Disease heterogeneity of adult diabetes based on routine clinical parameters at diagnosis: Results from the German/Austrian DPV registry.

AIMS To cluster adults with diabetes using parameters from real-world clinical care at manifestation. MATERIALS AND METHODS We applied hierarchical clustering using Ward's method to 56,869 adults documented in the Prospective Diabetes Follow-up Registry (DPV). Clustering variables included age, sex, BMI, HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidemia/hyperuricemia), and beta-cell antibody status. Time until use of oral antidiabetic drugs (OAD), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy, or neuropathy were assessed using Kaplan Meier analysis and Cox regression models. RESULTS We identified eight clusters: Four clusters comprised early diabetes onset (median age between 40 and 50 years), but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were characterized by late diabetes onset (median age 69 and 77 years) and relatively low BMI, but differences in HbA1c. Earlier insulin use was observed in adults with high HbA1c, and earlier OAD use was observed in those with high BMI. Time until CKD or CVD was shorter in those with late onset, whereas retinopathy occurred earlier in adults with late onset and high HbA1c, and in adults with early onset, but high HbA1c and high percentage of antibody positivity. CONCLUSIONS Adult diabetes is heterogeneous beyond classical type 1/type 2 diabetes, based on easily available parameters in clinical practice using an automated clustering algorithm which allows both continuous and binary variables. This article is protected by copyright. All rights reserved

Link between Organ-specific Antigen Processing by 20S Proteasomes and CD8+ T Cell–mediated Autoimmunity

Adoptive transfer of cross-reactive HSP60-specific CD8+ T cells into immunodeficient mice causes autoimmune intestinal pathology restricted to the small intestine. We wondered whether local immunopathology induced by CD8+ T cells can be explained by tissue-specific differences in proteasome-mediated processing of major histocompatibility complex class I T cell epitopes. Our experiments demonstrate that 20S proteasomes of different organs display a characteristic composition of α and β chain subunits and produce distinct peptide fragments with respect to both quality and quantity. Digests of HSP60 polypeptides by 20S proteasomes show most efficient generation of the pathology related CD8+ T cell epitope in the small intestine. Further, we demonstrate that the organ-specific potential to produce defined T cell epitopes reflects quantities that are relevant for cytotoxic T lymphocyte recognition. We propose tissue-specific antigen processing by 20S proteasomes as a potential mechanism to control organ-specific immune responses

Effect of surgical experience and spine subspecialty on the reliability of the {AO} Spine Upper Cervical Injury Classification System

OBJECTIVE The objective of this paper was to determine the interobserver reliability and intraobserver reproducibility of the AO Spine Upper Cervical Injury Classification System based on surgeon experience (< 5 years, 5–10 years, 10–20 years, and > 20 years) and surgical subspecialty (orthopedic spine surgery, neurosurgery, and "other" surgery). METHODS A total of 11,601 assessments of upper cervical spine injuries were evaluated based on the AO Spine Upper Cervical Injury Classification System. Reliability and reproducibility scores were obtained twice, with a 3-week time interval. Descriptive statistics were utilized to examine the percentage of accurately classified injuries, and Pearson’s chi-square or Fisher’s exact test was used to screen for potentially relevant differences between study participants. Kappa coefficients (κ) determined the interobserver reliability and intraobserver reproducibility. RESULTS The intraobserver reproducibility was substantial for surgeon experience level (< 5 years: 0.74 vs 5–10 years: 0.69 vs 10–20 years: 0.69 vs > 20 years: 0.70) and surgical subspecialty (orthopedic spine: 0.71 vs neurosurgery: 0.69 vs other: 0.68). Furthermore, the interobserver reliability was substantial for all surgical experience groups on assessment 1 (< 5 years: 0.67 vs 5–10 years: 0.62 vs 10–20 years: 0.61 vs > 20 years: 0.62), and only surgeons with > 20 years of experience did not have substantial reliability on assessment 2 (< 5 years: 0.62 vs 5–10 years: 0.61 vs 10–20 years: 0.61 vs > 20 years: 0.59). Orthopedic spine surgeons and neurosurgeons had substantial intraobserver reproducibility on both assessment 1 (0.64 vs 0.63) and assessment 2 (0.62 vs 0.63), while other surgeons had moderate reliability on assessment 1 (0.43) and fair reliability on assessment 2 (0.36). CONCLUSIONS The international reliability and reproducibility scores for the AO Spine Upper Cervical Injury Classification System demonstrated substantial intraobserver reproducibility and interobserver reliability regardless of surgical experience and spine subspecialty. These results support the global application of this classification system

Dynamics of HbA1c, BMI and rates of severe hypoglycemia in 4,434 adults with type 1 or type 2 diabetes after initiation of continuous glucose monitoring.

BACKGROUND Continuous glucose monitoring (CGM) might have beneficial effects on glycemic control and body-mass-index (BMI) in adults with type 1 (T1D) or type 2 diabetes (T2D). METHODS The diabetes prospective follow-up registry was used to identify individuals with T1D or T2D ≥18 years starting CGM management in 2015 or later and follow-up information available. HbA1c, BMI and event rates of severe hypoglycemia in the year prior to CGM start were compared to two follow-up periods: 1) CGM use for 3-6 months and 2) CGM use for >6 months. Repeated measurements linear and negative binomial regression were used (adjustment for sex, age at diabetes onset and baseline parameters) and stratified by diabetes type. RESULTS Mean follow-up time was 1.8 years in T1D (n=2,994) and 1.9 years in T2D (n=1,440). In T1D, adjusted mean HbA1c decreased significantly from 7.65% (95%-confidence interval: 7.62-7.68) at baseline to 7.54% (7.51-7.57) during follow-up. BMI increased slightly (baseline: 25.4 kg/m2 (25.3-25.5), follow-up >6 months: 25.8 kg/m2 (25.7-25.9)), whereas event rates of severe hypoglycemia were significantly lower after >6 months with CGM (9.0 events/100 PY (8.0-10.1)) compared to baseline (11.3 events/100 PY (10.4-12.2)) in adults with T1D. In T2D, HbA1c decreased from 7.21% (7.17-7.25) to 7.00% (6.95-7.04%) and BMI did not change after CGM initiation. CONCLUSION Our results provide real world evidence on CGM management in adult individuals with T1D or T2D. We suggest to strengthen patients' and physicians' readiness towards diabetes technology in T2D and more openness of health insurance to cover cost based on proven benefits

Comparative characteristics of older people with type 1 diabetes treated with continuous subcutaneous insulin infusion or insulin injection therapy : data from the German/Austrian DPV registry

Aim: To compare clinical characteristics and outcomes in adults with type 1 diabetes aged ≥ 60 years using continuoussubcutaneous insulin infusion (CSII) vs. insulin injection therapy. Further, to determine the percentage of older adults with type 1 diabetes using CSII. Research design and methods: Retrospective study using data of the Diabetes Prospective Follow-up Registry (DPV). Including percentage CSII use from 2008 to 2018, and the characteristics of 9547 individuals extracted from the DPV in March 2019 (N=1404 CSII; N=8143 insulin injection therapy). Wilcoxon rank sum tests were used for continuous variables and chi-square tests for categorical variables to compare clinical characteristics of people using CSII vs. insulin injection therapy. Adjusted analyses used generalized linear models to compare diabetes-related outcomes. Results: CSII usage has increased in older adults (from 12% in 2008 to 23% in 2018). After adjustment, CSII was associated with lower HbA1c [60.7 mmol/mol (7.7±0.1%) vs. 62.8% (7.9±0.1%)], lower daily insulin dose (0.49±0.02 vs. 0.61±0.01 IU/kg), fewer days in hospital (8.1±0.12 vs. 11.2±0.11 days/person-year), fewer severe hypoglycaemic events (0.16±0.02 vs. 0.21±0.03 events/person-year) and fewer diabetic ketoacidosis (0.06±0.01 vs. 0.08±0.01 events/person-year). Individuals on CSII showed lower rates of microalbuminuria and also have a diagnosis of depression and neuropathy. Conclusions: A growing number of older adults are using insulin pumps. Older age in itself should not be seen as a contraindication for CSII