The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.

The role of patient navigators in ambulatory care: overview of systematic reviews.

BACKGROUND: Patient navigators have been introduced across various countries to enable timely access to healthcare services and to ensure completion of diagnosis and follow-up of care. There is an increasing evidence on the the role of patient navigation for patients and healthcare systems. The aim of this study was to analyse the evidence on patient navigation interventions in ambulatory care and to evaluate their effects on individuals and health system outcomes. METHODS: An overview of reviews was conducted, following a prespecified protocol. All patients in ambulatory care or transitional care setting were included in this review as long as it was related to the role of patient navigators. The study analysed patient navigators covering a wide range of health professionals such as physicians, nurses, pharmacists, social workers and lay health workers or community-based workers with no or very limited training. Studies including patient-related measures and health system-related outcomes were eligible for inclusion. A rigorous search was performed in multiple data bases. After reaching a high inter-rater agreement of 0.86, title and abstract screening was independently performed. Of an initial 14,248 search results and an additional 62 articles identified through the snowballing approach, a total of 7159 hits were eligible for title/abstract screening. 679  articles were included for full-text screening. RESULTS: Eleven systematic reviews were included covering various patient navigation intervention in cancer care, disease screening, transitional care and for various chronic conditions and multimorbidity. Nine systematic reviews primarily tailored services to ethnic minorities or other disadvantaged groups. Patient navigators performed tasks such as providing education and counselling, translations, home visits, outreach, scheduling of appointments and follow-up. Eight reviews identified positive outcomes in expanding access to care, in particular for vulnerable patient groups. Two reviews on patient navigation in transitional care reported improved patient outcomes, hospital readmission rates and mixed evidence on quality of life and emergency department visits. Two reviews demonstrated improved patient outcomes for persons with various chronic conditions and multimorbidity. CONCLUSIONS: Patient navigators were shown to expand access to screenings and health services for vulnerable patients or population groups with chronic conditions who tend to underuse health services.