Presentation and characteristics of children with screen-detected type 1 diabetes: learnings from the ELSA general population pediatric screening study.

INTRODUCTION: We describe the identification and management of general population screen-detected type 1 diabetes (T1D) and share learnings for best practice. RESEARCH DESIGN AND METHODS: Children diagnosed with T1D through a general population screening initiative, the EarLy Surveillance for Autoimmune diabetes (ELSA) study, were reviewed and described.Parents provided written, informed consent for inclusion in the case series. RESULTS: 14 children with insulin requiring (stage 3) T1D are described. These cases offer unique insights into the features of screen-detected T1D. T1D is identified sooner through screening programs, characterized by absent/short symptom duration, median presenting glycated hemoglobin 6.6% (49 mmol/mol) and insulin requirements<0.5 units/kg/day. ELSA identified four children at stage 3 and another 4 progressed within 4 months of ELSA completion, including two single seropositive children. Six children developed stage 3 T1D prior to ELSA completion, including two children (14%, n=2/14) with diabetic ketoacidosis prior to confirmed antibody status. CONCLUSIONS: There are three main learnings from this case series. First, T1D identified through screening is at an earlier stage of its natural history and requires personalized insulin regimens with lower total daily insulin doses. Second, single autoantibody seropositivity can rapidly progress to stage 3. Finally, insulin requirement can manifest at any stage of the T1D screening pathway, and therefore early education around symptom recognition is essential for families participating in screening programs.

Long-term TNF-alpha therapy for preserving beta cell function in new onset type 1 diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by destruction of pancreatic islet beta-cells. There is significant residual beta-cell function, measured through circulating C-peptide, present at the time of T1D diagnosis but this subsequently decreases with time. Higher residual beta-cell function at diagnosis associates with better glycaemic control and less glucose variability, and later in the disease course with less hypoglycaemia, lower glucose variability and fewer microvascular complications. There is therefore value in preserving residual beta cell function in new onset T1D Immunotherapeutic agents can protect residual beta-cell function in type 1 diabetes. However, clinical trials of such agents, whilst demonstrating C-peptide preservation in short term studies, have yet to be taken forward into routine clinical care due to concerns around safety and long-term efficacy. Here we report the case of a gentleman with newly diagnosed T1D whose glycaemic control and insulin requirement improved whilst on a five year infusion programme of infliximab, a monoclonal antibody against TNF-alpha, for colitis. CASE PRESENTATION: A 52-year-old White Caucasian man was diagnosed with T1D in August 2018. Glucose was 25.6 mmol/L, HbA1c was 98mmol/mol and GAD antibodies were strongly positive. HbA1c marginally improved to 91mmol/mol following initiation of insulin detemir 5 units at night and 1:10 g of insulin aspart (November 2018). In June 2019, he developed rectal bleeding and abdominal pain. Following colonoscopy, he was diagnosed with "indeterminate colitis" and commenced on 6-weekly infusions of 400-450 mg infliximab. Thus far, he has received 32 doses and achieved colitis remission. Following infliximab initiation there was increased frequency of mild-moderate hypoglycaemia and he was gradually weaned off and discontinued detemir in June 2020. Since then, HbA1c improved from 57mmol/mol in August 2019 to 52mmol/mol in April 2022, remaining stable at 51mmol/mol. His most recent HbA1c is 54mmol/mol in February 2024. His c-peptide was 550pmol/L in October 2022 and 442pmol/L in February 2024, suggesting well-preserved beta-cell function almost 6 years post-diagnosis. CONCLUSIONS: Our patient's improvement in glycaemic control can be explained by immunomodulation and C peptide preservation from infliximab. With the growing focus on type 1 diabetes disease modulation and working towards an 'insulin free T1D', our findings strengthen the evidence base for the repurposing of and long-term treatment with anti-TNF-α agents to preserve beta-cell function in new onset T1D.

Preferences for Peer Support Amongst Families Engaged in Paediatric Screening Programmes: The Perspectives of Parents Involved in Screening for Type 1 Diabetes in Children Aged 3-13.

INTRODUCTION: This work describes a secondary analysis of a qualitative data set originally used to understand parent participants' preferences for the design and implementation of a screening programme for paediatric Type 1 diabetes (T1D). From this, their spontaneous preferences for peer support emerged, described here in the context of existing peer support programmes for the newly diagnosed alongside suggestions for their incorporation into screening programmes for T1D and a range of other conditions. METHODS: Data were collected from semi-structured interviews conducted with parents of children aged 3-13 years to explore their expectations, perceptions and preferences of a T1D paediatric screening programme. A secondary analysis of interviews from participants who spontaneously raised preferences for peer support was used to populate a novel framework informed by NHS England's key principles for the same, namely, Shared experiences and reciprocated support, Accessibility and inclusivity and Person-centred and integrated peer support. RESULTS: Parents in 29 of 33 interviews spontaneously described the potential value of peer support if receiving a result indicating a positive (presymptomatic T1D result) from a screening programme. Specifically, the value of 'Shared experiences and reciprocated support' in terms of emotional support and reassurance, and access to more directly interpretable and relevant information related to the condition; 'Accessibility and inclusivity' relating to access to a community of similar individuals, whether in person or online; 'Person-centred and integrated peer-support' and the need for support reflecting the changing need of the child and the integration of peer support with clinical care. CONCLUSIONS: The needs of peer support described by parents involved in T1D paediatric screening appear to be shared with those of families with children diagnosed with a range of life-altering conditions. Although the needs of peer support for paediatric screening may differ across conditions, our findings are a valuable starting point for its design both in T1D and other examples of similar population screening programmes. PATIENT OR PUBLIC CONTRIBUTION: Patients and the public have been involved throughout the design of the ELSA study and have worked with us to inform the study process. They contributed to the design and content of patient-facing materials, the content of our topic guides and the analysis and interpretation of our findings.

Rejuvenation of leukocyte trafficking in aged mice through PEPITEM intervention.

Inflammageing leads to uncontrolled leukocyte trafficking in response to inflammatory insults. Here, we used a zymosan-induced peritonitis mouse model on inflammation to investigate the role of the PEPITEM pathway on leukocyte migration in ageing. We then analysed whether PEPITEM could modulate leukocyte migration in older adults. We observed a loss of functionality in the PEPITEM pathway, which normally controls leukocyte trafficking in response to inflammation, in older adults and aged mice and show that this can be rescued by supplementation with PEPITEM. Thus, leading to the exciting possibility that PEPITEM supplementation may represent a potential pre-habilitation geroprotective agent to rejuvenate immune functions.

General population screening for paediatric type 1 diabetes-A qualitative study of UK professional stakeholders.

AIMS: Identifying children at risk of type 1 diabetes allows education for symptom recognition and monitoring to reduce the risk of diabetic ketoacidosis at presentation. We aimed to explore stakeholder views towards paediatric general population screening for type 1 diabetes in the United Kingdom (UK). METHODS: Qualitative interviews were undertaken with 25 stakeholders, including diabetes specialists, policymakers and community stakeholders who could be involved in a future type 1 diabetes screening programme in the UK. A thematic framework analysis was performed using the National Screening Committee's evaluative criteria as the overarching framework. RESULTS: Diabetic ketoacidosis prevention was felt to be a priority and proposed benefits of screening included education, monitoring and helping the family to better prepare for a future with type 1 diabetes. However, diabetes specialists were cautious about general population screening because of lack of evidence for public acceptability. Concerns were raised about the harms of living with risk, provoking health anxiety and threatening the child's right to an 'open future'. Support systems that met the clinical and psychological needs of the family living with risk were considered essential. Stakeholders were supportive of research into general population screening and acknowledged this would be a priority if an immunoprevention agent were licensed in the UK. CONCLUSIONS: Although stakeholders suggested the harms of UK paediatric general population screening currently outweigh the benefits, this view would potentially be altered if prevention therapies were licensed. In this case, an evidence-based screening strategy would need to be formulated and public acceptability explored.

Educational preferences in individuals with cardiometabolic disease differs with age, ethnicity and educational status.

OBJECTIVES: To evaluate how sociodemographic factors influence educational modality preferences in people with cardiometabolic disease. METHODS: This was a cross-sectional study performed in people with diabetes and cardiovascular disease, who completed a questionnaire to denote their previous experience and ranked preferences for different educational modalities. RESULTS: The questionnaire was completed by 3751 people, of whom 59% were men, median (interquartile range) age was 68 (59-76) years, and 78% were White European. In total, 73% had diabetes, 35% had heart disease, and 10% had history of stroke; the majority (83.4%) had one of these conditions. Overall preference was for one-to-one education (77% ranked first choice), and telephone education ranked the lowest. People tended to prefer modalities they had previously experienced. CONCLUSIONS: We highlight the importance of considering factors that could influence selection of educational modalities including age, ethnicity, gender and educational level. We anticipate this approach will aid in the design, delivery and tailoring of educational programmes that are accessible to the diverse cohort of people living with chronic diseases, including diabetes and cardiovascular disease. PRACTICE IMPLICATIONS: Given the influence of multiple demographic factors and previous experiences on expressed preferences, providers should support individuals to make informed decisions about educational interventions to maximise engagement.

Chronotype and well-being in adults with established type 2 diabetes: A cross-sectional study.

AIMS: 'Chronotype' describes an individual's sleep-wake schedule, and can be classified into morning, intermediate or evening types. Evening chronotype has been widely associated with increased cardiometabolic risk and mortality in people with type 2 diabetes. We explored associations between chronotype and markers of well-being in people with type 2 diabetes. METHODS: Participants of the 'Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control' (CODEC) observational study completed questionnaires to determine chronotype (Morningness-Eveningness Questionnaire, MEQ) and concurrent measures of well-being (Diabetes-related Distress scale, Patient Health Questionnaire-9 to measure depression, and Self-Compassion Scale), as a secondary endpoint of the study. Adjusted generalised linear models were used to compare well-being between chronotype subgroups in this cohort. RESULTS: Of the 808 individuals included in the CODEC study, from convenience sampling, 476 individuals completed the psychosocial questionnaire substudy. Of these, 67% (n = 321) were male, and 86% (n = 408) were white European. From the MEQ, 24% (n = 114) were morning chronotype, 24% (n = 113) were evening and 52% (n = 249) were intermediate chronotype. Diabetes-related distress was significantly higher in evening chronotypes (exponentiated adjusted coefficient = 1.18 (CI: 1.05-1.32)), compared to morning (padjusted  = 0.005) and intermediate chronotypes (padjusted  = 0.039). Similarly, depression was significantly higher in evening chronotypes (exponentiated adjusted coefficient = 1.84 (CI: 1.28-2.65)) compared to morning (padjusted  = 0.001) and intermediate chronotypes (padjusted  = 0.016). DISCUSSION: Evening chronotype in people with type 2 diabetes may be associated with higher levels of diabetes-related distress and depression. These findings warrant further investigation to establish causality and evidence-based interventions that negate the effects of evening chronotype in people with type 2 diabetes.

Low Branched Chain Amino Acids and Tyrosine in Thai Patients with Type 2 Diabetes Mellitus Treated with Metformin and Metformin-Sulfonylurea Combination Therapies.

Type 2 diabetes mellitus (T2DM) is a growing public health challenge for Thailand (current prevalence ~10.0%). Amino acids offer novel biomarkers to predict risk of T2DM and indicate sub-optimal disease management, which could facilitate earlier treatment. We studied amino acid profiles in a Thai cohort comprising of individuals with T2DM (n = 65 single-drug-treated; n = 38 multi-drug-treated) compared to healthy controls (n = 104) using liquid chromatography-mass spectrometry. Age and BMI were significantly lower in the healthy controls compared to the single or multi-treated T2DM groups. The BCAA (leucine and valine) were significantly lower in the single and multi-treated T2DM groups compared to healthy controls (p < 0.001 and p < 0.001) and isoleucine was significantly lower in the single-treated compared to the healthy controls (p = 0.014). These findings beg the question whether BCAAs supplementation be beneficial in T2DM patients treated with single or multi-drug therapy? Tyrosine was significantly lower in the single and multi-treated T2DM groups compared to healthy controls (p < 0.001 and p = 0.002), whereas phenylalanine was significantly higher in the multi-treated T2DM group compared to the single treated T2DM group (p = 0.045). We provide novel insights into the effects of diabetes treatments on these amino acids in insulin resistant states such as T2DM in a unique but understudied Thai population.

Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality.

The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.

Virtual Consultations and the Role of Technology During the COVID-19 Pandemic for People With Type 2 Diabetes: The UK Perspective.

The coronavirus disease (COVID-19) pandemic has presented unique challenges for people with diabetes, in addition to their high-risk stratification for infection. Supporting people with diabetes to self-care has been critical to reduce their risk of severe infection. This global pandemic has presented an opportunity to digitalize diabetes care and rapidly implement virtual diabetes clinics, with the aim of optimizing diabetes management and well-being, while keeping patients safe. We performed a rapid review of the literature to evaluate the feasibility and effectiveness of virtual clinics in diabetes care before and during the COVID-19 pandemic and have combined these findings with our own reflections in practice. We identified examples demonstrating safety and feasibility of virtual diabetes clinics, which aligns with our own clinical experience during the pandemic. The advantages of virtual clinics include reduced treatment burden, improved therapeutic alliances, societal and psychological benefits, and in our experience, innovative solutions to overcome the challenges presented by the transition from in-person to virtual care. We have provided three infographics to illustrate lessons learned and key recommendations, including steps to establish a virtual diabetes clinic, a checklist guide for health care professionals conducting virtual clinics, and a patient guide for making the most out of the virtual clinic. It is important to continue adapting to this pandemic and to make technology a sustainable option for the future of diabetes care.

Long-term testosterone undecanoate replacement therapy: Impact of ethnicity.

BACKGROUND: Testosterone replacement therapy (TRT) is indicated for symptomatic male hypogonadism. However, the safety and efficacy profiles across different ethnicities for long-term TRT remain unclear. OBJECTIVE: To measure the impact of ethnicity on various biochemical parameters following testosterone undecanoate (TU) replacement. METHOD: A retrospective analysis of 50 male patients treated with TU from 2006 to 2017 in a large secondary care centre was performed. Changes in total testosterone, PSA, haematocrit, haemoglobin, total cholesterol and low-density lipoprotein (LDL) over eight years of treatment were analysed. Wilcoxon rank sum test was used to assess differences in these parameters between Caucasians and South Asians. RESULTS: Thirty-one Caucasians (age: median (IQR) 55.0 years (49.0-68.0); total duration of follow-up 6.1 years (2.9-9.3)) and 19 South Asians (age: median (IQR) 52.0 years (38.0-69.0); duration of follow-up 6.5 years (1.3-8.4)) were treated with TU during the study period. There was no significant difference in total testosterone levels between the two ethnicities. We noted a higher free and bioavailable testosterone in South Asians than Caucasians, albeit within their reference range. PSA was higher in Caucasians than South Asians at two and eight years of TU therapy. After one year of TRT, haematocrit was higher in South Asians than Caucasians at one year, whereas LDL and total cholesterol were significantly higher in Caucasians than South Asians. CONCLUSIONS: Caucasians have a tendency towards increased PSA, total cholesterol and LDL compared with South Asians with TU replacement therapy. There is a higher increment of haematocrit in South Asians following one year of TU replacement therapy. All biochemical changes following TRT were within the respective reference ranges suggesting no apparent risk of prostate cancer and venous thromboembolism.

Retinopathy and microalbuminuria are common microvascular complications in cystic fibrosis-related diabetes.

AIMS: To study the prevalence of microvascular complications and renal changes associated with cystic fibrosis-related diabetes (CFRD). METHODS: This retrospective cohort study was conducted at the West Midlands Adult Cystic Fibrosis centre, United Kingdom. Data regarding age, sex, microalbuminuria, retinopathy neuropathy, and biochemical results were collected for all people with CFRD who had an annual review from 1 January 2018 to 31 December 2018 at the centre. Descriptive statistics were analysed using STATAv15.1. RESULTS: A total of 189 patients were included, of which 56.6% were male and median age (interquartile range) was 33 (27-39) years; 79.4% (150/189) had their annual review in 2018. Those with a biochemically impaired renal function numbered 7.2% (13/180) and 22.7% (32/141) had microalbuminuria; 17.2% (10/58) had diabetes related retinopathy. No one in our cohort had diabetic ulcers; however, 10.3% (13/126) had absent foot pulses. CONCLUSION: We found a higher prevalence of microalbuminuria compared with retinopathy in a large cohort of cystic fibrosis adults. This study demonstrates the need for regular specialist follow-up to facilitate early identification of such complications and a long-term prospective cohort to understand underlying mechanisms.

Prognostic significance of circumferential resection margin involvement in patients receiving potentially curative treatment for oesophageal cancer.

INTRODUCTION: The utility of Circumferential Resection Margin (CRM) status in predicting prognosis in oesophageal cancer is controversial, with different definitions used by the College of American Pathologists and the Royal College of Pathologists. We aimed to determine prognostic significance of CRM involvement and evaluate which system is the best predictor of prognosis. METHODS: A cohort of 390 patients who had potentially curative oesophagectomy (- + neoadjuvant chemotherapy) were analysed. Associations between CRM involvement and patient outcome were assessed for the whole cohort, and for pre-specified subgroups of T3 tumours and those who received neo-adjuvant chemotherapy. RESULTS: CRM-involvement was associated with higher T and N stage, tumour differentiation, increased tumour length and both lymphovascular and perineural invasion. Overall Survival (OS) and Recurrence Free Survival (RFS) significantly worsened with CRM-involvement (p = 0.001, p < 0.001). R1a (<1 mm but no macroscopic involvement) resulted in significantly improved OS (p = 0.037) and RFS (P = 0.026) compared to R1b (macroscopic involvement), but did not differ significantly from R0 (≥1 mm). The association between CRM-involvement and both OS and RFS remained significant regardless of whether neoadjuvant chemotherapy was given. However, CRM-involvement was not a significant prognostic marker in T3 patients (p = 0.148). Multivariable analysis found N stage, lymphovascular invasion, patient age and neoadjuvant chemotherapy to be significantly predictive of patient outcome. CRM-involvement was not a significant independent prognostic marker. CONCLUSIONS: CRM-involvement was not found to be independently predictive of prognosis, after accounting for other prognostic markers. As such, CRM should not be considered a major prognostic factor in patients with oesophageal cancer.

Prognostic significance of tumor length in patients receiving esophagectomy for esophageal cancer.

AIMS: We investigated the prognostic value of tumor length measurements acquired both from pre-operative imaging and post-operative pathology in esophageal cancer. METHODS: Tumor lengths were examined retrospectively for 389 esophagectomy patients with respect to Endoscopy, EUS (Endoscopic Ultrasound), CT and PET-CT, and pathology. Correlations between the measurements on the different approaches were assessed, and associations between tumor length and survival were analyzed. RESULTS: Only the tumor lengths assessed on pathology were found to be significantly associated with overall (P = 0.001) and recurrence free (P < 0.001) survival on univariable analysis. The median overall survival was 47.1 months in those patients with tumor lengths <3.0 cm, falling to 19.6 and 18.0 months in those with 3.0-4.4 and 4.5+ cm tumors, respectively, demonstrating a reduction in patient survival at a tumor length of around 3 cm. Tumor length on pathology was significantly correlated with tumor differentiation and both T- and N-categories. After accounting for these factors, tumor length on pathology was a significant independent predictor of recurrence-free (P = 0.016), but not overall (P = 0.128) survival. CONCLUSIONS: Tumor lengths on pathology were found to be the most predictive of patient outcome. However, after accounting for other tumor-related factors, tumor length only resulted in a marginal improvement in predictive accuracy.

Serum potassium and glucose regulation in the ADDITION-Leicester screening study.

INTRODUCTION: Previous observational studies have shown conflicting results between plasma K+ concentrations and risk of type 2 diabetes. To help clarify the evidence we aimed to determine whether an association existed between serum K+ and glucose regulation within a UK multiethnic population. METHODS: Participants were recruited as part of the ADDITION Leicester study, a population based screening study. Individuals from primary care between the age of 40 and 75 years if White European or 25 and 75 years if South Asian or Afro Caribbean were recruited. Tests for associations between baseline characteristics and K+ quartiles were conducted using linear regression models. RESULTS: Data showed individuals in the lowest K+ quartile had significantly greater 2-hour glucose levels (0.53 mmol/L, 95% CI: 0.36 to 0.70, P ≤ 0.001) than those in the highest K+ quartile. This estimation did not change with adjustment for potential confounders. Conversely, participants in the lowest K+ quartile had a 0.14% lower HbA1c (95% CI -0.19 to -0.10: P ≤ 0.001) compared to those in the highest K+ quartile. CONCLUSION: This cross-sectional analysis demonstrated that lower K+ was associated with greater 2 hr glucose. The data supports the possibility that K+ may influence glucose regulation and further research is warranted.