TNF promoter hypomethylation is associated with mucosal inflammation in IBD and anti-TNF response.

Background and aims: Inflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders. Methods: We obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency. Results: TNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1, one of which had reduced function in vivo. Conclusions: Our study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.

Creation of an asynchronous faculty development curriculum on well-written narrative assessments that avoid bias.

BACKGROUND: The COVID-19 pandemic in parallel with concerns about bias in grading resulted in many medical schools adopting pass/fail clinical grading and relying solely on narrative assessments. However, narratives often contain bias and lack specificity. The purpose of this project was to develop asynchronous faculty development to rapidly educate/re-educate > 2000 clinical faculty spread across geographic sites and clinical disciplines on components of a well-written narrative and methods to minimize bias in the assessment of students. METHODS: We describe creation, implementation, and pilot data outcomes for an asynchronous faculty development curriculum created by a committee of volunteer learners and faculty. After reviewing the literature on the presence and impact of bias in clinical rotations and ways to mitigate bias in written narrative assessments, the committee developed a web-based curriculum using multimedia learning theory and principles of adult learning. Just-in-time supplemental materials accompanied the curriculum. The Dean added completion of the module by 90% of clinical faculty to the department chairperson's annual education metric. Module completion was tracked in a learning management system, including time spent in the module and the answer to a single text entry question about intended changes in behavior. Thematic analysis of the text entry question with grounded theory and inductive processing was used to define themes of how faculty anticipate future teaching and assessment as a result of this curricula. OUTCOMES: Between January 1, 2021, and December 1, 2021, 2166 individuals completed the online module; 1820 spent between 5 and 90 min on the module, with a median time of 17 min and an average time of 20.2 min. 15/16 clinical departments achieved completion by 90% or more faculty. Major themes included: changing the wording of future narratives, changing content in future narratives, and focusing on efforts to change how faculty teach and lead teams, including efforts to minimize bias. CONCLUSIONS: We developed a faculty development curriculum on mitigating bias in written narratives with high rates of faculty participation. Inclusion of this module as part of the chair's education performance metric likely impacted participation. Nevertheless, time spent in the module suggests that faculty engaged with the material. Other institutions could easily adapt this curriculum with provided materials.

Utilization of Text Messages to Supplement Rounding Communication: a Randomized Feasibility Study.

BACKGROUND: Fragmented communication with patients and families during hospitalizations often leaves patients confused about the daily plan. OBJECTIVE: To pilot a supplemental text message-based platform for improving bidirectional communication about the clinical plan and patients' goals. DESIGN: Randomized controlled trial PARTICIPANTS: Thirty adult patients, thirty caregivers of pediatric patients, and the interns caring for them on inpatient general medicine and pediatric services. INTERVENTIONS: Patients and caregivers were texted or emailed daily to report their personal goal and assess their understanding of the team's clinical plan. Interns were texted daily to report the team's clinical plan and to assess their understanding of the patient's personal goal. MAIN MEASURES: Primary outcomes were feasibility, defined as survey response rates, and acceptability. Secondary outcomes were patient comprehension of the clinical plan, trainee comprehension of the patient's goal, patient-centered communication scores, and educational satisfaction scores. KEY RESULTS: Thirty adult patients, thirty caregivers of pediatric patients, fourteen general medicine interns, and six general pediatric interns enrolled. Intervention feasibility was met, with survey response rates of 80% for general medicine trainees, 67% for general pediatric trainees, 58% for adult patients, and 70% for caregivers. Patients and caregivers in the intervention arm had higher understanding of medication changes (76% vs 50%, p = 0.02) and new consultations (90% vs 61%, p = 0.002). Interns had higher understanding of patients' goals in the intervention arm (93% vs 40%, p < 0.001), particularly for adult patients (97% vs 17%, p < 0.001). Caregivers rated communication higher regarding information to help make decisions (p = 0.04). Interviews demonstrated high acceptability. CONCLUSIONS: Our text message-based communication intervention was feasible and acceptable to all involved participants, with preliminary signals of efficacy. The intervention may contribute to improved understanding of medication changes and new consultations, as well as help in making decisions. A large, randomized efficacy trial of this intervention is warranted. Graphical abstract.

Sleep quality, depressive symptoms, and transplant outcomes: Follow-up analyses from the ADAPT prospective pilot study.

BACKGROUND: Previous studies suggested that depressive symptoms and sleep quality may be important for long-term clinical outcomes following cardiothoracic transplant. Few studies, however, have systematically examined objective markers of these behavioral factors among ambulatory transplant recipients, or their association with clinical outcomes. METHODS: We examined sleep quality and depressive symptoms with subsequent clinical outcomes (hospitalizations and death) in a sample of 66 lung or heart transplant recipients using a single-center, prospective cohort study. Recipients were assessed at approximately 6 months post-transplant and completed one week of actigraphy assessment to examine sleep quality and self-report measures of mood (Centers for Epidemiologic Studies of Depression [CESD]). Recipients were followed for clinical outcomes. RESULTS: At 6-months following transplantation, recipients spent the majority of daytime activity at a sedentary level (61% of daily activity [SD = 10]) and elevated depressive symptoms were common (subclinical = 17%, mild = 12%, or moderate = 8%). Over a median follow-up of 4.5 years (IQR = 0.9, 5.1), 51 participants (77%) had at least one unplanned hospitalization and 11 (17%) participants died. In addition, sleep efficiency measurements suggested that a subset of participants exhibited suboptimal sleep (mean efficiency = 87% [SD = 7]). Poorer sleep quality, indexed by lower sleep efficiency and greater sleep fragmentation, was associated with greater depressive symptoms (r's = 0.37-0.50, P < .01). Better sleep quality at 6-months (HR = 0.75 [0.60, 0.95], P = .015), including sleep efficiency (HR = 0.74 [0.56, 0.99], P = .041) and sleep fragmentation (HR = 0.71 [0.53, 0.95], P = .020) were associated with lower risk of hospitalization or death. Compared with individuals without elevated depressive symptoms or sleep difficulties, individuals with either factor (HR = 1.72 [1.05, 2.81], P = .031) or both factors (HR = 2.37 [1.35, 4.18], P = .003) exhibited greater risk of clinical events in adjusted analyses. CONCLUSIONS: Sleep quality is associated with depressive symptoms among cardiothoracic transplant recipients and enhances the prognostic association between biobehavioral risk factors and clinical outcomes.

Fetal extracellular matrix nerve wraps locally improve peripheral nerve remodeling after complete transection and direct repair in rat.

In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery. However, the number of neurofilament positive axons, remyelination, and whisker-evoked response properties of ION axons were unaltered, indicating improved tissue remodeling per se does not predict axon regrowth, remyelination, and the return of mechanoreceptor cortical signaling. This study shows fUB-ECM nerve wraps are biocompatible, bioactive, and good experimental and potentially clinical devices for treating epineurial repairs. Moreover, this study highlights the value provided by precise, analytic models, like the ION repair model, in understanding how PN tissue remodeling relates to axonal regrowth, remyelination, and axonal response properties.

Urinary bladder extracellular matrix hydrogels and matrix-bound vesicles differentially regulate central nervous system neuron viability and axon growth and branching.

Central nervous system neurons often degenerate after trauma due to the inflammatory innate immune response to injury, which can lead to neuronal cell death, scarring, and permanently lost neurologic function. Extracellular matrix bioscaffolds, derived by decellularizing healthy tissues, have been widely used in both preclinical and clinical studies to promote positive tissue remodeling, including neurogenesis, in numerous tissues, with extracellular matrix from homologous tissues often inducing more positive responses. Extracellular matrix hydrogels are liquid at room temperature and enable minimally invasive extracellular matrix injections into central nervous system tissues, before gelation at 37℃. However, few studies have analyzed how extracellular matrix hydrogels influence primary central nervous system neuron survival and growth, and whether central nervous system and non-central nervous system extracellular matrix specificity is critical to neuronal responses. Urinary bladder extracellular matrix hydrogels increase both primary hippocampal neuron survival and neurite growth to similar or even greater extents, suggesting extracellular matrix from non-homologous tissue sources, such as urinary bladder matrix-extracellular matrix, may be a more economical and safer alternative to developing central nervous system extracellular matrices for central nervous system applications. Additionally, we show matrix-bound vesicles derived from urinary bladder extracellular matrix are endocytosed by hippocampal neurons and positively regulate primary hippocampal neuron neurite growth. Matrix-bound vesicles carry protein and RNA cargos, including noncoding RNAs and miRNAs that map to the human genome and are known to regulate cellular processes. Thus, urinary bladder matrix-bound vesicles provide natural and transfectable cargoes which offer new experimental tools and therapeutic applications to study and treat central nervous system neuron injury.