Faculty Bibliography

B cells play critical roles in humoral immunity to infection, vaccination, and autoimmunity. The differentiation of B cells into antibody-producing plasma cells (PCs) has been extensively studied, but the role of metabolic transporters that mediate nutrient uptake during PC differentiation is not well-understood. Here, we characterized the dependence of B cells and PC differentiation on the neutral amino acid transporter SLC7A5. We demonstrate that SLC7A5 promotes B cell functions including proliferation and PC differentiation in vitro and in vivo after immunization with T dependent and independent antigens. Deletion of SLC7A5 in B cells suppressed the function of mTORC1 and enforced mTORC1 activity rescued PC differentiation. The role of SLC7A5 in B cells appears to be unrelated to leucine uptake because B cells were insensitive to extracellular leucine depletion. Defects in SLC7A5-deficient B cells could, however, be rescued by extracellular methionine supplementation, suggesting a role for methionine in SLC7A5-dependent B cell function and PC differentiation. Our study provides evidence for a leucine-independent role of SLC7A5 in B cell function and PC differentiation.

OBJECTIVES/OBJECTIVE:Documentation of gender identity (GI) and anatomy data in the electronic health record (EHR) is a proposed standard of care for transgender populations. However, there is limited research on implementation of proposed best practices, particularly anatomy data collection. This study aims to characterize factors that influence patient preferences and comfort around the collection and documentation of GI and anatomy in EHRs. MATERIALS AND METHODS/METHODS:From November 2023 to January 2024, 17 one-on-one, semi-structured virtual interviews were conducted with transgender adults residing in the Metropolitan New York area. Transcriptions were analyzed using inductive thematic analysis. RESULTS:Themes clustered around comfort and preferences for data collection processes and outcomes. Factors that influenced preferences and comfort around anatomy data were distinct from those impacting GI documentation preferences and comfort. The tension between the categories of GI and sex assigned at birth impacted anatomy data documentation preferences. Clinical context emerged as a consistent factor that impacts both preferences and comfort of GI and anatomy data documentation. DISCUSSION AND CONCLUSION/CONCLUSIONS:GI data collection efforts in clinical settings must consider the implication of anatomy data collection when determining data collection best practice methodologies. Anticipated and experienced stigma remain significant hurdles to patient comfort and willingness to collect GI and anatomy data, and their impact on actual data collection should be further elucidated among diverse gender identities. Clinical data collection methods, tools, and education warrant ongoing research investment to further elucidate best practices.

BACKGROUND:Few studies have evaluated the ototoxic effects of in utero antiretroviral (ARV) exposure on hearing in children HIV-exposed uninfected (CHEU). Concerns have been identified for some ARVs: tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), lamivudine (3TC), zidovudine (ZDV) and atazanavir (ATV). The aims are to describe hearing outcomes in 5-year-old CHEU in the Surveillance Monitoring for Antiretroviral Therapy Toxicities study and evaluate their association with in utero ARV exposures. METHODS:Hearing evaluations including pure-tone thresholds and distortion product otoacoustic emissions (DPOAEs) were completed in CHEU at 5 years. Log-binomial regression models were fit to assess associations of maternal ARV exposures with risk of sensorineural hearing loss (SNHL) and incomplete DPOAE responses. RESULTS:Among 1078 CHEU, 13% had SNHL. Among those exposed to <13 weeks gestation, there was 28% higher risk (95% confidence interval: -37% to 158%) of SNHL with TDF/FTC with ATV and 38% lower risk (95% confidence interval: -68% to 19%) with ZDV/3TC without ATV than for regimens containing TDF/FTC without ATV. There was a higher risk of incomplete DPOAE responses for ZDV/3TC without ATV and a lower risk for TDF/FTC with ATV. For CHEU with first ARV exposure at 13-26 weeks gestation, those exposed to TDF/FTC with ATV or ZDV/3TC without ATV had a lower risk for SNHL compared with TDF/FTC without ATV. Despite nontrivial relative risks, all confidence intervals were wide. CONCLUSIONS:While SNHL was relatively common, there were no consistent associations between in utero ARV exposure and SNHL or incomplete DPOAEs. Further research is needed on ARV exposures and other hearing measures in CHEU.

OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) often follows generalized tonic-clonic seizures during sleep, likely resulting from impaired brainstem cardiorespiratory function. We used ictal electrocardiogram (ECG)-based cross-frequency phase-amplitude coupling (PAC) to detect cardiorespiratory disruptions, comparing SUDEP to non-SUDEP cohorts. Leveraging respiratory modulation of ECG signals can provide a robust indirect proxy of respiratory monitoring despite high-amplitude noise. METHODS:We analyzed ictal ECG and electroencephalographic recordings in 21 SUDEP cases and 21 non-SUDEP epilepsy controls. Ictal ECG segments from 76 seizures (38 SUDEP, 38 non-SUDEP) were processed using continuous wavelet transformation to compute PAC between respiratory (.1-.55 Hz, 6-33 breaths per minute) and cardiac (.7-3.7 Hz, 42-222 beats per minute) frequencies. Relative PAC coupling strength was evaluated for respiratory frequencies > .25 Hz (15 breaths per minute) and cardiac frequencies > 1.7 Hz (102 beats per minute). Furthermore, a 3 × 3 grid of PAC ranges was derived for each 20-s window, yielding 18 features (mean and SD) as inputs to a logistic regression model. RESULTS:Elevated ictal PAC at higher respiratory (>.25 Hz, p < .0001) and cardiac (>1.7 Hz, p < .0142) frequencies in SUDEP patients suggests ictal respiration modulates ictal tachycardia, leading to cardiorespiratory dysfunction, probably brainstem-mediated. The logistic model accurately distinguished 38 seizures in SUDEP cases from 38 seizures in non-SUDEP cases (receiver operating characteristic area under the curve = 91%). Seizures in SUDEP patients had higher propensity scores (p < .001) both per seizure and per patient. All six test seizures (three SUDEP, three non-SUDEP) were correctly classified using the optimal threshold. SIGNIFICANCE/CONCLUSIONS:Ictal ECG-based PAC analysis is a potential noninvasive biomarker for SUDEP risk, capturing cardiorespiratory dysregulation during seizures. Its integration into wearable ECG devices could enable real-time risk assessment, informing clinical interventions such as rescue medications, antiseizure medication adjustments, or surgical evaluations.

The benefit of rituximab maintenance after first-line (1L) bendamustine and rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010-2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS, median 49.9 vs 29.7 months, P < 0.001) as well as overall survival (OS, median 109.5 vs 74.2 months, P < 0.001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n=590; median EFS 62.7 vs 31.1 months, P < 0.001; median OS 136.1 vs 75.3 months, P < 0.001), but the analysis in those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Complementary feeding (CF) influences infants' long-term dietary preferences, growth, and food allergy (FA) risk. However, guidance given to families and the implementation of FA prevention guidelines by healthcare professionals (HCPs) remain unclear. This study explored HCPs' perspectives and practices regarding CF strategies in the context of FA prevention across different regions and professional backgrounds. An online survey conducted by an EAACI task force between December 2023 and May 2024 assessed CF timing, allergenic food introduction, nutrient supplementation, and FA preventive measures. 550 HCPs (pediatricians, allergists, dietitians), 68% from Europe, participated. HCPs recommended CF initiation at a median of six months for breastfed infants and five months for formula-fed and FA high-risk infants. Atopic dermatitis (94%) and family history of allergies (87%) were the most recognized FA risk factors. Vitamin D (49%), probiotics (28%), and omega-3 fatty acids (18%) were commonly recommended supplements. Regional, professional, and educational influences differences emerged, with Northern European HCPs favoring earlier CF and allergen introduction, often without structured guidance. Southern European HCPs preferred a structured sequence and later CF initiation. A flexible, evidence-based framework is needed to guide FA prevention while accommodating cultural and geographical differences.

Hepatic encephalopathy (HE) is a common complication of decompensated cirrhosis that can be reversed with treatment. Frequent episodes of recurrence are common, impacting patients, caregivers and healthcare systems, increasing morbidity and mortality statistics and resulting in grave financial consequences. Uptake and adherence to formal recommendations for HE diagnosis and management are low. There is an unmet need to advocate for the use of these recommendations in a more pragmatic form. Clinicians from multiple disciplines, dedicated to raising liver disease awareness, convened in a roundtable format to review and discuss the latest HE guidelines and relevant peer-reviewed literature on HE. The result was this clinical care publication on the screening, diagnosis and management of HE which seeks to facilitate clinicians' recognition and diagnosis of HE, apply a pathway of care for HE that addresses steps for initial management, long-term maintenance and prevention; it also addresses practical recommendations concerning situations encountered in HE. Resources are provided to address the different needs of the three key players in HE: patients, caregivers, and healthcare professionals.