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Open-access drug discovery platforms have accelerated hit identification and lead prioritization across multiple diseases and enable systematic repurposing of bioactive compounds beyond their original indications. However, there remains a need for new chemotypes for African trypanosomiasis with improved efficacy and resilience to emerging drug resistance. In this study, we evaluated the antitrypanosomal potential and cellular effects of two Pathogen Box compounds, MMV667494 and MMV028694. The compounds were selected through a resazurin-based in vitro phenotypic viability screen that measures metabolic activity as a proxy for parasite viability against bloodstream-form Trypanosoma brucei brucei. To explore cellular phenotypes consistent with potential mechanisms of action, we applied cytological profiling using flow cytometry- and microscopy-based assays, including Annexin V/propidium iodide staining, cell-cycle DNA-content analysis, mitochondrial membrane potential (TMRE), and mitochondrial reactive oxygen species (MitoSOX) measurements. Both MMV667494 and MMV028694 (IC50 = 0.44 ± 0.05 µM and 0.33 ± 0.03 µM, respectively) displayed sub-micromolar antitrypanosomal potency and preferential toxicity toward trypanosomes over mammalian cells (selectivity indices >10). Growth profiling demonstrated dose-dependent inhibition of parasite proliferation, with evidence of trypanocidal activity at higher concentrations and longer exposure times. Treatment resulted in increased populations of phosphatidylserine-exposed and membrane-compromised cells, which is consistent with apoptosis-like phenotypes in trypanosomes. Although both compounds induced mitochondrial membrane depolarization in treated T. b. brucei cells, this effect was observed predominantly in a subpopulation of cells and is therefore unlikely to represent the primary cause of cell death. Increased mitochondrial production of reactive oxygen species and altered cell-cycle progression were also observed, which might indicate disruption of key cellular processes. These findings shows that MMV667494 and MMV028694 are selective antitrypanosomal compounds and their activities are associated with induce apoptosis-like features, cell-cycle disruption, and mitochondrial stress signatures in bloodstream-form T. b. brucei. These findings provide phenotypic insights into the activity of the compounds, warranting further target deconvolution and optimization, although validation in human-infective subspecies and in vivo systems will be required.

Pseudomonas aeruginosa is a high-priority pathogen and significant burden to health care worldwide. Although often regarded as an extracellular pathogen, P. aeruginosa is also capable of existing intracellularly in multiple cell types, including epithelial cells, goblet cells, and macrophages. This designation is attributed to two of its type three secretion system (T3SS)-dependent exotoxins, ExoS and ExoT, which inactivate host proteins that facilitate phagocytosis. However, studies investigating intracellular bacteria show that ExoS can paradoxically facilitate survival and replication, seemingly overriding the anti-internalization properties of itself and ExoT through its ADP-ribosylation activity. Here, we set out to define the individual and combined contributions of ExoS and ExoT by examining how each of their two functional domain activities affects epithelial cell invasion. Through in vitro biochemical assays, we found that ExoS is capable of ADP-ribosylating ExoT and their shared human cofactor, 14-3-3. We also found that ExoT ADP-ribosylates itself, unexpectedly enhancing its GTPase-activating protein (GAP) activity. Using fluorescence microscopy, we found that GAP activity of either exotoxin does not block internalization events, but is instead associated with fewer internalized bacteria entering a phase of rapid cytoplasmic replication. We demonstrate that ExoS ADP-ribosyltransferase activity is positively associated with vacuolar exit and cytoplasmic replication, and delivery of ExoS from extracellular bacteria triggers the intracellular T3SS⁻ subpopulation to become T3SS+ and exit the vacuole. Overall, this study highlights the underappreciated ability of P. aeruginosa to become intracellular and delineates how the enzymatic domains of ExoS and ExoT dictate the intracellular localization of the pathogen.

Parkinson disease (PD) is characterized by motor symptoms as well as progressive cognitive decline leading to long-term functional impairment and diminished quality of life. Mild cognitive impairment in PD (PD-MCI) is a risk factor for developing PD-related dementia. PD-MCI provides a window to assess interventions that can improve cognition. Repetitive transcranial magnetic stimulation (rTMS) shows promise as an effective treatment to improve cognitive performance. This study aims to test the safety and feasibility of a 10-session, high-frequency rTMS protocol applied to the left dorsolateral prefrontal cortex and the rTMS efficacy in improving cognitive test performance among veterans with PD-MCI. This is a double-blind randomized controlled trial. We will enroll US military veterans with PD-MCI. Participants will be randomized to either active or sham rTMS treatment groups, each with 10 treatment sessions (2 sessions/day). Treatment need not be consecutive; rather, they can be spread across approximately 10 days (eg, Monday, Wednesday, Thursday, Monday, Tuesday, and Wednesday). Participants randomized to active rTMS will receive stimulation applied to the left dorsolateral prefrontal cortex at 110% the resting motor threshold, a 15-Hz rate, 5 seconds per train of pulses, a 10-second intertrial interval, and 40 trains of pulses per session. Each patient will receive approximately 3000 pulses per session. Sham stimulation will be administered at the same parameters as real rTMS; however, no magnetic field will be produced on the placebo side of the active or placebo coil. This protocol was approved by the Edward Hines Jr Veterans Administration Hospital and Jesse Brown Department of Veterans Affairs Medical Center institutional review boards. This study includes a Food and Drug Administration investigational device exemption (G190076). Safety will be assessed using the number of research-related adverse events experienced by the active rTMS group compared to the sham rTMS group. Feasibility will be assessed using protocol completion rates. To examine preliminary effects of rTMS, participants will complete a standardized neurocognitive battery assessment at baseline, end point, and 1-month follow-up. The primary study outcome is the change in score from baseline to end point on the National Institutes of Health-sponsored Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research Executive Composite score. This project was funded in June 2019, with additional funding secured in April 2024. As of April 2025, a total of 18 veterans with PD-MCI have completed the randomized controlled trial phase. Data collection is ongoing and will be completed by March 2027. We expect the results of this study to be available by March 2028. The knowledge gained on the safety, feasibility, and efficacy of rTMS will set the stage for future research optimizing therapeutic gains for existing cognitive rehabilitation treatments or developing new and adjunct treatments for PD-MCI. ClinicalTrials.gov NCT03836950; https://clinicaltrials.gov/study/NCT03836950. DERR1-10.2196/77241.

The rising burden of Type 2 diabetes mellitus (DM), heart disease, and chronic kidney disease (CKD) is associated with substantial healthcare expenditures among U.S. adults. We described total healthcare, out-of-pocket (OOP) healthcare, and OOP prescription medication expenditure among individuals with DM, heart disease, CKD, or ≥ 2 of these conditions. We pooled data from the 2021, 2022, and 2023 Medical Expenditure Panel Survey (MEPS). DM, heart disease, and CKD were identified using ICD-10 codes in the Medical Conditions file. The analytic sample included adults with DM only (n = 4805), heart disease only (n = 3229), CKD only (n = 44), or ≥ 2 of these conditions (n = 1423). Generalized linear and two-part models were used to estimate the predicted mean annual total healthcare expenditure and OOP prescription medication expenditure associated with these conditions, adjusting for participants' socio-demographic characteristics. Participants with DM only, heart disease only, and CKD only represented 50.57%, 33.99%, and 0.46% of the sample, respectively; 14.98% had ≥ 2 conditions. Approximately half of the participants were female (~ 49.61%), about half were ≥ 65 years (60.18%), most were non-Hispanic White (62.49%), and nearly two-fifths lived in the South (39.17%). Adjusted mean OOP prescription medication expenditure was lowest among adults with CKD only ($341.87; 95% CI: $184.12 - $499.61) and highest among those with ≥ 2 conditions ($679.01; 95% CI: $584.21 - $773.95). However, CKD estimates should be interpreted with caution because of uncertainty due to low sample size. Adjusted mean total healthcare expenditure was lowest among adults with DM only ($15,481.31, 95% CI: 14,545.56-16,417.09) and highest among those with ≥ 2 conditions only ($30,618.53, 95% CI: 27,900-33,336.78 3). Multimorbidity (≥ 2 conditions) is a growing problem in the U.S. and was associated with the highest annual total healthcare and OOP prescription medication expenditure among U.S. adults, highlighting the need for targeted financial and clinical interventions for this high-burden group.

The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) concluded that addition of transfemoral carotid artery stenting to intensive medical therapy (IMT) among patients with high-grade Asymptomatic Carotid Artery Stenosis (AsxCS) led to a significantly lower risk of periprocedural stroke/death or postprocedural ipsilateral stroke within 4 years as compared with IMT alone. In contrast, addition of carotid endarterectomy (CEA) did not lead to statistically significant benefit. The current article critically reviews the results of CREST-2 and shows that with a longer follow-up, CEA + IMT may show a significant benefit compared with IMT alone (similarly with carotid artery stenting + IMT). Secondly, it provides the rationale showing why IMT alone may not provide adequate stroke prevention for patients with severe (70% to 99%) AsxCS. Thirdly, it compares CREST-2 with another recent randomized controlled trial comparing CEA + optimized medical treatment vs optimized medical treatment alone for patients with AsxCS and low-to-intermediate risk symptomatic carotid stenosis, the European Carotid Surgery Trial-2. Furthermore, it discusses the flaws and limitations in European Carotid Surgery Trial-2. Finally, it provides the rationale to refute the often-quoted argument that the vast majority of AsxCS patients are offered an unnecessary intervention. There is now Level I Evidence suggesting that a carotid intervention + IMT may be superior to IMT alone for the management of AsxCS patients.

Currently, there are no standardized outcome domains or measures in clinical trials for facial aging. Heterogeneity in outcome domains and measurement instruments across clinical trials creates difficulty in directly comparing interventions, determining superior therapies, and developing high-quality meta-analyses. To develop a core outcome set (COS) of essential domains to be reported in clinical trials evaluating the efficacy of interventions for facial aging. PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL were searched from September 2005 to September 2015. An updated search of the same databases was performed from September 2015 to February 2026. Studies were included if (1) they were randomized clinical trial or controlled clinical trial in design, (2) they assessed the efficacy or safety of an intervention for facial aging, (3) they were published in English, and (4) they involved human participants. Complementary sources, including patient interviews, were used to capture further relevant outcomes. Two rounds of Delphi surveys, followed by consensus meetings, were used to identify outcome domains considered most important by both patient and physician stakeholders. The final COS consists of 6 outcome domains: (1) overall convenience of treatment; (2) time to return to normal work and social activity; (3) overall assessment of focused area of treatment (at the point in time when treatment is expected to provide peak benefit); (4) duration of treatment effect; (5) severity of persistent local or systemic adverse events, including pigmentary change, skin texture change, delayed healing, scarring, and serious adverse events; and (6) patient satisfaction with treatment. The 6 outcome domains identified through a Delphi consensus are recommended for reporting in future facial aging trials to ensure that outcomes that matter most to patients and clinicians are measured and that results are comparable across interventions.

Studies performed in urban communities with access to technology suggest high patient satisfaction with telehealth. While virtual visits can increase the reach of clinical practice in rural communities, technological barriers may reduce patient satisfaction. This study aimed to compare satisfaction with telehealth visits between patients living in rural and urban communities. A telephone survey was developed and administered to hepatology patients seen at outpatient clinics from March 2020 through March 2021. Patient characteristics and survey responses were compared by urban and rural location as defined by the census tract based on zip code using univariable and multivariable logistic regression. Of 400 patients, 164 (41%) completed the survey. Compared with urban patients, rural patients had twice the transportation time to clinic (mean 59, SD 35 vs mean 30, SD 15 min) and were more likely to cancel due to transportation issues (21/48, 46% vs 15/116, 13%). Rural patients reported less proficiency with technology and more technical difficulties, including an inability to log on to the portal or access the camera or microphone (35/48, 75% vs 29/116, 25%) and less comfort with their devices (26/48, 54% vs 10/116, 9%). Overall, urban patients were more likely to prefer telehealth (adjusted odds ratio 5.20, 95% CI 2.15-13.7) and were more satisfied with telehealth vs in-person visits than rural patients (72/116, 62.1% vs 10/48, 20.8%). Rural patients reported more technical challenges with telehealth and more transportation issues than urban patients but favored in-person hepatology visits. Urban patients were more satisfied with telehealth visits compared with in-person visits. Research is needed to improve telehealth delivery and satisfaction for rural patients.

Transitions of care place patients at elevated risk for adverse events that may result in hospital readmission, including medication non-adherence after discharge. We sought to apply principles of quality improvement to improve medication adherence after hospitalization by implementing a pharmacist-led bedside medication delivery program at the time of hospital discharge. Our program was not associated with reduced 30-day hospital readmissions in the one-year period analyzed. We further stratified patients by demographic characteristics, insurance status, and zip code to better identify those at elevated risk of readmission or ineligible for enrollment in the program. After comparing our results with similar programs reported in the literature, we postulate that isolated bedside medication-delivery programs, as presently implemented, do not meaningfully reduce hospital readmissions in most cases. There is some evidence that these programs may benefit from being bundled with multi-faceted interventions in the future.

Inhibiting epithelial sodium channel (ENaC) provides clinical benefit in cystic fibrosis treatment, whereas activated alveolar ENaC attenuates acute lung injury/acute respiratory distress syndrome. However, seldom bibliometric analysis of respiratory ENaC systematically evaluates hotspots and trends in ion transport, as well as providing few overviews for researchers. This review aims to provide a comprehensive overview of respiratory ENaC over the past 40 years, identifying the research frontier and topic evolution. Searching the literature in Science Citation Index Expanded from Web of Science (WOS) and PubMed, a total of 1634 publications in 409 journals, authored by 5457 researchers from 60 countries/regions, were analyzed by CiteSpace, VOSviewer, and sciMAT software. The earliest highly cited article, titled 'Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770', had accumulated 1011 citations. The most prolific author, country, and journal were MA Mall, USA, and Am J Physiol Lung Cell Mol Physiol, respectively. In the most recent phase of annual focus, research areas could be clustered by immunology, cell biology, pharmacology and pharmacy, biotechnology and applied microbiology, and physiology. In summary, this bibliometric research reveals that respiratory ENaC is not only responsible for alveolar fluid clearance, but has converted into a broader modulator in immune-inflammatory responses.

Keratoconus (KC) disproportionately affects young and underserved populations, yet clinical research participation remains unevenly distributed. To inform equitable recruitment strategies, we investigated demographic, behavioral, and perceptual factors influencing engagement in a non-interventional KC study. We compared demographic and socioeconomic profiles of patients solicited for participation in a non-interventional clinical study involving the laboratory analysis of excess tissue produced during a corneal cross-linking procedure. We conducted structured telephone surveys of participants and non-participants to assess barriers, facilitators, and attitudes toward clinical research. Here we show that, compared to participants, non-participants of the non-interventional KC study were older (33.2 ± 10.3 vs. 27.6 ± 7.3, p = 0.001) and predominantly male (90.2% vs. 64.8%, p = 0.003), while socioeconomic indices did not differ significantly. Prior clinical research participation strongly predicted future willingness to participate (p = 0.01). Key barriers included concerns about side effects, insurance copays, and job flexibility. Facilitators included transportation assistance, provider-led information sessions, and work absence documentation. Despite participants and non-participants sharing similar preferred language profiles, non-participants were significantly more likely to report availability of translated materials as important interventions (p = 0.04). Demographic variables alone did not predict participation. Behavioral and contextual factors, rather than fixed demographics, shaped clinical research engagement. Strategies such as personalized provider outreach, logistical support, and culturally tailored materials may improve recruitment and retention in KC clinical research; supporting participant-centered frameworks that address practical needs and readiness to engage, particularly in underserved populations.

Facklamia species are Gram-positive, catalase-negative cocci within the family Aerococcaceae. Historically misidentified as streptococci or enterococci due to phenotypic similarity and conventional biochemical testing limitations, their clinical significance remains incompletely defined. This narrative review synthesizes the current literature on the microbiology, epidemiology, clinical manifestations, diagnostic challenges, and antimicrobial susceptibilities of Facklamia infections, with emphasis on urogynecologic relevance. A structured literature search identified peer-reviewed reports of microbiologically confirmed human infection published through December 2025. These reports indicate global distribution and a broad clinical spectrum. Invasive infections were reported most often in older adults and individuals with structural abnormalities, chronic comorbidities, or recent surgical interventions; however, cases in otherwise healthy patients are described. Emerging microbiome data suggest that F. hominis may be enriched in adult females with lower urinary tract symptoms, supporting the possibility that the female urogenital tract functions as a potential reservoir and site of pathogenic activity. Antimicrobial susceptibility patterns vary, with documented resistance to penicillin, macrolides, clindamycin, and tetracyclines, and susceptibility to cephalosporins, vancomycin, and linezolid. Overall, Facklamia species should be recognized as underdiagnosed opportunistic pathogens with both invasive and urogynecologic relevance. Increased awareness, improved diagnostic identification, and systematic susceptibility profiling are needed to clarify their pathogenic role and guide appropriate antimicrobial therapy.

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential and endothelial responses remain incompletely defined. This study compared the impact of LMWHs (enoxaparin, tinzaparin), apixaban, and quercetin on cancer cell viability, thrombin generation, and CaCe-dEVs-induced endothelial injury. Methods: Pancreatic (BXPC3) and breast (MCF7) cancer cells and their vesicles were analyzed for TF expression and thrombin generation. Human umbilical vein endothelial cells (HUVECs) were pretreated with each agent prior to vesicle exposure. Cell viability, thrombin generation, and endothelial morphology were assessed using standard assays and microscopy. Results: Tinzaparin and quercetin significantly reduced cancer cell viability, whereas enoxaparin and apixaban showed no cytotoxicity. None of the agents affected HUVEC viability. All suppressed TF-mediated thrombin generation induced by cancer cells, with tinzaparin being most effective in BXPC3 cells. Quercetin exhibited a partial and limited protective effect on endothelial cells against CaCe-dEVs-induced dysfunction, while LMWHs and apixaban did not prevent endothelial damage. Conclusions: These findings suggest that LMWHs, apixaban, and quercetin modulate cancer-cell-driven hypercoagulability beyond anticoagulation, with quercetin and tinzaparin showing additional cytotoxic potential. Such dual effects may reduce thrombosis risk while impacting tumor progression, meriting further investigation.

Concerns persist within the surgical community that completion of an accredited surgical residency no longer consistently ensures that trainees are ready for independent practice. In response, the Independent Committee for Graduate Surgical Education (ICGSE) was established in January 2025 to address the unique requirements of surgical training. The committee's mandate was to recommend program standards that would potentially optimize education and training for surgical residents, with the goal of improving patient care. The ICGSE, consisting of 71 surgeons across 16 specialties, reviewed the history of surgical accreditation and relevant literature. Workgroup-led discussions identified strategies for improving trainee readiness and modernization of program accreditation standards. A literature review showed a "readiness gap" affecting 20%-30% of surgical trainees across multiple specialties. Key areas for improvement include:1. Designing curricula that increase clinical exposure, promote progressive autonomy, and facilitate transition to independent practice.2. Aligning training with the realities of surgical practice.3. Balancing accreditation requirements with efforts to reduce administrative burden and enhance faculty development.4. Emphasizing program evaluation beyond board passage rates and surveys to include real-time and longitudinal tracking of skill and clinical judgment acquisition.5. Supporting faculty education in teaching and assessment.6. Providing clear developmental roadmaps for lifelong learning. 1. Modernize accreditation through application of continuous quality improvement processes.2. Implement an outcomes-focused curriculum adaptable to each specialty that encourages innovation.3. Supplement case logs with an evidence-based framework for assuring procedural competency.4. Require standardized nontechnical skills training and assessment.5. Establish a longitudinal, competency-based assessment system.6. Mandate verifiable faculty development with institutional support. The ICGSE recommends that the graduate surgery education community, in collaboration with oversight organizations and professional associations, work to develop common surgery-focused accreditation standards that would drive the excellence required in surgical care.

The rates of severe obesity, the proportion of the population aged 65 and older, and the utilization of biliopancreatic diversion with duodenal switch (BPD-DS) are increasing. In this context, we seek to define the safety profile of BPD-DS as patients age. We queried the MBSAQIP database from 2020 to 2024 to identify individuals undergoing primary BPD-DS. Patients were divided into three cohorts by age (<&#x2009;50&#xa0;years, 50-64&#xa0;years,&#x2009;&#x2265;&#x2009;65&#xa0;years). Baseline demographics and 30-day outcomes were compared using Fisher exact and Wilcoxon rank sum tests where appropriate. A 1:1 propensity match was created to compare the younger two cohorts. These cohorts were compared to the oldest with 1:4 propensity matches. Multivariable logistic regression modeling was used to assess predictors of complications. 10,305 patients were identified. 7470 (72.5%) were&#x2009;<&#x2009;50, 2488 (24.1%) were 50-64, and 347 (3.1%) were&#x2009;&#x2265;&#x2009;65&#xa0;years. Complication rates were higher in the older cohorts (6.9% vs 9.4% vs 10.4% (p&#x2009;<&#x2009;0.001)). Rates of anastomotic leak, organ space infection, reoperation, and readmission all increased across age groups (all p&#x2009;<&#x2009;0.028). After propensity matching, there were no differences in complication rates between patients&#x2009;&#x2265;&#x2009;65 and the younger cohorts. On direct comparison of the younger cohorts, patients aged 50-64 experienced higher rates of reoperation (2.6% vs 1.6%, p&#x2009;=&#x2009;0.025), readmission (5.8% vs 4.2%, p&#x2009;=&#x2009;0.015), minor complication (6.7% vs 5.1%, p&#x2009;=&#x2009;0.030), major complication (5.5% vs 3.2%, p&#x2009;<&#x2009;0.001), and any complication (9.0% vs 6.9%, p&#x2009;=&#x2009;0.008). The risk for postoperative complications following BPD-DS increases with age. When controlling for baseline associated conditions, patients 65 and older have outcomes equivalent to younger adults. In appropriately selected patients, BPD-DS is safe regardless of patient age.

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

This paper presents findings from a study of medical student reflections on a shadowing experience with hospital chaplains aimed to promote students' understanding of the importance of spirituality in patient care and the role of chaplains on a medical care team. Through a deductive content analysis, we identified key themes providing evidence that this shadowing experience increases student knowledge about spirituality, the role of chaplains, and meets the standards set forth in the National Competencies in Spirituality and Health for Medical Education. Exemplary quotes from student reflections demonstrate how they processed their experience. The student reflections consistently identified the value of the chaplain within health care, the importance of spirituality in patient care, and how this shadowing experience shaped their own Professional Identity Formation.

The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)-positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. There were no specific interventions based on lumpectomy margin width. Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (<1 mm), or negative (&#x2265;1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm (P&#x2009;=&#x2009;.04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm (P&#x2009;=&#x2009;.05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI,&#x2009;0.86-2.06). Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using&#x2009;margin width groupings of less than 1 mm&#x2009;or greater than or equal to 1 mm and margin width&#x2009;groupings of less than 2 mm&#x2009;or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. ClinicalTrials.gov Identifier: NCT00053898.

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with atherosclerosis and maladaptive vascular remodeling serving as central drivers of clinical events. Mechanistic investigation of arterial disease processes relies heavily on experimental animal models that permit precise control of vascular injury, hemodynamic forces, and ischemic stress. Over the past several decades, murine and rat models have become indispensable tools for studying endothelial dysfunction, intimal hyperplasia, flow-mediated remodeling, and ischemia-reperfusion injury. Each model reproduces distinct aspects of human vascular pathology while offering unique technical and biological advantages. This review summarizes commonly used murine and rat models of arterial disease, emphasizing the biological mechanisms they study, the surgical techniques used, pathophysiology, experimental endpoints, advantages, and limitations.

The entry inhibitor Bulevirtide (BLV) was recently approved in Europe for treatment of chronic hepatitis D virus (HDV) infection, which is considered the most severe viral hepatitis infection. Theory indicates that models that account for free virus and infected cells, but do not include target cell dynamics (historically called the two-equation model) are limited to predicting a monophasic viral decline for antiviral agents that act only to block viral entry/infection. We investigated herein a recently published two-equation type model against clinical data obtained from patients with HDV treated with BLV monotherapy for up to 96 weeks using non-linear mixed effects modelling (NLME). We found that (i) although the model parameters had a relative standard error (RSE) < 50% suggesting that they were 'precisely estimated', the fits failed to reproduce the non-monophasic HDV kinetic patterns observed in most patients leading to incorrect predictions of the duration of treatment needed to reach a theoretical cure boundary, defined as less than 1 virion in the entire patient extracellular body fluid. (ii) The model cannot explain viral breakthrough, and (iii) the model wrongly predicts that viral load will remain at the same level once treatment is stopped. Lastly, we showed that including target cell dynamics in the model can explain not only monophasic viral decline during treatment but also non-monophasic HDV decline patterns such as biphasic, flat-partial response and viral breakthrough. Including target cell dynamics also predicts a viral rebound once BLV is stopped as observed in clinical studies.