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Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of specific anti-carbohydrate antibodies (ACAs) that are associated with pathogenesis and progression to T1D. We compare circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n = 278) and healthy controls (n = 298), as well as in a longitudinal cohort (n = 112). We identify 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans are associated with progression to T1D. ACAs against gentamicin and its related structures, G418 and sisomicin, are also associated with islet autoimmunity. ACAs improve discrimination of T1D status of individuals over a model with only clinical variables and are potential biomarkers for T1D. Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression. [ABSTRACT FROM AUTHOR]

Background: Most patients with diabetes do not meet all evidence-based goals of care, and many patients report poor communication and lack of involvement in decision-making during primary care visits.Objective: To test the hypothesis that a "Pre-Visit Prioritization" secure email message could improve visit communication and glycemic control among patients with type 2 diabetes.Design: We conducted a pragmatic, provider-randomized, multi-site clinical trial from March 2015 to October 2016 across 30 primary care practices within Kaiser Permanente Northern California (KPNC), a large integrated care delivery system.Participants: Eligible patients had at least 1 year of KPNC membership, type 2 diabetes with most recently measured hemoglobin A1c (HbA1c) > = 8.0%, and were registered users of the KPNC online patient portal.Interventions: Patients in the intervention arm, upon booking an appointment, received a secure email through the KPNC online portal with a link to the EHR allowing them to submit their top one or two priorities prior to the visit. Control patients received usual care.Main Measures: Glycemic control; change in HbA1c 6 and 12 months after the initial visit; patient-reported outcomes related to patient-provider communication and patient care experiences.Key Results: During the study period, 1276 patients had at least one eligible visit. In post-visit surveys (n = 457), more intervention arm patients reported preparing questions for their visit (72% vs 63%, p = 0.048) and being given treatment choices to consider (81% vs 73%, p = 0.041). Patients in both arms had similar reductions in HbA1c over the 12-month study period (0.56% ± 1.45%), with no significant differences between arms.Conclusions: A "light touch" email-based pre-visit intervention resulted in improved measures of visit interaction but did not significantly improve glycemic control relative to usual care. Improving diabetes clinical outcomes through more effective primary care visits may require more intensive approaches to patient visit preparation.Trial Registry: NCT02375932. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. Methods: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. Results: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. Conclusions: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates. [ABSTRACT FROM AUTHOR]

Multiple populations of wake-promoting neurons have been characterized in mammals, but few sleep-promoting neurons have been identified. Wake-promoting cell types include hypocretin and GABA (γ-aminobutyric-acid)-releasing neurons of the lateral hypothalamus, which promote the transition to wakefulness from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Here we show that a subset of GABAergic neurons in the mouse ventral zona incerta, which express the LIM homeodomain factor Lhx6 and are activated by sleep pressure, both directly inhibit wake-active hypocretin and GABAergic cells in the lateral hypothalamus and receive inputs from multiple sleep-wake-regulating neurons. Conditional deletion of Lhx6 from the developing diencephalon leads to decreases in both NREM and REM sleep. Furthermore, selective activation and inhibition of Lhx6-positive neurons in the ventral zona incerta bidirectionally regulate sleep time in adult mice, in part through hypocretin-dependent mechanisms. These studies identify a GABAergic subpopulation of neurons in the ventral zona incerta that promote sleep. [ABSTRACT FROM AUTHOR]