NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer.

Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

"They were an advocate for me": A Qualitative Study Exploring Medical Student Longitudinal Relationships and Patient Well-Being.

BACKGROUND: Patient navigators, community health workers, and care management teams improve patient experience and health outcomes. Medical student involvement in these roles is limited. Evaluation of these programs focuses on the student experience with less attention to patient participants. OBJECTIVES: We sought (1) to understand the experience of being a participant in a medical education program; (2) to explore the patient-medical student relationship; and (3) to describe the impact of this relationship on patient health and well-being. DESIGN: This was a qualitative study that utilized in-depth semi-structured interviews. PARTICIPANTS: Participants were selected based on enrollment in a preceptorship program at an urban academic medical center between 2017 and 2020. Participants worked with a medical student during an 18-month period in which the medical student was embedded in a primary care medical home, serving as a health systems navigator for 1-2 medically and socially complex patients. APPROACH: Nine participants completed 1-h compensated phone interviews. This study was deemed IRB exempt. KEY RESULTS: Three themes and eight subthemes were identified, including Navigators Were Key to Accessing the System, Interpersonal Partnerships Improved Health, and Fulfillment in Teaching of Lived Experience. Navigators eased the burden of chronic illness by being a point of contact in the health system, which improved participants' overall experience. Participants also described the relationship as therapeutic, citing improvement and stability in both mental and physical health. Lastly, participants found meaning in chronic illness by teaching their students empathy. CONCLUSIONS: Longitudinal patient-medical student relationships may provide stability and health benefits. These partnerships have the possibility of adding value to patients' healthcare experiences. This study complements current literature highlighting the value of these relationships for pre-clinical medical students. As such, additional opportunities for and additional research regarding the value of longitudinal patient connection should be incorporated in undergraduate medical education.

Pilot longitudinal kidney transplant transition program promotes peer connections and transition readiness.

BACKGROUND: Adolescents who have received a kidney transplant are at high risk of graft rejection and transplant-related comorbidities around the time of transition from pediatric to adult care. While there has been a progress in tracking transition readiness, further work is needed to prepare adolescents for healthcare transitions. We describe a longitudinal cohort-based transition curriculum designed to prepare kidney transplant recipients for adult transplant care. METHODS: Adolescent kidney transplant recipients aged 17 and older participated in the pilot cohort of the 2-year transition curriculum. Session topics included communication with the healthcare team, insurance, job skills, reflective practice, reproductive health, medications, and adult clinic introduction. Surveys were given to obtain narrative feedback, assess participant self-management behavior, and track curriculum knowledge. RESULTS: Each participant attended an average of two sessions, with 18 out of 30 eligible adolescents participating in at least one session. After transitioning to a virtual platform, there was increased attendance of participants who live greater than 150 miles from the transplant center. Adolescents highlighted the value of the program's group structure to relate to and learn from other participants. CONCLUSIONS: The pilot transition program successfully provided adolescent kidney transplant recipients the opportunity to learn alongside their peers and gain interdisciplinary knowledge to prepare for healthcare transition. The program converted to a virtual platform during the COVID-19 pandemic, with increased accessibility for participants who live further from the transplant center. Group-based programming for adolescents should be enhanced to further prepare them for transitions to adult medicine.

The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function.

CD4+Foxp3+ regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2, in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2-deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity.

Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients.

Polymorphisms at IFNL4 strongly influence spontaneous resolution and interferon therapeutic response in hepatitis C virus (HCV) infection. In chronic HCV, unfavorable alleles are associated with elevated interferon (IFN)-stimulated gene (ISG) expression in the liver, but extrahepatic effects are less well characterized. We used RNA sequencing (RNA-Seq) to examine whether IFNL4 genetic variation (rs368234815) modulates ISG expression in peripheral blood mononuclear cells (PBMC) during chronic HCV infection. ISG expression was elevated in unstimulated PBMC homozygous for the unfavorable ΔG IFNL4 variant; expression following IFN-α stimulation was comparable across genotypes. These findings suggest that lambda interferons may have broader systemic effects during HCV infection.

Symptomatic Acute Myocarditis in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination.

Trials of coronavirus disease 2019 (COVID-19) vaccination included limited numbers of children, so they may not have detected rare but important adverse events in this population. We report 7 cases of acute myocarditis or myopericarditis in healthy male adolescents who presented with chest pain all within 4 days after the second dose of Pfizer-BioNTech COVID-19 vaccination. Five patients had fever around the time of presentation. Acute COVID-19 was ruled out in all 7 cases on the basis of negative severe acute respiratory syndrome coronavirus 2 real-time reverse transcription polymerase chain reaction test results of specimens obtained by using nasopharyngeal swabs. None of the patients met criteria for multisystem inflammatory syndrome in children. Six of the 7 patients had negative severe acute respiratory syndrome coronavirus 2 nucleocapsid antibody assay results, suggesting no previous infection. All patients had an elevated troponin. Cardiac MRI revealed late gadolinium enhancement characteristic of myocarditis. All 7 patients resolved their symptoms rapidly. Three patients were treated with nonsteroidal antiinflammatory drugs only, and 4 received intravenous immunoglobulin and corticosteroids. In this report, we provide a summary of each adolescent's clinical course and evaluation. No causal relationship between vaccine administration and myocarditis has been established. Continued monitoring and reporting to the US Food and Drug Administration Vaccine Adverse Event Reporting System is strongly recommended.

The Student Navigator Project (SNaP): Preparing Students Through Longitudinal Learning.

INTRODUCTION: Early medical school education has historically focused on teaching basic medical sciences. More recently, medical schools are encouraged to incorporate health systems science (HSS) into early curricula. Addressing all of these components in an overcrowded curriculum remains challenging. METHODS: We report on the Student Navigator Project (SNaP), a pre-clinical experience where students engage longitudinally with medically and socially complex patients. SNaP is built on a foundation of trust, responsibility, and ownership in the student-patient relationship. Early learners take an active role in navigating, advocating, and coaching for their patients. In addition, students are integrated as medical assistants into a primary care clinic; complete a mentored, team-based quality improvement project; and engage in evidence-based medicine, teaching, and handoff activities. RESULTS: As a result of these activities, students learn firsthand about HSS, contribute meaningfully to their patients' care, and are immersed in a systems-based practice approach early in their medical school education. Preliminary outcomes (2016-2019) show satisfaction with the program and knowledge of program focus areas. CONCLUSIONS: The authors are engaged in improvement cycles to modify program structure and curriculum in order to promote dissemination in diverse clinical settings. Ultimately, we plan to measure longer-term outcomes, including clerkship and residency preparation, career choice, and practice setting.

Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data?

OBJECTIVE: We determined whether self-reported new or recurrent yeast infections were a risk factor for and/or consequence of vulvodynia and then determined the extent to which various levels of misclassification of self-reported yeast infections influenced these results. MATERIALS AND METHODS: In this case-control study we retrospectively assessed self-reported new and recurrent yeast infections prior and subsequent to first vulvar pain onset among 216 clinically confirmed cases and during a similar time period for 224 general population controls. RESULTS: A history of >10 yeast infections before vulvodynia onset was strongly but imprecisely associated with currently diagnosed vulvodynia after adjustment for age, age at first intercourse, and history of urinary tract infections [adjusted odds ratio = 5.5, 95% confidence interval (CI) 1.7-17.8]. Likewise, a history of vulvodynia was associated with a twofold risk of subsequent new or recurrent onset of yeast infections after adjustment for age, age at first intercourse, and history of yeast infections before vulvodynia onset (comparable time period among controls, 95% CI 1.5-2.9). Bias analyses showed that our observed associations were an underestimation of the true association when nondifferential misclassification of self-reported yeast infections and certain differential misclassification scenarios were present. However, if women with vulvodynia more frequently misreported having them when they truly did not, our observed associations were an overestimate of the truth. CONCLUSIONS: There appears to be a positive relationship between yeast infections preceding and following the diagnosis of vulvodynia, but this relationship varies from strong to nonexistent depending on the relative accuracy of the recalled diagnosis of yeast infections among cases and controls. To better understand the bidirectional associations between yeast infections and vulvodynia, future validation studies are needed to determine the extent to which misclassification of self-reported yeast infections differs between women with and without vulvodynia.