Aims/hypothesis The long-term effects of successful immune therapies for treatment of type 1 diabetes have not been well studied. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial evaluated teplizumab, an Fc receptor non-binding humanised anti-CD3 monoclonal antibody in individuals with new-onset type 1 diabetes, and ended in 2011. Clinical drugtreated responders showed an increased frequency of 'partially exhausted' CD8 + T cells. We studied the clinical, immunological and metabolic status of participants after an average follow-up of 7 years. Methods Participants with detectable C-peptide at year 2 of AbATE returned for follow-up. C-peptide responses were assessed by 4 h mixed-meal tolerance test. Autoantibodies and HbA 1c levels were measured and average daily insulin use was obtained from patient logs. Peripheral blood mononuclear cells were analysed by flow cytometry and cytokine release. Results Fifty-six per cent of the original participants returned. Three of the original control group who did not return had lost all detectable C-peptide by the end of the 2 year trial. The C-peptide responses to a mixed-meal tolerance test were similar overall in the drug vs control group of participants but were significantly improved, with less loss of C-peptide, in drug-treated responders identified at 1 year. However, the improvements in C-peptide response were not associated with lower HbA 1c levels or insulin use. Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central memory and anergic CD8 + T cells at follow-up. Conclusions/interpretation These findings suggest there is reduced decline in C-peptide and persistent immunological responses up to 7 years after diagnosis of diabetes in individuals who respond to teplizumab. Trial registration ClinicalTrials.gov NCT02067923; the protocol is available at www.immunetolerance.org (ITN027AI).

In type 1 diabetes, cytotoxic CD8+ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell-reactive CD8+ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell-reactive CD8+ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell-specific effector memory CD8+ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8+ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57- counterparts, and network association modeling indicated that the dynamics of β cell-reactive CD57+ effector memory CD8+ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell-specific CD8+ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Objectives The purpose of this study was to determine the prevalence and scope of point‐of‐care ultrasound (US) education in internal medicine, pediatric, and medicine‐pediatric residency programs nationwide. Methods Program directors were surveyed between January and June 2016 with a 15‐item online questionnaire to assess the state of point‐of‐care US training in their programs. The survey aimed to identify whether programs had an established point‐of‐care US curriculum and, if not, what reasons may have existed for a lack of point‐of‐care US training in their programs. Results The survey was distributed to 685 program directors, and the response rate was 19.2%. Only 31.5% of respondents reported having a formal point‐of‐care US curriculum in their program, and in 12.4% of programs, there was no US training at all. The presence of point‐of‐care US training as reported by internal medicine (n = 64) and medicine‐pediatric (n = 24) respondents showed formal point‐of‐care US curriculum rates of 37.5% and 43.5%, respectively. Pediatric programs (n = 24) reported limited point‐of‐care US training, with formal curriculum in only 12.4% of programs and 27.3% having no point‐of‐care US training at all. The most common reasons for lack of a point‐of‐care US curriculum among program directors were lack of trained faculty/instructors (70.4%), lack of guidelines/standards by governing societies (44.4%), and lack of the necessary technology (33.3%). Conclusions Less than half of residents with internal medicine training will have trained at a program with a point‐of‐care US curriculum, and point‐of‐care US training in pediatrics is even more limited. The major reason for the lack of point‐of‐care US education is a lack of trained faculty or instructors.