggests that psilocybin therapy is well-tolerated in individuals with AN. Understanding the unique medical complications of AN, and how they may be impacted by common physiologic adverse effects of psilocybin administration, leads to tailored risk mitigation strategies to enhance safety and tolerability of this novel intervention.

For patients with functional mitral regurgitation (FMR) and symptomatic heart failure (HF), randomized trials of mitral transcatheter edge-to-edge repair (M-TEER) have produced conflicting results. This study sought to assess the impact of M-TEER on hospitalization rates, and explore the effects of M-TEER on patients who did or did not have a history of recent HF hospitalizations before undergoing M-TEER. RESHAPE-HF2 (Randomized Investigation of the MitraClip Device in Heart Failure: 2nd Trial in Patients with Clinically Significant Functional Mitral Regurgitation) included patients with symptomatic HF and moderate to severe FMR (mean effective regurgitant orifice area 0.25 cm2; 14% >0.40 cm2, 23% <0.20 cm2) and showed that M-TEER reduced recurrent HF hospitalizations with and without the addition of cardiovascular (CV) death and improved quality of life. We now report the results of prespecified analyses on hospitalization rates and for the subgroup of patients (n = 333) with a HF hospitalization in the 12 months before randomization. At 24 months, the time to first event of CV death or HF hospitalization (HR: 0.65; 95% CI: 0.49-0.85; P = 0.002), the rate of recurrent CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.57-0.99; P = 0.046), the composite rate of recurrent CV hospitalizations and all-cause mortality (RR: 0.74; 95% CI: 0.57-0.95; P = 0.017), and of recurrent CV death and CV hospitalizations (RR: 0.76; 95% CI: 0.58-0.99; P = 0.040), were all lower in the M-TEER group. The RR of recurrent hospitalizations for any cause was 0.82 (95% CI: 0.63-1.07; P = 0.15) for patients in the M-TEER group vs control group patients. Patients randomized to M-TEER lost fewer days due to death or HF hospitalization (13.9% [95% CI: 13.0%-14.8%] vs 17.4% [95% CI: 16.4%-18.4%] of follow-up time; P < 0.0001, and 1,067 vs 1,776 total days lost; P < 0.0001). Patients randomized to M-TEER also had better NYHA functional class at 30 days and at 6, 12, and 24 months of follow-up (P < 0.0001). A history of HF hospitalizations before randomization was associated with worse outcomes and greater benefit with M-TEER on the rate of the composite of recurrent HF hospitalizations and CV death (P interaction = 0.03) and of recurrent HF hospitalizations within 24 months (P interaction = 0.06). These results indicate that a broader application of M-TEER in addition to optimal guideline-directed medical therapy should be considered among patients with symptomatic HF and moderate to severe FMR, particularly in those with a history of a recent hospitalization for HF. [ABSTRACT FROM AUTHOR]

Single-pill combinations of 3 or more low-dose blood pressure (BP)–lowering drugs hold promise for initial or early treatment of hypertension. The authors conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety. This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event. From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were −7.3 mm Hg (95% CI: −4.5 to −10.2) for GMRx2 ¼ dose and −8.2 mm Hg (95% CI: −5.2 to −11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group. In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306) [ABSTRACT FROM AUTHOR]

The diversity and delicate balance of the oral microbiome contribute to oral health, with its disruption leading to oral and systemic diseases. Toothpaste includes elements like traditional additives such as sodium lauryl sulfate (SLS) as well as novel postbiotics derived from probiotics, which are commonly employed for maintaining oral hygiene and a healthy oral cavity. However, the response of the oral microbiota to these treatments remains poorly understood. In this study, we systematically investigated the impact of SLS, and toothpaste containing postbiotics (hereafter, postbiotic toothpaste) across three systems: biofilms, animal models, and clinical populations. SLS was found to kill bacteria in both preformed biofilms (mature biofilms) and developing biofilms (immature biofilms), and disturbed the microbial community structure by increasing the number of pathogenic bacteria. SLS also destroyed periodontal tissue, promoted alveolar bone resorption, and enhanced the extent of inflammatory response level. The postbiotic toothpaste favored bacterial homeostasis and the normal development of the two types of biofilms in vitro, and attenuated periodontitis and gingivitis in vivo via modulation of oral microecology. Importantly, the postbiotic toothpaste mitigated the adverse effects of SLS when used in combination, both in vitro and in vivo. Overall, the findings of this study describe the impact of toothpaste components on oral microflora and stress the necessity for obtaining a comprehensive understanding of oral microbial ecology by considering multiple aspects. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to evaluate the modulating effects of five commonly used sweetener (glucose, inulin, isomaltulose, tagatose, trehalose) containing mouth rinses on the oral microbiome. Methods: A single-centre, double-blind, parallel randomized clinical trial was performed with healthy, 18–55-year-old volunteers (N = 65), who rinsed thrice-daily for two weeks with a 10% solution of one of the allocated sweeteners. Microbiota composition of supragingival dental plaque and the tongue dorsum coating was analysed by 16S RNA gene amplicon sequencing of the V4 hypervariable region (Illumina MiSeq). As secondary outcomes, dental plaque red fluorescence and salivary pH were measured. Results: Dental plaque microbiota changed significantly for two groups: inulin (F = 2.0239, p = 0.0006 PERMANOVA, Aitchison distance) and isomaltulose (F = 0.67, p = 0.0305). For the tongue microbiota, significant changes were observed for isomaltulose (F = 0.8382, p = 0.0452) and trehalose (F = 1.0119, p = 0.0098). In plaque, 13 species changed significantly for the inulin group, while for tongue coating, three species changed for the trehalose group (ALDEx2, p < 0.1). No significant changes were observed for the secondary outcomes. Conclusion: The effects on the oral microbiota were sweetener dependant with the most pronounced effect on plaque microbiota. Inulin exhibited the strongest microbial modulating potential of the sweeteners tested. Further full-scale clinical studies are required. [ABSTRACT FROM AUTHOR]

Participation in a paediatric, complex randomized controlled trial (RCT) might add to the family burden when a child is diagnosed with a severe disease. Although important, there are only a limited number of papers describing this aspect of research from the family point of view. This study explored parents' and children's experiences of participation in a research study shortly after the child had been diagnosed with type 1 diabetes. Sixteen parents (nine mothers, seven fathers) and nine children were interviewed by an independent researcher about their inducement, the decision-making process within the family which led to their participation, and their experience of having done so. The result showed that the parents wanted to contribute to improve treatment for children with diabetes in general but also specifically for their own child. Older children were more involved in the decision making than the younger children. Study information needs to be communicated clearly and effectively since decision-making based on information of a clinical trial directly after the child's diabetes onset proved difficult. Being randomized to the intervention group in this specific study was considered somewhat burdensome. However, parental participants in both intervention and control group claimed that they would recommend participation in research studies to other parents in a similar situation, and so did the children. There was no difference between the mothers' and fathers' experiences. Implications: Parents' expectations: A predominant driving force for the parents was the expectation that the study outcome could lead to something good for both their own child and other children with type 1 diabetes. Children's perspective on participation: Older children appreciated being involved in the decision-making process and valued their role in potentially helping others with diabetes. However, younger children were less involved and often relied on their parents for decision-making. Personal benefits: Both children and parents considered it important to gain something for themselves; by participating, they could benefit from more advanced technology and more rigorous follow-ups. Importance of control group: It was important for the families' motivation for completing the study that the researchers conveyed that the control group was as important for the outcome of the study as the intervention group. Future treatments: The parents felt that participation in the clinical trial could eventually lead to new treatments that could help their own child. Perceived safety: The fact that the clinical trial was considered well-planned and safe and implied no risk for the child made it easier to agree to participation. Effective communication: Since the onset of diabetes is emotionally stressful, and diabetes treatment itself is demanding, effective communication about the content of such a clinical trial is necessary, otherwise families may not understand what they are agreeing to. Burden on the intervention group: This clinical trial was somewhat burdensome for the intervention group to participate in; nevertheless, all of the families remained committed to their reasons for participating and completed the study [ABSTRACT FROM AUTHOR]

The benefit of the delivery of the right form of cancer care, tailored to the right patient, at the right time is increasingly being recognized in the global oncology community. Information on the role and feasible potential of precision oncology during the management of genitourinary cancer in Nigeria, the most populous country in Africa, is limited. This article, therefore, describes the present application of personalized medicine in Nigeria and its barriers and facilitators. It provided granular details on manpower distribution and epidemiological disparities. It also explored the use of clinical and biological markers for screening and early diagnosis, the application of team science to support genomic profiling, cost-effective approaches for image-based phenotypic precision oncology, the emerging role of molecular imaging, access to clinical trials; and their potential to support data driven diagnosis, treatment decision and care availability in order to address gaps in genitourinary cancer management in the country. [ABSTRACT FROM AUTHOR]

Rationale: Neurological conditions like Stroke and Alzheimer's disease (AD) often include inflammatory responses in the nervous system. Stroke, linked to high disability and mortality rates, poses challenges related to organ-related complications. Recent focus on understanding the pathophysiology of ischemic stroke includes aspects like cellular excitotoxicity, oxidative stress, cell death mechanisms, and neuroinflammation. Objective: The objective of this paper is to summarize and explore the pathophysiology of ischemic stroke, elucidates the gut-brain axis mechanism, and discusses recent clinical trials, shedding light on novel treatments and future possibilities. Results: Changes in gut architecture and microbiota contribute to dementia by enhancing intestinal permeability, activating the immune system, elevating proinflammatory mediators, altering blood-brain barrier (BBB) permeability, and ultimately leading to neurodegenerative diseases (NDDs). The gut-brain axis's potential role in disease pathophysiology offers new avenues for cell-based regenerative medicine in treating neurological conditions. Conclusion: In conclusion, the gut microbiome significantly impacts stroke prognosis by highlighting the role of the gut-brain axis in ischemic stroke mechanisms. This insight suggests potential therapeutic strategies for improving outcomes. [ABSTRACT FROM AUTHOR]

Background: Asthma is a leading cause of pediatric hospitalization and morbidity, necessitating the development of educational interventions for its management and control. Objective: To evaluate the effectiveness of an educational intervention in promoting parent/caregiver self-efficacy in the management and control of their children's asthma. Methods: A clinical trial was conducted in Fortaleza, Ceará, Brazil, involving two randomized groups of parents/caregivers of children: the comparison group (CG) (n = 42) and the intervention group (IG) (n = 42). Data collection took place in two phases: the first included face-to-face sessions followed by the educational intervention in the IG, and the second included telephone follow-up. The educational intervention included the use of an educational booklet and a brief motivational interview. Results: The groups were homogeneous at baseline. After the intervention, the mean self-efficacy scores of the IG were significantly higher than those of the CG (p < 0.05), and children whose parents/caregivers were in the CG were 1.43 times more likely to experience an asthma crisis than those in the IG. Conclusions: The educational intervention proved effective in increasing parent/caregiver self-efficacy in asthma management and control. Furthermore, children whose parents/caregivers did not receive the educational intervention were more likely to experience an asthma crisis. Significance: What is Already Known on this Subject?: Asthma is a chronic, non-communicable disease that contributes to morbidity and mortality in children. In addition, the crisis of this disease can be prevented if parents/caregivers are able to manage and control their children's asthma. What does this Study add?: This randomized clinical trial confirms that the use of an educational intervention consisting of an educational booklet and a brief motivational interview increases parent/caregiver self-efficacy to manage and control childhood asthma, thereby reducing the likelihood of an asthma crisis. [ABSTRACT FROM AUTHOR]

Background: Physical therapy seems the most promising treatment for temporomandibular disorders (TMD), although their effectiveness is controversial in general, due to high heterogeneity regarding study designs, applied treatments and outcomes measures. Objectives: The aim of this scoping review is to analyse the methodological characteristics of clinical trials evaluating physical therapy treatments in subjects with TMD. Methods: A systematic search was conducted in Medline/PubMed, SPORTDiscus, Scopus, Web of Science, SciELO, Cochrane, ScienceDirect and EMBASE databases on 31 October 2023. Clinical trials evaluating physical therapy interventions in patients older than 18 years with TMD, published in English or Spanish languages. Data regarding content reporting of study designs, sample characteristics, interventions and outcome measures was extracted. Descriptive summary statistics were reported. Results: The search retrieved 15 322 records, and 136 were included. There were 107 randomised clinical trials, 5 non‐randomised controlled trials and 24 non‐controlled trials. Most studies had moderate to high risk of bias, small sample sizes (median, 44 subjects) and short follow‐up periods (1–3 months). The most common diagnostic criteria used was the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (48.9%). The most reported experimental interventions were manual therapy (40.4%), exercise (30.2%) and electrotherapy modalities (27.2%), and the most common outcome measure domains were pain (83.8%), range of movement (61.8%), disability (45.6%) and mechanosensitivity (29.4%). There was poor content reporting of experimental interventions. Conclusions: Current literature of clinical trials of physical therapy interventions for TMD has moderate to high risk of bias, poor content reporting, small sample size and short‐term follow‐ups which limit internal and external validity, as well as applicability into clinical practice. [ABSTRACT FROM AUTHOR]

• Meta-analysis covers 2004–2024 data on MSC use in ischemic cardiomyopathy. • Studies assessed the safety and efficacy of MSCs from 3 different tissue origin. • Forty-nine trials with 1408 participants were followed up for 1–10 years. • Eighty deaths (52% of cases) reported post-MSC treatment. • LVEF increase was reported 5.75% (95% CI: 3.38%–8.11%, p < 0.0001) from baseline. This meta-analysis and systematic review compiles comparative data from 2004 to 2024, investigating the safety and efficacy of mesenchymal stem/stromal cells (MSCs) derived from various tissues for the treatment of ischemic cardiomyopathy (ICM) and associated heart failure. In addition, this review highlights the limitations of these interventions and provides valuable insights for future therapeutic approaches. Relevant articles were retrieved from the PubMed® database using targeted keywords. Our inclusion criteria included clinical trials with patients over 18 years of age, case reports and pilot studies. Animal experiments, in vitro studies, correlational and longitudinal studies, and study designs and protocols were excluded. Forty-nine original articles resulted in follow-up reports of 45 trials. MSCs from bone marrow, umbilical cord and adipose tissue were moderately well tolerated. Of the 1408 participants who received MSCs, 33 trials (67.3%) reported the occurrence of death or serious adverse events. These events resulted in 80 deaths (52% of reported cases) following MSC administration. Importantly, 41.3% of these deaths (n = 33) were not considered to be related to the intervention itself, while 40% of these deaths had no reported cause. As the primary outcome, the mean increase in left ventricular ejection fraction (LVEF) from baseline was 5.75% (95% CI: 3.38% –8.11%, p < 0.0001, I2 = 90,9%) in the randomized controlled trials only (n = 24) within the treatment groups and 3.19% (95% CI: 1.63% to 4.75%, p < 0.0001, I2 = 74,17%) in the control groups after the intervention. When the above results were compared using the standardized mean difference (SDM), a significance in favor of the treatment group was also found (SDM = 0.41; 95% CI: 0.19–0.64, p < 0.001, I2 = 71%). Although improvements were also seen in the control groups, 33.3% (n = 15) of the studies showed no significant difference between the control and treatment groups. The 6-minute walking test (6MWT) and New York Heart Association (NYHA) class scores, used for assessing exercise tolerance and quality of life (QoL), respectively, further supported the improvements in the treatment group. These improvements were noted as 62.5% (n = 10) for the 6MWT and 54.5% (n = 12) for the NYHA class scores. According to the risk of bias analysis, 4 trials were of good quality (11.8%), 15 were of fair quality (44.1%), and 15 were of poor quality (44.1%). Major limitations of these studies included small sample size, diagnostic challenges/lack, uncertain cell dosage and potential bias in patient selection. Despite the ongoing debate surrounding cell administration for ICM, there are supporting signs of improved clinical and laboratory outcomes, as well as improved QoL in the MSC-treated groups. However, it is important to recognize the limitations of each study, highlighting the need for larger, controlled trials to validate these findings. [ABSTRACT FROM AUTHOR]

Background and purpose: Ambulance trials assessing interventions in suspected stroke patients will recruit patients with currently active symptoms that will resolve into transient ischaemic attack (TIA). The safety and efficacy of glyceryl trinitrate (GTN) in the pre‐specified subgroup of patients with TIA in the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke Trial 2 (RIGHT‐2) was assessed. Methods: RIGHT‐2 was a pre‐hospital‐initiated multicentre randomized sham‐controlled blinded‐endpoint trial that randomized patients with presumed ultra‐acute stroke within 4 h of symptom onset to transdermal GTN or sham. Final diagnosis was determined by site investigators. The primary outcome was a shift in modified Rankin Scale (mRS) scores at 90 days analysed using ordinal logistic regression reported as adjusted common odds ratio with 95% confidence intervals (CIs). Secondary outcomes included death or dependence (mRS >2). Results: In all, 109 of 1149 (9.5%) patients had a final diagnosis of TIA (GTN 57, sham 52) with mean age 73 (SD 13) years, 19 (17.4%) had pre‐morbid mRS >2, and onset to randomization was 80 min (interquartile range 49, 105). GTN lowered blood pressure by 7.4/5.2 mmHg compared with sham by hospital arrival. At day 90, GTN had no effect on shift in mRS scores (common odds ratio for increased dependence 1.47, 95% CI 0.70–3.11) but was associated with increased death or dependence (mRS >2): GTN 29 (51.8%) versus sham 23 (46.9%), odds ratio 3.86 (95% CI 1.09–13.59). Conclusions: Pre‐hospital ultra‐acute transdermal GTN did not improve overall functional outcome in patients with investigator‐diagnosed TIA compared with sham treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: This study evaluated associations of brain amyloid with 2‐year objective and subjective cognitive measures in a trial‐ready older general population at risk for dementia. Methods: Forty‐eight participants in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability underwent 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET) scans and assessment of cognition (modified Neuropsychological Test Battery [NTB]) and subjective memory complaints (Prospective and Retrospective Memory Questionnaire). Results: Mean age was 71.4 ± 5.06 years, and 20 participants (42%) had positive baseline PiB‐PET scans. Amyloid positivity was associated with lower NTB executive function at baseline and less favorable 2‐year NTB total score and memory trajectories, but not with other objective or subjective cognitive measures. Overall, there was little cognitive decline during 2 years. Conclusions: Amyloid accumulation may affect objective but not necessarily subjective cognition from a very early at‐risk stage, although substantial decline likely requires >2 years to occur. [ABSTRACT FROM AUTHOR]

Aim: To investigate the blood pressure (BP) and ductal calibre patterns associated with early ductal closure in very low gestational age (<32 weeks) infants. Methods: Blood pressure was continuously measured intra‐arterially among 43 infants participating in a randomised, double‐blind trial of 4 days prophylactic intravenous paracetamol. Early closure of the ductus was verified by daily ultrasound examinations. The BP recordings, before and after the verified ductal closure, were examined and compared to control infants without ductal closure. In the 24‐h preceding the ultrasound‐verified ductal closure, periods of increased BP were searched and identified as suggestive ductal closure time points. In control infants without ductal closure, BP trends were examined during the corresponding age. Results: Mean arterial BP increased significantly before ductal closure (p < 0.001) and stayed higher than in the control group. Mean BP during the 8 h preceding closure significantly predicted the ductal closure [OR 2.094 (95% CI 1.209–3.630), p = 0.008], and multiple potential confounders failed to abolish this association. A linear decrease pattern in ductal calibre was significantly associated with the ductal closure. Conclusion: Blood pressure increased and stabilised before the early ductal closure, offering potential implications on treatment strategies of very premature infants. [ABSTRACT FROM AUTHOR]

Introduction: Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing–remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Methods: Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years. Results: Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0–7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. Conclusions: These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. Trial registration: NCT02282826, NCT02977533, NCT02313285. [ABSTRACT FROM AUTHOR]

Background: Inadequate health literacy in people with chronic kidney disease is associated with poorer disease management and greater complications. Adherence to the renal diet is known to be suboptimal and patient feedback about the renal diet suggests that patients leave nephrology clinics feeling confused. The present study aimed to evaluate the impact of a health literacy sensitive model of care (MOC) in outpatient nephrology dietetic clinics. Methods: This quasi‐experimental non‐randomised pre‐post study recruited adults attending three renal dietitian clinics. The revised MOC consisted of a renal diet question prompt sheet, teachback, and plain language materials and instructions. Outcomes assessed included clinical, dietary, patient‐reported satisfaction and quality of life. Differences between and within groups were analysed using paired t‐tests, independent sample t‐tests (or non‐parametric equivalent), chi‐squared and McNemar's tests. Linear mixed models evaluated change in total diet quality score, fruit, vegetable, protein and dairy intake with time as a fixed effect and a random subject specific effect. Results: Fail to attend rates at the initial appointments were lower in the revised MOC (21.5% vs. 9.1%). The revised MOC was associated with significantly improved fruit (p = 0.03) and vegetable (p = 0.003) intake and an improved proportion with adequate diet quality (p = 0.03). These impacts were of moderate effect size (d = 0.5, 95% confidence interval = 0.0–1.0). The revised MOC was also associated with greater satisfaction at baseline (p = 0.04) and higher acceptability scores for all questions at the review appointments. Quality of life improved clinically but not significantly in the revised MOC (p = 0.92). Conclusions: This low‐cost health literacy sensitive intervention is a promising strategy to improve fruit and vegetable intake in adults attending renal dietitian clinics. Further research to determine fidelity of teachback use and cost utility analysis would be beneficial. Larger scale trials powered to detect changes in quality of life would also be informative. Key points: There was no improvement in overall adherence to the renal diet in the usual care or revised model of care.However, the revised model of care was associated with a significant improvement in fruit and vegetable intake and diet qualityPatient satisfaction was high in both models of dietetic care, however, the revised model of care was associated with greater satisfaction at baseline. [ABSTRACT FROM AUTHOR]

Aim: To explore the efficacy and safety of once‐weekly insulin icodec (icodec) in Japanese adults (≥20 years old) with type 2 diabetes from the global ONWARDS 1, 2 and 4 trials. Materials and Methods: Insulin‐naive (ONWARDS 1) and insulin‐experienced (ONWARDS 2 and 4) individuals were randomized to icodec or a once‐daily insulin comparator: insulin glargine U100 [ONWARDS 1 (basal insulin only) and 4 (basal–bolus regimen)] or insulin degludec [ONWARDS 2 (basal insulin only)]. The primary outcome was change in glycated haemoglobin from baseline to end of treatment (EOT) (ONWARDS 1: Week 52; ONWARDS 2 and 4: Week 26). Here, we present the Japanese subgroup results. Results: Similar reductions in glycated haemoglobin from baseline to EOT were observed in each trial for icodec and comparators. The proportion of time in range (blood glucose 3.9–10.0 mmol/L) at EOT was also comparable across treatment groups (time in range: 58%–68%), as was time spent with blood glucose below 3.0 mmol/L (<1.0%). Combined clinically significant (blood glucose <3.0 mmol/L) or severe (requiring external assistance for recovery) hypoglycaemia rates were low, with no severe events (ONWARDS 1 and 2) or a single severe event (ONWARDS 4; icodec group) reported. These results generally aligned with findings from the respective global populations. No new safety issues were identified. Conclusions: Icodec improved glycaemic control to a similar degree as once‐daily basal insulin comparators while maintaining low levels of clinically significant or severe hypoglycaemia. The findings support icodec use in Japanese individuals with different levels of type 2 diabetes progression. [ABSTRACT FROM AUTHOR]

Aims: The combination of cagrilintide and semaglutide (CagriSema) is being developed for the treatment of obesity and type 2 diabetes. The objective of this thorough QT study was to confirm that cagrilintide does not result in a clinically relevant prolongation in cardiac repolarization compared with placebo. Materials and Methods: This was a double‐blind study (NCT05804162) in which healthy participants were randomized to cagrilintide, administered as a once‐weekly subcutaneous injection dose escalated to 4.5 mg, or a placebo. The primary end point was the time‐matched change from baseline in Fridericia heart rate–corrected QT interval (QTcF) at 12‐, 24‐, 48‐ and 72 h after the last cagrilintide 4.5‐mg dose. To conclude that cagrilintide does not induce a clinically relevant prolongation, the upper limit of the two‐sided 90% confidence interval (CI) for the treatment difference at each of the four time points must fall below 10 ms. To establish QT assay sensitivity, participants in the placebo arms received a single 400‐mg oral moxifloxacin dose as a positive control and moxifloxacin placebo in a nested cross‐over fashion. Results: A total of 105 participants received cagrilintide (n = 53) or placebo (n = 52). No clinically relevant QTcF prolongation occurred after the last cagrilintide 4.5‐mg dose; the upper limits of the two‐sided 90% CIs of the placebo‐adjusted QTcF changes from baseline were below 10 ms at all time points. QT assay sensitivity was demonstrated with moxifloxacin as a positive control. Conclusions: Cagrilintide did not result in clinically relevant QTcF prolongation, indicating no increased risk of ventricular tachyarrhythmias. [ABSTRACT FROM AUTHOR]

The article "Representation of women in randomized controlled trials of novel antidiabetic drugs: A cohort study" published in Diabetes, Obesity & Metabolism highlights the underrepresentation of women in clinical trials for diabetes drugs, impacting the precision of medical interventions. The study focused on trials with primary outcomes related to cardiac and renal events, revealing a significant lack of female participants. Despite efforts to reduce gender disparities in clinical research, women were notably underrepresented, affecting the accuracy of treatment practices. The study recommends future research prioritize recruiting women in proportions reflective of their representation in the population to enhance the relevance of medical interventions. [Extracted from the article]

Aim: Automated insulin delivery (AID) systems have demonstrated improved glycaemic outcomes in people with type 1 diabetes (T1D), yet limited data exist on these systems in very young children and their impact on caregivers. We evaluated psychosocial outcomes following use of the tubeless Omnipod® 5 AID System in caregivers of very young children. Materials and Methods: This 3‐month single‐arm, multicentre, pivotal clinical trial enrolled 80 children aged 2.0–5.9 years with T1D to use the Omnipod 5 AID System. Caregivers completed questionnaires assessing psychosocial outcomes—diabetes distress (Problem Areas in Diabetes), hypoglycaemia confidence (Hypoglycemia Confidence Scale), well‐being (World Health Organization 5 Well‐Being Index), sleep quality (Pittsburgh Sleep Quality Index), insulin delivery satisfaction (Insulin Delivery Satisfaction Survey) and system usability (System Usability Scale) at baseline with standard therapy and after 3 months of AID use. Results: Following 3 months of Omnipod 5 use, caregivers experienced significant improvements across all measures, including diabetes‐related psychosocial outcomes (Problem Areas in Diabetes; p < 0.0001, Hypoglycemia Confidence Scale; p < 0.01), well‐being (World Health Organization 5 Well‐Being Index; p < 0.0001) and perceived system usability (System Usability Scale; p < 0.0001). Significant improvements were seen in the Pittsburgh Sleep Quality Index total score and the overall sleep quality, sleep duration and efficiency subscales (all p < 0.05). Insulin Delivery Satisfaction Survey scores improved on all subscales (greater satisfaction, reduced burden and reduced inconvenience; all p < 0.0001). Conclusions: Caregivers face unique challenges when managing T1D in very young children. While glycaemic metrics have unquestioned importance, these results evaluating psychosocial outcomes reveal additional meaningful benefits and suggest that the Omnipod 5 AID System alleviates some of the burdens caregivers face with diabetes management. [ABSTRACT FROM AUTHOR]

Unblinded interim analyses in clinical trials with adaptive designs are gaining increasing popularity. Here, the type I error rate is controlled by defining an appropriate conditional error function. Since various approaches to the selection of the conditional error function exist, the question of an optimal choice arises. In this article, we extend existing work on optimal conditional error functions by two results. Firstly, we prove that techniques from variational calculus can be applied to derive existing optimal conditional error functions. Secondly, we answer the question of optimizing the conditional error function of an optimal promising zone design and investigate the efficiency gain. [ABSTRACT FROM AUTHOR]

Background: Valid measurement of drug use in patients enrolled in clinical trials that treat substance use disorder is vital to determine the trial's outcome. Self-reports are often used but their validity has been studied with mixed results. Urinalysis may sometimes be employed as an alternative or supplement to self-reports. Objectives: This study examined how estimating drug use by either method would affect the results from a randomized clinical trial conducted in a methadone treatment program. At the initial Baseline interview and four follow-up interviews, participants were asked about their drug use history and provided a urine specimen for drug testing. Results: In most cases, the urinalyses detected more drugs than the patients had reported using. A major exception was heroin, whose use was an eligibility criterion for enrollment in the study and methadone treatment. Conclusions: The patients' self-reports would have led us to conclude that the use of heroin and fentanyl had declined from the initial Baseline interview to the final follow-up interview, while the urinalysis results indicated no change in exposure to heroin and an increase in exposure to fentanyl. Clinical trials would be well served to employ the use of biological tests in addition to self-reports to measure recent drug use and to accurately estimate the efficacy of the experimental protocols and patients' exposure to drugs. [ABSTRACT FROM AUTHOR]