Citations

Introduction/Objective: As fewer physicians enter primary care, Advanced Practice Providers (APPs) play an increasingly important role in meeting the demand for patient care. Factors contributing to work status changes among primary care APPs are not well studied. We aimed to evaluate differences in primary care APP work status across electronic health record (EHR) workload measures. Methods: We conducted a retrospective cohort study within a Midwestern healthcare system from 2020 to 2022, evaluating the relationship between primary care APP work status defined as retention at current full-time equivalent (FTE), reduction of FTE within primary care, or relocation outside of primary care and 3 time-based EHR workload metrics. Descriptive statistics, univariate, and multivariable analyses were reported. Results: There were no differences between work status (retained, reduced, or relocated) across the EHR workload measurements of in-basket time per appointment, system time per appointment and note time per appointment ( P > .05) on univariate analysis. With multivariable analysis, there was no difference in likelihood of combined relocation/reduction adjusting for EHR workload variables ( P > .05). Conclusion: The EHR workload was not associated with work status changes for primary care APPs in our study. Further exploration is needed to identify factors that may contribute to reduction in primary care APP workforce capacity.

Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of >2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

BACKGROUND: Morel-Lavallée lesions (MLLs) are closed degloving injuries that occur throughout the body and present treatment challenges due to their rarity and variability in management. We aimed to compare characteristics and outcomes for MLL patients undergoing early (less than 48 hours) vs late (more than 48 hours) surgical intervention, hypothesizing decreased length of stay (LOS) with early intervention. STUDY DESIGN: Fifteen centers participated in this prospective observational study, including all adult patients who sustained a MLL and underwent surgery. No patients were excluded. Bivariate comparisons for early vs late intervention cohorts were performed. RESULTS: Of 150 MLL patients, 101 (67.3%) underwent early intervention. Both cohorts had comparable ages, BMI, vitals, Charlson Comorbidity Index, and injury severity scores (all p > 0.05). However, early intervention patients more commonly had abdominal (37% vs 6.3%, p < 0.001) MLLs, whereas late intervention patients more often had hip (16.7% vs 3.0%, p = 0.01) and thigh (41.7% vs 22%, p = 0.03) MLLs. Early patients had shorter ICU LOS (2 vs 5, p = 0.003) but statistically similar hospital LOS (12 vs 20, p = 0.06). There was no difference in wound-related complications (19.8% vs 24.5%, p = 0.51) or mean number of additional surgeries (p = 0.41) between cohorts. CONCLUSIONS: Over two-thirds of MLL patients underwent early operation. These patients had decreased ICU LOS and a statistically similar albeit clinically shorter overall LOS, despite similar demographics, comorbidities, injury severity, and number of additional surgeries. Therefore, early operation appears beneficial and should be pursued in MLL patients when clinically indicated and feasible.

Abstract Pediatric high-grade gliomas (pHGG) are aggressive primary brain neoplasms with a dismal prognosis, making them the leading cause of brain tumor-related deaths in children. pHGGs occur in specific anatomical locations at specific ages underscoring their origin in neurodevelopment and the critical importance of the brain tumor microenvironment. Many pHGGs originate from oligodendroglial precursor cells (OPC) and, like OPCs, neuronal activity promotes pHGG proliferation. Neuronal activity drives pHGG growth through the secretion of activity-regulated mitogens and electrochemical communication with pHGG cells that integrate into neural circuits. In turn, pHGG increases neuronal excitability and remodels functional neural circuits. The interconnected network of glioma cells and neurons is fundamental to pHGG progression. We developed a two-color in vivo imaging method to study neuron-glioma cell interactions over time in freely behaving mice enabling us to record the frequency, pattern, and synchronicity of calcium transients in neurons, glioma cells, and their coactivity, giving us a comprehensive view of the changes in neuron-glioma circuit dynamics over time. Our imaging paradigm offers a unique ability to study neuron-glioma interactions at the systems level. We have observed increasing neuronal activity and synchronicity throughout the disease. We have also observed that different gliomas exhibit unique patterns of calcium transients and show increased levels of activity and synchronicity as the tumor progresses. We verified our findings through longitudinal in vivo local field potential recordings, finding an increase in all power bands, especially in high-gamma activity over time. Using single nuclei RNA sequencing of mice harboring murine H3K27M-­altered DMG, we observed gene expression changes indicating an increase in synaptogenesis and axonogenesis processes in glioma-associated neurons. Performing in vitro neurite outgrowth assays, we observed increased axonogenesis in hiPSC-derived neurons in the presence of pHGGs compared to other neurons, confirming our snRNA-seq findings. Based on this data, we hypothesize that as gliomas progress, the neuron-glioma malignant circuitry evolves through synaptogenesis and axonogenesis to promote glioma progression.

Background Suicidal behaviour shows notable sex differences, and understanding whether genetic factors contribute to these differences is critical for identifying at-risk individuals and prevention. Objective We aim to investigate the genetic contribution to suicide attempts and examine whether genetics account for sex differences in incidence. Methods This population-based cohort study includes 3.1 million individuals born 1963–1998 and followed through Swedish National Registers, including hospitals and specialist outpatient diagnoses and cause of death data. Suicide attempts were identified using ICD codes, indicating intentional self-harm, self-harm using lethal methods or leading to hospitalisation, or resulting in death. Familial aggregation, coaggregation, pedigree heritability and genetic correlations were estimated using genealogical data. For sex-specific analyses, we examined mother–daughter, female sibling, father–son and male sibling pairs, separately. Findings Suicide attempts were more common among females than males (3.3% vs 2.6%). In both sexes, risk aggregated within families (ORs ranged 1.6–3.4 across relative types) and was higher in first-degree than second-degree relatives. Familial aggregation was stronger in females than in males, and in same-sex first degree relatives compared with cross-sex pairs. Pedigree heritability was 41.9% (95% CI 36.0 to 48.4%) and did not differ significantly by sex (female 51.4% (95% CI 40.1% to 58.6%), male 45.1% (95% CI 32.3% to 52.5%), Bootstrap p value 0.40). Suicide attempt showed moderate to high pedigree genetic correlations with psychiatric disorders, strongest with substance use disorders (SUD, r g =0.85 (95% CI 0.83 to 0.96)), with no significant sex differences. The genetic correlation between female and male suicide attempts was high (0.85 (95% CI 0.80 to 0.99)), suggesting a substantial genetic overlap. Conclusions Suicide attempt has a moderate heritable component that largely overlaps between females and males and with other psychiatric disorders, particularly SUD. Stronger familial aggregation in females and in same-sex pairs highlights the potential role of sex-specific environmental or social factors. Future research should focus on non-genetic contributors and their potential interaction with genetic factors to better understand and address sex disparities in suicidal behaviour Clinical implications Genetic risk for suicide attempt is substantial but does not fully explain sex differences in incidence. Clinicians should, therefore, consider non-genetic, including sex-specific environmental and social factors, alongside family history and psychiatric comorbidity when assessing suicidal risk.

ABSTRACT Objective The Minnesota Electronic Health Record Consortium (MNEHRC) was established during the early days of the COVID‐19 pandemic to provide data for public health surveillance from the eleven largest health care systems in Minnesota. Methods This is a descriptive study of the Consortium, which is a federated network that implements best practices for governance and data infrastructure to support public health surveillance and clinical research. We conducted an analysis of the Consortium members, governance structure, infrastructure, and the characteristics of the patient population. Results The Consortium health systems collect information from 105 hospitals, 773 clinics, 100 emergency departments and 29 040 providers. Information about the health systems and the demographic and clinical characteristics of its 5 471 367 patients is provided, which represents more than 90% of the patients in Minnesota. This manuscript also details the MNEHRC governance structure, working groups, data use agreements and technical infrastructure. The Consortium has produced several studies with state‐wide impact. One study, Health Trends Across Communities in Minnesota, is described in detail to illustrate aspects of this collaboration. Conclusion MNEHRC has been a successful collaboration and vital resource for public health surveillance in the state of Minnesota. Initially, the Consortium focused on surveillance related to COVID‐19 infections and vaccinations but has recently expanded into other public health and chronic disease research.

Abstract Objectives Diagnosing adult T-cell leukemia/lymphoma (ATLL) remains challenging due to its clinical and histopathologic heterogeneity. While HTLV-1 serology is a key diagnostic criterion, it is often unavailable at the time of diagnosis and does not confirm viral integration in tumor cells. The HTLV-1–encoded HBZ RNA is a reliable diagnostic biomarker for ATLL. We evaluated the diagnostic performance of RNAscope in situ hybridization (ISH) for HBZ RNA in formalin-fixed, paraffin-embedded (FFPE) tissues to distinguish ATLL from other T-cell lymphomas. Methods HBZ ISH was evaluated in 72 cases, including 52 ATLLs and 20 non-ATLL T-cell lymphomas, to determine diagnostic sensitivity and specificity, interobserver agreement, interlaboratory reproducibility, and comparison with digital gene expression. Results This assay demonstrated 86.5% sensitivity and 100% specificity, with sensitivity improving to 97% when excluding bone marrow clot sections and FFPE blocks older than 5 years. Interobserver agreement among 3 pathologists was excellent (κ = 0.92, percent agreement: 94%). Interlaboratory reproducibility of HBZ ISH was high, with 93% to 95% concordance across these Clinical Laboratory Improvement Amendments–certified laboratories. HBZ RNA ISH–positive cases demonstrated significantly higher HBZ gene expression levels by digital gene expression profiling. Conclusions We established HBZ ISH as a reliable tissue-based surrogate for HTLV-1 infection in ATLL. This assay will enhance diagnostic accuracy, expedite definitive diagnosis, and improve patient selection for targeted therapies and clinical trials, particularly in regions with a high prevalence of HTLV-1.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.