Citations

Abstract Rationale Pulmonary hypertension (PH) is a major determinant of peri- and post-transplant outcomes in liver-transplant recipients. While baseline mean pulmonary artery pressure (mPAP) is routinely assessed, the prognostic value of dynamic hemodynamic improvement during the transplant hospitalization remains poorly defined. This study evaluated whether changes in mPAP (ΔmPAP) independently predict one-year mortality after liver transplantation. Methods This retrospective study utilized data obtained from the Medical Information Mart for Intensive Care (MIMIC-IV) database to identify patients who underwent allogenic liver transplant (ICD-10-PCS code 0FY00Z0) between 2008 and 2019. Patients were excluded if they did not have invasive pulmonary hemodynamics data available through the database. The primary outcome of interest was one year mortality. Among 278 patients who underwent allogenic liver transplant in the given timeframe, 195 liver-transplant were included in the final analysis. Pulmonary pressures were extracted longitudinally and summarized as the first (baseline) and last mPAP values; ΔmPAP was defined as (first − last). The primary outcome was one-year all-cause mortality. Logistic regression models evaluated associations between ΔmPAP (continuous), baseline mPAP, age, and Charlson Comorbidity Index (CCI). Results The cohort included 195 patients (mean age 56 ± 9 years), of whom 62% were male. The mean baseline mPAP was 27 ± 8 mm Hg, and the average ΔmPAP was −8 ± 6 mm Hg. Compared with survivors, non-survivors had higher baseline mean mPAP (29 ± 9 mm Hg vs. 26 ± 7 mm Hg, p = 0.02) and smaller ΔmPAP improvement (−6 ± 5 mm Hg vs. −9 ± 6 mm Hg, p = 0.01). Age and CCI were similar between groups (p > 0.1 for both). On univariate analysis, both higher baseline mPAP (OR 1.09 per mm Hg, p = 0.011) and greater ΔmPAP reduction (OR 0.92 per mm Hg, p = 0.013) predicted one-year mortality. In the multivariable model including ΔmPAP, baseline mPAP, age, and CCI, we noted that ΔmPAP remained the only independent predictor (OR 0.90 per mm Hg, 95 % CI 0.83-0.97, p = 0.009) for 1 year mortality. Increase in baseline mPAP, age and CCI demonstrated non-significant trend towards 1-year mortality risk. Conclusions Greater reduction in mean pulmonary artery pressure during hospitalization independently predicted improved one-year survival after liver transplantation. These findings highlight hemodynamic reversibility being as a key determinant of post-transplant outcomes. Further large scale prospective studies are warranted to evaluate the prognostic utility of hemodynamic parameters in liver transplant patients. This abstract is funded by: None

Summary Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1–3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

Abstract Superior mesenteric artery (SMA) thrombosis is rare yet critical illness that can result in lethal bowel ischemia and infarction. This report details a case of SMA thrombosis with associated superior mesenteric vein (SMV) narrowing, secondary to mesenteric torsion in a 26-year-old female with history of Roux-en-Y gastric bypass surgery. The patient’s presenting symptoms were severe epigastric pain, vomiting, and significant anemia. Imaging confirmed SMA thrombosis with early signs of bowel ischemia. Interventional radiology promptly performed an SMA angiogram and initiated thrombolysis with a tenecteplase infusion, which led to near-complete resolution of the thrombus. This case draws attention to the necessity for early diagnosis and swift management of SMA thrombosis, particularly in post-surgical patients with altered gastrointestinal anatomy. The resolution of this case demonstrates the value of a collaborative care, combining interventional radiology and general surgery to prevent bowel ischemia.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary motor cortex (PMC) and spinal cord. Aging is a key factor in ALS onset and progression, with evidence suggesting that biological aging—a process involving cellular decline— far outpaces chronological aging in ALS. This promotes senescent cell accumulation—marked by irreversible cell-cycle arrest, impaired apoptosis, and chronic inflammation—disrupting tissue homeostasis and impairing neuronal support functions. Thus, targeting senescence presents a novel therapeutic strategy for ALS. Here, we investigated the senolytic combination Dasatinib and Quercetin (D&Q) in TDP-43 Q331K ALS mice. D&Q improved neuromuscular function and reduced plasma neurofilament light chain, a biomarker of axonal damage. The most pronounced improvement was the improved cortical excitability, accompanied by reductions in senescence and TDP-43 in the PMC. These findings highlight the potential of senolytics to mitigate ALS-related dysfunction, supporting their viability as a therapeutic strategy. *Jose A. Viteriab, Nathan R. Kerrab, and Charles D. Brennana are co-first authors.

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

Abstract Background We compared long-term mortality and readmission rates after COVID-19 hospitalization based on rural-urban status and assessed the impact of COVID-19 vaccination introduction on clinical outcomes by rurality. Methods The study comprised adults hospitalized for COVID-19 at 17 hospitals in 4 US states between March 2020 and July 2022, followed until May 2023. The main analysis included all patients, whereas a sensitivity analysis focused on residents from 4 states containing 17 hospitals. Additional analyses compared the pre- and postvaccination periods. Results The main analysis involved 9325 COVID-19 hospitalized patients: 31% were from 187 rural counties in 31 states; 69% from 234 urban counties in 44 states; the mean age was 65 years (rural, 66 years; urban, 64 years); 3894 women (rural, 41%; urban, 42%); 8007 Whites (rural, 87%; urban, 83%); 1738 deaths (rural, 21%; urban, 17%); and 2729 readmissions (rural, 30%; urban, 29%). During a median follow-up of 602 days, rural residence was associated with a 22% higher all-cause mortality (log-rank, P < .001; hazard ratio, 1.22; 95% confidence interval, 1.10-1.34, P < .001), and a trend toward a higher readmission rate (log-rank, P = .038; hazard ratio, 1.06; 95% confidence interval, .98-1.15; P = .130). The results remained consistent in the sensitivity analysis and in both pre- and postvaccination time periods. Conclusions and Relevance Patients from rural counties experienced higher mortality and tended to be readmitted more frequently following COVID-19 hospitalization over the long term compared with those from urban counties, a difference that remained even after the introduction of COVID-19 vaccines.

Abstract Background Vancomycin resistant enterococcus (VRE) infective endocarditis (IE) is associated with poor outcomes. There are limited data to guide the antimicrobial choice and duration of therapy. Several in vitro and limited clinical studies demonstrate the synergistic effect of β-lactams with other agents, particularly daptomycin, in this setting. We sought to compare clinical outcomes in patients with VRE IE treated with adjunctive β-lactam therapy. Methods This was an IRB-approved, retrospective, single-center cohort study. The study included patients ≥18 years of age diagnosed with VRE IE via modified Duke criteria from 2011-2021. Data were collected by electronic medical record review. Descriptive statistics were obtained. The primary outcome was 90-day treatment failure compared between those receiving and not receiving adjunctive β-lactams. Treatment failure was defined as recurrence of bloodstream infection (BSI) or death within 90 days of diagnosis. Failure-free survival was analyzed by Kaplan-Meier curve with log-rank test. Results A total of 32 cases were identified. 12 received adjunctive β-lactams. Mean age was 67 years, and 71% were male. 13 (41%) had a prosthetic valve and 6 (19%) had a CIED (Table 1). A majority (78%) had E. faecium IE. Mean duration of bacteremia was 9 days (Table 2). About one-third had treatment failure with 7 deaths and 4 BSI recurrences. Adjunctive β-lactams included ampicillin (3), cefepime (1), ceftaroline (6) and ceftriaxone (2). There was no statistical difference in failure-free survival in patients treated with adjunctive β-lactam therapy (Figure 1). The results were similar when restricted only to those who received daptomycin with or without adjunctive β-lactam therapy.Table 1.Patient CharacteristicsTable 2.Disease characteristics Figure 1. Kaplan-Meier curve comparing failure-free survival between patients who were primary treated with adjunctive β-lactams versus non-adjunctive therapy. The p-value is calculated via the log-rank test. Conclusion VRE IE is associated with poor prognosis, including high rates of mortality and relapses. In our experience, adjunctive B-lactam use did not result in improved outcome. Limitations include small sample size, and heterogenous antibiotic use. More prospective randomized data are needed. Disclosures All Authors: No reported disclosures

Abstract Aims We developed new machine learning (ML) models and externally validated existing statistical models [ischaemic stroke predictive risk score (iScore) and totalled health risks in vascular events (THRIVE) scores] for predicting the composite of recurrent stroke or all-cause mortality at 90 days and at 3 years after hospitalization for first acute ischaemic stroke (AIS). Methods and results In adults hospitalized with AIS from January 2005 to November 2016, with follow-up until November 2019, we developed three ML models [random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBOOST)] and externally validated the iScore and THRIVE scores for predicting the composite outcomes after AIS hospitalization, using data from 721 patients and 90 potential predictor variables. At 90 days and 3 years, 11 and 34% of patients, respectively, reached the composite outcome. For the 90-day prediction, the area under the receiver operating characteristic curve (AUC) was 0.779 for RF, 0.771 for SVM, 0.772 for XGBOOST, 0.720 for iScore, and 0.664 for THRIVE. For 3-year prediction, the AUC was 0.743 for RF, 0.777 for SVM, 0.773 for XGBOOST, 0.710 for iScore, and 0.675 for THRIVE. Conclusion The study provided three ML-based predictive models that achieved good discrimination and clinical usefulness in outcome prediction after AIS and broadened the application of the iScore and THRIVE scoring system for long-term outcome prediction. Our findings warrant comparative analyses of ML and existing statistical method–based risk prediction tools for outcome prediction after AIS in new data sets.

Objectives: This article describes key data sources and methods used to estimate hearing loss in the United States, in the Global Burden of Disease study. Then, trends in hearing loss are described for 2019, including temporal trends from 1990 to 2019, changing prevalence over age, severity patterns, and utilization of hearing aids. Design: We utilized population-representative surveys from the United States to estimate hearing loss prevalence for the Global Burden of Disease study. A key input data source in modeled estimates are the National Health and Nutrition Examination Surveys (NHANES), years 1988 to 2010. We ran hierarchical severity-specific models to estimate hearing loss prevalence. We then scaled severity-specific models to sum to total hearing impairment prevalence, adjusted estimates for hearing aid coverage, and split estimates by etiology and tinnitus status. We computed years lived with disability (YLDs), which quantifies the amount of health loss associated with a condition depending on severity and creates a common metric to compare the burden of disparate diseases. This was done by multiplying the prevalence of severity-specific hearing loss by corresponding disability weights, with additional weighting for tinnitus comorbidity. Results: An estimated 72.88 million (95% uncertainty interval (UI) 68.53 to 77.30) people in the United States had hearing loss in 2019, accounting for 22.2% (20.9 to 23.6) of the total population. Hearing loss was responsible for 2.24 million (1.56 to 3.11) YLDs (3.6% (2.8 to 4.7) of total US YLDs). Age-standardized prevalence was higher in males (17.7% [16.7 to 18.8]) compared with females (11.9%, [11.2 to 12.5]). While most cases of hearing loss were mild (64.3%, 95% UI 61.0 to 67.6), disability was concentrated in cases that were moderate or more severe. The all-age prevalence of hearing loss in the United States was 28.1% (25.7 to 30.8) higher in 2019 than in 1990, despite stable age-standardized prevalence. An estimated 9.7% (8.6 to 11.0) of individuals with mild to profound hearing loss utilized a hearing aid, while 32.5% (31.9 to 33.2) of individuals with hearing loss experienced tinnitus. Occupational noise exposure was responsible for 11.2% (10.2 to 12.4) of hearing loss YLDs. Conclusions: Results indicate large burden of hearing loss in the United States, with an estimated 1 in 5 people experiencing this condition. While many cases of hearing loss in the United States were mild, growing prevalence, low usage of hearing aids, and aging populations indicate the rising impact of this condition in future years and the increasing importance of domestic access to hearing healthcare services. Large-scale audiometric surveys such as NHANES are needed to regularly assess hearing loss burden and access to healthcare, improving our understanding of who is impacted by hearing loss and what groups are most amenable to intervention.