Faculty Bibliography

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca²⁺ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

INTRODUCTION/BACKGROUND:We previously reported the results of tofacitinib induction therapy in the prospective multi-site US real-world TOUR registry. We now assessed patient-reported outcomes (PRO's) and predictors of success during tofacitinib maintenance therapy. METHODS:TOUR included 103 patients with refractory ulcerative colitis (UC); 67% had failed ≥ 2 biologics. Patients reported the simple clinical colitis activity index (SCCAI), PRO Measurement Information Systems measures (PROMIS) for anxiety, depression, social satisfaction, and adverse events between weeks 8 and 52 using a web-based system. Paired t-tests and p for trend were utilized to compare changes in PRO measures over time. Bivariate analyses and logistic regression models were used to determine factors associated with response (SCCAI<5) or remission (SCCAI<2) at week 52. RESULTS:Of 103 patients, 82.5% entered the maintenance phase and 43.7% remained on tofacitinib at week 52. Tofacitinib de-escalation to 5 mg BID occurred in 15% of patients. At week 52, 42.7% and 31.1% of all patients reported an SCCAI<5 and SCCAI≤2, respectively. Normalization of bowel frequency, rectal bleeding, and urgency occurred in 79%, 61%, and 48% of patients remaining on maintenance therapy. Social satisfaction improved significantly (p<0.001), while anxiety and depression scores only numerically improved. No consistent predictors for tofacitinib long-term treatment efficacy were identified, and safety findings were consistent with the known safety profile of tofacitinib. DISCUSSION/CONCLUSIONS:Tofacitinib is an effective maintenance therapy in refractory UC patients. Dose reductions infrequently occurred during maintenance. Unmet needs in UC maintenance include improvement of urgency and psychosocial factors. (NCT03772145).

In recent years, legislation targeting the sexual and gender minority (SGM) community has been passed at an increasingly alarming rate, affecting access to safe and effective gender-affirming care and forcing many SGM patients, including those with inflammatory bowel disease (IBD), to withhold their identities and health concerns. Additionally, SGM patients with IBD may have unique health considerations that have not yet been well-studied OBJECTIVE: This article aims to explore the intersection of IBD and sexual health in patients who identify as SGM and to identify limitations for gastroenterologists in caring for SGM patients. The article also aims to provide suggestions for improvement in SGM-competent care within gastroenterology METHODS: A thorough literature review was conducted regarding sexual health and the SGM community with IBD. This included a review of surgical considerations in SGM patients, sexually transmitted infections (STIs) and prevention, and sexual dysfunction RESULTS: Overall, little is known about the impact of IBD on patients who identify as sexual and gender minorities. Surgery, medications, and STIs continue to be a concern in the SGM community with IBD and these areas represent opportunities to improve SGM-competent IBD care. Additionally, implementation of an SGM-focused curriculum is urgently needed in medical education to improve provider knowledge and care for this unique group of patients CONCLUSIONS: Patients with IBD who identify as SGM experience challenges that are not well described in prior literature. More research is needed and is actively being pursued to guide provider awareness and improve sexual health for this patient population.

OBJECTIVE:This study aimed to explore the prognostic impact of cognitive impairment on the long-term risk of major adverse cardiovascular events (MACEs) in older patients with non-ST-elevation acute coronary syndrome (NSTEACS) undergoing invasive treatment. METHODS:Patients aged ≥75 years with NSTEACS undergoing an invasive strategy were included in the multicentre prospective study (NCT01933581). Montreal Cognitive Assessment was used to evaluate cognitive status at baseline (scores ≥26 classified as normal, <26 as cognitive impairment). Long-term follow-up data were obtained from electronic patient care records. The primary endpoint was MACE as a composite of all-cause deaths, reinfarction, stroke/transient ischaemic attack, urgent revascularisation and significant bleeding. RESULTS:239 patients with baseline cognitive assessment completed long-term follow-up. Median age was 80.9 years (IQR 78.2-83.9 years) and 62.3% were male. On 5-year follow-up, there was no significant difference in the occurrence of MACE between the cognitively impaired group and the normal cognition group (p=0.155). Cognition status was not associated with MACE (HR 1.37 (95% CI 0.96 to 1.95); p=0.082). However, there was significantly more deaths (p=0.005) in those with cognitive impairment. Kaplan-Meier survival analysis (log-rank p=0.003) and Cox regression analysis (aHR 1.85 (95% CI 1.11 to 3.08); p=0.018) revealed increased risk of all-cause mortality, even after adjusting for frailty and GRACE (Global Registry of Acute Coronary Events) score. CONCLUSION/CONCLUSIONS:Cognitive impairment in older patients with NSTEACS undergoing an invasive strategy was associated with long-term all-cause mortality. Routine cognitive screening may aid risk stratification and further studies are needed to identify how this should influence management strategies and individual decision-making in this patient group. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT01933581.

BACKGROUND:EM Talk is a communication skills training program designed to improve emergency providers' serious illness conversational skills. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, this study aims to assess the reach of EM Talk and its effectiveness. METHODS:EM Talk consisted of one 4-h training session during which professional actors used role-plays and active learning to train providers to deliver serious/bad news, express empathy, explore patients' goals, and formulate care plans. After the training, emergency providers filled out an optional post-intervention survey, which included course reflections. Using a multi-method analytical approach, we analyzed the reach of the intervention quantitatively and the effectiveness of the intervention qualitatively using conceptual content analysis of open-ended responses. RESULTS:A total of 879 out of 1,029 (85%) EM providers across 33 emergency departments completed the EM Talk training, with the training rate ranging from 63 to 100%. From the 326 reflections, we identified meaning units across the thematic domains of improved knowledge, attitude, and practice. The main subthemes across the three domains were the acquisition of Serious Illness (SI) communication skills, improved attitude toward engaging qualifying patients in SI conversations, and commitment to using these learned skills in clinical practice. CONCLUSION/CONCLUSIONS:Our study showed the extensive reach and the effectiveness of the EM Talk training in improving SI conversation. EM Talk, therefore, can potentially improve emergency providers' knowledge, attitude, and practice of SI communication skills. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov: NCT03424109; Registered on January 30, 2018.

The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3^GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3^GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (T_H17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4⁺ and CD8⁺ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3^GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T_H17-driven autoimmunity that phenotypically resembles human STAT3^GOF disease.

BACKGROUND:There is a paucity of data on the real-world effectiveness of therapies in patients with Crohn's Disease of the Pouch (CDP). METHODS:This was a prospective, multicenter study evaluating the primary outcome of remission at 12 months of therapy for CDP. RESULTS:134 patients were enrolled. Among the 77 patients with symptoms at baseline, 35 (46.7%) achieved remission at 12-months. Of these, 12 (34.3%) changed therapy. There was no significant association between therapy patterns and remission status. CONCLUSION/CONCLUSIONS:Approximately 50% with symptoms at enrollment achieved clinical remission at 12 months, the majority of whom did so without a change in therapy.

How B cells assess risk in the intestine.

BACKGROUND:Hidradenitis suppurativa (HS) is a debilitating cutaneous disease characterized by severe painful inflammatory nodules/abscesses. At present, data regarding the epidemiology and pathophysiology of this disease are limited. OBJECTIVE:To define the prevalence and comorbidity associations of HS. METHODS:examining over 180 million US patients. Prevalences were calculated by demographic and odds ratios (OR) and identified comorbidity correlations. RESULTS:All examined metabolism-related, psychological, and autoimmune/autoinflammatory (AI) diseases correlated with HS. The strongest associations were with pyoderma gangrenosum [OR 26.56; confidence interval (CI): 24.98-28.23], Down syndrome (OR 11.31; CI 10.93-11.70), and polycystic ovarian syndrome (OR 11.24; CI 11.09-11.38). Novel AI associations were found between HS and lupus (OR 6.60; CI 6.26-6.94) and multiple sclerosis (MS; OR 2.38; CI 2.29-2.48). Cutaneous malignancies were largely not associated in the unsegmented cohort; however, among Black patients, novel associations with melanoma (OR 2.39; CI 1.86-3.08) and basal cell carcinoma (OR 2.69; CI 2.15-3.36) were identified. LIMITATIONS/CONCLUSIONS:International Classification of Diseases (ICD)-based disease identification relies on coding fidelity and diagnostic accuracy. CONCLUSION/CONCLUSIONS:This is the first study to identify correlations between HS with melanoma and basal cell carcinoma (BCC) among Black patients as well as MS and lupus in all patients with HS.

INTRODUCTION/BACKGROUND:Data suggest atherosclerotic-related inflammation may play a role in the pathogenesis of inflammatory bowel disease (IBD), but large-scale studies are missing. METHODS:In this nationwide case-control study, we used the Swedish Patient Register and the Epidemiology Strengthened by histoPathology Reports in Sweden cohort to identify adult cases of incident IBD between 2002 and 2021, with each case matched to up to 10 general population controls. We used conditional logistic regression to calculate odds ratios (OR) for exposure to an atherosclerotic-related condition (myocardial infarction, thromboembolic stroke, or atherosclerosis itself) before being diagnosed with IBD. RESULTS:There were a total of 56,212 individuals with IBD and 531,014 controls. Of them, 2,334 (4.2%) cases and 18,222 (3.4%) controls had a prior diagnosis of an atherosclerotic-related condition, corresponding to an OR of 1.30 (95% confidence interval [CI] 1.24-1.37). Results were statistically significant for both Crohn's disease (OR 1.37, 95% CI 1.26-1.48) and ulcerative colitis (OR 1.27, 95% CI 1.20-1.35) and for individuals who developed IBD at 40-59 years of age and 60 years or older. In addition, associations persisted when adjusting for underlying comorbidities, including the presence of immune-mediated diseases and prior aspirin and/or statin use. The highest odds of an atherosclerotic-related condition were seen in the 6-12 months before IBD diagnosis, though odds were increased even ≥5 years before. A higher magnitude of odds was also observed when having 2 or more atherosclerotic-related conditions when compared with having only 1 condition. DISCUSSION/CONCLUSIONS:A history of an atherosclerotic-related condition is associated with increased odds of developing IBD, particularly among older adults. Future studies should investigate whether drugs targeting atherosclerotic-related inflammation may prevent IBD in higher-risk individuals.