Citations

AbstractAimThere is increasing adoption of nonoperative management of rectal cancer; however, the extent to which trainees are proficient in nonoperative management is unclear. The aim of this work was to describe the exposure of recent colorectal resident graduates to nonoperative management, their comfort level in assessing clinical responses and their comfort in performing rectal cancer surgeries.MethodThis was an online survey of Accreditation Council for Graduate Medical Education‐certified colorectal surgery residency graduates of training programmes in 2020, 2021 and 2022 utilizing their respective WhatsApp class chat groups. Data on resident comfort in assessing complete or near complete clinical response as part of nonoperative management, adoption in practice and perceived effects on rectal cancer operative experience were collected.ResultsForty five graduates responded, with 83.3% exposed to nonoperative management in training. Eighty five per cent utilize nonoperative management in their own practices and 37.1% felt it had a negative impact on preparing them for rectal cancer surgeries. While 82.4% felt comfortable assessing a complete clinical response, only 61.8% felt comfortable assessing a near complete response. Residents who perceived a positive effect on their training felt more comfortable assessing a complete or near complete response.ConclusionMost recent graduates were exposed to nonoperative management in training and utilize it in practice, although many did not feel comfortable assessing a near complete response. A significant portion felt it had a negative impact on their experience and quantity of rectal cancer surgeries. This suggests a need to improve colorectal resident education in nonoperative management of rectal cancer while simultaneously preserving surgical experience for trainees.

ABSTRACT Background Advancements in organ transplant technology are pushing global transplant capabilities to new heights. However, challenges persist in pediatric surgical and medical transplant fellowship training, primarily due to a limited number of adequate training programs and gaps in education. Addressing these gaps is essential for improving patient outcomes and advancing the field of pediatric transplantation. Methods An international survey was distributed to 416 pediatric transplant fellows via multiple global transplant associations. The 29‐question survey, available in English and Spanish, assessed current clinical knowledge, training satisfaction, and preferred learning formats. The survey received responses from 237 pediatric transplant fellows. Results One of the key findings was that respondents felt most confident in their pre‐transplantation clinical knowledge. About 75.5% of fellows reported being extremely or very aware of pre‐transplant workups and assessments. However, significant gaps were identified in other areas of training. Notably, 24% of respondents felt extremely knowledgeable about the side effects of immunosuppression, and only 22.8% were very confident in managing acute rejection. Fellows expressed strong interest in dynamic educational formats, particularly clinical case discussions (88.8%). Preferred methods to enhance training included continuing medical education (64.6%), hands‐on workshops, and support for transition protocols and psychosocial counseling. Conclusion This global survey highlights critical educational gaps in pediatric transplant fellowship training and identifies preferred learning methods among fellows. Targeted improvements such as standardized curricula, case‐based learning, interdisciplinary collaboration, and accessible continuing education are essential to enhance training. These strategies will ensure that future transplant professionals are well‐equipped to deliver high‐quality care across diverse healthcare settings.

Abstract Celiac disease (CeD) is an immune-mediated condition driven by dietary gluten resulting in small intestinal mucosal inflammation and injury, along with myriads of symptoms. The only treatment is a lifelong gluten-free diet (GFD) and although most patients improve, the restriction can lead to nutrient deficiencies including fiber. While duodenal microbiota is altered in CeD, its fiber metabolic capacity is unknown. Here we show that both active and GFD-treated CeD patients had impaired microbial fiber metabolism in the small intestine which associates with depletion of the carbolytic taxa Prevotella spp. Colonization of germ-free mice with Prevotella spp increased small intestinal short chain fatty acids (SCFA). In gluten-sensitized mice expressing the celiac risk gene, HLA-DQ8, an inulin-supplemented diet facilitated microbial carbolytic function, SCFAs production and accelerated mucosal healing in the small intestine during GFD. The results support clinical investigations of dietary fiber supplementation and microbial carbolytic function to enhance responses to GFD in CeD.

Abstract RATIONALE: Vascular dysfunction contributes to pathological tissue remodeling in aging-associated disease such as Idiopathic Pulmonary Fibrosis (IPF). IPF is an incurable lung disease characterized by progressive accumulation of scar-forming fibroblasts and several vascular alterations, including endothelial transcriptional changes leading to a pro-fibrotic endothelial secretory phenotype. To date, the mechanisms governing these transcriptional changes remain largely unexplored. To fill this gap, we sought to investigate whether microRNAs (miRNAs), small non-coding RNA that function as key gene expression regulators, modulate the transcriptional changes of the endothelium associated with progressive pulmonary fibrosis. METHODS AND RESULTS: miRNA expression profiling of lung ECs (LECs) sorted from aged mice with persistent lung fibrosis revealed upregulation of miR-205-5p. Further analysis demonstrated that endothelial miR-205-5p was strongly upregulated in an additional mouse model of progressive lung fibrosis induced by repetitive bleomycin dose as well as in human LECs purified from IPF lungs. RNA-seq analysis of normal human LECs overexpressing miR-205-5p revealed reduction of genes associated to endothelial identity (e.g. PECAM1, ERG, NOS3), and an increase of genes encoding for soluble pro-inflammatory and pro-fibrotic molecules, including TGFBI, TGFB2, TGFB3, CXCL10, CCL5, IL1B and FAS compared to normal LECs transfected with a control mimic. Consistently, conditioned medium from miR-205-5p overxpressing LECs exerted a pro-fibrotic activity on quiescent human lung fibroblasts, as demonstrated by upregulation of a panel of profibrotic transcripts (e.g. COL1A1, CTHRC1, FN1 and TNC) and elevated Collagen I deposition compared to human lung fibroblasts exposed to conditioned medium generated by human LECs transfected with a control mimic. CONCLUSION: Altogether, our findings suggest that lung endothelail miR-205-5p induces loss of endothelial cell identity and drives the secretion of pro-fibrotic molecules that promote the transition of quiescent fibroblasts into scar-forming fibroblast through paracrine signal. Our data set the stage for further investigations into the role of miR-205-5p and associated pathways in lung vascular injury responses, with the long term goal of targeting endothelial dysfunction for slowing the progression of pulmonary fibrosis.

ImportanceUnderstanding the global barriers to otolaryngology–head and neck surgery (OHNS) care is crucial in addressing disparities in access to care, particularly in low-income and middle-income countries (LMICs).ObjectiveTo characterize barriers to comprehensive otolaryngology care across World Bank income groups.Design, Setting, and ParticipantsUsing an online cross-sectional survey that was administered by the Global OHNS Initiative via international and national professional societies, personal contacts, and social media, this study captured the perceptions of otolaryngologists regarding barriers to OHNS care at the levels of the country, health sector, clinician, and patient. Participants included otolaryngologists from the 194 World Health Organization member states and Taiwan. Eligibility criteria included a medical degree and specialized training in managing conditions of the ear, nose, and throat. The nonresponse rate was not recorded. The data collection period spanned from October 2022 to June 2023.ExposuresExposures included World Bank income group classification.Main Outcomes and MeasuresThe primary outcomes were Likert scale responses regarding frequency of barriers to OHNS care. The a priori hypothesis was that LMICs would report more frequent barriers to OHNS care.ResultsThe study involved 146 otolaryngologists (47 female individuals [32%]), with 69 (47%) from high-income countries and 77 (53%) from LMICs. Male individuals represented 45 high-income country respondents (65%) and 54 LMIC respondents (70%). Barriers were reported across income groups at all levels of the health system, with a higher frequency in LMICs. Several barriers were reported to be more substantial in LMICs, such as the national volume and distribution of otolaryngologists, financial compensation for clinicians, and patient stigma, and others were common across income settings, such as the availability of operating rooms and inflexible working hours. Common concerns included national and health sector barriers: OHNS workforce, referral networks, government support; clinician barriers: excessive clinician workloads, understaffing, poor administration support; patient barriers: distance to health care facilities, financial burdens such as medical costs and foregone wages, stigma, and health literacy.Conclusions and RelevanceThe results of this cross-sectional study suggest that there are barriers to otolaryngology care globally that affected all levels of the health care system. This work may inform prioritization of otolaryngology within research and policy, and it emphasizes the need for effective strategies to expand access to otolaryngology care, particularly in lower-income settings.

Abstract Introduction: The standard of care for metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the expanded approval of androgen receptor pathway inhibitors (ARPIs) alongside androgen deprivation therapy (ADT). ADT alone has been shown to affect cognitive function. However, the cognitive impact of distinct treatment combinations remains unclear. We investigated the association between first-line systemic treatments and the trajectory of subjective cognitive function among mHSPC survivors in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). Methods: This analysis included 2435 newly diagnosed mHSPC patients enrolled across 15 countries between July 2017 and August 2024. Treatments were reported by site personnel and physicians. For this analysis, we focused on first-line systemic treatment and classified treatment groups at enrollment as ADT monotherapy (referent), ADT + ARPIs, or ADT + chemotherapy. Subjective cognitive function was assessed via the EORTC QLQ-C30 Cognitive Function subscale, with patient-reported scores (range 0-100) collected at enrollment and every 3 months for up to 5 years; higher scores reflect better cognitive function. Associations were estimated using linear mixed effects models with clustering by study site and country to examine differences at enrollment and across trajectories of subjective cognitive function by first-line treatment, adjusting for demographic and clinical factors. Results: Median age at enrollment was 70 years, with a median follow-up of 1.7 years. 724 (30%) participants were treated with ADT monotherapy, 1317 (54%) with ADT + ARPIs, and 394 (16%) with ADT + chemotherapy. Mean cognitive function scores at enrollment were 85.4 (Standard Deviation [SD] 19.5) for participants treated with ADT monotherapy, 86.7 (SD 17.3) for ADT + ARPIs, and 86.7 (SD 18.0) for ADT + chemotherapy. Cognitive function scores decreased by -0.60 points (95% Confidence Interval [CI] -0.72, -0.48) per year among those treated with ADT monotherapy, with similar rates observed for those treated with ADT + chemotherapy. Participants treated with ADT + ARPIs had a slower decline in cognitive function, with scores decreasing by -0.36 points (95% CI -0.60, -0.08) per year. Conclusion: In this international cohort of mHSPC survivors, subjective cognitive function scores were generally high at enrollment but declined over time. There was no evidence of worse cognitive function in those treated with ADT + ARPIs nor ADT + chemotherapy over time compared to ADT monotherapy. Cognitive functioning is a key component of survivorship, and defining cognitive trajectories associated with first-line treatment can inform supportive interventions, patient treatment decision-making, and clinical guidelines. Citation Format: Michelle O. Sodipo, Alicia K. Morgans, Erica T. Warner, Emily M. Rencsok, Lauren E. Howard, Colleen B. McGrath, Anna Siefkas, Konrad H. Stopsack, Christopher Sauer, Robert Drecier, Emilio Esteban, Hassan M. Dogo, Ademola Popoola, Charles Waihenya, Anders Bjartell, Kim Chi, Sebastien Hotte, Richard Cathomas, Deborah Enting, Scott Tagawa, Michael Ong, David Lorente, Elisabeth Heath, Rana McKay, Stefanie Fischer, Heather H. Cheng, Young E. Whang, Frederic Pouliot, Simon Crabb, Monica Chatwal, Miguel A. Climent, Raymond McDermott, Ian D. Davis, Camille Ragin, Folakemi Odedina, Natalie Greaves, Simone Badal, Simon Anderson, Sharon Harrison, Karen Autio, Laurel Cannon, Marie Grant, Alyssa Chan-Cuzydlo, Travis Gerke, Hannah D. McManus, Philip W. Kantoff, Daniel George, Sebastien Haneuse, Lorelei A. Mucci, on behalf of the IRONMAN Registry. First-line therapies and subjective cognitive function trajectories among international metastatic hormone-sensitive prostate cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3630.

ABSTRACT Purpose Pulmonary toxicity (PT) remains a concern following total body irradiation (TBI). This study describes the incidence and factors associated with PT in a cohort of patients homogeneously treated with the lateral opposed fields technique. Methods Medical records of 61 patients ≤21 years of age treated with TBI as a component of stem cell transplantation from 1993–2017 were retrospectively reviewed. The incidences of PT, graft‐versus‐host disease (GVHD), and other toxicities were recorded for each patient. PT was subdivided into its etiologies, and symptomatic PT was established by clinical diagnosis. The association of PT with other variables was examined using chi‐square tests, and overall survival (OS) was estimated using Kaplan–Meier. Results Three‐year OS was 65% (54%–79%). Median TBI dose rate was 7.7 cGy/min (4.0–10 cGy/min). PT occurred in 20 patients (33%). A higher rate of PT was observed in patients with GVHD (65% vs. 35%, p ≤ 0.01). TBI dose rate (</≥ 7.7 cGy/min) was not associated with the risk of PT; however, on continuous analysis, a higher dose rate increased the risk of PT (HR = 1.9, p = 0.04). PT (HR = 3.4, p = 0.01), noninfectious PT (HR = 5.0, p ≤ 0.01), and pneumonitis (HR = 4.3, p = 0.01) were associated with inferior OS. Conclusions This cohort of patients treated with a low dose rate, bilateral technique, and total dose of 1000–1320 cGy experienced an acceptable incidence of PT, comparable to other published studies. Because PT correlated with reduced survival, current practice should seek to address factors associated with PT by aiming to prevent GVHD and by choosing low dose rates, such as in the range of 4.0–10 cGy/min.

Abstract Aims Artificial intelligence (AI) has the potential to transform cardiac electrophysiology (EP), particularly in arrhythmia detection, procedural optimization, and patient outcome prediction. However, a standardized approach to reporting and understanding AI-related research in EP is lacking. This scientific statement aims to develop and apply a checklist for AI-related research reporting in EP to enhance transparency, reproducibility, and understandability in the field. Methods and results An AI checklist specific to EP was developed with expert input from the writing group and voted on using a modified Delphi process, leading to the development of a 29-item checklist. The checklist was subsequently applied to assess reporting practices to identify areas where improvements could be made and provide an overview of the state of the art in AI-related EP research in three domains from May 2021 until May 2024: atrial fibrillation (AF) management, sudden cardiac death (SCD), and EP lab applications. The EHRA AI checklist was applied to 31 studies in AF management, 18 studies in SCD, and 6 studies in EP lab applications. Results differed between the different domains, but in no domain reporting of a specific item exceeded 55% of included papers. Key areas such as trial registration, participant details, data handling, and training performance were underreported (&lt;20%). The checklist application highlighted areas where reporting practices could be improved to promote clearer, more comprehensive AI research in EP. Conclusion The EHRA AI checklist provides a structured framework for reporting AI research in EP. Its use can improve understanding but also enhance the reproducibility and transparency of AI studies, fostering more robust and reliable integration of AI into clinical EP practice.

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n = 8) or Wilms tumor (n = 1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing–altered 1 subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875 to 1:4,843 but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and Wilms tumor are also associated with DICER1 GPVs, our results suggest that the tissues of origin for these tumors are uniquely tolerant of general miRNA loss. The miRNA processing–altered 1 pineoblastoma subtype is associated with older age of diagnosis and better outcomes than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest that genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, Wilms tumor, or other DICER1-/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.