Journal of Antimicrobial Chemotherapy

Artemisinin partial resistance has not yet been reported in southern Africa. Therefore, the magnitude of the spread of artemisinin partial resistance in this region is yet to be quantified. Using a two strain metapopulation modelling framework, we explored possible spread of artemisinin partial resistance in eight connected countries with high level of human movement. We explored three scenarios in which artemisinin partial resistance may first enter circulation: low malaria transmission level country; high malaria transmission level country and all countries and compared to an artemisinin partial resistance free scenario. Partial rank correlation coefficient sensitivity analysis was performed to identify key parameters that drive artemisinin partial resistance spread. Our model simulations show that high mobility between countries can increase the spread of mutations associated with delayed clearance. Suggesting that artemisinin partial resistance will be confirmed (>5% partial resistant cases) after 14 years of circulation if it is to appear in southern Africa. We confirm that human movement, both human-to-mosquito and mosquito-to-human probabilities of transmission, were significant and highly sensitive parameters in the spread of artemisinin partial resistance. Human mobility between countries can facilitate the spread of artemisinin partial resistance. More research is needed to identify strategies to preserve the efficacy of artemisinin-based combination therapies in the presence of partial artemisinin resistance, which may eventually lead to treatment failure and necessitate regimen replacement.

Background: This study aimed to evaluate real-world adverse event (AE) signals of EV to provide evidence-based guidance for its safe clinical application. Methods: Data from the FDA Adverse Event Reporting System (FAERS) database from the period of 2019 Q1-2025 Q3 were analyzed. Disproportionality analysis algorithms, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM), were utilized to mine safety signals.The time to onset (TTO) was evaluated using the Weibull distribution model. Results: Among 11,697,906 reports, 4,177 EV-treated patients experienced 14,511 AEs. The most common System Organ Classes (SOCs) were skin and subcutaneous tissue disorders (18.23%), general disorders and administration site conditions (13.17%).Multi-algorithm consensus identified 179 positive signals. Alongside known toxicities (rash, peripheral neuropathy, hyperglycemia), potential new signals emerged, including dysgeusia, atypical skin lesions, and myelosuppression. Median TTO was 14 days, with the Weibull {beta} of 0.736, confirming an "early failure" profile. Subgroup analysis revealed toxicity heterogeneity: patients aged [&ge;]65 and females exhibited stronger signals for fatal severe cutaneous adverse reactions, while patients aged < 65 and males showed higher susceptibility to neurological and metabolic toxicities. Conclusions: The real-world safety profile of EV confirms known toxicities, reveals new risks (e.g., dysgeusia), and shows toxicity concentrated in the first treatment cycle. Clinical practice requires proactive monitoring during the first two weeks using demographic-specific strategies: vigilance for fatal skin toxicity in elderly and female patients, and close follow-up of neurological and metabolic indicators in younger and male populations.

Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.

Background: Reliable inference of Plasmodium vivax recurrence states - relapse, recrudescence and reinfection (the ``3Rs'') - improves estimates of antimalarial efficacy. The R package Pv3Rs features a Bayesian model designed for P. vivax molecular correction, i.e., using parasite genetic data to infer recurrence states. The model is an extension of a prototype built to analyse microsatellite data from the Vivax History (VHX) and Best Primaquine Dose (BPD) trials. Methods: We re-analysed data from 212 VHX and BPD trial participants (493 recurrences) using Pv3Rs, comparing results with those from the prototype and with genetic relatedness estimated using Dcifer, a tool for estimating relatedness based on identity-by-descent. Posterior recurrence state probabilities were computed using both uniform and time-to-event priors: artificial but equal prior probabilities facilitate posterior interpretation, while time-to-event priors leverage all available information and enable re-computation of failure rates. Relatedness estimates were used to identify and correct instances of model misspecification. Results: The Pv3Rs model generated posterior probabilities for all recurrences and was able to jointly model data on all episodes per participant for 89% of participants, compared with 73% using the prototype. Recurrence state probabilities were broadly consistent across methods, though the Pv3Rs model elevated reinfection probabilities slightly. Relatedness estimates exposed various outliers consistent with half-sibling parasites and/or genotyping errors. Outlier correction impacted some per-participant failure probabilities, but reinfection-adjusted radical-cure failure rates of high-dose primaquine remained near 3%, in line with previous findings. Conclusion: Re-analysis of VHX and BPD P. vivax genetic data restates earlier reinfection-adjusted efficacy estimates. It demonstrates the increased computational capability and misspecification sensitivity of Pv3Rs, highlighting a need for careful analyses. Using relatedness-based diagnostics alongside model-based inference, we were able to harness the advantages of model-based inference and provide a framework for future P. vivax molecular correction.

Background Artemisinin derivatives are central to first-line treatment of both uncomplicated and severe Plasmodium falciparum malaria. Emerging artemisinin partial resistance in East Africa threatens to spread across the continent. Methods In two cross-sectional studies in Zambia in 2024, we genotyped the artemisinin resistance-associated gene Pfkelch13. In Kaoma, western Zambia, we evaluated the percentage of patients with day-3 parasite positivity following treatment with artemisinin-based combination therapy, and ex vivo parasite susceptibility to dihydroartemisinin (the active metabolite of artemisinin). We also assessed longitudinal changes in Pfkelch13 mutation prevalence in Kaoma using isolates collected from 2018 through 2026. Results We identified a novel mutation, Pfkelch13 A724E, in 52% (113 of 217) of isolates from Western Province, 51% (94 of 184) of isolates from North-Western Province, and 11.7% (229 of 1,949) of isolates country-wide. In Kaoma, 28% (21 of 75) of patients carrying Pfkelch13 A724E mutant parasites before treatment were parasite positive on day 3, compared with 0% (0 of 23) of patients with the wild-type allele (P=0.003). Within day-3 positive patients, the proportion of A724E mutant parasites increased significantly after treatment (P = 0.013). The prevalence of Pfkelch13 A724E in Kaoma increased steadily from 0% (95% confidence interval [CI], 0 to 22%) in 2018 to 79% (95% CI, 73 to 85%) in 2026. Conclusions A novel Pfkelch13 mutation conferring partial resistance to artemisinin is spreading in Zambia. Additional clinical evaluations are urgently needed in the region. (Funded by the Gates Foundation, INV-048316).

Abstract Introduction Onchocerciasis is targeted for elimination with community-directed treatment with ivermectin (CDTI). Alternative strategies are needed in areas where transmission persists despite long-term CDTI and/or are co-endemic with loiasis. This study assessed the efficacy of 35-day treatment with 100mg doxycycline on Wolbachia density at 6 months and microfilaridermia and palpable nodules at 30 months post-treatment. Methods A treatment follow-up study was conducted in 20 high-transmission onchocerciasis communities in a co-endemic loiasis area of South-West Cameroon. Community-based directly observed treatment with 100mg doxycycline was administered to community members aged [&ge;]9 years. Wolbachia clearance at 6-months and treatment efficacy on microfilaridermia and palpable nodules were assessed at 30-months post treatment. Factors associated with reductions in microfilaridermia post treatment, including adherence to doxycycline treatment were assessed with mixed-effects logistic regression. Results Over 92% (2835/3080) of eligible participants took 35 days of 100mg doxycycline over 5 or 6 weeks. This regimen achieved a 62.8% microfilaridermia reduction and 99% palpable nodule reduction in the 720 participants included at follow-up. Wolbachia depletion was observed in 92% of skin samples at 6 months post treatment. The most important factor associated with microfilaridermia after 30 months was having missed at least 7 doxycycline consecutive doses (OR 3.11, 95%CI: 1.17-8.26). Incomplete treatment to a lesser extent was not associated with reduced efficacy at follow-up. Conclusion This large-scale community intervention shows that a 5-week treatment with 100mg doxycycline is feasible and has high curative efficacy against adult O. volvulus as measured by the dramatic reduction in the proportion of palpable nodules at 30-months post treatment. The high efficacy shows the tremendous potential of anti-Wolbachia drugs as part of the arsenal for onchocerciasis elimination and paves the way for the next generation of anti-Wolbachia drugs with shorter treatment courses, which will facilitate the implementation of alternative strategies to accelerate onchocerciasis elimination.

PURPOSE: As the armamentarium of BPH therapies continues to expand, it remains imperative to maximize patient satisfaction and minimize decisional regret. We sought to determine the impact of time from BPH diagnosis to index treatment on symptom improvement and subsequent procedural events. MATERIALS AND METHODS: We queried the American Urological Association Quality Registry for men [&ge;] 40 years old with BPH, available IPSS data, and no receipt of prior BPH treatment. Index treatment included medication, surgery, or minimally invasive surgical therapy (MIST). Outcomes included IPSS over 3 years of follow-up, change in percentage of mild lower urinary tract symptoms (LUTS) by 3 months, and time to procedural event. Patients were stratified by time from index diagnosis to treatment by <12 months, 1-3 years, and >3 years. Outcomes were compared across time-to-treatment cohorts with appropriate statistical tests with p < 0.05 as significant. RESULTS: 43,919 patients met criteria with 19,642 pursuing treatments. Patients pursued treatment at comparably lower baseline IPSS compared to prior prospective series. Patients undergoing surgery and MIST had significantly higher baseline IPSS, while medical comorbidities were significantly more common among men initiating pharmacotherapy. Early surgery and MIST were associated with significant improvement in IPSS within 6-12 months and an increase in mild LUTS by 3 months. All forms of early treatment were associated with delayed time to procedural events, including catheterization and fulguration. CONCLUSIONS: Early procedural intervention for BPH is associated with early symptom improvement and delayed time to procedural events among real-world, contemporary practice.

Introduction: Differentiated service delivery (DSD) models aim to reduce time healthcare providers spend with DSD clients, increasing time available for non-DSD clients. We measured nurses' time allocation and explored their experiences with DSD models in South Africa. Methods: We conducted time and motion observations and surveyed nurses at 24 public primary healthcare facilities across two SENTINEL study rounds (09/2022-07/2023 and 11/2023-07/2024). We report median time nurses spent by activity, model of care, and interaction type. Log binomial regression investigated factors associated with high direct nurse-client interaction (above median minutes) and extended work-days ([&ge;]9 hours), and estimated adjusted risk ratios (aRR). Survey questions were related to client care, additional time availability, and policy changes post DSD implementation, with key themes presented alongside illustrative quotes. Results: 176 nurses (88% female, median age 44) were observed for 344 working days; of these, 60 (34%) participated in the provider survey. Nurses spent a median of 293 minutes (53% of their work-day) on direct nurse-client interaction, 89 minutes (22%) on client-support or facility-related tasks, and the remainder on other activities including personal breaks. Time spent per client was similar across conventional care clients (11 [IQR: 8-15] minutes) but ranged between 9 (7-13) to 11 (8-15) minutes for DSD clients; number of direct nurse-client interactions did not differ meaningfully. Nurses at facilities with 2,000-3,999 total remaining on ART (TROA) (aRR 1.56, 95% CI: 1.02-2.37) and in urban areas (aRR 1.43, [1.08-1.89]) had more direct nurse-client interactions than those at facilities with <1,999 TROA and in rural areas, respectively. Nurses at facilities with 4,000+ TROA (aRR 2.22, [1.36-3.63]) and those observed in SENTINEL 3.0 (aRR 1.53, [1.13-2.07]) were more likely to work standard or longer workdays than those at lower TROA facilities (<1,999), those in SENTINEL 2.0 and urban areas. Nurses reported DSD models improved client care (90%), freed up time (60%), and changed clinic procedures and policies (60%). Conclusions: While DSD models did not significantly reduce direct nurse-client interaction time, nurses reported improved client care and gained additional time. DSD impact may vary by facility context. As DSD implementation expands, effective time reallocation may enhance facility performance and provider productivity.

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 Healthcare-associated infections pose a major burden to neonatal health worldwide and remain difficult to track in low-resource hospitals because patient movement data and pathogen genomic data are rarely integrated into actionable transmission models. Existing approaches are often restricted to specific settings, highly structured electronic health records (EHRs), or analyses focused on either patient movements or pathogen characteristics alone. To address this gap, we developed PathoPath, an open-source integrative modelling platform, and evaluated its utility in a high burden paediatric hospital in Dhaka, Bangladesh. Methods PathoPath is an open-source R package that combines electronic health records with whole genome sequencing data to generate contact networks from direct and indirect contacts using minimal structured inputs. We retrospectively applied PathoPath to 373 cases of Klebsiella pneumoniae species complex (KpSC) infection identified in 2021 at the largest paediatric referral hospital in Dhaka, Bangladesh. Ward level patient movement trajectories were used to reconstruct contact networks, and genomic data from isolates from children <60 days were integrated to identify probable dissemination of bacterial clones and antimicrobial resistance plasmids. Findings PathoPath identified 750 direct contacts among 317 patients, forming 25 connected components, with the largest including 93 patients. KpSC infections were identified across 21 of 37 wards, with the neonatal intensive care unit accounting for 77.9% of all cases. Integration of genomic and network data distinguished sustained clustering of ST147 from multiple probable inter-clonal dissemination events involving IncFII plasmids carrying blaNDM-5 and/or blaOXA-181 within ST16. Four dominant sequence types accounted for 65.6% of sequenced isolates, and carbapenemase genes were detected in 95.8%. Interpretation PathoPath reconstructs hospital-wide contact networks and integrates them with pathogen genomics to map probable dissemination of pathogens and antimicrobial resistance using minimal structured clinical data. It could support more targeted infection prevention and control in hospitals where granular digital records are not available.

Effective filtration and concentration of stool specimens is an essential pre-analytical step for reducing fecal debris and improving organism recovery using microscopy-based ova and parasite (O&P) examination. This study evaluated three commercially available fecal sedimentation-based filtration/concentration systems, ParaPak SpinCon (Meridian Bioscience), Mini Parasep SF (Apacor), and the newly-available ParadeviceReingenuity), for qualitative parasite detection and workflow logistics using conventional and artificial intelligence (AI)-assisted microscopy. Forty clinical stool specimens (20 parasite-positive and 20 parasite-negative) were processed with the 3 devices, and the resultant 120 wet mount and 120 trichrome stained smear preparations were examined using conventional microscopy. Trichrome-stained slides were also scanned at 40x magnification using a Hamamatsu NanoZoomerS360 flatbed digital slide scanner and images were analyzed using the Techcyte Fusion Human Fecal Trichrome AI algorithm. Positive and indeterminate digital findings were confirmed by conventional glass slide microscopy. Slides and digital images were reviewed in a blinded manner. Concordance was assessed among the 360 initial evaluations (microscopy and AI-assisted), and discrepant parasitology results were resolved through re-review and specimen reprocessing as needed. Final qualitative agreement across slide/image evaluations using all three concentration systems was 100%. Minor discrepancies in protozoan and white/red blood cell detection/identification were noted in 5 and 7 cases, respectively, and likely reflected sampling and observer variability. While the three concentration systems produced equivalent qualitative results, the Paradevice and Mini Parasep SF offered the most streamlined workflows. These findings support the Paradevice and Mini Parasep SF as efficient, analytically equivalent systems that are compatible with traditional and AI-assisted O&P workflows.

Background: The Universal Periodic Review (UPR) is a peer-review mechanism established to hold UN Member States accountable for human rights including the right to health, yet evidence on its impact on health outcomes is limited. We evaluated whether UPR engagement is associated with accelerated improvements in maternal health trajectories. Methods and Findings: We conducted a longitudinal ecological analysis of 89 countries with a baseline maternal mortality ratio (MMR) of 70 or greater per 100,000 live births in 2005. Outcomes were trajectories of annual MMR, skilled birth attendance (SBA), and contraceptive prevalence rate (CPR), from 2005 to 2023. The exposure was the volume of health-related UPR recommendations received across three cycles, thematically classified using a validated rule-based algorithm. Mixed-effects models adjusted for time-varying GDP per capita and historical fragility. The 89 countries received 41,733 UPR recommendations across three cycles, of which 405 (1%) were related to maternal health. Maternal health recommendations were preferentially directed at countries with higher baseline MMR and lower SBA. After adjustment, each additional maternal health recommendation was associated with a 0.24% [95% confidence interval (CI): 0.08, 0.40] faster annual reduction in MMR, a 0.52% [0.12, 0.91] faster annual gain in the odds of SBA, and a 0.21% [0.09, 0.34] faster annual gain in the odds of CPR. Broader recommendations on women's health and health systems and services were also associated with faster annual improvements in trajectories across all three outcomes; recommendations on abortion, family planning, sexual health and wellbeing, and sexual education tended to be directed towards lower-burden countries and were not associated with differences in any trajectories. It is important to note that the ecological design precludes causal inference. Conclusions: Receiving UPR recommendations on the themes of maternal health, womens health, and health systems and services are associated with accelerated improvements in maternal health trajectories among high-burden countries. These findings suggest that international human rights accountability mechanisms may have a role in supporting national progress on maternal health.

Abstract Background Peripheral artery disease (PAD) is a major contributor to morbidity and mortality, particularly among individuals with diabetes mellitus (DM), in whom its prevalence is markedly increased. PAD is often asymptomatic and under-diagnosed, especially in low-resource settings. This study aimed to determine the prevalence of PAD and associated factors among adults with DM in Eastern Uganda. Methods We conducted a hospital-based cross-sectional study at Mbale Regional Referral Hospital from 10th/12/ 2024 to 30th/4/2025. A total of 300 adult patients with DM were consecutively enrolled. Data on sociodemographic characteristics, clinical characteristics, comorbidities, and behavioural risk factors were collected using an interviewer-administered data tool. PAD was assessed using the ankle-brachial index (ABI), defined as [&le;] 0.90. Modified Poisson regression was used to identify factors associated with PAD. As a secondary measure for PAD, we administered the Edinburgh Claudication Questionnaire (ECQ) to capture symptomatic PAD. Results The majority of the participants had a low fruit intake (68%), physical inactivity (54%), and elevated low-density lipoprotein (60%). The prevalence of PAD as measured by ABI was 42.3% (127/300; 95% CI 0.38-0.48), while the magnitude of PAD as measured by ECQ, combining participants with possible claudication and definite claudication was 37.3% 95% CI 31.9 - 42.8). Out of participants with PAD, 15.8% (20/127) were classified as having severe PAD (ABI <0.4). Socio-demographic and clinical factors were assessed for association with PAD. We found no evidence of association between the examined factors such as age (aPR 1.24 95% CI 0.73 - 2.09), sex (aPR 1.46 95% CI 0.84 - 2.55), cholesterol level (aPR 1.39 95% CI 0.86 - 2.25), glycemic control (aPR 1.35 95% CI 0.72 - 2.53), and sedentary behaviour (aPR 1.28 95% CI 0.79-2.08) and PAD. Conclusion The prevalence of PAD was high among adults with DM in Eastern Uganda. Routine health education, and ABI screening of PAD should be done for patients living with DM. The absence of significant associations despite high prevalence of PAD may reflect unmeasured factors e.g. chronic inflammation that may be unique to this population, future prospective studies with larger sample size and more detailed objective measures e.g. inflammatory markers are needed to determine locally relevant modifiable risk factors.

Background: Chronic diseases and symptom syndromes often develop after prolonged biological changes that may precede formal diagnosis. RNA-based metatranscriptomics captures active microbial and human gene expression and may provide a functional layer for disease risk evaluation. To address this translational gap, we developed and validated a Disease Risk Score (DRS) framework that integrates metatranscriptome-derived pathway activity scores from stool, saliva, and blood samples, and evaluated its potential clinical utility as an adjunct risk-evaluation tool. Methods: DRS uses disease-specific sets of pathway activity scores derived from stool and saliva microbial functions, stool and saliva microbial taxa, and blood human gene expression. For each disease, 'not optimal' pathway scores are aggregated into a normalized cumulative odds ratio, or cOR, using score-level odds ratios, statistical significance, and literature-supported biological relevance derived from a Development Cohort of 22,369 individuals. A cOR [&ge;] 5 is defined as high risk. Performance is evaluated in an independent Validation Cohort of 15,908 individuals using self-reported diseases as the reference. Disease support requires both significant cOR separation between self-reported and not-reported (Cohen's d [&ge;] 0.2) and risk ratio enrichment of self-reported disease among individuals classified as high risk (95% CI of Risk Ratio > 1). Results: Of 20 initially evaluated diseases, 15 meet the prespecified validation criteria on the independent validation cohort: ADHD, anxiety, chronic fatigue syndrome, depression, GERD, hypertension, inflammatory bowel disease, IBS-C, IBS-D, insomnia, MASLD, obesity, obstructive sleep apnea, Sjogren's syndrome, and type 2 diabetes. Five selected clinical scenarios illustrate how DRS can support clinician-mediated decision making, including IBS subtype reclassification, improved diagnostic acceptance in IBS-D, personalized lifestyle counseling in MASLD and early type 2 diabetes, and diagnostic uncertainty in atypical GERD. Conclusions: DRS is a metatranscriptomics-based risk-stratification framework that aggregates active microbial and human pathway signals into interpretable disease-specific risk estimates across a wide range of disease conditions. Validation against self-reported disease labels in an independent cohort shows significant risk enrichment for each of 15 diseases. DRS is intended as an adjunct to clinical evaluation: a decision support tool in situations where routine care encounters uncertainty, delay, or low patient engagement. Future prospective studies using clinically adjudicated endpoints are needed to assess calibration and clinical outcomes.

Background Slow walking in older adults with mild parkinsonian signs (MPS) is a complex, multifactorial phenomenon arising from the cumulative burden of subclinical age-associated pathologies. This decline reflects age-associated neuronal loss in the dopaminergic system. A recent study suggests that levodopa treatment may enhance gait parameters. The goal of this small pilot study is to explore the effect of levodopa treatment on slow walking gait in older adults with MPS. Method This study was a randomized, placebo-controlled clinical pilot trial. Slow walking older adults without clinical evidence of PD were recruited and randomized into 2 groups (active treatment group or placebo control group). Participants in the active group were pre-treated with carbidopa for three days, followed by carbidopa-levodopa for seven days. Spatiotemporal gait parameters were evaluated at baseline and post-intervention. Results Gait factor analysis identified three main factors explaining gait characteristics at baseline, which included gait efficiency, gait rhythmicity, and gait turning.No effect of treatment was observed in the placebo group (p=0.111, p=0.616), no group difference was observed between the placebo and active group at baseline ({beta}=0.310, p=0.547), but a strong trend for a treatment-related increase was observed in the active treatment group ({beta}=0.506, p=0.076). Conclusion Our preliminary data suggest that sustained levodopa treatment (one week) in conjunction with carbidopa pre-treatment and concomitant carbidopa supplementation is feasible in slow walking older adults with MPS. Moreover, the data indicate potential efficacy, showing improvements in cadence, and step durations.

Background. Capillary refill time, an examiner-dependent bedside test of distal microvascular perfusion, has become a resuscitation target in septic shock,1,2,3,4 motivating a continuous surrogate computed from the photoplethysmogram (PPG, the optical waveform the pulse oximeter on every ICU patient already records).5,6,7,8 Objective. We attempted three PPG-derived candidate measures on the MIMIC-IV Waveform Database (MIMIC-IV-WDB v0.1.0) and asked, by inspecting randomly drawn examples, whether each captured its intended physiology before any downstream modeling. Methods. MIMIC-IV-WDB v0.1.09 was linked to MIMIC-IV.10 The signals were a cuff-anchored perfusion-index recovery (reactive hyperemia when the cuff shares an arm with the probe), a slow Mayer-wave-band power ratio of the perfusion index (sympathetic vasomotor tone), and a per-beat diastolic exponential decay time constant (a refill-like recovery time). For each signal we drew 10 random examples at a fixed seed and checked them against a checklist fixed in advance. Each was read by the author and, separately, by MedGemma 1.5, a multimodal medical language model run locally. A synthetic test with a known time constant checked the third signal. Results. The cuff-anchored signal showed the expected occlusion-reperfusion shape on 268 of 6,236 evaluable cuff cycles (4.30%) in 15 of 19 patients, consistent with opposite-limb placement of the probe and cuff. The slow-band ratio returned a stable cohort value, but a clear, stationary peak appeared in only4 of 10 random windows. The per-beat fit met its goodness-of-fit threshold in 10 of 10 beats, yet a cardiac-frequency heuristic flagged a possible fit on the heart-rate oscillation in 7 of 10, and in 5 of 17 patients the time constant lay where an exponential is indistinguishable from a straight line. A 0.5Hz high-pass pre-filter implanted its own approximately 318 ms time constant regardless of truth. The language model tracked the human on clear positives but reported the pattern present on every call it returned, never absent. Conclusions. Two of the three candidate signals did not reflect their intended physiology in most examples, and the third was constrained by sensor placement. Inspecting a few random raw inputs against a checklist written in advance is an inexpensive upstream check before downstream inference on PPG-derived microvascular signals.

Background Electronic health record documentation patterns may reflect workflow complexity, monitoring intensity, and operational strain in intensive care settings. However, documentation-derived features can be sensitive to local documentation culture, data capture systems, and outcome definitions. Retrospective validation across multiple datasets is therefore needed before these signals are used in workflow intelligence or clinical AI governance tools. Objective To evaluate whether documentation-density and documentation-timing features show reproducible retrospective signal for ICU workflow complexity and long-stay proxy outcomes across de-identified critical care datasets, while distinguishing workflow and long-stay associations from unsupported claims about mortality prediction, burden reduction, or deployment readiness. Methods We synthesized retrospective validation results from de-identified ICU and workflow datasets generated through a prespecified documentation-density validation program. Feature families included Documentation Burden Score style features, Shift-End Documentation Rate style features, documentation reliability style metadata, and all-documentation feature sets where available. Outcomes included long ICU length of stay proxies, mortality where available, and workflow proxy endpoints. Models compared baseline feature sets with enhanced models containing documentation-density or workflow features. Performance was summarized using area under the receiver operating characteristic curve, Brier score where reported, delta AUROC, bootstrap confidence intervals where reported, and label-shuffle controls where available. Results The strongest external long-stay proxy evidence came from the NWICU chartevents analysis, which included 28,612 ICU stays, 20,267 stays with chart events, and 9,619,759 chart events. For ICU length of stay greater than the median, baseline AUROC was 0.5252. Enhanced AUROC was 0.9512 for Documentation Burden Score features, 0.9214 for Shift-End Documentation Rate features, 0.8470 for documentation reliability style features, and 0.9517 for all documentation features. Corresponding label-shuffle enhanced AUROCs were near random, ranging from 0.4897 to 0.5064. For ICU length of stay greater than the 75th percentile, baseline AUROC was 0.5155. Enhanced AUROC was 0.9433 for Documentation Burden Score features, 0.9194 for Shift-End Documentation Rate features, 0.8118 for documentation reliability style features, and 0.9427 for all documentation features, with label-shuffle enhanced AUROCs from 0.4836 to 0.4999. Additional retrospective support was observed in eICU workflow analyses, HiRID first-24-hour documentation-density analyses, MIMIC-IV HF ICU internal analyses, MIMIC-IV-Note metadata extensions, and nursing-chart or lab density proxy analyses. However, cross-institution discrimination transfer was weak without recalibration, and several analyses remained proxy validations rather than final clinical validations. Conclusions Documentation-density and documentation-timing features show promising retrospective signal for ICU workflow complexity and long-stay proxy outcomes, especially in NWICU chartevents and selected internal dataset-specific analyses. These findings support further preregistered, prospective, silent-mode validation of documentation-derived workflow intelligence. They do not establish prospective clinical performance, mortality reduction, clinician burden reduction, autonomous deterioration prediction, or deployment readiness.

Large language models embedded in autonomous agents process trusted instructions and untrusted data in one context window, leaving them open to direct and indirect prompt injection. In healthcare this is not hypothetical: a 2025 JAMA Network Open study found commercial medical LLMs followed injected instructions in 94.4% of simulated patient encounters, including life threatening recommendations . Yet the clinically decisive problem we quantify here is different. Most real clinical threats protected health information PHI exfiltration, cross patient access, bulk export, out of scope advice are fluent, legitimate looking requests that carry no attack signal, so even a state of the art injection detector passes them. Existing runtime guardrails trade safety against latency: model based auditors are accurate but add hundreds of milliseconds of Python inference, while lexical filters are fast but blind to obfuscated or semantically disguised payloads. We present QFIRE, an inline, provider agnostic prompt firewall implemented as a single self contained Rust toolchain proxy, CLI, and benchmark harness. QFIRE combines three mechanisms: (i) positive security scope constraints, which restrict a model call to a declared natural language purpose and block out of scope drift even when no overt attack token is present; (ii) an asynchronous detector graph that runs N rules and their detector nodes concurrently, cheapest checks first; and (iii) a de obfuscation pass that decodes Base64 hex ROT13, folds homoglyphs and leetspeak, and strips zero width characters before detection. QFIRE ships 106 versioned firewall rules and a dedicated HIPAA Safe Harbor 18 identifier PHI panel, and runs a local DeBERTa v3 injection classifier via embedded ONNX Runtime. On 1968 public prompt injection and jailbreak prompts QFIREs deterministic hybrid attains F1 0.86, statistically tied with Metas state of the art PromptGuard 2 0.86 and above protectai DeBERTa v3 0.83; lexical baselines lag 0.16 to 0.50. Our central result is on QFIRE HealthBench, a new 2000 prompt healthcare benchmark we build and release with real garak and Microsoft PyRIT payloads. There the same PromptGuard-2 recovers only 0.40 recall DeBERTa v3 0.57, because most clinical threats carry no injection signal; QFIREs combined scope plus PHI chain reaches 0.83 recall F1 0.87 at a calibrated 0.08 false positive rate. Generic injection detection, even state of the art, is therefore necessary but not sufficient for healthcare agents. A bare LLM judge also closes most of this static corpus gap F1 0.90; QFIREs contribution beyond static accuracy is auditable determinism, bounded latency, and adaptive robustness, where the bare judge falls to 34 to 59% recall section 5.5. End to end, placing QFIRE in front of a tool using agent over a mock EHR sandbox cuts the agents harmful action rate from 0.38 to 0.00 at a 0.13 benign utility cost. All code, rules, corpora snapshots, and scripts are released, and every table regenerates from a single make paper target against local models with no paid API keys.

Background: Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment across addictive disorders including Cannabis Use Disorder (CUD). Targeting incentive-salience circuitry via the ventromedial prefrontal cortex (vmPFC) and central-executive circuitry via the left dorsolateral prefrontal cortex (LDLPFC) are both promising treatment approaches; however, to date structural targets have predominated whereas functional targeting may allow for more precision. In this pilot trial we adapted a functional Magnetic Resonance Imaging (fMRI) Regulation of Craving (ROC) task to generate fMRI-based rTMS targets in the vmPFC and LDLPFC. Methods: We recruited treatment-seeking participants with moderate or severe CUD as a part of an open-label trial and administered an adapted ROC-task during fMRI following 24-hours of cannabis abstinence. We identified sub-portions of maximal activation of the LDLPFC when participants thought of long-term consequences of cannabis use (Later) and of the vmPFC when participants thought of short-term positive aspects of cannabis use (Now). We hypothesized that our task would generate acceptable rTMS targets in >66% of baseline fMRI scans. Results: A total of 20-participants enrolled in the trial (50%F, age=33.3+9.8) and completed the baseline fMRI. The adapted ROC-task elicited group level activation in the LDLPFC and precuneus in the Later>Now and in the bilateral vmPFC, ACC, and striatum in the Now>Later contrast. Acceptable functional targets resolved in both the vmPFC and LDLPFC in 19 of 20 participants (one participant did not tolerate MRI). Conclusions: The adapted ROC-task elicits activation in incentive salience and central executive circuitry and can feasibly generate rTMS targets when using a cluster selection algorithm.

**Abstract** **Background:** Transcatheter edge-to-edge repair (TEER) is an established treatment for mitral regurgitation but remains highly dependent on operator experience and complex transesophageal echocardiography (TEE)-guided intraprocedural imaging. Artificial intelligence (AI)-based semantic segmentation may improve procedural reproducibility and intraprocedural guidance; however, no TEER-specific segmentation framework has been reported. **Objectives:** To develop and evaluate AutoClip, a clinician-driven AI-guided TEE semantic segmentation model designed for simultaneous delineation of mitral valve anatomy and in-vivo TEER device components. **Methods:** A retrospective proof-of-concept study was conducted using 987 intraprocedural TEE frames derived from 10 video clips in 3 patients undergoing MitraClip G4 implantation. Seven semantic labels, including mitral leaflets and device components, were manually annotated using ITK-SNAP. Following standardized preprocessing and region-of-interest extraction, an Attention U-Net architecture was trained frame-wise on bicommissural and corresponding X-plane TEE views. Model performance was assessed using mean intersection-over-union (IoU) and Dice coefficient on an independent test set. **Results:** The Attention U-Net demonstrated improved sensitivity to small device structures compared with conventional U-Net architectures. Preliminary training performance achieved a mean IoU of approximately 0.93, while independent test performance reached a mean IoU of 0.46 across foreground classes. Qualitative assessment demonstrated feasible simultaneous segmentation of mitral leaflets, clip arms, grippers, and delivery shaft during TEER procedures. **Conclusions:** AutoClip represents a proof-of-concept TEER-specific TEE semantic segmentation framework initiated through a clinician-oriented workflow without formal computer science expertise. Although preliminary accuracy remains modest due to limited sample size, this study establishes a reproducible pathway for future AI-assisted intraprocedural guidance systems and larger multicenter development efforts in structural heart interventions.