Citations

Importance Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development. Observations Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear. Conclusions and Relevance In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

Background. The adoption of technical variant grafts has expanded the donor pool for pediatric liver transplantation, but it also poses a risk of portal vein thrombosis (PVT). This study evaluated risk and prognostic factors of PVT in children undergoing liver transplantation with technical variant grafts. Methods. A total of 3137 pediatric patients from 19 centers were included: 470 received split/reduced deceased donor grafts and 2667 received living donor grafts. Multivariable logistic regression was used to identify risk factors, whereas time-dependent Cox models were used to assess the impact on survival. Results. PVT occurred in 102 patients (3.3%) and was associated with increased mortality (adjusted hazard ratio, 2.86; 95% confidence interval [CI], 1.13-7.25; P = 0.027) and graft loss (adjusted hazard ratio, 9.97; 95% CI, 4.90-20.3; P < 0.001). Risk factors included younger age, lower weight, higher Pediatric End-Stage Liver Disease score, longer cold ischemia and operation times, higher graft-to-recipient weight ratio, increased red blood cell transfusions, and biliary atresia. After adjusting for center, lower weight (odds ratio, 0.84 per kg; 95% CI, 0.71-1.00; P = 0.047) and biliary atresia (odds ratio, 2.34; 95% CI, 1.10-5.00; P = 0.027) remained predictors. Five-year patient (88.4% versus 93.1%) and graft survival (82.7% versus 96.3%) were significantly inferior in patients with PVT. Conclusions. Low-weight children with biliary atresia constituted a high-risk group, highlighting the necessity for early detection and management.

Background. Pancreas transplantation (PT), historically limited to patients with type 1 diabetes (T1D), is currently performed successfully in selected patients with type 2 diabetes (T2D). However, contemporary practice patterns and eligibility criteria for PT in T2D remain incompletely characterized. Methods. The International Pancreas and Islet Transplant Association Pancreas Transplant Interest Group developed an electronic survey to assess center-level approaches to patient phenotyping, candidacy, and peri- and posttransplant management for PT in patients with T2D. The survey was distributed to international transplant professionals during an International Pancreas and Islet Transplant Association Pre-Congress meeting on June 15, 2025. Results. Thirty-seven participants completed the survey. Most respondents’ programs offer PT for T2D only when a kidney transplant is also indicated. Fewer respondents’ programs also offer PT alone (10%), evaluate T2D candidates on a case-by-case basis (3%), or do not offer PT to patients with T2D (10%). Total daily insulin requirement and body mass index (BMI) were the most selected factors in determining eligibility. Considerable variability existed in metabolic thresholds: 62% of programs reported no C-peptide cutoff, whereas nearly half required a BMI of <30 kg/m 2 for C-peptide-positive candidates. Respondents frequently recommend weight-optimization strategies, including lifestyle modification, glucagon-like peptide-1 receptor agonists, and bariatric surgery for candidates exceeding acceptable BMI thresholds. Surgical technique, induction, and maintenance immunosuppression and early posttransplant glycemic management were largely uniform between T2D and T1D recipients. Conclusions. International practice reflects broad but heterogeneous adoption of PT for T2D, with most participants restricting its use to candidates requiring kidney transplantation and emphasizing integrated clinical phenotyping approaches.

e15722 Background: Despite overall improvements in colorectal cancer (CRC) outcomes, concerning trends have emerged in younger populations. We examined two decades of US mortality data to characterize age-specific trajectory differences and identify inflection points in the epidemiologic landscape of CRC. Methods: Using CDC WONDER data (1999–2020), we analyzed age-adjusted CRC mortality rates (ICD-10: C18–C20) stratified by age: early-onset (≤44 years) versus late-onset (≥45 years). Joinpoint regression analysis (Version 5.4.0.0) with permutation testing identified significant trend changes. Annual Percent Change (APC) estimates with 95% confidence intervals assessed temporal patterns, with statistical significance set at α = 0.05. Results: Late-onset CRC (≥45 years): Mortality rates declined substantially from 69.26 to 40.49 per 100,000, representing a 41.6% reduction. A critical inflection point occurred in 2014 (95% CI: 2011–2015), marking a deceleration in the rate of improvement. The pre-2014 period showed robust decline (APC: −3.06%; 95% CI: −3.18 to −2.93; p < 0.000001), which slowed significantly post-2014 (APC: −1.61%; 95% CI: −2.12 to −1.09; p = 0.000006)—a 47% reduction in the pace of mortality improvement.Early-onset CRC (≤44 years): In stark contrast, mortality rates increased from 0.92 to 1.13 per 100,000, representing a 22.8% rise. No inflection points were identified; instead, a persistent upward trajectory characterized the entire 22-year period (APC: +0.78%; 95% CI: +0.54 to +1.02; p = 0.000001). This yielded a continuous, unabated increase in deaths among young adults. Conclusions: This analysis reveals a troubling paradox in US colorectal cancer mortality: while older adults experienced substantial but decelerating improvements, young adults faced steadily worsening outcomes throughout the study period. The 2014 inflection point in older adults, coinciding with slowed screening expansion and potential changes in risk factor prevalence, coupled with the relentless rise in early-onset mortality, signals an urgent need to reassess prevention strategies, lower screening age thresholds, and investigate biological and environmental drivers of early-onset disease. The nearly 23% increase in mortality among those ≤44 years represents a growing public health crisis demanding immediate action.

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: &gt;50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of &lt; 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 &lt; 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

ABSTRACT Background Metabolic dysfunction‐associated steatotic liver disease (MASLD) exhibits marked heterogeneity in fibrosis progression and liver‐related outcomes. Liver biopsy is not feasible for longitudinal risk stratification at scale, creating a need for validated non‐invasive biomarkers, particularly imaging biomarkers, that can predict clinically meaningful disease progression and liver‐related outcomes. Aims To describe the design and rationale of the GOLDMINE study, established to determine whether non‐invasive imaging biomarkers predict MASLD progression and liver‐related clinical outcomes. Methods GOLDMINE is an investigator‐initiated, multi‐centre, international longitudinal cohort enrolling up to 1000 adults with either biopsy‐proven MASLD or MASLD cirrhosis across the full fibrosis spectrum. Participants are recruited from 15 sites in the US and 4 international sites (Japan, Singapore and France). At baseline, participants undergo clinical phenotyping, vibration‐controlled transient elastography, and advanced magnetic resonance imaging (MRI), including proton‐density‐fat‐fraction and magnetic resonance elastography (MRE). MRI (and biospecimen banking) is repeated at 2‐year intervals (years 2 and 4), with annual follow‐up visits for up to 10 years. Baseline liver histology is centrally processed, digitized and reviewed by a single expert hepatopathologist; all MRI/MREs are centrally interpreted. Results The prespecified clinical outcomes include progression to cirrhosis, clinically significant portal hypertension, major adverse liver‐related outcomes (ascites, hepatic encephalopathy, portal hypertensive bleeding, liver transplantation/qualification), hepatocellular carcinoma, major adverse cardiovascular events, and all‐cause mortality, with independent central adjudication of all events. Conclusions GOLDMINE establishes a rigorously phenotyped MASLD cohort integrating centralized histology, advanced MRI‐based biomarkers, longitudinal biobanking, and adjudicated outcomes, providing a platform to validate imaging and blood‐based prognostic biomarkers in MASLD.