Faculty Bibliography

IMPORTANCE/UNASSIGNED:Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. OBJECTIVE/UNASSIGNED:To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. EXPOSURES/UNASSIGNED:Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy-related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. RESULTS/UNASSIGNED:Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro-B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate (P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). CONCLUSIONS AND RELEVANCE/UNASSIGNED:These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01915615.

INTRODUCTION/UNASSIGNED:Pseudofolliculitis barbae (PFB) is a chronic inflammatory condition of hair follicles characterized by inflamed papules and pustules, with increased risk in individuals with curly or coarse hair. While psychiatric comorbidities in acne are well studied, limited research exists on PFB's psychological impact. METHODS/UNASSIGNED:dataset, which includes EHR data from US adults since 2018. RESULTS/UNASSIGNED:= 0.15). DISCUSSION/UNASSIGNED:Our study demonstrated a significant association between PFB and mood disorders like depression or anxiety. Future studies should examine PFB severity and treatment efficacy on psychological outcomes.

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.

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.

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.

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..

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.