Citations

Introduction: Underrepresented in family medicine (URiFM) physicians hold 14.42% of US family medicine faculty positions. Scholarship is critical to academic advancement. We explored family medicine department chairs’ racial allyship, their identification of scholarship barriers faced by URiFM faculty, and the existence of initiatives to increase scholarship. Methods: We used the 2022 Council of Academic Family Medicine Educational Research Alliance (CERA) Department Chair survey to examine the percentage of chair-perceived URiFM departmental faculty members and their scholarly productivity and chair-perceived barriers to productivity and initiatives. We measured chairs’ racial allyship. We calculated descriptive statistics, weighted means, and used regression to identify whether chair characteristics or allyship scores were associated with support of URiFM faculty scholarship initiatives and identification of the minority tax. Results: One hundred nine chairs completed the survey (response rate 48.4%); 13.76% identified as URiFM; 6.4% reported they perceived more than 50% of their faculty were URiFM; 90.8% of chairs did not report programs supporting URiFM scholarship; and 44.9% described URiFM faculty scholarly output as minimal or none. Department chairs’ mean allyship score was 2.59 (SD = 0.80) out of 5. Chairs ranked lack of research skills and lack of funding for protected time higher than the minority tax from a list of scholarship barriers. We found no association between chair allyship scores, chair characteristics, total department full-time equivalents, and the existence of a URiFM faculty scholarly support program. Discussion: Despite chairs reporting low URiFM faculty scholarly output, few departments have a dedicated support program. Chair allyship scores were not associated with identification of scholarship barriers or existence of scholarship programs.

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Objective Age of symptom onset is highly variable in familial frontotemporal lobar degeneration (f‐FTLD). Accurate prediction of onset would inform clinical management and trial enrollment. Prior studies indicate that individualized maps of brain atrophy can predict conversion to dementia in f‐FTLD. We used a Bayesian linear mixed‐effect (BLME) prediction method for identifying accelerated brain volume loss to predict conversion to dementia. Methods Participants included 234 asymptomatic or prodromal carriers of C9orf72 , GRN , or MAPT mutations (including 21 dementia converters) with ≥3 longitudinal magnetic resonance imaging (MRI) T1‐weighted scans. The BLME models established individual voxel‐wise gray matter trajectories using the first 2 scans. Person‐specific clusters of accelerated volume loss were estimated in subsequent scans and tested as predictors of dementia conversion compared with other approaches in time‐varying Cox proportional hazard models covarying for age. Receiver‐operating characteristic (ROC) curves estimated utility of cluster volume in discriminating which participants converted to dementia within 24 months. Results The BLME cluster volume predicted conversion to dementia in f‐FTLD mutation carriers overall and separately in C9orf72 , GRN , and MAPT , with comparable hazard ratios observed for atrophy W‐maps and regional volumes. Within a 24‐month timeframe, BLME cluster volume discriminated dementia converters from non‐converters with larger areas under the curve (AUCs) than other approaches. Interpretation Bayesian‐modeled individualized atrophy scores predict dementia progression among asymptomatic f‐FTLD mutation carriers and may have increased utility compared with other structural imaging methods when studying individuals over shorter timeframes that align with clinical trial design. ANN NEUROL 20269999:n/a–n/a

ABSTRACT Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) can reduce seizures in patients with drug-resistant epilepsy. However, seizure freedom is rare, and there is no early response biomarker to predict long-term seizure suppression. To evaluate a short-term biomarker of therapeutic response to DBS, we studied 18-minute trials of ANT stimulation in patients with drug-resistant epilepsy undergoing intracranial electroencephalography. We compared a standard high-frequency periodic versus a non-periodic pulse pattern. We found that short-term ANT stimulation within the clinically used amplitude range preferentially altered the first 150 ms of anterograde ANT to anterior cingulate and superior frontal connectivity. Non-periodic ANT stimulation selectively modified early cortico-cortical evoked potentials more than periodic stimulation, and these changes were driven by the response phase. These pattern-specific changes in connectivity between the ANT and spatially restricted cortical areas suggest differing mechanisms and are a promising biomarker for patients being treated with ANT-DBS.

Abstract Objective Recent studies suggest a unique disease profile in elderly patients with primary aldosteronism (PA), who have a high prevalence of comorbidities and low clinical cure rate post-adrenalectomy. This study aims to investigate histopathology and genetic characteristics of PA in late adulthood. Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 114 patients with PA who underwent unilateral adrenalectomy at age 60 or older were used. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed for histopathologic analysis. Somatic DNA variants were identified in aldosterone-producing tissue following CYP11B2 IHC-guided sequencing. Results Histopathologic analysis revealed that 56 adrenals contained an aldosterone-producing nodule (APN) (49%), 44 contained an aldosterone-producing adenoma (APA) (39%), 7 contained multiple APN (6%), and 7 contained only non-functioning adenomas [NFA, of which 6 had at least one aldosterone-producing micronodule (APM) in the adjacent tissue] (6%). NFAs were also identified alongside APN/APA in 24 cases. An APN was the most common histologic subtype in men (51/88, 58%), while APA was predominant in women (18/26, 69%). Of 67 APNs with successful sequencing, the majority had variants in CACNA1D (40/67, 60%). KCNJ5 variants were the most common alteration in APA (14/44, 32%). Conclusions Older individuals with lateralized PA exhibit distinct genetic and histologic causes of disease with sex differences in mutation prevalence and adrenal histopathology. In APN, the most frequently altered gene is CACNA1D, while KCNJ5 variants are most common in APA. Unlike young patients with PA, the presence of NFA is a frequent observation in late adulthood individuals with PA.

ABSTRACT Background and Aims Alpha‐gal syndrome (AGS) is an IgE‐mediated hypersensitivity to galactose‐α‐1,3‐galactose, triggered by tick bites. It typically presents with delayed onset allergic or gastrointestinal symptoms after red meat consumption. This study aims to evaluate the prevalence of clinical symptoms and outcomes in AGS patients. Methods A systematic search of PubMed, Embase, and Cochrane Central was conducted to identify studies with at least five AGS patients that utilized alpha‐gal IgE for diagnosis and reported symptomatology. A random‐effects model calculated pooled prevalence and 95% confidence intervals (CIs) for clinical characteristics of AGS. Results Of the 739 studies screened, 15 met the inclusion criteria, comprising 1162 AGS patients (57% female). Urticaria was identified as the most prevalent symptom (63.8%, CI: 34.5–88.3, I 2 = 98.8%). At least one gastrointestinal symptom was reported in 69.2% of patients (CI: 49.3–85.9, I 2 = 97.5%), including abdominal pain (58.3%, CI: 36.0–78.9, I 2 = 96.0%), diarrhea (41.7%, CI: 22.3–62.5, I 2 = 93.4%), nausea (39.1%, CI: 29.2–49.6, I 2 = 79.1%), and vomiting (31.1%, CI: 21.9–41.2, I 2 = 70.4%). Tick bite history was recalled by 78.7% (CI: 46.4–98.1; I 2 = 99.1%), and 91.8% (CI: 84.6–96.8; I 2 = 70.3%) had symptom onset ≥ 1 h post red meat intake. Symptomatic improvement was observed in 86.5% (CI: 73.9–95.4, I 2 = 80.9%) of patients, with complete resolution in 42.7% (CI: 26.4–59.8, I 2 = 73.8%). Conclusion AGS typically presents with delayed onset allergic and GI symptoms after red meat intake, often with tick bite history. Majority of patients report symptomatic improvement on follow‐up.

ABSTRACT Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome‐wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure (‘generic’) versus minimally opioid‐exposed control (‘exposed’). First, at the phenotypic level, we conducted phenome‐wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD‐related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 ( p generic = 8.83E‐03 vs. p exposed = 1.83E‐02) and genetic correlations with prior OUD GWAS ( r g‐generic = 0.83 ± 0.26 vs. r g‐exposed = 0.78 ± 0.27). Although GWASs were limited by sample size ( N generic = 6269, N exposed = 6365), compared to an independent OUD GWAS ( N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.