Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren

Over a 15 year period, the incidence of type 1 diabetes has doubled in Lithuania, whilst increasing by a third in England, however England still has the higher incidence. Analysis of sera collected from non-diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody positive schoolchildren between the populations, but a higher prevalence of islet antigen-2 autoantibodies (IA-2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests, to characterise differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD(96-585), the protein tyrosine phosphatase region of islet antigen-2 (PTPA), and the related IA-2βA while autoantibodies to IA-2A were re-assayed using the current harmonized method. IA-2 related autoantibodies PTPA (0.13% vs. 0.45%, p=0.027) and IA-2βA (0% vs. 0.35%, p<0.001), but not IA-2A measured using the harmonized method, were less common in Lithuanian compared to English schoolchildren. Lithuanian schoolchildren who were islet autoantibody positive, were positive for fewer biochemical autoantibodies compared with English schoolchildren (p=0.043). Background rates of islet autoimmunity in childhood differ subtly between countries which have different incidences of type 1 diabetes. The optimal screening strategy (age and combination of markers) for detection of islet autoimmunity may vary between countries dependent on the pattern of autoantibodies found in the general population

Islet Autoantibody Standardization Program 2018 Workshop:Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance

BACKGROUND: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring type 1 diabetes (T1D)-associated autoantibodies and the concordance of results among laboratories. IASP organizes international interlaboratory assay comparison studies in which blinded serum samples are distributed to participating laboratories, followed by centralized collection and analysis of results, providing participants with an unbiased comparative assessment. In this report, we describe the results of glutamic acid decarboxylase autoantibody (GADA) assays presented in the IASP 2018 workshop. METHODS: In May 2018, IASP distributed to participants uniquely coded sera from 43 new-onset T1D patients, 7 multiple autoantibody-positive nondiabetic individuals, and 90 blood donors. Results were analyzed for the following metrics: sensitivity, specificity, accuracy, area under the ROC curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95), and concordance of qualitative and quantitative results. RESULTS: Thirty-seven laboratories submitted results from a total of 48 different GADA assays adopting 9 different formats. The median ROC-AUC and pAUC95 of all assays were 0.87 [interquartile range (IQR), 0.83-0.89] and 0.036 (IQR, 0.032-0.039), respectively. Large differences in pAUC95 (range, 0.001-0.0411) were observed across assays. Of formats widely adopted, bridge ELISAs showed the best median pAUC95 (0.039; range, 0.036-0.041). CONCLUSIONS: Several novel assay formats submitted to this study showed heterogeneous performance. In 2018, the majority of the best performing GADA immunoassays consisted of novel or established nonradioactive tests that proved on a par or superior to the radiobinding assay, the previous gold standard assay format for GADA measurement

Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort.

OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged ≥5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

ims/hypothesis The aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes. Methods Immunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8+ T cells were quantified using peptide–HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs. Results Islet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4+ and CD8+ T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4+ T cells with a central memory phenotype (CD27int, CD127+, CD95int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4+ T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8+ T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06). Conclusions/interpretation In this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications

Breathlessness and presentation to the emergency department : a survey and clinical record review

BACKGROUND: Breathlessness is a frequently occurring symptom of cardiorespiratory conditions and is a common cause of emergency department presentation. The aim of this study was to estimate the prevalence of acute-on-chronic breathlessness as a cause for presentation to the major emergencies area of the emergency department. METHODS: A prospective patient self-report survey and clinical record review of consecutive attendees to the major emergencies area of the emergency department in a single tertiary hospital between 12/5/14 and 29/5/14 was conducted. Eligible patients were clinically stable and had mental capacity to provide data. RESULTS: There were 2,041 presentations during the study period, of whom 1,345 (66%) were eligible. There was a 90% survey response rate (1,212/1,345); 424/1,212 (35%) self-reported breathlessness most days over the past month of whom 245 gave breathlessness as a reason for this presentation. Therefore, the prevalence of acute-on-chronic breathlessness as a reason to present to the major emergencies area was 20.2% (245/1,212, 95% CI 17.9% to 22.5%). During this period there were 4,692 major and minor presentations; breathlessness was therefore a cause of at least 5.2% (245/4,692, 95% CI 4.6 to 5.9%) of all emergency department presentations. CONCLUSIONS: This study found that one in five ambulance presentations to the ED were due to acute-on-chronic breathlessness. Most patients had non-malignant underlying conditions, had experienced considerable breathlessness for an extended period, had discussed breathlessness with their GP and presented out of daytime hours. Others were often involved in their decision to present. This represents clinically significant burden for patients, their family carers and the emergency health services

BVRI Light Curves for 29 Type Ia Supernovae

BVRI light curves are presented for 27 Type Ia supernovae discovered during the course of the Calan/Tololo Survey and for two other SNe Ia observed during the same period. Estimates of the maximum light magnitudes in the B, V, and I bands and the initial decline rate parameter m15(B) are also given.Comment: 17 pages, figures and tables are not included (contact first author if needed), to appear in the Astronomical Journa

Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome

Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia including surreptitious insulin administration. No standardized treatment regimen exists. Objectives: To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting: Observational study in the UK Severe Insulin Resistance Service. Patients: 6 patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main outcome measures: Glycemia, plasma insulin and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and IA were further characterized using radioligand binding studies. Results: All patients were diagnosed with IAS (5 IgG, 1 IgA) based on high insulin:C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. 1 patient was managed conservatively, 4 were treated with diazoxide without sustained benefit, and 4 were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions: IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin:C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON) : a randomised controlled phase III trial

Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).Peer reviewedPublisher PD

Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

OBJECTIVE: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes. RESEARCH DESIGN AND METHODS: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay. RESULTS: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes–associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort. CONCLUSIONS: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility