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10585 Background: Prior studies suggest that thyroid cancer (TC) survivors may have an elevated risk of secondary malignancies. However, whether this risk differs by TC histology, specifically with breast cancer (BC), remains unclear. We aimed to investigate the association between TC subtype—papillary thyroid carcinoma (PTC) versus medullary thyroid carcinoma (MTC)—and subsequent BC risk, adjusting for demographic factors. Methods: We conducted a retrospective cohort study using the SEER (2000–2022), including adults with a primary, microscopically confirmed PTC or MTC. Subsequent BC occurrence was defined as a binary outcome (yes/no). Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for MTC versus PTC, controlling for age (<50 vs ≥50 years), sex, and race. Stratified analyses by age and race were also performed. Stata 15 was used for statistical analyses. Results: 14,840 patients (14,563 PTC, 277 MTC) were included. MTC patients were older (mean 59.08±12.66 vs 56.16±12.98 years, p<0.001) and had a higher proportion of males (44.4% vs 29.4%, p<0.001). The overall incidence of secondary BC was lower in MTC patients (7.6% vs 22.5%, p<0.001). In unadjusted logistic regression, MTC was associated with significantly lower BC risk (OR=0.28, 95% CI: 0.18–0.44, p<0.001). After adjustment, MTC remained significantly protective (aOR=0.34, 95% CI: 0.22–0.55, p<0.001). Stratified analyses demonstrated consistent findings across age groups (<50: aOR=0.10, 95% CI: 0.03–0.42; ≥50: aOR=0.34, 95% CI: 0.21–0.54), , as well as white and Hispanic patients. Conclusions: Survivors of MTC have a substantially lower risk of developing secondary BC compared to PTC survivors. This association persists after adjustment for age, sex, and race, and is consistent across age and most racial subgroups. However, different BC types were not assessed due to limited number of BC patients among MTC survivors, and the small MTC sample size and potential survival differences between groups may affect the results. These findings highlight a possible effect of TC subtype on BC risk, suggesting the potential influence of underlying biological or genetic mechanisms. Baseline demographic characteristics of patients with papillary and medullary thyroid carcinoma. Characteristic Papillary Thyroid Carcinoma (PTC) (N=14,563) Medullary Thyroid Carcinoma (MTC) (N=277) P-value Age at Diagnosis 0.0002* Mean ± SD, years 56.16 ± 12.98 59.08 ± 12.66 Median, years 57 61 Sex, n (%) <0.001† Female 10,288 (70.6) 154 (55.6) Male 4,275 (29.4) 123 (44.4) Race, n (%) 0.015† White 10,263 (70.5) 197 (71.1) Black 921 (6.3) 15 (5.4) American Indian 77 (0.5) 1 (0.4) Asian 1,379 (9.5) 13 (4.7) Hispanic 1,903 (13.1) 50 (18.1) SD: Standard Deviation. *P-value from two-sample t-test (equal variances assumed). †P-value from chi-square test for the overall distribution across categories.

Objective The Accreditation Council for Graduate Medical Education (ACGME) introduced Milestones in 2013 to aid the assessment of residents and fellows within the framework of the six core competencies of practice. Feedback from program directors and trainees, clinical competency committee processes, and milestone reporting identified the need for modification. This study represents a consensus-driven educational quality improvement initiative which describes the development, revision process, and key features of Critical Care Anesthesiology (CCA) Milestones 2.0, and provides lessons learned in adapting competency-based assessment to a one-year subspecialty training program. Methods A Critical Care Anesthesiology (CCA) working group was convened by the ACGME in 2021 to revise the content, enhance relevance to training, clarify goals for program leadership, and develop supplemental resources to aid implementation. The group consisted of a diverse group of experienced educators and clinicians from CCA fellowship programs nationwide. A modified Delphi process, stakeholder feedback, Milestones performance data, and public comment were used to iteratively revise Milestones. In addition, a supplemental guide was developed to provide examples and resources to aid the Milestones assessment. Conclusion The Milestones 2.0 simplify the use, implementation, and interpretation of this competency framework for program directors, trainees, faculty, and the American Board of Anesthesiology. The resulting CCA Milestones 2.0 provide updated specialty-specific, competency-based behavioral anchors to guide the developmental progression of competencies and outcomes for CCA fellows and facilitate the design of curricula and the advancement of CCA training programs. Lessons learned in the development of the CCA Milestones 2.0 include the importance of simplification, behavioral specificity, and supplemental.

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P &lt; .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P &lt; .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P &lt; .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

ABSTRACT Pulmonary arterial hypertension (PAH) is associated with significant symptoms and impaired health‐related quality of life (HRQOL) and survival. Specialty palliative care (SPC), an intervention delivered by a multidisciplinary team, is focused on improving HRQOL. We performed a randomized controlled trial (RCT) of SPC among adults with PAH and impaired HRQOL to determine the impact of SPC on HRQOL as assessed by PAH‐SYMPACT. PAH‐SYMPACT is a validated PAH disease‐specific patient‐reported outcome measure that assesses HRQOL across four domains: cardiopulmonary symptoms, cardiovascular symptoms, physical impact, and cognitive/emotional impact. Sixty‐two patients were included (36 usual care, 26 SPC plus usual care), but only 58% of patients randomized to SPC completed their SPC visits. In the intention‐to‐treat analysis, SPC was associated with similar changes in total, symptom, and physical impact domain scores and increased cognitive/emotional impact scores, indicative of worse HRQOL. In the per‐protocol analysis, SPC was not associated with significant changes in total or individual domain scores. According to a survey of patients who completed SPC visits, most were satisfied with their visit and were likely to recommend SPC for other patients with PAH. In conclusion, limited SPC visits in this single‐center RCT were not associated with significant improvements in HRQOL among patients with PAH and impaired HRQOL, but the majority of patients who participated in a SPC intervention were satisfied and would recommend SPC to other PAH patients. Future studies of SPC in PAH are needed to determine the appropriate patient selection and timing for SPC. www.clinicaltrials.gov (NCT03905421).

Abstract INTRODUCTION To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Abstract Rationale Low-sodium oxybate (LXB; Xywav®) is FDA approved for treatment of cataplexy and excessive daytime sleepiness (EDS) in people ≥7 years of age with narcolepsy, and for idiopathic hypersomnia in adults. LXB Prescribing Information includes a Warning and Precaution for respiratory depression and sleep-disordered breathing; therefore, data on safety of LXB in people with obstructive sleep apnea (OSA; a common comorbidity among people with narcolepsy or idiopathic hypersomnia) are needed. This post hoc analysis of DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974), a prospective, open-label phase 4 study, evaluated respiratory parameters in participants taking LXB with or without comorbid OSA, in 3 cohorts: narcolepsy or idiopathic hypersomnia (LXB ≤9 g/night), or narcolepsy (LXB &gt;9 g/night). Methods Participants underwent the following study periods: screening, 8-day baseline (BL; off-LXB for narcolepsy and idiopathic hypersomnia cohorts; on-LXB 9 g/night for &gt;9 g cohort), 2-8-week dose titration, 2-week stable-dose, 8-day end-of-treatment (EOT; on optimized total nightly dosage; ≤12 g for the &gt;9 g cohort), and 2-week safety follow-up. Participants with BL apnea-hypopnea index (AHI) &gt;10 (treated/untreated OSA) were excluded from the study. Overnight polysomnography assessments conducted at BL and EOT included respiratory parameters: AHI, central apnea index (CAI), and percentage of total sleep time spent with oxygen saturation (SpO2) &lt;90% (T90). Treatment-emergent adverse events (TEAEs) were assessed by OSA group. Least squares mean changes were adjusted for BL values. Results Fifty-five participants enrolled in the narcolepsy cohort, 9% (5/55) had comorbid OSA; 22% (10/46) and 31% (15/48) had comorbid OSA in the idiopathic hypersomnia and narcolepsy &gt;9 g cohorts, respectively (3, 9, and 12 were on OSA treatment throughout the study). Most participants (narcolepsy, idiopathic hypersomnia, narcolepsy &gt;9 g) were female (72.7%, 80.4%, 62.5%) and White (80.0%, 84.8%, 77.1%). No worsening of sleep-disordered breathing was observed during LXB treatment, as evidenced by respiratory parameters AHI, CAI, and T90 assessed at BL and EOT in either participants with or without OSA (Table 1). Percentages of participants with/without OSA reporting ≥1 TEAE were 60.0%/62.0% (narcolepsy), 80.0%/72.2% (idiopathic hypersomnia), and 66.7%/78.8% (narcolepsy &gt;9 g). Most TEAEs were mild or moderate; 1 serious TEAE each occurred in the idiopathic hypersomnia cohort (with OSA) and the narcolepsy &gt;9 g cohort (without OSA). Conclusions No worsening respiratory signals were observed with LXB treatment in participants with or without comorbid (mild or treated) OSA in the narcolepsy, idiopathic hypersomnia, or narcolepsy taking &gt;9 g LXB dosage cohorts. This abstract is funded by: Jazz Pharmaceuticals

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.