A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA 1c for 1 year in new-onset type 1 diabetes. Subjects ( N = 89) were randomized to 1 ) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2 ) ATG alone, or 3 ) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA 1c , prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex ( n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo ( P = 0.00005) but not ATG/GCSF versus placebo ( P = 0.032). HbA 1c was significantly reduced at 2 years in subjects treated with ATG ( P = 0.011) and ATG/GCSF ( P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1 + CD4 + T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA 1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

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Context Once islet autoantibody positive individuals are identified, predicting which individuals are at highest risk for type 1 diabetes (T1D) is important. A metabolic risk score derived from 2-hour oral glucose tolerance test (OGTT) data, the Diabetes Prevention Trial-Type 1 risk score (DPTRS), can accurately predict T1D. However, 2-hour OGTTs are time consuming and costly. Objective We aimed to determine whether a risk score derived from 1-hour OGTT data can predict T1D as accurately as the DPTRS. Secondarily, we evaluated whether a 1-hour glucose value can be used for diagnostic surveillance. Methods The DPTRS was modified to derive a 1-hour OGTT risk score (DPTRS60) using fasting C-peptide, 1-hour glucose and C-peptide, age and BMI. Areas under receiver operating curves (ROCAUC) were used to compare prediction accuracies of DPTRS60 with DPTRS in Diabetes Prevention Trial-Type 1 (DPT-1) (n=654) and TrialNet Pathway to Prevention (TNPTP) (n=4610) participants. Negative predictive values (NPV) for T1D diagnosis were derived for 1-hour glucose thresholds. Results ROCAUC for T1D prediction 5 years from baseline was similar between DPTRS60 vs. DPTRS (DPT-1: 0.805 and 0.794; TNPTP: 0.832 and 0.847, respectively). DPTRS60 predicted T1D significantly better than 2-hour glucose (p&0.0001 in both cohorts). A 1-hour glucose &180 mg/dl had a similar NPV, PPV and specificity for T1D development before the next 6-month visit as the standard 2-hour threshold &140 mg/dl (both ≥98.5%). Conclusion A 1-hour OGTT can predict T1D as accurately as a 2-hr OGTT with minimal risk of missing a T1D diagnosis before the next visit.

Study Objectives: Asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea (OSA) are very prevalent disorders. Their coexistence in the same individual has an unclear effect on natural history and long-term outcomes. Methods: The OLDOSA (Obstructive Lung Disease and Obstructive Sleep Apnea) cohort enrolled 4,980 veterans with an acute hospitalization and in whom asthma, COPD, OSA, overlapping conditions, or none of these disorders at baseline had been diagnosed. Pulmonary function, polysomnography, positive airway pressure (PAP) recommendations and adherence, and vital status were collected and analyzed. Various proportional hazards models were built for patients with OSA to test the effect of PAP therapy on survival. Results: Ten-year all-cause cumulative mortality rate was 52.8%; median time to death was 2.7 years. In nonoverlapping asthma, OSA and COPD, mortality rates were 54.2%, 60.4%, and 63.0%, respectively. The overlap syndromes had the following mortality: COPD-OSA 53.2%, asthma-COPD 62.1%, asthma-OSA 63.5%, and triple overlap asthma-COPD-OSA 67.8%. In patients with OSA not on PAP therapy, after adjustment for age, comorbidities, and lung function, risk of death was 1.34 (1.05-1.71) times higher than those undergoing treatment. Similarly, in patients with OSA nonadherent to PAP therapy the adjusted risk of death was 1.78 (1.13-2.82) times higher versus those using it at least 70% of nights and more than 4 hours nightly. Conclusions: In this large longitudinal cohort of hospitalized veterans with high comorbid burden, asthma, COPD, OSA and their overlap syndromes had very high long-term mortality. In patients with OSA, PAP initiation and superior therapeutic adherence were associated with significantly better survival.

BackgroundNecrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality in premature infants. To date, no effective biomarkers exist to predict which premature infants will develop NEC, limiting targeted prevention strategies. Multiple observational studies have reported an association between the exposure to red blood cell (RBC) transfusion and/or anemia and the subsequent development of NEC; however, the underlying physiologic mechanisms of how these factors are independently associated with NEC remain unknown.MethodsIn this paper, we outline our prospective, multicenter observational cohort study of infants with a birth weight ≤ 1250 g to investigate the associations between RBC transfusion, anemia, intestinal oxygenation and injury that lead to NEC. Our overarching hypothesis is that irradiation of RBC units followed by longer storage perturbs donor RBC metabolism and function, and these derangements are associated with paradoxical microvascular vasoconstriction and intestinal tissue hypoxia increasing the risk for injury and/or NEC in transfused premature infants with already impaired intestinal oxygenation due to significant anemia. To evaluate these associations, we are examining the relationship between prolonged irradiation storage time (pIST), RBC metabolomic profiles, and anemia on intestinal oxygenation non-invasively measured by near-infrared spectroscopy (NIRS), and the development of NEC in transfused premature infants.DiscussionOur study will address a critical scientific gap as to whether transfused RBC characteristics, such as irradiation and metabolism, impair intestinal function and/or microvascular circulation. Given the multifactorial etiology of NEC, preventative efforts will be more successful if clinicians understand the underlying pathophysiologic mechanisms and modifiable risk factors influencing the disease.Trial registrationOur study is registered in ClinicalTrials.gov Identifier: NCT02741648.