Trials

Introduction: While growing evidence suggests that music training supports child development, few long-term randomized controlled trials (RCTs) have rigorously tested these claims. Moreover, it remains unclear whether the benefits are confined to music-specific domains or extend to higher-order cognitive functions such as inhibitory control (IC), a core executive function associated with long-term outcomes in academic achievement, career success, socio-emotional health, and physical well-being. This paper presents the protocol for the Extracurricular Activity and Child Early Learning and Development (EXCEL) trial, an RCT designed to assess the feasibility of a long-term music training program focusing on the brain and behavioral correlates of IC. Methods: A total of 126 children, aged 6 to 8 years and residing in neighborhoods with limited resources in Los Angeles, were individually randomized to either a music (intervention) or theatre (active control) after-school program. Both programs were delivered over 24 months by established community arts organizations. Eligibility criteria included: average intellectual functioning, no major medical or psychiatric conditions, and MRI eligibility. Children with prior formal music training exceeding six months or severe hearing impairment were excluded. Before the intervention began, all participants completed baseline behavioral and neuroimaging assessments. The primary trial aim was to assess the effects of extended music training, relative to theatre training, on changes in measures of IC (i.e., Go/No-Go task and delayed gratification) and related neural functional activation. A secondary interim aim of the trial was to evaluate the feasibility of conducting a long-term RCT of music education in a first cohort, measured by participant retention, adherence to the program, willingness to continue at the 12-month mark, and fidelity. Progress: Recruitment, screening, baseline testing, randomization, and program enrollment began in August 2022, and after-school programming began in October 2022. The randomized interventions and all data for the first cohort (N = 42) have been collected. Intervention and active control programs for a second cohort are ongoing and will end in Fall 2026. Discussion: This paper reports the EXCEL trial protocol and provides feasibility estimates for implementing a long-term randomized controlled trial of music training in real-world, community-based settings with children. While similar neuroimaging RCTs are currently underway in Europe, the EXCEL trial is among the first in the United States to integrate longitudinal neuroimaging with arts intervention. Findings will inform the viability of scaling such programs and contribute to our understanding of how sustained music engagement may influence the development of inhibitory control circuitry in childhood.

Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefit in type 2 diabetes and obesity, with recent observational data suggesting favorable associations after transcatheter aortic valve replacement. Whether similar associations exist after surgical aortic valve replacement (SAVR) is unknown. Methods: Retrospective propensity-matched cohort analysis using the TriNetX U.S. Collaborative Network. Adults with type 2 diabetes or obesity (BMI [≥]30 kg/m2) undergoing SAVR were categorized by GLP-1 RA exposure (any use within 3 months before through 1 year after SAVR) versus no use. One-to-one matching was performed on 44 covariates. Primary outcomes were 1-year all-cause mortality, heart failure, acute kidney injury, acute myocardial infarction, cerebral infarction, and atrial fibrillation. Sensitivity analyses included 30-day landmark restriction and falsification outcomes. Results: After matching, 1,984 patients were retained per cohort. GLP-1 RA use was associated with lower 1-year risks of all-cause mortality (4.8% vs 10.4%; HR, 0.44; 95% CI, 0.34-0.56), acute kidney injury (6.9% vs 10.1%; HR, 0.65; 95% CI, 0.49-0.85), myocardial infarction (3.0% vs 5.1%; HR, 0.57; 95% CI, (0.40-0.82), heart failure (11.3% vs 15.7%; HR, 0.68; 95% CI, (0.51-0.90), and atrial fibrillation or flutter (10.1% vs 13.9%; HR, 0.69; 95% CI, 0.54-0.90; all P[≤]006). Cerebral infarction did not differ. In landmark analysis, mortality, heart failure, and acute kidney injury associations persisted; myocardial infarction and atrial fibrillation associations were attenuated. Falsification outcomes were null. Conclusions: Perioperative GLP-1 RA use was associated with lower 1-year cardiovascular event rates after SAVR. These hypothesis-generating findings support prospective randomized investigation.

Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.

As genetic testing becomes increasingly integrated into Parkinson disease (PD) research, including targeted testing for variants in LRRK2 and GBA1, the return of individual research results is becoming more common. However, limited qualitative data exists regarding how research participants experience genetic results disclosure and post-test genetic counseling in PD research settings. We conducted semi-structured qualitative interviews with participants (n=13) enrolled in the Parkinson Precision Medicine Initiative (formerly Parkinson Progression Markers Initiative; PPMI) who had received PD-related genetic test results and post-test genetic counseling. Interviews were conducted 1 to 3 weeks following result disclosure and analyzed using thematic analysis with a primarily deductive coding approach informed by study aims and inductive identification of emergent themes. Four primary themes were identified: (1) personal connection and motivations for participation, (2) centrality of result disclosure and information preferences, (3) emotional experiences and support needs, and (4) communication quality and alignment with participant needs. Overall, our findings underscore the importance of person-centered genetic counseling within PD research. As return of genetic and biomarker results in research and clinical trial contexts expand, thoughtful integration of relational, informational, and communication-focused practices will be essential to support participant engagement and trust.

Abstract Background: Kaposi sarcoma (KS) is the most common cancer among men in several Eastern African countries, yet treatment monitoring relies on imprecise, time-consuming ruler-based measurements defined by the AIDS Clinical Trial Group (ACTG). This method suffers from inter-observer variability, fails to capture lesion height or true geometric area, and performs poorly on dark skin. SkinScan3D (SS3D) is a portable, low-cost, AI-enabled 3D imaging device that provides objective measurements of KS skin lesion area, height, volume, and color. The Precision Imaging to Evaluate Kaposi Sarcoma (PRIME-KS) study evaluates whether SS3D provides more reproducible and accurate lesion measurements than the standard method, and validates its integration into routine clinical workflows in Kenya and Uganda. Methods: PRIME-KS is a multicountry prospective mixed-methods study with two clinical objectives. Objective 1 is a cross-sectional diagnostic accuracy study comparing SS3D with ruler-based measurement in 50 adults with KS (150 lesions) across sites in Kenya and Uganda. Two clinicians independently measure three lesions per participant using both methods. The primary outcomes are concordance correlation coefficient (CCC) for inter-rater reproducibility, and co-efficient of determination for accuracy. Objective 2 is a non-randomized before-and-after pilot study in 100 patients at three sites, evaluating device usability, acceptability, appropriateness, and feasibility using validated instruments, along with time-and-motion studies and activity-based micro-costing. Prior to these clinical objectives, a formative study used focus group discussions, discrete choice experiments, and human-centered design workshops to refine the SS3D device and protocols with end-user input. Discussion: PRIME-KS will provide the first rigorous evaluation of a 3D imaging device for monitoring KS treatment response in routine clinical settings. If SS3D demonstrates superior reproducibility and clinical utility, it could reduce unnecessary chemotherapy exposure and associated toxicities by enabling earlier, more objective assessment of treatment response. Trial registration: ClinicalTrials.gov NCT06898203, registered 27 March 2025. Pan African Clinical Trials Registry PACTR202603523439856. Keywords Kaposi sarcoma, SkinScan3D, 3D imaging, treatment monitoring, diagnostic accuracy, implementation science, usability, human-centered design, Kenya, Uganda

Introduction Education is a core social determinant of health for children and adolescents. Unfortunately, academic achievement, health, and wellbeing of adolescents have decreased in many developed countries in the past decade. The purpose of the Wellbeing and Education linkages in school-aged children (WELL-ED) study is to examine associations of school absences and academic achievement with use of school-based and community-based health and social welfare services. In addition, we will assess user experiences and multi-sector services pathways of school-aged children for a better understanding of how the service system could respond to the needs of children. Methods and analysis WELL-ED is a large population-based study that combines register data on school absences and educational support from municipalities with register data on healthcare and social service use collected from wellbeing services counties in Finland. The study cohort includes all children who attended mandatory education in public schools in Southern Finland in school year 2023-2024. A smaller cohort of adolescents in school year 8 was invited to complete a user experience survey. The primary outcomes of this study are related to equity of service use. Ethics and dissemination The Regional Committee on Medical Research Ethics of the Helsinki and Uusimaa Hospital District (2803/2024) has approved the WELL-ED study protocol. For the survey, adolescents in year 8 and parents of adolescents younger than 15 provided informed consent. Results will be published in peer-reviewed journals, summaries will be sent to participating municipalities and wellbeing services counties and press releases will be written on key findings.

Objective To determine if it is possible to assess individual patient risk of the development of colorectal cancer (CRC) in people in high-risk groups due to their family history. Design/Method Retrospective observational study of prospectively collected data from consecutive patients referred for a colonoscopy. 2,478 consecutive patients were referred to a single colorectal surgical practice in Sydney, Australia between 1977 and 2018 for a colonoscopy because of a family history of CRC. Of these, 1,963 have been followed for more than 10 years and are the subject of this paper. Histopathological findings categorised as normal (N), non-advanced adenoma (NAA) or advanced neoplasia (AN) with AN proven to be the precursor to CRC. Intervention Colonoscopic screening on the basis of contemporary practice to 2006 and subsequently according to Australian National Health and Medical Research Council guidelines. Results Participants with normal or low-risk findings in the first decade remain at lower risk of CRC for 30 years from the commencement of screening. Conclusion It is possible to stratify individual patients in a high relative risk cohort into those with high or low personal risk of CRC based on colonoscopic findings in the first 10 years of surveillance. Those with no AN in the first ten years have a lower 30-year risk of developing AN than the general community. This offers the possibility of structuring surveillance programs around individual risk rather than group risk, lessening the need for multiple surveillance colonoscopies in the majority of such patients and improving the cost effectiveness of CRC screening at the population level.

Background: Medical registries have gained importance in the evaluation of healthcare quality outcomes. In the absence of high-quality evidence, such as randomized controlled trials, studies based on registry data are essential for informing clinical guidelines. Methods for assessing data quality are rarely described in detail. To ensure the credibility of registry-based studies, registries must use all available technical and operational means to guarantee high data quality. Method: Eurocrine(R) is a pan-European endocrine surgical database and quality registry initially funded by the EU healthcare programme, which started in 2015 and now includes more than 200,000 interventions as of April 2025. To ensure high data quality, interactive and standardized reports are created via Microsoft Power BI, which are created both centrally and locally. In addition, comprehensive data quality analyses were performed via the R-based package dataquieR. Results: Although a multitude of technical measures (for example, input screen design and real-time plausibility checks during data entry) are in place, they are not sufficient to prevent human errors at data entry. Errors identified in the reports were corrected, and preventive measures were implemented. Overall, the data quality was assessed as very good in terms of completeness, accuracy, and consistency. Conclusion: It is very important to provide registry users with an efficient and smart tool to identify data issues, as they have the clinical information to correct them. Data quality reports generated with dataquieR represent an effective tool for registry administrators. Predesigned Microsoft Power BI reports enable participating Eurocrine(R) clinics to self-audit their data.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

Background Endoscopic pituitary surgery involves navigating high-stakes anatomy where complications, such as carotid artery injury, cause devastating morbidity. While computer vision AI offers potential for real-time anatomical recognition to mitigate these risks, successful translation requires rigorous human-factors and performance evaluation. We present the iterative development and preclinical evaluation of a surgeon-controlled, real-time AI-assisted navigation system. Methods Guided by IDEAL Stage 0 and DECIDE-AI frameworks, the study was conducted in two phases. Phase 1 was an exploratory study where surgeons used the system during high-fidelity simulated surgery and provided feedback via "Think Aloud" protocols and surveys. Following prototype iteration, a Phase 2 randomized crossover comparative trial was conducted with 19 neurosurgeons (15 trainees, 4 experts) performing high-fidelity simulated tumour resections with and without AI assistance, separated by a minimum 2-week washout. The primary outcome was surgical technical performance (OSATS). Workload, educational value, usability, trust, and implementation outcomes were also assessed. Results Phase 1 informed hardware, model, and interface refinements, including optimized pedal-controlled overlays and prediction confidence metrics. In the comparative trial, AI assistance significantly improved overall technical performance (OSATS 19.79+/-4.06 vs. 17.32+/-4.11; p=0.027). This gain was experience-dependent; AI significantly augmented trainee performance (19.20+/-3.76 vs. 16.60+/-3.78), narrowing the proficiency gap, while expert performance remained high and stable. 100% of participants identified the system as a useful training tool. However, subjective workload was significantly higher in the AI arm (SURG-TLX 26.42+/-9.56 vs. 22.26+/-7.81; p=0.014). Despite this, usability (SUS 75.13+/-14.31) and implementation feasibility, acceptability, and appropriateness scores were consistently high (means >4.4/5). Conclusions This study provides a stepwise process for real-time AI development using pituitary surgery as a high-stakes exemplar. The refined surgeon-centric AI system improves training and technical performance, particularly for trainees. Next steps involve first-in-human studies and further exploration of longer-term human factors such as over-reliance, cognitive overload mitigation and trust calibration.

Abstract Purpose: Published clinical outcome data on preconception carrier screening (PCS) in Central Asia are limited. We report the first clinical implementation study from Uzbekistan of a whole-exome sequencing (WES)-based multi-platform PCS program combining exome sequencing with targeted SMA, FMR1, and DMD assays. Methods: We retrospectively analyzed anonymized data from 65 individuals (19 couples, 27 singletons) screened at IMC Genomics, Tashkent, between January 2024 and May 2026. WES covering the protein-coding regions of approximately 20,000 genes was followed by exome-wide bioinformatics filtering and clinical geneticist interpretation. Partly overlapping cohorts underwent SMA carrier screening (n=179), FMR1 CGG-repeat analysis in females (n=155), and DMD deletion/duplication testing in preconception females (n=29). Variants were classified by ACMG/AMP criteria against gnomAD v4.1. Results: Sixty-one of 65 WES-screened individuals (93.8%; 95% CI 85.2 - 97.6%) carried at least one reportable variant (152 instances across 126 genes). Four of 19 couples (21.1%; 95% CI 8.5 - 43.3%) were concordant for pathogenic or likely pathogenic variants in the same autosomal recessive gene; two were referred for preimplantation genetic testing for monogenic disease. SMA screening identified four carriers, including two 2+0 silent carriers; FMR1 analysis identified one intermediate allele; DMD MLPA identified no exonic rearrangements. Conclusion: This first reported WES-based multi-platform PCS program in Uzbekistan was feasible and clinically informative, identifying actionable couple-level reproductive risks and supporting structured implementation of reproductive genetic screening in Central Asia.

Large language models (LLMs) such as ChatGPT are rapidly reshaping healthcare education and simulation-based training in non-technical skills (NTS), yet no bibliometric analysis has mapped this landscape. We searched seven open-access databases (OpenAlex, PubMed, Europe PMC, Crossref, Semantic Scholar, CORE, DOAJ) for English-language publications from January 2020 to March 2026. From 100,277 initial records, a sequential keyword funnel yielded 830 candidate papers, which were screened by 83 independent Claude Sonnet 4.6 AI agents applying pre-specified inclusion criteria (PRISMA-trAIce compliant; Cohen's kappa = 0.86 pre-reconciliation, 1.0 post-reconciliation). The final AI-verified corpus comprised 551 papers with a compound annual growth rate of 109%, contributions from 2,398 authors across 279 journals in 58 countries, and an h-index of 41. ChatGPT dominated the model landscape (46% of papers), with open-source models virtually absent. Virtual patient chatbots were the leading simulation modality (106 papers). Among NTS domains, communication (145 papers) and decision-making (135 papers) were most studied, whereas teamwork, leadership, situational awareness, and crisis resource management were markedly underrepresented. Only 6 urology-relevant papers were identified, none examining LLM integration within boot camp training formats. The field is growing at extraordinary pace but remains concentrated in a narrow range of NTS domains and a single proprietary model. Critical gaps persist in team-based skills training, open-source model evaluation, and specialty-specific simulation. AI-assisted bibliometric screening using multiple independent agents is feasible, reliable, and scalable, offering a replicable methodology for mapping fast-evolving research fields.

In February 2026, the FDA announced that a single pivotal phase 3 (P3) trial would become the new default standard for drug approval - a regulatory direction that had been legally enabled since the FDA Modernization Act of 1997. This announcement has strategic, scientific, and economic implications for drug developers, contract research organizations (CROs), and biotech investors. We argue that the expansion of this framework, originally reserved for various niche submissions, represents a paradigm change, dramatically increasing the value of rigorous early phase (P1 and P2) trial design, requiring sponsors to establish both statistical efficacy signals and mechanistic biological understanding before entering phase 3. Using a CNS indication cost model, we show that single P3 approval can reduce total development expenditure from approximately $447 million over 14 years to $297 million over 12 years - a savings of $150 million and providing two years of additional commercial runway for a modeled CNS drug. Case examples including lecanemab, omaveloxolone, and tofersen illustrate how biomarker-informed early phase strategies can establish the confirmatory evidence necessary for single-trial approval. We provide practical guidance for maximizing the value of P1 and P2 under this evolving framework.

Background: Occupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging. Objective: The purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers. Methods: To develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first- and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes. Results: Initial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage. Conclusion: By providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.

Objective To map national Parkinsons disease (PD) research capability to inform an inclusive delivery strategy for a large-scale clinical trial. Background Few people with PD participate in clinical trials, particularly from under-served populations. The Edmond J Safra Accelerating Clinical Trials in PD initiative (EJS ACT-PD) aims to deliver an inclusive multi-arm multi-stage (MAMS) disease modification PD trial. Methods A survey disseminated to National Health Service (NHS) hospitals assessed PD research capability regarding trial experience, rater expertise, trial facilities and specialist investigations. A process was developed to categorise sites into 3 tiers, with tier 1 having the least PD-research capability or experience, and tier 3 being experienced specialist centres. We mapped tiers to PD prevalence, social deprivation and ethnic diversity to identify infrastructure gaps. We developed trial delivery strategies to facilitate rapid and inclusive recruitment. Results Out of 97 survey responses, 43 sites were categorised as tier 1, 33 as tier 2 and 21 as tier 3. Diversity and social deprivation index were higher for tier 3 sites (predominantly urban). A greater proportion of tier 1 and 2 sites were situated in areas of higher PD prevalence (predominantly rural). Ninety one percent of sites reported experience with remote trial delivery methods. Our delivery strategy included: initial trial set-up at tier 3 sites to enable rapid and ethnically diverse recruitment; core funded staff within strategic sites to develop regional solutions for inclusive trial participation and to enable research opportunity provision in areas where currently very little exists, and a hybrid delivery model of in-person and remote study visits, ensuring maximal acceptability and deliverability. Conclusions The mapping of current PD research delivery capability has allowed us to develop a trial delivery strategy that will broaden the provision of research participation opportunity to under-served groups. It has also enabled existing infrastructure to be maximised while mitigating identified gaps.

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods: In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14; vg of an AAV9 vector encoding human NAGLU) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results: The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 {+/-} 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions: A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.

Background: Endoscopic endonasal transsphenoidal surgery (EETS) requires navigation around neurocritical anatomy. Today, artificial intelligence clinical decision support systems (AI-CDSSs) can orientate surgeons, but clinician trust in AI remains unclear, limiting safe deployment. This study evaluates how modifiable design affects trust and performance in a real-world pituitary surgery AI-CDSS. Method: Online, 70 clinicians with pituitary surgery experience were randomised evenly to a Basic or Enhanced AI-CDSS which outline the sella on EETS operative video. The Enhanced group additionally received explanation of the model and previous publications, alongside confidence labels depicting outline reliability. Both groups annotated the sella on six video clips, first alone then with the optional AI-CDSS. Clips were ordered by declining AI performance, except for the final clip. Self-reported trust was measured using a 1-7 scale after each annotation, and performance was the DICE overlap between user annotations and the ground truth. Comparisons used Mann-Whitney U and permutation analysis. Results: Sixty-four participants (91%) finished the exercise (31 Basic, 33 Enhanced). When AI performed best, median trust was 5.00 in both arms (U=559, p=.521). However, when AI performed worst, trust was significantly lower for the Enhanced group (3.00 vs 3.67, U=668, p=.035), sustained in the final clip (3.67 vs 4.33 U=687, p=.019). User performance improved with the AI-CDSS, but with no significant difference between the groups on the best or worst AI performing clips. Nevertheless, for the best AI, senior clinicians had higher median performance in the Enhanced group (0.95 vs 0.90, U=75, p=.066). There was also less dispersion in the Enhanced group when AI was inaccurate (IQR: 0.07 vs 0.21, p=.004). Conclusion: Interface design can improve trust calibration in a surgical AI-CDSS and may increment performance in seniors when AI is accurate, and consistency when AI is inaccurate. In future, these features may form important safety checks during translation to the operating room.

Background: Maternal mental health problems are common after prenatal diagnosis of congenital heart disease (CHD), with long-term implications for child and family wellbeing. HEARTPrep is a prenatal psychosocial intervention with three self-paced modules and corresponding telehealth sessions, delivered during pregnancy via mobile app to improve mental health and wellbeing for mothers expecting a baby with CHD. This proof-of-concept study evaluated the feasibility of HEARTPrep and examined maternal mental health and psychosocial functioning throughout participation. Methods: Participants were mothers receiving care for a fetal CHD diagnosis within one health system. Feasibility was assessed via rates of enrollment and completion. Mothers completed 4-item PROMIS questionnaires assessing anxiety, depression, and social isolation and reported self-efficacy and hope on a weekly basis throughout HEARTPrep. Results: Of 34 recruited mothers, 29 (85%) enrolled and two were subsequently not eligible (delivery prior to participation, change in fetal diagnosis), resulting in a final sample of 27 mothers. The majority (n = 22, 81%) completed all three telehealth sessions and Modules 1 (n = 22, 81%) and 2 (n = 19, 70%), with just over half (n = 14, 52%) completing Module 3 prior to delivery. Mean PROMIS depression T-scores decreased from 57.5 to 52.9, and 48% of mothers had a decrease in depression scores exceeding the meaningful change threshold (half standard deviation). The percentage of mothers reporting high self-efficacy increased from 19% to 48%. Conclusions: HEARTPrep is feasible and corresponds with reduced maternal depression and increased self-efficacy, supporting proof-of-concept. A randomized controlled trial is needed to determine whether HEARTPrep improves outcomes compared to a control group.

Background: Artemisinin-based combination therapies remain the mainstay of malaria control strategies; nevertheless, the advent of genetic markers linked to partial artemisinin resistance in Plasmodium falciparum has elicited substantial concern across African settings. To assess the prevalence, geographic distribution, and clinical associations of these molecular markers, we undertook a systematic review and meta-analysis of observational cohort studies.Methods: We conducted a search of cohort studies published between January 2015 and June 2025, following PRISMA 2020 guidelines. We queried databases including PubMed/MEDLINE, Scopus, Web of Science, and CINAHL. Eligibility required prospective enrollment of patients, longitudinal monitoring (therapeutic efficacy studies), and pfkelch13 propeller domain genotyping.Results: A meta-analytical synthesis of 888 isolates from six core prospective cohorts revealed a pooled prevalence of 6% (95% CI: 2.1%-11.8%) for validated pfkelch13 mutations. A profound geographic dichotomy was identified: while West and Central African cohorts maintained a 0% prevalence, East African hotspots showed significant expansion, with prevalence reaching 12.8% in Rwanda and up to 25.5% in Northern Uganda; high statistical heterogeneity (, ) reflects this biological divergence. Conclusions: These findings highlight the established and expanding presence of artemisinin partial resistance in East Africa. Standardized surveillance is essential to adapt malaria control policies across the continent. Keywords: Africa; artemisinin resistance; clinical indicators; pfkelch13 gene; molecular markers; partial resistance; Plasmodium falciparum.

Background: Epic Cosmos is a relatively new centralized electronic health record dataset with high potential utility in perinatal epidemiologic research. Objectives: The study objectives were to develop replicable steps to create longitudinal, linked maternal-infant cohorts in Cosmos, assess completeness of key variables, evaluate potential selection bias with restrictions for longitudinal healthcare encounters, and provide an example epidemiologic analysis. Methods: We created maternal-infant cohorts by starting with live births during 2023-2024 recorded in the BirthFact data table and joining with additional data tables as needed. We selected and created variables for perinatal characteristics, common comorbidities, and routinely measured vital signs and laboratory values, and assessed variable completeness. We sequentially restricted the birth cohort for maternal-infant linkage and longitudinal healthcare from first-trimester prenatal care encounter through infant follow-up care within 12 weeks post-discharge from birth hospitalization. Finally, we conducted an example analysis of the association between high systolic blood pressure in the first trimester ([≥]140 mm Hg) and later onset of preeclampsia among those with chronic hypertension. Results: The total linked birth cohort included 2,624,186 pregnancies. Completeness was >90% for most variables assessed but was 77% for racial and ethnic group and 76% for body mass index at delivery. Characteristics of the cohort were similar to those reported for the entire United States birth population based on birth certificate data, including similar regional and racial-ethnic composition. Longitudinal cohort restriction requiring linked records from first trimester prenatal care through infant follow-up care reduced the cohort size to 509,148 pregnancies. However, restriction had minimal effects on cohort characteristics. In the example analysis, high systolic blood pressure was associated with increased risk of preeclampsia among those with chronic hypertension (aRR: 1.26; 95% CI: 1.22, 1.30). Conclusions: This study provides a rigorous and reproducible approach to creating longitudinal, linked maternal-infant cohorts in Epic Cosmos and the analytical findings suggest high data quality and representativeness.