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501 Background: EA1181 (NCT04266249) is a single-arm trial of neoadjuvant THP for patients with clinical anatomic stage II/III HER2+ breast cancer; patients with cT4 or cN3 disease were excluded . Assessing the primary endpoint, 3-year recurrence-free survival in patients with a pCR (ypT0/Tis, ypN0), requires longer follow-up. Here, we present results for the secondary objective of pCR rate and its relation to clinicopathologic factors and the HER2DX pCR likelihood score (Reveal Genomics) derived from gene expression and clinical features. Methods: Patients received 4 cycles of trastuzumab and pertuzumab (HP) with weekly paclitaxel (12 weeks) or docetaxel (q3w x 4), followed by surgery. Clinicopathologic features were assessed for all patients and HER2DX pCR score (stratified by ER status) was determined using the diagnostic biopsy in a representative subset of study participants. Results: 2175 patients were enrolled. Median age was 55 years (range 22-88 years); 58% had clinical stage IIA, 33% stage IIB, and 9% stage III. 45% had nodal involvement (mostly cN1). 781 tumors were HER2+/ER- and 1394 HER2+/ER+ (locally tested ). 2141 patients started THP, for whom the pCR rate was 44% overall, 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Disease progressed during THP in 16 patients (0.7%). The pCR rate varied inversely to the proportion of cells staining for ER among patients with HER2+/ER+ breast cancer: 1-10%+, 62.5%; 11-69%, 51.6%; ≥70%, 22.5% (p <0.001). The pCR rate was significantly associated with higher grade, especially in HER2+/ER+ disease. T and N stage did not significantly affect pCR rate. Among 569 patients assessed for the HER2DX pCR score, the pCR rate was significantly greater for patients with a higher vs lower score, regardless of ER status (Table). Further correlations and interactions will be presented. Conclusions: Neoadjuvant THP resulted in pCR in nearly two-thirds of pts with clinical stage II/III HER2+/ER- and in one-third with HER2+/ER+ breast cancer. There was no association with clinical stage. Lower ER expression and higher grade were associated with higher pCR rates. The HER2DX pCR score was a significant predictor of pCR, regardless of ER status. Clinical trial information: NCT04266249 . All Participants HER2+/ER- HER2+/ER+ # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) # patients enrolled pCR rate (95% CI) Evaluable Cohort 2141 44%(42-46%) 774 64%(60-67%) 1367 32%(30-35%) HER2DX Cohort 569 48%(44- 52%) 230 69% (63-75%) 339 34%(29-39%) HER2DX pCR-high score 182 (32%) 68%(60-74%) 147 (64%) 70% (62-77%) 36 (11%) 58%(41-74%) HER2DX pCR-medium score 161 (28%) 67% (59- 74%) 70 (30%) 74%(62- 84%) 89 (26%) 61%(50-71%) HER2DX pCR-low score 226 (40%) 19%(14- 25%) 13 (6%) 31%(9-61%) 214 (63%) 18%(13-24%) P-value HER2DX score <0.001 0.010 <0.001

Background and Objectives The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs). Methods Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy. Results One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction. Discussion This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Abstract Background: The hidden curriculum refers to the implicit norms and behaviors in academic environments that can particularly disadvantage scholars from backgrounds underrepresented in the scientific workforce (URSW). Critically, scientific mentors can support URSW mentees by making the hidden curriculum explicit to help these scholars navigate academia more effectively. However, mentors often lack the lived experience or training necessary to understand and fully address relevant hidden curriculum challenges. Methods: We developed a set of 16 hidden curriculum competencies specifically for scientific mentors working with URSW mentees. A survey was conducted among diversity, equity, inclusion, and accessibility experts in translational science to assess the perceived importance of each competency. Their feedback was used to refine the final competencies, from which a conceptual framework was developed. Results: Survey results (n = 62) showed broad agreement on the competencies’ critical importance for mentoring across diversity, with several competencies, including identifying unconscious biases, acting as allies, and demystifying career pathways, receiving over 90% agreement for their importance for mentoring URSW mentees. Respondents from URSW backgrounds placed greater emphasis (p < 0.05) on several competencies, including understanding mentee perspectives, expanding professional networks, and allyship. Conclusion: The 16 competencies, grouped into four domains (Foundation, Career, Science, and Overcoming Bias), collectively offer a comprehensive approach for mentors to build trust, support mentee career development, overcome practical barriers to mentee engagement in research, and actively combat bias. Our conceptual framework offers structured guidance for mentors and mentor training programs, identifying the skills needed to foster inclusive academic environments and enhance URSW retention and success.

ImportanceThe De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity.ObjectiveTo determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Design, Setting, and ParticipantsThis was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025.InterventionsThe DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2.Main Outcome and MeasurePFS.ResultsThe analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67).Conclusions and RelevanceThis secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02908477

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Introduction Comparing sleep and rest-activity rhythms (RARs) across the spectrum of cognitive aging can reveal novel risk factors and potential mechanisms underlying dementia disorders. However, our current understanding is restricted by differences in sleep measurement, limited longitudinal data, and heterogeneous cognitive aging processes. We aimed to determine (1) which sleep/RAR features exhibit meaningful changes within three distinct cognitive pathways; and (2) which sleep/RAR features differ between cognitive aging pathways prior to and after the onset of mild cognitive impairment (MCI) and/or dementia. Methods Longitudinal self-reported sleep and actigraphy data were obtained from 1,449 participants in the Rush Memory and Aging Project (mean age= 81.2±7.1 years, 75.2% female, 5.2% Black, 94.8% White). We applied flexible cubic spline models to quantify differences in the levels and trajectories of sleep amount (self-reported duration; actigraphy rest interval length and alpha), regularity (actigraphy interdaily stability, intradaily variability, and midpoint standard deviation), and timing (self-reported midpoint; actigraphy midpoint and acrophase) within and between three cognitive aging pathways over 12 years: Normal Cognitive Aging (‘Normal’), Progression to MCI (‘Stable MCI’), and Progression to Dementia (‘Dementia’). Models were adjusted for key sociodemographic and health variables. Results Sleep amount was lowest in the Dementia pathway prior to MCI or dementia, but increased with age, most rapidly following dementia. The greatest effect was observed in self-reported duration (standardized mean change, d[95%CI]=0.912 [0.47, 1.36]. Regularity declined across all pathways, most rapidly after cognitive diagnoses, with the largest increases in intradaily variability occurring among the Stable MCI (d=0.97 [0.70, 1.23]) and Dementia paths (d=1.11 [0.84, 1.38). Shifts toward earlier sleep timing were observed in actigraphy measures across all three pathways (-0.54≤d≤-0.31). Conclusion Shorter sleep amount in cognitively healthy older adults may be a risk factor or prodromal indicator of dementia, while longer sleep amounts and decreasing regularity following dementia may reflect neurodegeneration. Advances in sleep timing may be less useful as a clinical indicator of future cognitive impairment or decline. Differences between self-reported and actigraphy-measured sleep/RAR outcomes may reflect distinct underlying mechanisms, warranting further research. Support (if any) NIH: T32HL082610, RF1AG056331, R01AG052488, R01AG071638, RF1AG070436, R01AG17917

Large language models pose unique cybersecurity risks in health care, including vulnerability to malicious attacks and data breaches. This article equips professionals with strategies to mitigate these threats for safe use.

Introduction: A person’s sex and/or gender may influence the pathogenesis, presentation, and therapeutic response to disease; yet, the impact of sex and gender is not routinely evaluated in medical research, nor adequately emphasized in medical school curricula. Little is known about medical school faculty knowledge and attitudes regarding sex and gender-based medicine (SGBM). Methods: We administered an online survey to 158 faculty members at WMU Homer Stryker M.D. School of Medicine. The survey of knowledge on SGBM was adapted from two prior surveys used in medical student and resident populations and modified for faculty participants. Hidden curriculum theory, which proposes students learn through formal curriculum as well as through passive perceptions of faculty and institutional attitudes, was used as a theoretical lens. Results: Thirty-eight of 158 recipients completed the survey, for a 24% response rate. Respondents answered an average of 48.53% of the knowledge questions correctly; percent correct did not differ significantly between men and women faculty members (P= .2732). Seventy one percent of respondents indicated it was important or very important to consider sex and gender when providing patient care. Only 24% indicated they had some formal or continuing education on the topic. Respondents indicated interest in educational opportunities for SGBM in the form of online modules or lectures. Conclusion: Though faculty respondents endorsed SGBM, few have had formal education related to the topic. Faculty development on SGBM may close knowledge gaps and facilitate integration of this curriculum. The survey tool developed through this project may be useful for other institutions engaged in similar efforts related to SGBM.

Abstract RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by chronic and progressive decline in lung function with unknown cause. Previous economic burden of IPF estimates were based on data from 2011 or earlier. Thus, more current estimates will help inform policymaking. This study aimed to quantify the healthcare resource utilization (HCRU) and direct costs associated with IPF, overall and by payer type (commercial or Medicare Advantage Prescription Drug [MAPD] plan). METHODS: This retrospective cohort study used the Optum® Research claims database from 01/01/2016 through 12/31/2023. Adult patients with IPF (defined as ≥2 claims with IPF diagnosis code within 365 days) were identified (IPF cohort), with the date of the first IPF medical diagnosis code set as the index date. A general population without IPF (control cohort) was exact matched to the IPF cohort in 1:4 ratio, based on age group, sex, geographical region, payer type (commercial vs. MAPD), and race/ethnicity. The assigned index date for the control cohort was the same as the index date of the matched IPF patient. Continuous enrollment of 12 months before and 3 months after the index date was required for both cohorts. All-cause and respiratory-related HCRU and direct costs were compared between the cohorts during the variable follow-up period, reported as observation time-weighted per-patient-per-month (wPPPM). RESULTS: A total of 7,670 IPF patients were exact matched to 30,680 control patients. The mean age was 76 years and 59% were male. HCRU during the follow-up was significantly greater across all categories in the IPF cohort compared to control cohort (p&lt;0.001) (Table 1). The mean (standard deviation [SD]) wPPPM all-cause total healthcare costs were nearly four times higher for the IPF cohort compared to control cohort ($4,724 [$8,368] vs. $1,197 [$2,134], p&lt;0.001). Hospitalization costs accounted for the largest proportion of all-cause medical costs for the IPF cohort (55%), whereas ambulatory costs were the largest for the control cohort (49%). The IPF cohort had significantly higher wPPPM pharmacy costs compared to the matched control cohort ($2,289 [$3,861] vs. $321 [$1,133], p&lt;0.001) (Table 1). Similar trends were observed in respiratory-related HCRU and costs. When stratified by payer types, the total costs were significantly higher for commercially insured patients compared to patients with MAPD plan. CONCLUSION: The study demonstrated that patients with IPF incur higher economic burden compared to those without the disease, highlighting the need for more effective treatments to reduce costly healthcare resource utilization.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P &amp;lt; .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177