Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor.

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNFΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.

Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections.

Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection.

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation.

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103+ gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter-specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103+ and CD103- migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103+ migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103- DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance.

Effects of mood and aging on keystroke dynamics metadata and their diurnal patterns in a large open-science sample: A BiAffect iOS study.

OBJECTIVE: Ubiquitous technologies can be leveraged to construct ecologically relevant metrics that complement traditional psychological assessments. This study aims to determine the feasibility of smartphone-derived real-world keyboard metadata to serve as digital biomarkers of mood. MATERIALS AND METHODS: BiAffect, a real-world observation study based on a freely available iPhone app, allowed the unobtrusive collection of typing metadata through a custom virtual keyboard that replaces the default keyboard. User demographics and self-reports for depression severity (Patient Health Questionnaire-8) were also collected. Using >14 million keypresses from 250 users who reported demographic information and a subset of 147 users who additionally completed at least 1 Patient Health Questionnaire, we employed hierarchical growth curve mixed-effects models to capture the effects of mood, demographics, and time of day on keyboard metadata. RESULTS: We analyzed 86 541 typing sessions associated with a total of 543 Patient Health Questionnaires. Results showed that more severe depression relates to more variable typing speed (P < .001), shorter session duration (P < .001), and lower accuracy (P < .05). Additionally, typing speed and variability exhibit a diurnal pattern, being fastest and least variable at midday. Older users exhibit slower and more variable typing, as well as more pronounced slowing in the evening. The effects of aging and time of day did not impact the relationship of mood to typing variables and were recapitulated in the 250-user group. CONCLUSIONS: Keystroke dynamics, unobtrusively collected in the real world, are significantly associated with mood despite diurnal patterns and effects of age, and thus could serve as a foundation for constructing digital biomarkers.

To Improve Homicide Firearm Information Reporting - Rhode Island State Crime Laboratory.

Information on homicide firearms can be used to help state and local communities understand the problems of violence and decrease injuries and deaths. However, it is difficult to collect these data. To our knowledge, in the public health arena, the National Violent Death Reporting System (NVDRS) is the only system that collects detailed firearm information. The Rhode Island State Crime Laboratory (RISCL) can provide detailed information about the firearms and cartridge cases\bullets involved in firearm deaths. With help from the RISCL, the firearm information related to homicides in Rhode Island has improved dramatically. In 2015, information on caliber/gauge increased by 80%, the firearm type by 50%, the make by 50%, and the model by 20%. By documenting the process of using information from the RISCL, it is hoped that this process can be used as a model by other states when reporting on violent deaths.

Using Plan-Do-Study-Act Cycle to Enhance Completeness of Suicide Firearm Reporting.

The Rhode Island Violent Death Reporting System (RIVDRS) collects comprehensive surveillance data on violent deaths to support violence prevention programs in Rhode Island and nationwide. Successful collection of firearm information is critical to understanding gun violence in public health. A recent quality improvement (QI) project was performed to improve gun information collection in the RIVDRS program. Our aim was to increase the presence of firearm model information for 2014 suicides from 50% to 80% by December 31, 2015. We used the 2014 RIVDRS data and the Plan-Do-Study-Act cycle for this project. Our efforts achieved a 50% increase in the number of firearm model reporting. If we work more closely with police departments, they may understand the data importance, and be more likely to include the firearm information in their reports. We describe this process and provide lessons learned that can be generalizable to other states' violent death reporting system. [Full article available at http://rimed.org/rimedicaljournal-2017-02.asp].