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BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCAs) and angina with nonobstructive coronary arteries (ANOCAs) present diagnostic and therapeutic challenges. We assessed the frequency of coronary microvascular disease (CMD) and its subtypes in MINOCA compared with ANOCA and evaluated long-term cardiovascular outcomes. METHODS: Patients with nonobstructive coronary arteries undergoing invasive coronary function testing from 2012 to 2022 were prospectively enrolled and retrospectively classified as MINOCA or ANOCA (reference group). Myocardial infarction due to atherothrombosis, myocarditis, and Takotsubo syndrome were excluded. Invasive provocation testing was performed. CMD was classified as endothelium-independent (coronary flow reserve <2.5 with adenosine) and endothelium-dependent (<50% increase in coronary blood flow with acetylcholine). Major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, heart failure hospitalization, urgent revascularization, stroke) were recorded over 8 years. RESULTS: Of 622 patients, 73 (12%) had MINOCA (69% female, median age 56 years) and 549 (88%) ANOCA (72% female, median age 53 years). CMD was common in both groups (71% versus 64%; P =0.271), while endothelium-independent CMD was more frequent in MINOCA (41% versus 21%; P <0.001). Over a median follow-up of 4.5 years, major adverse cardiovascular events occurred more often in MINOCA (40% versus 11%; adjusted hazard ratio, 2.4; P =0.001). CMD predicted higher major adverse cardiovascular events in both MINOCA (hazard ratio, 3.6 [95% CI, 1.1–12.0]; P =0.038) and ANOCA (hazard ratio, 7.9 [95% CI, 2.9–21.8]; P <0.001). CONCLUSIONS: CMD is common in both MINOCA and ANOCA. The higher prevalence of endothelium-independent CMD in MINOCA suggests a potential mechanistic role in infarction. Patients with MINOCA have a worse prognosis than ANOCA, particularly when CMD is present.

Abstract Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

Background/Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and hemophagocytic lymphohistiocytosis (HLH) are life-threatening conditions characterized by immune dysregulation. Several reports have identified an overlap between these entities; however, clinical characteristics, triggers, and outcomes remain poorly defined. The objective of this study was to characterize the clinical features and outcomes of DRESS/HLH overlap syndrome. Methods: We conducted a PRISMA-guided systematic review of PubMed, Embase, and MEDLINE. Studies were included if they reported cases meeting criteria for DRESS syndrome and HLH. Results: Thirty-six patients were included, 75% female and 27.8% pediatric. Initial misdiagnosis occurred in 30.6% and was associated with higher mortality (45.5% vs. 20.0%). Antibiotics were the most frequent triggers (36.1%) and 11.1% of patients had no trigger identified. Mean latency was 27.9 days for DRESS syndrome and 35 days for HLH, with shorter latency in antibiotic-associated cases. DRESS syndrome and HLH most commonly occurred sequentially (n = 22, 61.1%) and in 52.8% of cases DRESS preceded HLH. Fever and rash were present in 88.9%. Laboratory abnormalities included hyperferritinemia (91.7%), eosinophilia (77.8%), anemia (75.0%), and thrombocytopenia (75.0%). Hepatic involvement was nearly universal (94.4%), followed by renal involvement (36.1%). Viral reactivation was observed in 38.9%, multiorgan failure in 36.1%, and ICU admission in 19.4% of cases. Mortality was 27.8% and higher in steroid-refractory cases and those with multiorgan failure. Treatment included corticosteroids (97.2%), with IVIG (33.3%), etoposide (13.9%), and cyclosporine (5.6%) used in severe cases. Conclusions: DRESS-HLH overlap represents a severe hyperinflammatory syndrome with high mortality. Early recognition and escalation of therapy are essential to improve outcomes. This is the largest and most uniformly characterized cohort of DRESS/HLH overlap reported to date, and the first to stratify mortality by diagnostic accuracy, temporal pattern, corticosteroid responsiveness, and multiorgan failure. Because the syndrome is rare and the evidence base consists almost entirely of single-case reports, multicenter collaboration and a prospective registry are needed to define incidence and optimal therapy.

Background/Objectives: Hospital-at-home (HaH) programs have emerged as an alternative model to brick-and-mortar (BaM) hospital management of acute conditions such as heart failure, pneumonia, pyelonephritis, and chronic obstructive pulmonary disease exacerbation among the others. However, the clinical management of acute pancreatitis in the HaH setting has never been described in the literature. The primary objective of this study was to describe the demographic and clinical characteristics of patients with acute pancreatitis managed in a Mayo Clinic Advanced Care at home (ACH) program. The secondary objective was to describe feasibility and short-term clinical outcomes. Methods: This multistate, multicenter, retrospective descriptive study included 40 unique patients with acute pancreatitis managed at ACH between 13 October 2020 and 1 June 2024. Repeat admissions were excluded from the primary analysis. Results: The most common etiologies were idiopathic (42.5%), gallstone-related (22.5%), and alcohol-related (12.5%). Peripancreatic fluid collections occurred in 17.5%, necrotizing pancreatitis in 10.0%, pleural effusion in 12.5%, and infected pancreatitis in 7.5%. Intravenous antiemetics were administered to 22.5%, intravenous fluids to 62.5%, and intravenous opioids to 7.5%. Median total hospital length of stay was 5.0 days (IQR, 3.0–8.25), including a median of 3.0 days (IQR, 2.0–4.0) in ACH. Four patients (10.0%; exact 95% CI, 2.8–23.7%) were transferred from ACH to BaM care. Seven-day and 30-day readmission rates were 10% (95% CI: 2.8%, 23.7%) and 5% (95%CI: 0.6%, 16.9%), respectively. The 30-day emergency department visit was 0%. Although 30-day mortality was 2.5% (95% CI: 0.0%, 13.2%), in-program mortality was 0%. Conclusions: Among a highly selected group of clinically stable patients meeting the program’s eligibility criteria, management of acute pancreatitis in ACH was feasible and was associated with low observed rates of unplanned escalations and short-term adverse outcomes.

Prolonged durations of hypotension during septic shock promote organ injury and mortality. Empirical evidence suggests that earlier vasopressin initiation may improve outcomes in septic shock. The objective of this study was to determine the effect of a ready-to-use vasopressin formulation availability in intensive care unit automated dispensing cabinets on outcomes in septic shock. This was a pre-post quasi experimental study of adults admitted for septic shock who received vasopressin as a second line vasopressor after norepinephrine. Inverse probability of treatment weighting with propensity scores was used to balance baseline covariates between those who received the ready-to-use vasopressin product and the traditional pharmacy-compounded vasopressin product. Outcomes included time from vasopressin order to administration, time to target mean arterial pressure, length of stay, and mortality. A total of 1104 patients with septic shock were included. After propensity score adjustment, the ready-to-use group was associated with faster time to vasopressin administration (17 vs 41 min, P < 0.001), faster time to target mean arterial pressure (hazard ratio 1.29, 95% CI 1.14 to 1.47, P < 0.001), and a shorter length of intensive care unit stay (hazard ratio 1.23, 95% CI 1.06 to 1.43, P = 0.006) as the compounded group. Mortality was not significantly different. In patients with septic shock, availability of a ready-to-use vasopressin product in the intensive care unit automated medication dispensing cabinet was associated with faster time to administration, improved time to target mean arterial pressure, and reduced duration of intensive care.

Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function.

ABSTRACT Background and Aim Significant health disparities persist in alcohol‐associated liver disease (ALD), largely driven by social determinants of health (SDOH). However, the influence of neighbourhood‐level SDOH on ALD outcomes remains underexplored. In this study, we aimed to evaluate how neighbourhood‐level SDOH are associated with disease burden, comorbid conditions, and mortality in individuals with ALD. Methods We conducted a retrospective cohort study of patients with ALD in the Banner Health System, representing hospitals across Arizona, California, Nevada, Wyoming and Colorado, from January 2012 to October 2024 using ICD codes. Neighbourhood‐level SDOH were quantified using the Social Deprivation Index (SDI). Patients were stratified into quartiles based on SDI score, with Quartile 4 representing the most socioeconomically disadvantaged neighbourhoods. Primary outcomes included incidence of mortality, cirrhosis, major adverse liver outcome (MALO), Type 2 diabetes mellitus, any cancer, and major adverse cardiovascular events (MACE). A multivariable competing risk analysis was performed adjusting for age, sex, race/ethnicity, insurance type, primary language, smoking status, Type 2 diabetes mellitus, hypertension, hyperlipidemia, aspirin use, statin use, alcohol use disorder and a composite mental‐health/substance‐use disorder variable encompassing depression, anxiety disorders, post‐traumatic stress disorder, bipolar disorder, schizophrenia, and non‐alcohol substance use disorders. Results Among 11,394 patients with ALD and available SDI data, 6747 had ≥ 365 days of follow‐up. The average age was 51 years and 65.6% were female; 68.8% were non‐Hispanic White, 19.7% Hispanic, 5.9% Native American/Alaskan Native (NA), 3.2% Black, and 0.4% Asian/Pacific Islanders. Patients residing in the most disadvantaged neighbourhoods (Quartile 4) were significantly younger, more likely to be female, had a higher median BMI, and more frequently reported a non‐English primary language compared with those in the least disadvantaged areas (Quartile 1). Patients in the most deprived neighbourhoods were more likely to be Hispanic, Black, or Native American/Alaska Native and to be uninsured or on Medicaid, whereas those in the least disadvantaged neighbourhoods predominantly had private insurance. Individuals in Quartile 4 had increased mortality (adjusted hazard ratio [aHR]: 1.48, 95% Confidence Interval [CI]: 1.09–2.01) compared with individuals in Quartile 1. Conclusions In this large and demographically diverse ALD cohort, residing in socioeconomically disadvantaged neighbourhoods was associated with increased risk of mortality. These findings support the need for contextually tailored clinical interventions and broader treatment strategies that target upstream sociocultural and environmental factors that are associated with health outcomes. Addressing neighbourhood‐level SDOH through community engagement, policy reform, and cross‐sector partnerships to improve collaborative care efforts is needed to reduce health disparities in ALD.

ABSTRACT Background While vaccination is a key strategy to mitigate the severity of coronavirus disease 2019 (COVID‐19) in children, the risk factors for symptomatic, medically attended (hereon referred to as “symptomatic”) COVID‐19 and the impact of vaccination are not well defined among pediatric solid organ transplant recipients (PSOTR). Methods PSOTR aged six months through 21 years at 11 centers in the Pediatric Infectious Diseases Transplant Network (PIDTRAN) were analyzed retrospectively for symptomatic COVID‐19 between July 2021 and May 2023. Using a Cox proportional hazards model, risk factors associated with COVID‐19‐associated hospitalization, in‐hospital oxygen use, mechanical ventilation, and the impact of COVID‐19 vaccination were analyzed. Results Of 1370 PSOTR, 410 (29%) had symptomatic COVID‐19 infection. Among those with symptomatic infection, 115 (28%) were hospitalized, 35 required in‐hospital oxygen, and three required mechanical ventilation. In the study, 45% were unvaccinated against COVID‐19. Compared to unvaccinated PSOTR, incompletely vaccinated PSOTR had 56% lower hazard (95% CI 0.26, 0.72, p = 0.001) of COVID‐19‐associated hospitalization whereas completely vaccinated did not have a statistically significant difference in hazard of hospitalization. Receipt of at least one dose of the bivalent vaccine was also associated with 92.5% lower hazard (95% CI 0.010, 0.55, p = 0.011) of hospitalization. Risk factors for hospitalization included chronic kidney disease, underlying heart disease, neurodevelopmental delay, and lymphocytopenia. Conclusions Most PSOTR with symptomatic COVID‐19 did not require hospitalization or respiratory support. Several comorbidities and lymphocytopenia are associated with severe COVID‐19 in PSOTR. COVID‐19 vaccination, mostly, protected PSOTR against COVID‐19‐associated hospitalization, but vaccine uptake among PSOTR was low. image

Objectives: To examine the effects of anterior load carriage on dynamic sagittal spinal alignment during the gait cycle in younger (<65 y) and older (≥65 y) adults. Design: Cross-sectional study of 47 participants aged 20–80 years categorized as young and older adults. Participants walked at self-selected speeds with and without a 4.5 kg anterior chest load. Whole-body kinematics were recorded using a 19-camera infrared motion capture system. Outcome measures included lumbar lordosis (LL), thoracic kyphosis (TK), trunk inclination (TI), sagittal trunk shift (STS), and pelvic tilt (PT). Gait-cycle–dependent differences were analyzed using statistical parametric mapping. Results: The mean age was 41 years in young adults (n=28) and 70 years in older adults (n=19). Anterior load carriage increased LL during portions of the gait cycle and reduced TI throughout the entire gait cycle. Younger adults demonstrated greater LL and lower TI than older adults. A significant age-by-load interaction for TI was observed during portions of the gait cycle. Conclusions: Anterior load carriage alters spinal alignment by increasing LL and reducing TI during walking, with distinct age-related patterns. These results provide valuable reference data and a foundation for future studies on load management and ergonomic interventions across the adult lifespan.