Citations

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

Abstract Disclosure: L. Miller-Wilson: Employee of Immunovant, Inc. N. Princic: Employee of Merative. K. Evans: Employee of Merative. N. Atreja: Employee of Immunovant, Inc. K. Tollefsen: Employee of Immunovant, Inc.. D. Toro-Tobón: None. Objectives: Graves’ disease (GD) is an autoimmune condition responsible for most cases of hyperthyroidism in the United States. An estimated 20%-50% of patients with GD will also develop thyroid eye disease (TED). Current treatments for GD focus on managing hyperthyroidism, but frequent monitoring, dose adjustments, and the high rate of relapse after discontinuation of antithyroid drugs can increase treatment costs and complicate long-term management. This study describes healthcare resource utilization (HCRU) and costs among patients with GD, with and without TED. Methods: This retrospective analysis utilized claims data from the Merative™ MarketScan® Research Databases. Individuals aged ≥18 years with ≥2 claims for a GD diagnosis from January 1, 2017-December 31, 2023 were included (first claim = index). To ensure a newly diagnosed cohort, patients with a history of GD-specific treatment or a GD diagnosis in the 12 months preceding the index were excluded. The final GD cohort was stratified into patients who had evidence of TED at any time during the 12-month pre-index period through 90 days post-index, and those who did not. Propensity score matching was used to balance patients with GD (with and without TED) with non-GD controls (1:3) on demographic and baseline clinical characteristics. Both GD cases (with and without TED) and controls were required to have ≥12 months of post-index follow-up. HCRU and costs were compared between cases and controls during a fixed 12-month post-index period. Categorical outcomes were compared using chi-squared tests, while continuous endpoints were compared using paired t-tests. Results: The analysis included 1,767 GD cases with TED matched with 5,301 controls (mean age, 53.1 years [standardized mean difference (SMD), 0.00]; 77% female [SMD, 0.00]; mean Charlson comorbidity score, 0.9 [SMD, 0.02]) and 43,120 GD cases without TED matched with 129,360 controls (mean age, 49.8 years [SMD, 0.00]; 78% female [SMD, 0.00]; mean Charlson comorbidity score, 0.7 [SMD, 0.01]). Compared with matched controls, patients with GD and TED had 78% more inpatient visits (0.16 vs 0.09), 104% more outpatient visits (65.06 vs 31.86), and 43% more prescriptions (30.21 vs 21.13) during the 12-month post-index period, while patients with GD without TED had 75% more inpatient visits (0.14 vs 0.08), 83% more outpatient visits (52.15 vs 28.48), and 38% more prescriptions (24.27 vs 17.56) (p<0.001 for all). Annual mean healthcare costs were 305% higher ($56,584 vs. $13,981) among GD patients with TED and 65% higher ($19,913 vs $12,076) in those without TED compared with matched controls. Conclusion: Patients with GD had significantly higher HCRU and healthcare costs than matched controls in the 12 months following diagnosis, and this difference was notably greater among GD patients who also had TED. More effective treatments are needed to address the health and financial burden of GD. Presentation: Monday, July 14, 2025

Abstract Background Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective The aim was to assess the frequency of dystonia‐linked pathogenic variants in PD. Methods We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership‐Parkinson's Disease (AMP‐PD) for variants in genes linked to isolated dystonia, dystonia‐parkinsonism, and myoclonus‐dystonia. Results Pathogenic variants were identified only in PD patients. Forty‐five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia‐linked genes, most frequently in GCH1 , followed by VPS16 . Conclusion Though rare, pathogenic variants in dystonia‐linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD‐relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective: To examine prospective associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity, coronavirus disease 2019 (COVID-2019) symptom severity, and COVID-2019 hospitalization with incident clinical diabetes among aging women. Methods: A cohort study was conducted using data from 34,405 eligible Women’s Health Initiative participants who completed ≥1 COVID-2019 surveys (Survey 1: June–December 2020; Survey 2: June 2021–February 2022) and were followed up for an average of 1.86 (±0.49) years, yielding 399 incident diabetes cases. Results: SARS-CoV-2 test positivity was associated with diabetes risk in the age-adjusted Cox regression model (hazard ratio [HR] = 1.76, 95% confidence interval [CI]: 1.10, 2.82), but not when fully adjusted (HR = 1.43, 95% CI: 0.88, 2.31). Diabetes risk was higher among those with 1–2 COVID-19 symptoms (HR = 1.39, 95% CI: 1.09, 1.77) and those with 3± COVID-2019 symptoms (HR = 1.53, 95% CI: 1.06, 2.22) compared with those without COVID-2019 symptoms in fully-adjusted models, irrespective of self-reported SARS-CoV-2 testing. COVID-2019 hospitalization was associated with 2–3 times the risk of clinical diabetes in age-adjusted (HR = 2.95, 95% CI: 1.52, 5.72) and fully-adjusted (HR = 1.90, 95% CI: 0.97, 3.72) models. Conclusions: Age-adjusted self-reported SARS-CoV-2 test positivity was associated with a higher incidence of diabetes. Reporting of COVID-2019 symptoms and being hospitalized for COVID-2019 were each associated with higher incidence of diabetes in aging women, after controlling for demographic, socioeconomic, lifestyle, and health characteristics.

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

ABSTRACT 3‐hydroxy acylcarnitines (3‐OH‐ACs) are key biomarkers for screening of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase and trifunctional protein deficiencies (LCHADD/TFPD). The utility of this biomarker for disease monitoring in identified patients remains debated, and recent suggestions have highlighted the potential use of lipidomics for diagnosis, monitoring, prognosis, and/or identification of new biomarkers. We evaluated the use of omics in LCHADD/TFPD patients by analyzing plasma acylcarnitine profiles, metabolomics, and lipidomics, combined with genotype, visual assessments, and dietary records. Fasting plasma from 39 participants with LCHADD/TFPD and 32 control subjects were analyzed through untargeted metabolomic and lipidomic analyses. In LCHADD/TFPD participants, acylcarnitine profiling, visual and retinal function assessments were performed, and 3‐day diet records were collected. Relationships between acylcarnitines, metabolomics, lipidomics, along with visual outcomes and dietary intake were investigated. Plasma of LCHADD/TFPD participants exhibited elevated 3‐OH‐ACs, which correlated with genotype and visual outcomes. Metabolomics successfully distinguished LCHADD/TFPD from controls, and the biggest divergence was observed in lipid pathways. Metabolomic profiles tightly correlated with 3‐OH‐ACs, genotype, and visual outcomes. Lower concentrations of total lipids and some individual lipid species such as phosphoethanolamines (PE) were detected in LCHADD/TFPD, except for elevations in several certain triglycerides. LCHADD/TFPD participants followed a diet low in long‐chain fat (LCFA) as recommended. LCFA intake did not correlate with either plasma 3‐OH‐ACs or metabolomics. 3‐OH‐ACs are strong consistent biomarkers of LCHADD/TFPD that are associated with clinical parameters of vision and genotype. We did not observe a relationship between dietary LCFA intake and 3‐OH‐ACs.

INTRODUCTION Gastroesophageal reflux is common in respiratory disease, but the interplay between gastrointestinal mechanisms that expose individuals to reflux and potentially aspiration, and lung mechanics and function remain incompletely understood. Our aim was to investigate this in patients with chronic obstructive pulmonary disease (COPD) and non-idiopathic pulmonary fibrosis (IPF) interstitial lung disease (non-IPF ILD), and compare with our published findings in IPF. METHODS Fifty-seven patients with COPD (aged: 34–75 years) and 64 with non-IPF ILD (22–75 years) who underwent high-resolution impedance manometry and 24-hour pH impedance together with pulmonary function assessment were compared with 35 IPF patients (51–84 years). RESULTS COPD patients were less likely to exhibit ineffective esophageal motility (IEM) and/or absent contractility ( P = 0.009; P = 0.028), and tended to exhibit esophagogastric junction outflow obstruction (EGJOO) and/or hypercontractility ( P = 0.09, P = 0.14) than IPF and non-IPF ILD patients. Notably, integrated relaxation pressure correlated with esophageal length index (ELI) ( P = 0.048) and inspiratory LESP ( P = 0.003), with latter 2 correlating with each other ( P < 0.001). EGJOO patients tended to have fewer proximal reflux events and reduced pulmonary function, with the latter inversely correlating with ELI ( P < 0.05). Non-IPF ILD patients were less likely to exhibit EGJOO than COPD patients ( P = 0.27), and less likely to exhibit IEM ( P = 0.07) than IPF patients. However, those with IEM or EGJOO exhibited greater proportions of reflux events reaching the proximal esophagus than those with normal motility ( P < 0.03), which in contrast to IPF, seemed not to associate with worse pulmonary function. DISCUSSION Associations between esophageal motility, and lung mechanics and function, and consequently reflux, are very disease-specific.

Hazardous alcohol use remains a major contributor to acute and chronic liver disease, while alcohol-associated liver disease (ALD) is a leading indication for liver transplantation. In recent years, embedded, interprofessional ALD clinics have improved access to alcohol use disorder care within hepatology and liver transplantation, but more work is needed to meet this challenge. The literature is lacking regarding scaling procedures to provide services for increasingly large ill patient populations. This article begins to fill this gap by describing “expanded ALD care”: broad, innovative, longitudinal, interprofessional care delivery strategies surpassing standalone clinics. Drawing from analogous patient populations served by collaborative models in primary care and comprehensive eating disorder treatment, the expanded ALD care framework proposes practical strategies toward specific innovations: equipoise between biomedical and psychosocial care elements, increased clinician number and reach, long-term patient relationships, harm reduction and palliative care, outreach to external agencies and clinicians, and enhanced support for patients and families. The article also defines attributes of innovative healthcare systems that support expanded ALD care.