Faculty Bibliography

High plasma cholesterol levels substantially contribute to cardiovascular disease. Hepatic delivery of the microRNA-30c analog C2 decreased plasma cholesterol in apoB-containing lipoproteins in hypercholesterolemic C57BL/6 mice, in African green monkeys that spontaneously developed diabetes and hyperlipidemia and prevented diet-induced hypercholesterolemia in mice with humanized livers. Furthermore, C2 significantly reduced plasma cholesterol and atherosclerosis in LDL receptor knockout mice. C2 did not affect hepatic triglyceride and cholesterol, plasma ALT, AST, CK-MB, ALP, IL-6, TNF-α, and INF-ϒ, thus indicating an absence of tissue lipid accumulation and inflammatory response. In contrast, MTP inhibitor lomitapide significantly reduced plasma lipids and caused hepatic steatosis. Mechanistic studies revealed that C2 reduced hepatic microsomal triglyceride transfer protein expression, secretion of apolipoprotein B-containing lipoproteins and FA synthesis and increased hepatic FA oxidation, plasma bile acids and fecal cholesterol excretion. C2 is a first-in-class microRNA therapeutic that decreases plasma cholesterol and atherosclerosis, without causing hepatic injury and inflammatory response.

Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.

Appendiceal tumors are uncommon, and their coexistence as collision tumors is exceedingly rare, with fewer than 20 cases reported to date. The objective is to report a multi-center case series and literature review of appendiceal collision tumors, providing a comprehensive summary of clinicopathological features and outcomes. Electronic records from five tertiary centers (2016-2024) were searched. Cases with appendiceal collision tumors composed of a neuroendocrine tumor (NET) and a second component of low- or high-grade appendiceal mucinous neoplasm (LAMN/HAMN) or adenocarcinoma were included. Additional cases with the same diagnostic combinations were identified through a PubMed literature search since 2000. Clinical, pathologic, and survival data were collected and analyzed. Thirty-three cases were identified, including 17 multi-institutional and 16 literature-derived cases, with an estimated incidence of 0.11% among appendectomies. Most tumors consisted of localized NET and LAMN. Gastrointestinal (GI) symptoms were present in 62.5-65.6% of cases, and tumors were identified by imaging in 53.1-75.0%. Outcome tracks the higher-stage and grade component. Patients with localized tumors had excellent outcomes (2-year progression-free survival [PFS] and overall survival [OS]: 100%). In contrast, cases with metastatic LAMN/HAMN had 2-year PFS 66.7% and OS 100%, while those with metastatic adenocarcinoma had 2-year PFS 0% and OS 66.7%. This study represents the largest series and literature review of appendiceal collision tumors to date. These rare tumors most often consist of localized NET and LAMN, typically present with GI symptoms, are often detected by imaging. The prognosis is dictated by the component of higher stage and grade.

PURPOSE/OBJECTIVE:ZIC1 encodes a transcription factor with critical roles in vertebrate neural and skeletal development. Heterozygous deletions encompassing ZIC1 and ZIC4 cause Dandy-Walker malformation, whilst in the final exon heterozygous ZIC1 variants result in a distinct phenotype of craniosynostosis with variable intellectual disability via a gain-of-function mechanism. We describe the largest group of individuals harboring ZIC1 variants to date, significantly expanding the phenotypic spectrum and allowing genotype-phenotype correlation. METHODS:Through international collaboration we identified 18 different heterozygous ZIC1 variants from 22 families, comprising 30 individuals. RESULTS:Twelve families segregated a phenotype comprising craniosynostosis with facial dysmorphism, structural brain abnormalities and developmental delay, while 10 families had a neurodevelopmental disorder alone without craniosynostosis. Variants associated with craniosynostosis were clustered in the final exon (3) and were predominantly truncating variants predicted to escape nonsense-mediated decay. Variants associated with neurodevelopmental disorder alone included missense substitutions within exons 1 and 2 predicted to disrupt the normal function of the zinc finger domain, leading to loss of ZIC1 function which was confirmed in a functional assay. CONCLUSION/CONCLUSIONS:This study presents evidence for a ZIC1 genotype-phenotype correlation differentiating variants that cause a neurodevelopmental phenotype with and without craniosynostosis.

OBJECTIVES/OBJECTIVE:The National Surgical Quality Improvement Program-Pediatric (NSQIP-P) recommends reducing computed tomography (CT) scan use to <25% in children with suspected appendicitis. Our multidisciplinary team developed a pediatric appendicitis clinical pathway that emphasizes the use of ultrasound as first-line imaging and reserves CT for patients with both non-diagnostic ultrasounds and agreement from pediatric emergency medicine and surgery teams. METHODS:For this local study, all cases of patients aged younger than 19 years who were diagnosed with appendicitis from 2021 to 2023 were reviewed, with emergency department (ED) length of Stay (LOS) as a balancing measure. A series of Plan-Do-Study-Act cycles was used to implement the clinical pathway and to involve multiple teams. A Statistical Process Control chart was generated and possible special cause variations were analyzed using Six Sigma rules. RESULTS:Ultrasound was the first-line imaging in over 90% of total cases. However, CT utilization steadily decreased from 39% to 22% by the end of our initiative. This was paralleled by a sharp increase in surgical consults before CT scan order from 21% to 41%, and a decrease in non-diagnostic ultrasounds from 35% to 20% across the 3 years of the study. ED LOS decreased from 538 to 435 minutes on average. In addition, 2 patients underwent an MRI in quarter 4 of 2023, demonstrating its potential in the workflow. CONCLUSIONS:Overall, by implementing a clinical pathway this team was able to significantly reduce CT scan utilization in the diagnosis of pediatric appendicitis. STUDY TYPE AND EVIDENCE LEVEL/UNASSIGNED:Cohort study, level III.

Dementia caregiving represents a major public health challenge, with spousal caregivers assuming the greatest burden. Spouses, themselves typically older adults, provide high intensity, long-term, and largely unpaid care across all stages of cognitive decline. Despite their central role in dementia care, the health consequences experienced by spousal caregivers remain insufficiently characterized in the literature and inadequately addressed in clinical and public health practice. This structured narrative review synthesizes current evidence on the multidimensional impact of dementia caregiving on the physical, psychological, cognitive, social, and financial health of spousal caregivers. It further contextualizes these consequences within the trajectory of dementia progression, and identifies interventions, support systems, and policy considerations necessary to mitigate caregiver burden. Spousal caregivers experience disproportionate burden due to continuous, escalating responsibilities that often mirror the progressive deterioration of their partners. Emotional burdens, including uncertainty during pre-diagnostic stages, role strain, conflict, loss of intimacy, and anticipatory grief. Physically, spouses endure musculoskeletal strain, sleep disruption, poor nutrition, and heightened frailty risk. Psychologically, spousal caregivers exhibit elevated rates of depression, anxiety, loneliness, and stress-related disorders. Socially, caregivers experience substantial isolation, stigma, and erosion of social networks. Financial hardship, including early retirement, reduced employment, and uncompensated care hours, further exacerbate stress. Evidence suggests that chronic caregiving stress contributes to biological changes such as immune dysregulation, inflammation, acceleration, aging, and potential cognitive decline in caregivers themselves. Caregiver burden influences patient outcomes as evidenced by increased emergency department use, falls, and earlier institutionalization in persons with dementia whose caregiver is subjected to a high burden. Current care models rarely include routine, caregiver assessment or structured guidance following diagnosis, resulting in substantial unmet needs. Effective mitigation requires integrated, stage-sensitive interventions, including psychosocial support, caregiver education, respite services, culturally tailored programs, and digital health tools, alongside broader policy reforms to reduce financial and structural barriers.

BACKGROUND:Antifibrotics including nintedanib and pirfenidone are effective in slowing the decline of lung function for patients with idiopathic pulmonary fibrosis (IPF). However, their adoption rates are remarkably low, and substantial proportions of patients undergo dose reduction or treatment discontinuation because of the high incidence of adverse events. RESEARCH QUESTION/OBJECTIVE:What is the impact of treatment modification on all-cause mortality and hospitalization? STUDY DESIGN AND METHODS/METHODS:Using a large administrative database, we identified patients with IPF who initiated antifibrotics. A nested case-control design was used to match cases and controls at a 1:1 ratio and conditional logistic regression was performed to estimate the effect of antifibrotic adherence and dosing. Adherence was measured using the proportion of days covered (PDC). Both adherence and dosing were determined based on the exposure period between antifibrotic initiation (cohort entry date) and outcome occurrence (index date). RESULTS:Adherence (PDC ≥ 0.75) was associated with lower risk of mortality (OR=0.563, p<0.001), regardless of which antifibrotic was used. Patients on reduced dose had a significantly greater risk of mortality compared to those on standard dose (OR=1.57, p=0.024), but this was only seen in those who started nintedanib. For hospitalization, adherence was associated with a lower risk (OR=0.692, p=0.016) overall, and reduced doses were associated with a higher risk (OR=1.667, p=0.008) only among patients who started nintedanib. Among patients who started pirfenidone, neither adherence nor dose was associated with the risk of hospitalization. INTERPRETATION/CONCLUSIONS:Results of this study suggest that antifibrotic adherence and dosing are important factors that influence mortality and hospitalization. A multidisciplinary approach involving nutritionists, drug clinical educators, and other key stakeholders to facilitate early access, affordable treatment, and adverse event mitigation may enhance adherence and ultimately improve patient outcomes.

OBJECTIVE/UNASSIGNED:Noninvasive prenatal screening (NIPS) screens for aneuploidy, but its positive predictive value for sex chromosome aneuploidies (SCA) is variable. NIPS reports include "atypical sex chromosome findings," which may indicate fetal/maternal SCAs or mosaicism, although sensitivity is unknown. Previous studies are limited by small cohorts and insufficient maternal testing and ultrasound data. This study evaluates confirmation rates and outcomes for screen-positive SCAs, including "atypical sex chromosome" on NIPS. STUDY DESIGN/UNASSIGNED:This retrospective study included singleton pregnancies that underwent diagnostic testing for screen-positive SCAs or atypical sex chromosome findings on NIPS from 2019 to 2024. Data collected included demographics, ultrasound findings, cytogenetics, maternal karyotype, and perinatal outcomes. The primary outcome was diagnostic confirmation, defined as proportion of NIPS screen-positive SCA and "atypical sex chromosome" confirmed by diagnostic testing. Secondary outcomes included fetal/placental mosaicism, incidental genetic findings, and maternal genetic results. Chi-squared and Kruskal-Wallis tests were used for categorical and continuous variables, respectively. RESULTS/UNASSIGNED: = 0.033). Perinatal outcomes were generally favorable. CONCLUSION/UNASSIGNED:Fewer than half of NIPS-predicted SCAs were confirmed, with low confirmation rates for monosomy X and atypical findings. Mosaicism accounted for nearly one-third of confirmed cases. False-positive results often included incidental fetal and maternal findings, which may contribute to high false-positive rates. These findings emphasize the need for comprehensive pretest counseling and standardized testing guidelines, given the risk of unexpected maternal SCAs and fetal copy number variants. KEY POINTS/UNASSIGNED:· Less than half of NIPS-predicted SCAs were true-positive.. · Nearly one-third of confirmed SCAs involved mosaicism.. · Abnormal maternal karyotype may drive false-positive rates..