Citations

Introduction BACH2-related immunodeficiency and autoimmunity (BRIDA) increases the risk of developing B cell lymphoma. We present a case of a patient with a known history of common variable immunodeficiency (CVID) and BACH2 variant of uncertain significance, presenting with hypercalcemia and acute kidney injury (AKI), found to have T cell histiocyte-rich large B cell lymphoma of the spleen. Case Description 46-year-old male with CVID-like clinical picture with variant of uncertain significance in BACH2 (Combined Annotation Dependent Depletion [CADD] 25.2, allele frequency 2) and granulomatous-lymphocytic interstitial lung disease (GL-ILD), admitted for acute kidney injury with hypercalcemia. He is pancytopenic, hypercalcemic, with marked splenomegaly on CT. PET-CT showed retroperitoneal and iliac chain lymphadenopathy along with mixed changes of osseous/marrow lesions with new lesions in the thoracic spine and left mid femur. There is a notable improvement in GL-ILD on CT chest while the patient is on prednisone. Renal biopsy showed acute tubular injury with increased deposition of calcium phosphate, along with moderate interstitial fibrosis and tubular atrophy with mild fibrointimal thickening of arteries. No monoclonal protein detected in the serum, negative JC virus, BK virus, EBV, CMV, and HIV. Splenic biopsy showed B cell lymphoma with features of micronodular T cell/histiocyte-rich large B cell lymphoma of the spleen. Patient initiated on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment protocol. Discussion BACH2 is a regulator of T and B cell differentiation and maturation. The effect of BACH2 on T cells involves limiting the differentiation of regulatory T (Treg) cells, which aid in preventing autoimmunity. BACH2 mutations have been described in the literature in patients with CVID and autoimmunity, such as ulcerative colitis. Lymphoma can cause hypercalcemia, which can lead to acute kidney injury. This patient has a variant of uncertain significance in BACH2 with CADD 25.2, allele frequency 2. His clinical picture of CVID, acute kidney injury in the setting of hypercalcemia, and newfound B cell lymphoma of the spleen may be due to this variant of uncertain significance. Further studies need to be conducted to better understand this gene and its role in CVID and B cell lymphoma. Tabular data are included as downloadable supplement files.

Abstract Purpose: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. Patients and Methods: Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months. Results: Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; P = 0.28), −33.33 % (IQR, 90; P = 0.04), and −38.6 % (IQR, 88.5; P = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; P = 0.37) and −26.3 % (IQR, 49.5; P = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (P = 0.04) and improved TPB at 12 months (P = 0.05) compared with daily dosing. Conclusions: eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.

Background: Previous studies suggest that internalized HIV stigma (IHS) results in HIV viral nonsuppression via directly increasing depression, which then reduces adherence leading to nonsuppression; however, the dynamics between IHS and mental health are likely more complex. We sought to better understand IHS-mental health dynamics using data from a longitudinal clinical cohort of people with HIV (PWH) receiving healthcare across 10 US primary care clinics. Methods: Among 8,506 PWH who had ≥2 timepoints in which IHS, depression, and anxiety were measured, we examined changes over time in both two-state (i.e., impact of IHS on depression or anxiety and vice versa) and four-state combinations of depression-IHS (i.e., no depression or IHS, depression/no IHS, no depression/IHS, both depression/IHS) and anxiety-IHS. Transition probabilities between states and factors influencing transitions were identified using multistate Markov models. Results: The impact of IHS on the transition rates of mental health measures (i.e., depression, anxiety) and vice versa were almost the same, suggesting that each influences the other. Over 50% of PWH remained in the same IHS-depression or IHS-anxiety state. PWH with IHS had almost twice the rate of transitioning from no depression/anxiety to having depression/anxiety compared to PWH without IHS; with similar results for the depression or anxiety with no IHS to reporting IHS transition. Conclusions: We demonstrate that IHS and mental health dynamics are more complex than previously suspected and that the associations are bidirectional, which has implications for both future analyses and optimal management of these conditions among PWH.

Background: Stable osteochondritis dissecans (OCD) lesions are primarily treated nonoperatively. Nonoperative treatment includes several recommendations, including the use of an unloader brace. However, little is known about the clinical effectiveness of unloader bracing and its influence on OCD healing, return to sports, and patient-reported outcomes (PROs). The purpose of this investigation was to evaluate the impact of unloader bracing on patients with stable medial femoral condyle (MFC) OCD lesions treated nonoperatively. Purpose: To investigate the influence of valgus unloader bracing on the success of treating stable MFC OCD with nonoperative treatment strategies. Study Design: Cohort study; Level of evidence, 2. Methods: The authors used a prospective cohort of patients receiving nonoperative care for stable MFC knee OCD lesions. The primary variable of interest was the efficacy of bracing. The primary outcomes were transition from nonoperative care to surgical intervention, return-to-play (RTP) clearance, and PROs. Bivariate testing was used to determine if there were differences between groups. Chi-square testing was used to determine if there were differences in rates of transition to surgery by group. The timing of the transition by each group was assessed using a Wilcoxon rank-sum test, given the nonparametric nature of the data. Kaplan-Meier survival analysis was used to calculate time at risk, incidence rate, and survival times for each group. Results: A total of 185 knees (bracing group: 123 [66.5%] knees; no-bracing group: 62 [33.5%] knees) were analyzed. Overall, 142 (76.8%) knees were successfully treated nonoperatively. Transition to surgery occurred in 43 (23.2%) knees. There were no differences in transition to surgery by groups, with no differences seen by group. Of the knees that did not transition to surgical care, 65 (71.4%) in the bracing group and 38 (74.5%) in the no-bracing group received RTP clearance ( P = .693). PRO scores were similar between the 2 groups at the time of RTP clearance. Conclusion: The inclusion of an unloader brace in the nonoperative treatment for stable MFC OCD lesions did not decrease the likelihood of patients undergoing surgical intervention or improve their PRO scores at the time of RTP clearance. Registration: NCT02771496 (ClinicalTrials.gov identifier).

Food allergies are a significant public health concern in the United States. Fatality from food-induced anaphylaxis is associated with delayed administration of epinephrine. Utah children were at increased risk for school-related anaphylaxis due to a lack of school nurses, adequately trained staff, and a standardized approach to food allergy emergency management. In collaboration with the Utah School Nurses Association, the Utah Food Allergy Network, and the Utah Department of Health & Human Services, among other contributors, we aimed to accomplish the following goals: (1) develop and implement a web-based curriculum to train school staff to recognize and respond to anaphylaxis in school settings; (2) educate school officials on existing legal protections for layperson first responders; and (3) facilitate acquisition of unassigned epinephrine for use in schools through existing charitable pharmaceutical programs. From 2012 to 2023, our training program was completed 5759 times by individuals representing 421 Utah schools. The course was most frequently completed by teachers (n = 3006, 52.2%), office staff (n = 1480, 25.7%), and principals (n = 276, 4.8%). Since 2015, we have maintained an average year-to-year retention rate of greater than 68%. We observed a 245% increase in the number of schools with unassigned epinephrine. Due to this intervention, many Utah schools now prepare employees to administer epinephrine in the case of anaphylactic emergencies. Although school nurses play a significant role, their coverage is inadequate to meet the needs of all students at risk for anaphylaxis. Training volunteers to recognize and respond to anaphylaxis in school settings is needed to reduce delays in treatment and improve outcomes.

Background. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising noninvasive biomarker for detecting allograft rejection in solid organ transplantation. However, its diagnostic utility in pancreas transplantation, including in multiorgan recipients, remains underexplored. Methods. We conducted a retrospective analysis of 42 pancreas transplant recipients (38 simultaneous pancreas-kidney, 4 pancreas transplant alone) who underwent for-cause organ biopsy and dd-cfDNA testing between April 2020 and December 2024. dd-cfDNA was measured using the Prospera assay, with a threshold of ≥1% considered high risk and <1% low-risk. Biopsy results were correlated with dd-cfDNA to assess test performance. Results. A total of 50 dd-cfDNA tests and 45 organ biopsies were analyzed. Among simultaneous pancreas-kidney recipients, dd-cfDNA demonstrated a sensitivity of 86.7%, specificity of 52.2%, positive predictive value (PPV) of 54.2%, and negative predictive value (NPV) of 85.7% for rejection. In pancreas transplant alone recipients, all high-risk dd-cfDNA results corresponded to biopsy-proven rejection, yielding 100% sensitivity, specificity, PPV, and NPV. When combining both cohorts, dd-cfDNA testing achieved an overall sensitivity of 88.2%, specificity of 57.7%, PPV of 57.7%, and NPV of 88.2%. Additionally, dd-cfDNA kinetics suggested its potential utility as a surveillance tool posttreatment, potentially reducing the need for closure biopsies. Conclusions. dd-cfDNA is a valuable noninvasive adjunct for monitoring of rejection in pancreas transplant recipients. Further prospective studies are needed to validate these findings and define the optimal role of dd-cfDNA in posttransplant care.

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.

Objective: To evaluate the associations between surgeon-patient sex concordance, long-term clinical outcomes and healthcare costs. Background Data: Emerging data suggest surgeon-patient sex concordance may improve short-term outcomes, especially for female patients, yet its long-term effects remain unknown. Methods: We conducted a population-based retrospective cohort study of adults undergoing common surgeries in Ontario, Canada (2007-2019). Patients were followed for 90 and 365 days. Surgeon-patient sex concordance was categorized into four dyads. Multivariate generalized estimating equations clustered by procedure type evaluated composite and individual (complications, readmission, mortality) clinical outcomes and healthcare costs. Results: A total of 1,165,711 patients were included. Female patients treated by male surgeons, compared with female surgeons, were more likely to experience an adverse composite event (90 d: aOR 1.12, 95% CI 1.08–1.17, P <0.001; 365 d: aOR 1.09, 95% CI 1.05–1.14, P <0.001), with no association among male patients (90 d: aOR 1.00, 95% CI 0.94–1.05, P =0.89; 365 d: 0.99, 95% CI 0.92–1.07, P =0.87). Long-term total healthcare costs were greater for patients treated by male surgeons - an effect seen in both male patients (90 d: aRR 1.08, 95% CI 1.03-1.14, P =0.002 and 365 d: aRR 1.08, 95% CI 1.02-1.14, P =0.007) and female patients (90 d: aRR 1.10, 95% CI 1.05-1.14, P <0.001, 365 d: aRR 1.09, 95% CI 1.05-1.14, P <0.001). Conclusions: Surgeon-patient sex concordance was associated with improved long-term outcomes for female, but not male, patients, and female surgeons’ patients had lower healthcare costs. Given these benefits, further investigation into the mechanisms driving these outcomes is warranted.

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with &lt; NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with &lt; NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.