BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized

A model-based economic evaluation of improved primary care management of patients with type 2 diabetes in Australia

BackgroundThere are few studies investigating the economic value of the Australian practice nurse workforce on the management of chronic conditions. This is particularly important in Australia, where the government needs evidence to inform decisions on whether to maintain or redirect current financial incentives that encourage practices to recruit practice nurses.ObjectiveThe objective of this study was to estimate the lifetime costs and quality-adjusted life-years (QALYs) associated with two models of practice nurse involvement in clinical-based activities (high and low level) in the management of type 2 diabetes within the primary care setting.MethodsA previously validated state transition model (the United Kingdom Prospective Diabetes Study Outcomes Model) was adapted, which uses baseline prognostic factors (e.g. gender, haemoglobin A1c [HbA1c]) to predict the risk of occurrence of diabetes-related complications (e.g. stroke). The model was populated by data from Australian and UK observational studies. Costs and utility values associated with complications were summed over patients' lifetimes to estimate costs and QALY gains from the perspective of the health care system. All costs were expressed in 2011 Australian dollars (AU$). The base-case analysis assumed a 40-year time horizon with an annual discount rate of 5$8,738; 95 % confidence interval [CI] -AU$12,522 to -AU$4,954), and a greater average gain in QALYs (0.3; 95 % CI 0.2-0.4). A range of sensitivity analyses were performed, in which the high-level model was dominant in all cases.ConclusionOur results suggest that the high-level model is a dominant management strategy over the low-level model in all modelled scenarios. These findings indicate the need for effective primary care-based incentives to encourage general practices not only to employ practice nurses, but to better integrate them into the provision of clinical services.Hossein Haji Ali Afzali, Jodi Gray, Justin Beilby, Christine Holton, Jonathan Karno