Citations

Abstract Lichen Planopilaris (LPP) is a lymphocyte-mediated scarring alopecia characterized by progressive follicular destruction and fibrosis. In this clinical trial, patients with biopsy proven LPP were treated with deucravacitinib (an oral inhibitor of tyrosine kinase 2 (TYK2)) 6 mg BID for 24 weeks (NCT-06091956). Bulk and single-cell RNA sequencing was performed on paired pre- and post-treatment scalp biopsies from baseline and week 4. Patients (N=10) demonstrated improvements in PGA (88.9%, p=0.008), LPPAI (−2.3 points, SD 1.1, p=0.002) and Skindex-16 (−21.0 points, SD 22.1, p=0.014) scores at week 24. Bulk transcriptomic analysis of untreated LPP revealed upregulation of type I Interferon (IFN)-stimulated genes and pathways related to inflammation, immune activation, keratinization, and extracellular matrix remodelling, with downregulation of immune and inflammatory pathways following treatment. Single-cell RNA-seq of LPP was characterized by enrichment of CD8+GZMK+ T cells which showed downregulation of T-cell receptor signaling as well as antiviral pathways with treatment. Basal keratinocytes exhibited reduced cytokine and interferon signaling and decreased communication with NK cells following treatment. CCL19+ fibroblasts were prominent in untreated disease was attenuated after treatment, with downregulation of type I IFN signaling. Selective TYK2 inhibition with deucravacitinib effectively suppresses these inflammatory circuits in LPP and represents a promising therapeutic strategy.

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.

Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.

Background and Aims: Upadacitinib, a selective janus kinase 1 (JAK1) inhibitor, and ustekinumab, an interleukin-12/23 inhibitor, are approved for the treatment of moderate-to-severe ulcerative colitis (UC). However, real-world data in patients with anti-tumor necrosis factor (TNF)-exposure are limited. Methods: We performed a retrospective cohort study in TriNetX US Collaborative Network. Adult patients with UC and prior anti-TNF exposure were identified. Patients who received upadacitinib or ustekinumab between April 2022 and August 2024 were stratified into two cohorts. Patients with Crohn’s disease, rheumatoid arthritis, psoriasis and ankylosing spondylitis were excluded. Propensity-score matching was performed to balance comorbidities, medications, and labs between the two cohorts. Study outcomes included rates of corticosteroid use, colectomies, change of therapy, hospital admissions or emergency department visit, and all-cause mortality. Results: A total of 724 patients in the upadacitinib cohort and 909 in the ustekinumab cohort met the inclusion criteria. After matching, 633 patients remained in each cohort, with balanced baseline characteristics. At 1-year follow-up, the rates of corticosteroid use were 40.1% in the upadacitinib group and 48.5% in the ustekinumab group (aOR= 0.71, 95% CI: 0.69-0.89), mainly driven by differences in oral corticosteroid use (aOR= 0.73, 95% CI: 0.58-0.91). All other outcomes were comparable between the two study groups. Conclusion: In patients with ulcerative colitis and prior anti-TNF exposure, upadacitinib was associated with lower oral corticosteroid use than ustekinumab over 1 year, with no significant differences in rates of colectomy, ED visits or hospitalizations. These findings suggest a potanial higher effectiveness of upadacitinib compared with ustekinumab and may help inform treatment selection in this population.

Transactive response DNA-binding protein of 43 kDa (TDP-43) type-A is associated with frontotemporal lobar degeneration (FTLD). In primary age-related tauopathy (PART), TDP-type-α displays similar features to FTLD-TDP type-A. We compared antemortem MRI volumes of amygdala nuclei and hippocampal subfields between 16 PART-TDP-α and 12 FTLD-TDP-A autopsy-confirmed cases. Hippocampal tail and CA1 body volumes were smaller in PART-TDP-α group, which also had smaller lateral and central amygdala nuclei compared to FTLD-TDP-A group, but differences were non-significant after FDR correction. There is no evidence suggesting that TDP-43 type-A in FTLD affects hippocampal and amygdala volume loss differently than TDP-43 type-α in PART.

Background TAR DNA-binding protein 43 (TDP-43) proteinopathy contributes to Alzheimer's disease progression, but diagnosis remains autopsy-dependent. Objective This study aimed to develop a predictive model using FDG-PET imaging to identify brain regions associated with TDP-43 pathology in vivo. Methods Penalized logistic regression analyzed data from 294 participants and a subset of 159 with Braak and Thal ≥4. Features included FDG standard uptake value ratios (SUVRs) from 123 brain regions and age. Participants were split into training (90%) and testing (10%) datasets, with significant predictors identified by non-zero coefficients at optimal lambda. Results The model achieved 68% accuracy (AUC = 0.70) in 294 participants, highlighting the middle temporal gyrus, parahippocampal gyrus, and hippocampus. In the subset (n = 159), accuracy was 65% (AUC = 0.71), with the medial amygdala and precentral gyrus as key predictors of TDP-43 pathology. Conclusions This study suggests a moderate predictive accuracy of FDG-PET to identify brain regions associated with Alzheimer's disease-related TDP-43 proteinopathy.

Background Resuming anticoagulation in patients with mechanical heart valves after intracranial hemorrhage presents a clinical dilemma. The optimal timing must balance the risk of thromboembolism against hemorrhagic expansion. Prior studies have addressed this issue, but most were limited by small sample sizes. This systematic review and meta‐analysis aimed to determine the optimal timing for anticoagulation resumption in this population. Methods We conducted a systematic review and meta‐analysis using PubMed, Embase, Web of Science, and Scopus from database inception to August 23, 2024. The target population included adults with intracranial hemorrhage who required anticoagulation for mechanical heart valves. Results Thirteen studies involving 788 patients were included: 12 retrospective and 1 prospective observational study. While off anticoagulation, 32 patients developed ischemic stroke, with a pooled event rate of 5.23% (95% CI, 3.80–7.20%) and negligible heterogeneity ( I 2 = 0%). The pooled average time to stroke was 8.08 days (95% CI, 1.99–14.18). After anticoagulation resumption, 73 patients experienced hemorrhagic recurrence, corresponding to a pooled event rate of 10.95%, with nonsignificant heterogeneity ( I 2 = 40.4%). Conclusions Withholding anticoagulation for up to 7 days after intracranial hemorrhage in patients with mechanical heart valves appears relatively safe. Hemorrhagic recurrence after resumption was more common than ischemic stroke during interruption. However, the included studies were observational and carried serious or critical risk of bias. Prospective multicenter studies, and ideally randomized trials, are needed to provide more definitive evidence.