The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-β) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.

ObjectiveThere is a paucity of data regarding prognosis in patients with acute versus chronic myocardial injury for long-term outcomes. We hypothesised that patients with chronic myocardial injury have a similar long-term prognosis as patients with acute myocardial injury.MethodsIn an observational cohort study of 22 589 patients who had high-sensitivity cardiac troponin T (hs-cTnT) measured in the emergency department during 2011–2014, we identified all patients with level >14 ng/L and categorised them as acute myocardial injury, type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI) or chronic myocardial injury through adjudication. We estimated adjusted HRs with 95% CIs for the primary outcome all-cause mortality and secondary outcomes MI, and heart failure in patients with acute myocardial injury, T1MI and T2MI compared with chronic myocardial injury.ResultsIn total, 3853 patients were included. During 3.9 (±2) years of follow-up, 48%, 24%, 44% and 49% of patients with acute myocardial injury, T1MI, T2MI and chronic myocardial injury died, respectively. Patients with acute myocardial injury had higher adjusted risks of death (1.21, 95% CI 1.08 to 1.36) and heart failure (1.24, 95% CI 1.07 to 1.43), but a similar risk for myocardial infarction (MI) compared with the reference group. Patients with T1MI had a lower adjusted risk of death (0.86, 95% CI 0.74 to 1.00) and higher risk of MI (2.09, 95% CI 1.62 to 2.68), but a similar risk of heart failure. Patients with T2MI had a higher adjusted risk of death (1.46, 95% CI 1.18 to 1.80) and heart failure (1.30, 95% CI 1.00 to 1.69) compared with patients with chronic myocardial injury.ConclusionsAbsolute long-term risks for death are similar, and adjusted risks are slightly higher, among patients with acute myocardial injury and T2MI, respectively, compared with chronic myocardial injury. The lowest risk of long-term mortality was found in patients with T1MI. Both acute and chronic myocardial injury are associated with very high risks of adverse outcomes.

Aims The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. Methods and results In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P < 0.001 and P = 0.008, respectively). Conclusion The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. Trial registration ClinicalTrials.gov number, NCT01852123.

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Background There is no clinical guidance on treatment in patients with non‐ischemic myocardial injury and type 2 myocardial infarction (T2MI). Methods and Results In a cohort of 22 589 patients in the emergency department at Karolinska University Hospital in Sweden during 2011 to 2014 we identified 3853 patients who were categorized into either type 1 myocardial infarction, T2MI, non‐ischemic acute and chronic myocardial injury. Data from all dispensed prescriptions within 180 days of the visit to the emergency department were obtained concerning β‐blockers, angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers, statins, and platelet inhibitors. We estimated adjusted hazard ratios (HR) with 95% CI for all‐cause mortality in relationship to the number of medications (categorized into 0–1 [referent], 2–3 and 4 medications) in the groups of myocardial injury. In patients with T2MI, treatment with 2 to 3 and 4 medications was associated with a 50% and 56% lower mortality, respectively (adjusted HR [95% CI], 0.50 [0.25–1.01], and 0.43 [0.19–0.96]), while corresponding associations in patients with acute myocardial injury were 24% and 29%, respectively (adjusted HR [95% CI], 0.76 [0.59–0.99] and 0.71 [0.5–1.02]), and in patients with chronic myocardial injury 27% and 37%, respectively (adjusted HR [95% CI], 0.73 [0.58–0.92] and 0.63 [0.46–0.87]). Conclusions Patients with T2MI and non‐ischemic acute or chronic myocardial injury are infrequently prescribed common cardiovascular medications compared with patients with type 1 myocardial infarction. However, treatment with guideline recommended drugs in patients with T2MI and acute or chronic myocardial injury is associated with a lower risk of death after adjustment for confounders.

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