Citations

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

Abstract Introduction Professional identity formation in healthcare professions education (HPE) is a complex and often fraught process. Physicians and trainees experience identity struggles as they navigate their personal and professional development, along with the conflicting expectations, cultural norms and systemic pressures within the healthcare environment. Despite growing attention to these challenges, conceptual clarity around identity struggle remains limited. Method To advance theoretical understanding of identity struggle, we conducted a critical narrative review of identity theories from developmental psychology, social psychology and sociology. We selected three major theoretical traditions—Neo‐Eriksonian, symbolic interactionist and social identity theories—and analysed their conceptualizations of identity, identity development and identity struggle. We examined these diverse perspectives to inform research and educational practice on professional identity formation in HPE. Results Each theoretical tradition offers distinct insights into identity struggle. Neo‐Eriksonian theories emphasize exploration and commitment as central processes, framing struggle as developmental and potentially productive. Symbolic Interactionist theories highlight the role of socialization and identity dissonance, viewing struggle as emerging from tensions between personal agency and societal norms. Social Identity theories focus on group belonging and intergroup dynamics, conceptualizing struggle at both individual and socio‐contextual levels. We provide common critiques and limitations of each theoretical tradition. These perspectives illuminate varied mechanisms through which identity struggle manifests and evolves. Discussion This review underscores the multifaceted nature of identity struggle and the value of theoretical pluralism in understanding professional identity formation. Struggle is not inherently negative; rather, it can be a catalyst for growth when appropriately framed and supported. We propose how educators and researchers might use these theoretical lenses to design interventions that foster productive identity development and address systemic contributors to identity struggles. We invite scholars drawing on critical perspectives of power and structure to challenge and deepen the conversation on identity struggle in HPE.

Background: Given the faster onset and shorter duration of action of ultra-rapid insulin lispro-aabc (URLi, Lyumjev™ insulin), compared with insulin lispro (a rapid-acting insulin [RAI]), the present study investigated the safety and glycemic outcomes of MiniMed™ 780G advanced hybrid closed-loop (AHCL) use with URLi in youths and adults with T1D. Methods: This 19-site, single-arm, clinical trial enrolled children and adolescents (aged 7–17 years) and adults (aged 18–80 years) with T1D who underwent a run-in period (∼2 weeks) using open loop or automated basal only with an RAI (aspart or lispro), followed by a 3-month study period using URLi with AHCL (AHCL + URLi). End-of-study glycemic metrics and A1c were compared to predefined thresholds and to data from baseline/run-in. Use of recommended optimal settings (ROS, 100 mg/dL glucose target with an active insulin time [AIT] of 2 h) was also assessed. Results: In an intention-to-treat population ( N = 101 pediatric and N = 110 adult participants), percentage of time in range (%TIR) during the last ∼6 weeks of the study period was significantly greater than the predefined thresholds for both the pediatric and adult participants. A1c was unchanged in the pediatric cohort but significantly reduced in the adult cohort (from 7.4 ± 0.9% to 6.9 ± 0.6% [ P < 0.001]). Compared with run-in, study period %TIR and percentage of time in tight target range (%TITR) were significantly increased (pediatric mean %TIRΔ [17.4%] and %TITRΔ [16.0%], respectively, and adult mean %TIRΔ [10.6%] and %TITRΔ [11.6%], respectively; P < 0.001 for all). Additionally, % time above range for both groups was significantly reduced. Use of ROS allowed more participants to achieve recommended glycemic targets. There were no severe hypoglycemia or diabetic ketoacidosis events. Most caregivers agreed that mealtime versus premeal URLi delivery simplified pediatric meal management. Conclusions: Similar to previous studies investigating automated URLi delivery, URLi use in the MiniMed™ 780G system was safe, and glycemic outcomes were favorable for pediatric and adult participants.

Abstract The International League Against Epilepsy (ILAE) is a global organization dedicated to improving the lives of people with epilepsy through education, research, and advocacy. Recognizing the need for broader engagement and multidisciplinary collaboration, the ILAE has established five sections: Young Epilepsy Section (YES), Nursing, Social Work and Social Services (SWSSS), Neurotechnology, and Pharmacy. These sections aim to strengthen professional networks, enhance education, and promote innovation in epilepsy care. YES fosters leadership and participation among early‐career professionals, whereas the Nursing Section addresses gaps in epilepsy‐specific training and competency development. SWSSS emphasizes psychosocial care, advocacy, and health equity, supporting Intersectoral Global Action Plan (IGAP) objectives through culturally sensitive interventions. The Neurotechnology section advances the integration and development of innovative tools for diagnosis and treatment, and the Pharmacy section focuses on optimizing medication management and access to antiseizure medications globally. Collectively, these sections contribute to the WHO IGAP by improving policy, care delivery, research, and public health responses. Looking ahead, ILAE seeks to expand multidisciplinary participation, encourage cross‐sectional collaboration, and maintain its role as a leading force in global epilepsy care. Through these initiatives, ILAE continues to build capacity, foster inclusivity, and drive progress toward equitable, comprehensive epilepsy services worldwide. Plain Language Summary The International League Against Epilepsy (ILAE) is the global organization responsible for all healthcare professionals involved in the care of those with epilepsy. Recognizing the increasing number of different disciplines now contributing to epilepsy care, and the need to develop professionals of the future, the ILAE has recognized “sections” of like‐minded individuals to encourage networking and communication. Together, these sections contribute to the WHO Intersectoral Global Action Plan (IGAP) by improving policy, care delivery, research, and public health responses. Moving forward, the ILAE seeks to expand multidisciplinary participation, encourage collaboration, and maintain its role as a leading force in global epilepsy care.

ABSTRACT In 2018, the International Niemann‐Pick Disease Alliance (INPDA) and the International Niemann‐Pick Disease Registry (INPDR) developed and published comprehensive clinical management guidelines to support inclusive and standardized care pathways in Niemann‐Pick disease type C (NPC)—an ultra‐rare, autosomal recessive, neurovisceral lysosomal disorder. Since then, advances in diagnostics, care, and the approval of two novel disease‐modifying agents have underscored the need to revise these guidelines to ensure safe, consistent, and high‐quality care for those affected by NPC. In response, the INPDA and INPDR convened a multidisciplinary Guidelines Development Group (GDG) comprising individuals with NPC expertise from 14 countries across five continents, representing a broad range of specialties, as well as patients and families involved in NPC care. Informed by a comprehensive literature review and two meetings, the GDG systematically reviewed, revised, and updated the 2018 guideline statements, re‐evaluating the level of evidence, strength of recommendations, and expert agreement for each. The resulting 2025 consensus clinical management guidelines constitute a timely, up‐to‐date, and internationally applicable resource for the diagnosis, treatment, and holistic management of individuals with NPC. These guidelines serve as a critical resource for specialist centers, hospital‐based medical teams, staff involved in NPC patient care, family physicians and other primary caregivers, and, importantly, patients and their families.

Importance Accurate prediction of patient mortality after kidney transplant is an unmet need. Objective To develop and validate an integrative prediction model that predicts short- and long-term patient mortality for kidney recipients. Design, Setting, and Participants This international cohort study included patients who underwent transplants between 2004 and 2023 from 14 academic medical centers from Europe and the US. The derivation cohort consisted of 1566 consecutive adult kidney recipients in a deeply phenotyped cohort prospectively recruited in 1 French center between 2004 and 2014. External validation cohorts consisted of 10 951 kidney recipients from 7 centers in France, 3 centers in Europe, and 3 centers in North America who underwent kidney transplants between 2006 and 2023. Data were analyzed from January 2023 to June 2025. Main Outcome and Measures All-cause mortality was assessed, and 121 candidate prognostic factors, comprising demographics and clinical, biological, imaging, and immunological parameters, were collected. Results Among 12 517 kidney transplant recipients, including 1566 in the derivation cohort (mean [SD] age, 50.05 [14.31] years; 942 male [60.15%]) and 10 951 in validation cohorts (mean [SD] age, 53.32 [13.97] years; 6766 male [61.78%]), 2486 patients (19.9%) died after a median (IQR) follow-up of 5.08 (2.97-7.00) years. Fourteen prognostic factors (including clinical, biological, and imaging risk factors) were independently associated with patient death (eg, patient age: hazard ratio per 1-year increase in age, 1.07 [95% CI, 1.06-1.08]; P &amp;lt; .001) and were combined into a risk prediction model (mBox). The model exhibited accurate calibration and discrimination in the derivation cohort, with C statistics of 0.82 (95% CI, 0.77-0.87) and 0.80 (95% CI, 0.78-0.82) at 1 and 10 years, respectively, after the transplant. Abbreviated models were developed and validated to ensure model generalizability. Performance of abbreviated models was confirmed in external validation cohorts from France (C statistic, 0.76 [95% CI, 0.73-0.78]), Europe (C statistic, 0.74 [95% CI, 0.72-0.76]), the US (C statistic, 0.74 [95% CI, 0.70-0.78]), the Greater Paris University Hospital database (C statistic, 0.79 [95% CI, 0.77-0.81]), and the University of California at San Francisco database (C statistic, 0.70 [95% CI, 0.65-0.74]). The model was also validated in a series of subpopulations (eg, women vs men: C statistic, 0.81 [95% CI, 0.77-0.84] vs 0.79 [95% CI, 0.77-0.82]) and clinical scenarios (eg, before COVID-19 era: C statistic, 0.79 [95% CI, 0.77-0.81]) with good and stable performance. Conclusions and Relevance In this study, an accurate prediction model for mortality among kidney recipients, computable at the time of transplant, was developed and externally validated. Results suggest that this model may help stratify patient risk of death, allowing for improved medical decisions.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract INTRODUCTION Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2‐weighted fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI‐associated WMH (RHI‐WMH). These lesions are punctate, circular, and located at the gray–white matter boundary, an area vulnerable to trauma‐related damage. METHODS We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non‐RHI participants. RHI‐WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS Individuals with RHI had greater RHI‐WMH by both detection methods in both cohorts. RHI‐WMH were associated with plasma neurofilament light and p‐tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION RHI‐WMH may represent a new supportive biomarker for the detection of RHI‐related neuropathologies later in life.

Abstract Background The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population. Content This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities. Summary A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality.

Abstract Despite long-standing interest in combining topoisomerase I (TOP1) poisons with PARP inhibitors (PARPis), the mechanistic basis for the variable and often unpredictable response to this strategy remains unclear. Early preclinical studies suggested that PARP inhibition amplifies TOP1 poison-induced DNA damage, implying broad therapeutic potential; however, emerging translational and clinical data—particularly in ovarian cancer—indicate that synergy is context-dependent and governed by tumor-intrinsic features that have not been fully defined.Here we assessed determinants of response in five HR proficient ovarian cancer (OC) patient-derived xenografts (PDXs) previously treated with the SN-38 prodrug etirinotecan pegol (NKTR-102) in combination with the PARPi rucaparib (C. Nitschmann, Clin. Cancer Res. 22(2) Suppl. B50, 2016). Although all models were refractory to single-agent rucaparib, 50% exhibited enhancement of NKTR-102-induced tumor regression with the addition of rucaparib. Neither PARP1 abundance nor extent of rucaparib-mediated poly(ADP-ribose) suppression correlated with therapeutic benefit. Instead, sensitization was restricted to PDXs intrinsically responsive to NKTR-102 and was strongly associated with high levels of NKTR-102-induced TOP1-DNA covalent complexes. In further analysis, 2 of 3 resistant PDXs exhibited high levels of the ABC transporter ABCG2 despite lack of previous therapy, revealing a previously underappreciated mechanism of de novo resistance that limits effective TOP1 inhibitor activity independent of homologous recombination status. Notably, NKTR-102 response did not track with platinum/taxane sensitivity, highlighting the distinct molecular circuitry governing TOP1 poison susceptibility.Collectively, these findings demonstrate that rucaparib can potentiate NKTR-102-induced regression in tumors capable of forming abundant TOP1-DNA covalent complexes. This work identifies TOP1-DNA complex trapping and lack of ABCG2 expression as mechanistic predictors of benefit, providing an updated framework for selecting patients most likely to respond to TOP1 poison/PARPi combinations and challenging the long-standing assumption that PARP inhibition can universally resensitize tumors to TOP1 poisons. Citation Format: Annapoorna Venkatachalam, Caroline C. Nitschmann, Karen S. Flatten, Rachel Hurley, Xiaonan Hou, Cristina Correia, Paula A. Schenider, Krista Goergen, Matthew Maurer, Ethan P. Heinzen, Ann L. Oberg, S John Weroha, Paul Haluska, Scott H. Kaufmann, Elizabeth M. Swisher. TOP1-DNA protein complex as a predictive biomarker for NKTR-102/Rucaparib combination therapy in PARP-inhibitor resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB364.