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Introduction Type 1 diabetes mellitus (T1DM) is a disorder that arises following the selective autoimmune destruction of the insulin-producing beta cells. Beta-cell protective or beta-cell regenerative approaches have gained wider attention, and pharmacological approaches to protect the patient’s own insulin-producing beta-cell mass have been proposed. Verapamil is an L-type calcium channel blocker that has been reported to effectively lowers beta-cell thioredoxin-interacting protein expression in rodent beta cells and islets, as well as in human islets, and thus promotes functional beta-cell mass.Methods and analysis The trial is a multicentre, randomised, double-blind, placebo-controlled trial in participants with T1DM, investigating the effect of verapamil on preservation of beta-cell function (Ver-A-T1D). A total of 120 participants will be randomised in a 2:1 ratio between 360 mg verapamil and placebo, administered orally once daily. T1DM patients aged ≥18 and

Type 1 diabetes (T1D) is a chronic condition caused by the immune destruction of the pancreatic beta cells. T1D has recognised asymptomatic pre-clinical stages, providing an opportunity for early diagnosis, education and treatment which may delay the onset of symptoms. The oral glucose tolerance test (OGTT) is the gold standard method to stage and monitor early-stage T1D, which can be poorly tolerated and may contribute to marked loss to follow-up. Our study aims to test the accuracy, feasibility, and acceptability of a capillary alternative (‘GTT@home’ test kit) to the gold standard OGTT. We will invite 45 children and young people (CYP) across the spectrum of glycaemia with or without diabetes, from established research platforms or clinical care, to have a standard 2-hour OGTT, with capillary samples collected alongside their venous samples, at 0 and 120 minutes. A subgroup (n=20) will also have 60-minute capillary and venous samples collected. We will also invite 45 CYP from established research platforms, who are known to have two or more islet autoantibodies and are not on insulin, to undergo a capillary OGTT at home, using the GTT@home kit. We will assess the agreement of capillary and venous glucose and measure diagnostic accuracy by calculating the sensitivity and specificity of capillary measures at established diagnostic thresholds (fasting [5.6 mmol/L, 7.0 mmol/L], 60 minutes post glucose load [11.1 mmol/L] and 120 minutes post glucose load [7.8 mmol/L and 11.1 mmol/L]), using venous glucose as the gold standard. These studies will inform our understanding of whether the GTT@home device can be used in CYP in routine clinical care.

Abstract Background Type 1 diabetes (T1D) is a CD4+ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8+ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells. Methods This first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D

Primary hypothyroidism affects about 3% of the general population in Europe. Early treatments in the late 19th Century involved subcutaneous as well as oral administration of thyroid extract. Until the early 1970s, the majority of people across the world with hypothyroidism were treated with natural desiccated thyroid (NDT) (derived from pig thyroid glands) in various formulations, with the majority of people since then being treated with levothyroxine (L-thyroxine). There is emerging evidence that may account for the efficacy of liothyronine (NDT contains a mixture of levothyroxine and liothyronine) in people who are symptomatically unresponsive to levothyroxine. While this is a highly selected group of people, the severity and chronicity of their symptoms and the fact that many patients have found their symptoms to be alleviated, can be viewed as valid evidence for the potential benefit of NDT when given after careful consideration of other differential diagnoses and other treatment options.

Summary: Background: Type 1 diabetes is a complex heterogenous autoimmune disease without therapeutic interventions available to prevent or reverse the disease. This study aimed to identify transcriptional changes associated with the disease progression in patients with recent-onset type 1 diabetes. Methods: Whole-blood samples were collected as part of the INNODIA study at baseline and 12 months after diagnosis of type 1 diabetes. We used linear mixed-effects modelling on RNA-seq data to identify genes associated with age, sex, or disease progression. Cell-type proportions were estimated from the RNA-seq data using computational deconvolution. Associations to clinical variables were estimated using Pearson's or point-biserial correlation for continuous and dichotomous variables, respectively, using only complete pairs of observations. Findings: We found that genes and pathways related to innate immunity were downregulated during the first year after diagnosis. Significant associations of the gene expression changes were found with ZnT8A autoantibody positivity. Rate of change in the expression of 16 genes between baseline and 12 months was found to predict the decline in C-peptide at 24 months. Interestingly and consistent with earlier reports, increased B cell levels and decreased neutrophil levels were associated with the rapid progression. Interpretation: There is considerable individual variation in the rate of progression from appearance of type 1 diabetes-specific autoantibodies to clinical disease. Patient stratification and prediction of disease progression can help in developing more personalised therapeutic strategies for different disease endotypes. Funding: A full list of funding bodies can be found under Acknowledgments.

Thyroid stimulating antibodies (TSAB) cause Graves’ disease and contribute to Graves’ Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants (TSHRv)) and/or nonclassical ligands such as thyrostimulin (α2β5) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO (p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv:TSHR ratio (Spearman correlation: TSH r = −0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis (p < 0.005) with no difference observed between non-GO and GO. β5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR.

Graves’ orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways.

Introduction Most individuals newly diagnosed with type 1 diabetes (T1D) have 10%–20% of beta-cell function remaining at the time of diagnosis. Preservation of residual beta-cell function at diagnosis may improve glycaemic control and reduce longer-term complications.Immunotherapy has the potential to preserve endogenous beta-cell function and thereby improve metabolic control even in poorly compliant individuals. We propose to test ustekinumab (STELARA), a targeted and well-tolerated therapy that may halt T-cell and cytokine-mediated destruction of beta-cells in the pancreas at the time of diagnosis.Methods and analysis This is a double-blind phase II study to assess the safety and efficacy of ustekinumab in 72 children and adolescents aged 12–18 with new-onset T1D.Participants should have evidence of residual functioning beta-cells (serum C-peptide level >0.2nmol/L in the mixed-meal tolerance test (MMTT) and be positive for at least one islet autoantibody (GAD, IA-2, ZnT8) to be eligible.Participants will be given ustekinumab/placebo subcutaneously at weeks 0, 4 and 12, 20, 28, 36 and 44 in a dose depending on the body weight and will be followed for 12 months after dose 1.MMTTs will be used to measure the efficacy of ustekinumab for preserving C-peptide area under the curve at week 52 compared with placebo. Secondary objectives include further investigations into the efficacy and safety of ustekinumab, patient and parent questionnaires, alternative methods for measuring insulin production and exploratory mechanistic work.Ethics and dissemination This trial received research ethics approval from the Wales Research Ethics Committee 3 in September 2018 and began recruiting in December 2018.The results will be disseminated using highly accessed, peer-reviewed medical journals and presented at conferences.Trial registration number ISRCTN14274380.

Abstract Background Whilst trials of combination levothyroxine/liothyronine therapy versus levothyroxine monotherapy for thyroid hormone replacement have not shown any superiority, there remains a small subset of patients who do not feel well on monotherapy. Whilst current guidelines do not suggest routine use of combination therapy they do acknowledge a trial in such patients may be appropriate. It appears that use of combination therapy and dessicated thyroid extract is not uncommon but often being used by non-specialists and not adequately monitored. This review aims to provide practical advice on selecting patients, determining dose and monitoring of such a trial. Main body It is important to select the correct patient for a trial so as to not delay diagnosis or potentially worsen an undiagnosed condition. An appropriate starting dose may be calculated but accuracy is limited by available formulations and cost. Monitoring of thyroid function, benefits and adverse effects are vital in the trial setting given lack of evidence of safe long term use. Also important is that patients understand set up of the trial, potential risks involved and give consent. Conclusion Whilst evidence is lacking on whether a small group of patients may benefit from combination therapy a trial may be indicated in those who remain symptomatic despite adequate levothyroxine monotherapy. This should be undertaken by clinicians experienced in the field with appropriate monitoring for adverse outcomes in both short and long term.

Hypothyroidism is common throughout the world and readily diagnosed with thyroid function tests. Management should be straightforward but appears not to be the case. Thyroid hormone replacement with levothyroxine monotherapy is the standard treatment which is effective in the majority of cases. However, 10–15% of patients established on levothyroxine do not feel their health is entirely restored and some patients prefer the addition of liothyronine. Proponents of liothyronine argue that the ratio of T3 and T4 hormones is substantially altered on T4 monotherapy and therefore both hormones may be needed for optimal health. This remains controversial as clinical trials have not demonstrated superiority of combination therapy (levothyroxine and liothyronine) over levothyroxine monotherapy. There is now a pressing need for further studies and in particular randomized controlled trials in this area. To help design and facilitate dedicated trials and better understand thyroid hormone replacement, this review summarizes the evidence where there is established knowledge and agreement (knowns) and areas where research is lacking (unknowns). Agreements include the extent of dissatisfaction with levothyroxine monotherapy, biases in testing for hypothyroidism and prescribing levothyroxine, as well as variable thresholds for prescribing levothyroxine and challenges in liothyronine dosing. The review will also highlight and summarize the unknowns including the long-term safety profile of liothyronine, and potential biomarkers to identify individuals who might benefit most from combination therapy.

Background: Suboptimal thyroid hormone replacement is common in patients with hypothyroidism and the behavioural factors underlying this are poorly understood. Aim: To explore the attitudes and perceptions of patients to thyroid hormone replacement therapy. Design & setting: An in-depth qualitative interview study with patients with hypothyroidism residing in Northumberland, and Tyne and Wear, UK. Method: Twenty-seven patients participated, of which 15 patients had thyroid stimulating hormone (TSH) levels within the reference range (0.4–4.0 mU/L) and 12 patients had TSH levels outside the reference range. A grounded theory approach was used to explore and develop emerging themes, which were mapped to the health belief model (HBM). Results: Patients generally had a low understanding of their condition or of the consequences of suboptimal thyroid hormone replacement. Patients that had experienced hypothyroid symptoms at initial diagnosis had a better perception of disease susceptibility, and this was reflected in excellent adherence to levothyroxine in this group of patients. The main benefits of optimal thyroid replacement were improved wellbeing and performance. However, patients who remained unwell despite a normal serum TSH level felt that their normal result presented a barrier to further evaluation of their symptoms by their GP. Conclusion: Educating patients with hypothyroidism regarding the consequences of inadequate thyroid hormone replacement may reduce barriers and improve treatment outcomes. An over-reliance on TSH as a sole marker of wellbeing reduced opportunities for clinicians to address patient symptoms. Evaluating symptoms in combination with biochemical indices, may lead to better patient outcomes than relying on laboratory tests alone.

There is growing evidence that primary care prescribed antibiotics lead to antibiotic resistance in bacteria causing minor infections or being carried by asymptomatic adults, but little research to date has investigated links between primary care prescribed antibiotics and resistance among more serious infections requiring hospital care. Knowledge of these effects is likely to have a major influence on public expectations for, and primary care use of, antibiotics. This study aimed to assess the feasibility of recruiting symptomatic adult patients admitted to hospital with urinary infections and to link primary and secondary data information to investigate the relationship between primary care prescribed antibiotics and antimicrobial resistance in these patients. A microbiology database search of in patients who had submitted a urine sample identified 740 patients who were potentially eligible to take part in the study. Of these, 262 patients did not meet the eligibility criteria, mainly due to use of a urinary catheter (40%). Two-hundred and forty three patients could not be recruited as the nurse was unable to visit the patients prior to discharge, as they were too unwell. Eighty patients provided complete information. Results indicate that there is evidence that prior antibiotic use is associated with resistant infections in hospital patients. A fully powered study, conducted using routinely collected data is proposed to fully clarify the precision of the association.

BACKGROUND:Patients' illness beliefs have been associated with glycaemic control in diabetes and survival in other conditions. OBJECTIVE:We examined whether illness beliefs independently predicted survival in patients with diabetes and foot ulceration. METHODS:Patients (n=169) were recruited between 2002 and 2007. Data on illness beliefs were collected at baseline. Data on survival were extracted on 1st November 2011. Number of days survived reflected the number of days from date of recruitment to 1st November 2011. RESULTS:Cox regressions examined the predictors of time to death and identified ischemia and identity beliefs (beliefs regarding symptoms associated with foot ulceration) as significant predictors of time to death. CONCLUSIONS:Our data indicate that illness beliefs have a significant independent effect on survival in patients with diabetes and foot ulceration. These findings suggest that illness beliefs could improve our understanding of mortality risk in this patient group and could also be the basis for future therapeutic interventions to improve survival.

We aimed to understand early alterations in kinin-mediated migration of circulating angio-supportive cells and dysfunction of kinin-sensitive cells in type-1 diabetic (T1D) patients before the onset of cardiovascular disease.Total mononuclear cells (MNC) were isolated from peripheral blood of 28 T1D patients free from cardiovascular complications except mild background retinopathy (age: 34.8+/-1.6 years, HbA(1C): 7.9+/-0.2%) and 28 age- and sex-matched non-diabetic controls (H). We tested expression of kinin receptors by flow cytometry and migratory capacity of circulating monocytes and progenitor cells towards bradykinin (BK) in transwell migration assays. MNC migrating towards BK (BK(mig)) were assessed for capacity to support endothelial cell function in a matrigel assay, as well as generation of nitric oxide (NO) and superoxide (O(2) (-)*) by using the fluorescent probes diaminofluorescein and dihydroethidium.CD14(hi)CD16(neg), CD14(hi)CD16(pos) and CD14(lo)CD16(pos) monocytes and circulating CD34(pos) progenitor cells did not differ between T1D and H subjects in their kinin receptor expression and migration towards BK. T1D BK(mig) failed to generate NO upon BK stimulation and supported endothelial cell network formation less efficiently than H BK(mig). In contrast, O(2) (-)* production was similar between groups. High glucose disturbed BK-induced NO generation by MNC-derived cultured angiogenic cells.Our data point out alterations in kinin-mediated functions of circulating MNC from T1D patients, occurring before manifest macrovascular damage or progressed microvascular disease. Functional defects of MNC recruited to the vessel wall might compromise endothelial maintenance, initially without actively promoting endothelial damage, but rather by lacking supportive contribution to endothelial regeneration and healing.

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.