Safety, Growth and Development After Dapagliflozin or Saxagliptin in Children With Type 2 Diabetes (T2NOW Follow-Up).

CONTEXT: The T2NOW trial of dapagliflozin or saxagliptin versus placebo in pediatric patients with type 2 diabetes (T2D) demonstrated promising efficacy data for dapagliflozin and did not raise any safety concerns over 52 weeks. OBJECTIVE: Assess long-term effects of prior dapagliflozin/saxagliptin administration on safety, growth and development. DESIGN: Multicenter, randomized, double-blind phase 3 trial (T2NOW). PATIENTS: 210 children with T2D aged 10-17 years, followed for up to one year after treatment. INTERVENTIONS: Previous treatment with once-daily dapagliflozin (5, 10 mg), saxagliptin (2.5, 5 mg) or placebo as add-on to diet, exercise, metformin and/or insulin for 52 weeks, plus a 52-week non-treatment follow-up period. MAIN OUTCOME MEASURES: Change in height, weight, body mass index (BMI), Tanner staging, growth and maturation markers, bone biomarkers and adverse events (AEs) from baseline to Week 104. RESULTS: As expected in a pediatric population, mean height and weight slightly increased from baseline to Week 104. BMI remained generally stable; Changes were similar across treatment groups. Sexual maturation progressed normally to Week 104, with similar shifts between Tanner stages and changes in growth and maturation markers and bone biomarkers across groups. The proportion of patients reporting ≥1 AE during the non-treatment follow-up period was similar across groups previously treated with dapagliflozin (18.5%) or saxagliptin (15.9%) compared to placebo (21.1%). No deaths occurred. CONCLUSION: Prior treatment with dapagliflozin or saxagliptin for 52 weeks did not raise any safety concerns relating to height, weight, BMI, Tanner staging, growth and maturation markers, bone biomarkers or AEs for up to 52 weeks following treatment discontinuation, in pediatric patients with T2D.

Health screening clinic to reduce absenteeism and presenteeism among NHS Staff: eTHOS a pilot RCT.

Background: Staff sickness absenteeism and presenteeism (attending work while unwell) incur high costs to the NHS, are associated with adverse patient outcomes and have been exacerbated by the COVID-19 pandemic. The main causes are mental and musculoskeletal ill health with cardiovascular risk factors common. Objectives: To undertake a feasibility study to inform the design of a definitive randomised controlled trial of the effectiveness and cost effectiveness of a health screening clinic in reducing absenteeism and presenteeism amongst the National Health Service staff. Design: Individually randomised controlled pilot trial of the staff health screening clinic compared with usual care, including qualitative process evaluation. Setting: Four United Kingdom National Health Service hospitals from two urban and one rural Trust. Participants: Hospital employees who had not previously attended a pilot health screening clinic at Queen Elizabeth Hospital Birmingham. Interventions: Nurse-led staff health screening clinic with assessment for musculoskeletal health (STarT musculoskeletal; STarT Back), mental health (patient health questionnaire-9; generalised anxiety disorder questionnaire-7) and cardiovascular health (NHS health check if aged ≥ 40, lifestyle check if < 40 years). Screen positives were given advice and/or referral to services according to UK guidelines. Main outcome measures: The three coprimary outcomes were recruitment, referrals and attendance at referred services. These formed stop/go criteria when considered together. If any of these values fell into the 'amber' zone, then the trial would require modifications to proceed to full trial. If all were 'red', then the trial would be considered unfeasible. Secondary outcomes collected to inform the design of the definitive randomised controlled trial included: generalisability, screening results, individual referrals required/attended, health behaviours, acceptability/feasibility of processes, indication of contamination and costs. Outcomes related to the definitive trial included self-reported and employee records of absenteeism with reasons. Process evaluation included interviews with participants, intervention delivery staff and service providers. Descriptive statistics were presented and framework analysis conducted for qualitative data. Due to the COVID-19 pandemic, outcomes were captured up to 6 months only. Results: Three hundred and fourteen participants were consented (236 randomised), the majority within 4 months. The recruitment rate of 314/3788 (8.3%) invited was lower than anticipated (meeting red for this criteria), but screening identified that 57/118 (48.3%) randomised were eligible for referral to either general practitioner (81%), mental health (18%) and/or physiotherapy services (30%) (green). Early trial closure precluded determination of attendance at referrals, but 31.6% of those eligible reported intending to attend (amber). Fifty-one of the 80 (63.75%) planned qualitative interviews were conducted. Quantitative and qualitative data from the process evaluation indicated that the electronic database-driven screening intervention and data collection were efficient, promoting good fidelity, although needing more personalisation at times. Recruitment and delivery of the full trial would benefit from a longer development period to better understand local context, develop effective strategies for engaging with underserved groups, provide longer training and better integration with referral services. Delivery of the pilot was limited by the impact of COVID-19 with staff redeployment, COVID-research prioritisation and reduced availability of community and in-house referral services. While recruitment was rapid, it did not fully represent ethnic minority groups and truncated follow-up due to funding limitations prevented full assessment of attendance at recommended services and secondary outcomes. Conclusions: There is both a clinical need (evidenced by 48% screened eligible for a referral) and perceived benefit (data from the qualitative interviews) for this National Health Service staff health screening clinic. The three stop/go criteria were red, green and amber; therefore, the Trial Oversight Committee recommended that a full-scale trial should proceed, but with modifications to adapt to local context and adopt processes to engage better with underserved communities. Trial registration: This trial is registered as ISRCTN10237475. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/42/42) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 23. See the NIHR Funding and Awards website for further award information.

Sickness absenteeism and presenteeism (attendance at work while ill, with poor work performance) are major problems in the NHS and associated with worse patient health care. The most common causes of NHS staff sickness absenteeism and presenteeism are muscular complaints and mental ill health. Poor lifestyle and illnesses associated with heart disease are also important factors. Staff health checks might improve the health of NHS staff, but no studies have included screening tests to address the most common causes of poor staff health. This pilot study tested whether it would be possible to deliver a randomised controlled trial of an NHS staff health screening clinic, where some people get the screening check and others do not (chosen at random, like flipping a coin). We used an electronic database to capture all data. Participants completed initial questionnaires either at home or at work, then attended a face-to-face screening clinic using recognised screening questionnaires and tests to detect problems with muscular, mental or heart health. We considered how NHS staff and healthcare organisations would want the screening clinic and trial to run, how a diverse range of NHS staff could best be approached, how many staff might need to be invited and what their healthcare needs would be. The study ran in four UK NHS hospitals during the COVID-19 pandemic. Two hundred and thirty-six NHS staff participated, but early trial closure due to the pandemic meant that some results were unavailable. For the primary feasibility outcomes, although recruitment rates of around 8% were lower than anticipated, half of staff screened needed referral for further health care and one-third reported intending to attend. Staff felt that the clinic addressed an important health need. The Trial Oversight Committee recommended proceeding to a full-scale trial but with modifications to address findings from the process evaluation, including ways to encourage a wider group of NHS staff to take part.

Prader-Willi syndrome: guidance for children and transition into adulthood.

Prader-Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues, especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.

Diabetes control is worse in children and young people with type 1 diabetes requiring interpreter support.

Introduction: Language barriers can pose a significant hurdle to successfully educating children and young people with type 1 diabetes (CYPD) and their families, potentially influencing their glycaemic control. Methods: Retrospective case-control study assessing HbA1c values at 0, 3, 6, 9, 12 and 18 months post-diagnosis in 41 CYPD requiring interpreter support (INT) and 100 age-, sex- and mode-of-therapy-matched CYPD not requiring interpreter support (CTR) in our multi-diverse tertiary diabetes centre. Data were captured between 2009-2016. English indices of deprivation for each cohort are reported based on the UK 2015 census data. Results: The main languages spoken were Somali (27%), Urdu (19.5%), Romanian (17%) and Arabic (12%), but also Polish, Hindi, Tigrinya, Portuguese, Bengali and sign language. Overall deprivation was worse in the INT group according to the Index of Multiple Deprivation (IMD [median]: INT 1.642; CTR 3.741; p=0.001). The median HbA1c was higher at diagnosis in the CTR group (9.95% [85.2 mmol/mol] versus 9.0% [74.9 mmol/mol], p=0.046) but was higher in the INT group subsequently: the median HbA1c at 18 months post diagnosis was 8.3% (67.2 mmol/mol; INT) versus 7.9% (62.8 mmol/mol; CTR) (p=0.014). There was no hospitalisation secondary to diabetes-related complications in either cohorts. Summary and conclusions: Glycaemic control is worse in CYPD with language barriers. These subset of patients also come from the most deprived areas which adds to the disadvantage. Health care providers should offer tailored support for CYP/families with language barriers, including provision of diabetes-specific training for interpreters, and explore additional factors contributing to poor glycaemic control. The findings of this study suggest that poor health outcomes in CYPD with language barriers is multifactorial and warrants a multi-dimensional management approach.

Analysis of autophagy deficiency and cytotoxicity in autophagy-deficient human embryonic stem cell-derived neurons.

Autophagy, a catabolic process governing cellular and energy homeostasis, is essential for cell survival and human health. Here, we present a protocol for generating autophagy-deficient (ATG5-/-) human neurons from human embryonic stem cell (hESC)-derived neural precursors. We describe steps for analyzing loss of autophagy by immunoblotting. We then detail analysis of cell death by luminescence-based cytotoxicity assay and fluorescence-based TUNEL staining. This hESC-based experimental platform provides a genetic knockout model for undertaking autophagy studies relevant to human biology. For complete details on the use and execution of this protocol, please refer to Sun et al. (2023).1.

Views of children with diabetes from underserved communities, and their families on diabetes, glycaemic control and healthcare provision: A qualitative evidence synthesis.

AIMS: Children and young people with diabetes (CYPD) from socio-economically deprived and/or ethnic minority groups tend to have poorer glucose control and greater risk of diabetes-related complications. In this systematic review of qualitative evidence (qualitative evidence synthesis, QES), we aimed to explore the experiences and views of clinical encounters in diabetes care from the perspectives of CYPD and their family/carers from underserved communities and healthcare professionals in diabetes care. METHODS: We searched 6 databases to March 2022 with extensive search terms, and used a thematic synthesis following methods of Thomas and Harden. RESULTS: We identified 7 studies and described 11 descriptive themes based on primary and secondary constructs. From these, three "analytical themes" were developed. (1) "Alienation of CYPD" relates to their social identity and interaction with peers, family and health service practitioners in the context of diabetes self- and family/carer management and is impacted by communication in the clinical encounter. (2) "Empowerment of CYPD and family/carers" explores families' understanding of risks and consequences of diabetes and taking responsibility for self- and family/carer management in the context of their socio-cultural background. (3) "Integration of diabetes (into self and family)" focuses on the ability to integrate diabetes self-management into the daily lives of CYPD and family/carers beyond the clinical consultation. CONCLUSIONS: The analytical themes are interdependent and provide a conceptual framework from which to explore and strengthen the therapeutic alliance in clinical encounters and to foster greater concordance with treatment plans. Communicating the biomedical aspects of managing diabetes in the clinical encounter is important, but should be balanced with addressing socio-emotional factors important to CYPD and family/carers.

Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.

Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5-/-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Developments in the design and delivery of self-management support for children and young people with diabetes: A narrative synthesis of systematic reviews.

AIMS: Facilitated self-management support programmes have become central to the treatment of chronic diseases including diabetes. For many children and young people with diabetes (CYPD), the impact on glycated haemoglobin (HbA1c ) and a range of self-management behaviours promised by these programmes remain unrealised. This warrants an appraisal of current thinking and the existing evidence to guide the development of programmes better targeted at this age group. METHODS: Create a narrative review of systematic reviews produced in the last 3 years that have explored the impact on CYPD of the four key elements of self-management support programmes: education, instruction and advice including peer support; psychological counselling via a range of therapies; self-monitoring, including diaries and telemetric devices; and telecare, the technology-enabled follow-up and support by healthcare providers. RESULTS: Games and gamification appear to offer a promising means of engaging and educating CYPD. Psychological interventions when delivered by trained practitioners, appear to improve HbA1c and quality of life although effect sizes were small. Technology-enabled interactive diaries can increase the frequency of self-monitoring and reduce levels of HbA1c . Telecare provided synchronously via telephone produced significant improvements in HbA1c . CONCLUSIONS: The cost-effective flexibility of increasing the reliance on technology is an attractive proposition; however, there are resource implications for digital connectivity in underserved populations. The need remains to improve the understanding of which elements of each component are most effective in a particular context, and how to optimise the influence and input of families, caregivers and peers.

Dapagliflozin or Saxagliptin in Pediatric Type 2 Diabetes.

BACKGROUND: Incidence of type 2 diabetes (T2D) in children and adolescents is increasing, but treatment options are limited. METHODS: This was a 26-week, phase 3 trial with a 26-week extension among patients (10 to 17 years of age) with uncontrolled T2D (A1C 6.5 to 10.5%) receiving metformin, insulin, or both. Participants were randomly assigned 1:1:1 to 5 mg of dapagliflozin (N=81), 2.5 mg of saxagliptin (N=88), or placebo (N=76). Patients in active treatment groups with A1C ≥7% at week 12 were further randomly assigned 1:1 at week 14 to continue the dose or up-titrate to a higher dose (10 mg of dapagliflozin or 5 mg of saxagliptin). The primary end point was change in A1C at week 26. Safety was assessed over 52 weeks. RESULTS: At week 26, the difference versus placebo in adjusted mean change in A1C was −1.03 percentage points (95% confidence interval [CI], −1.57 to −0.49; P<0.001) for dapagliflozin and −0.44 percentage points (95% CI, −0.93 to 0.05; P=0.078) for saxagliptin. Adverse events (AEs) and serious AEs occurred in 72.8% and 8.6% of patients receiving dapagliflozin, 69.3% and 8.0% of patients receiving saxagliptin, and 71.1% and 6.6% of patients receiving placebo. Severe hypoglycemia occurred in 4.9%, 4.5%, and 7.9% of patients in each group, respectively. Over 52 weeks, the most common AE was headache (dapagliflozin 14.8%; placebo 5.3%). Most events were mild and none was considered serious or resulted in discontinuation. CONCLUSIONS: Dapagliflozin, but not saxagliptin, showed significant improvement in A1C compared with placebo. Nonserious headaches were more common in participants treated with dapagliflozin than in those receiving placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03199053.)

Once-Weekly Semaglutide in Adolescents with Obesity.

BACKGROUND: A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking. METHODS: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68. RESULTS: A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group. CONCLUSIONS: Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.).

An effective and cost-saving structured education program teaching dynamic glucose management strategies to a socio-economically deprived cohort with type 1 diabetes in a VIRTUAL setting.

OBJECTIVES: Compare the clinical and cost-effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9-10.0 mmol/L) and incorporating these into a user-friendly teaching aid. DESIGN AND METHODS: Effectiveness of the F2F and VIRTUAL programs were ascertained by comparing the mean change (Δ) from baseline to 6 months in HbA1c, TIR and severe hypoglycemia. Delivery cost for the two programs were evaluated. Factors predicting TIR in the combined cohort were determined and incorporated into a user-friendly infographic. RESULTS: First 50 graduates per group were evaluated. The mean difference in Δ HbA1c, Δ TIR and Δ episodes of severe hypoglycemia between VIRTUAL and F2F groups were 1.16 (p = 0.47), 0.76 (p = 0.78) and -0.06 (p = 0.61) respectively. Delivery cost per 50 CYPD for VIRTUAL and F2F were $5752 and $7020, respectively. The strongest predictors of TIR (n = 100) were short bursts of exercise (10-40 min) to lower hyperglycemia (p < 0.001), using trend arrow adjustment tools (p < 0.001) and adjusting pre-meal bolus timing based on trend arrows (p < 0.01). These strategies were translated into a GAME (Stop highs), SET (Stay in target), MATCH (Prevent lows) mnemonic. CONCLUSION: Teaching DynamicGM VIRTUALLY is just as effective as F2F delivery and cost saving. Short bursts of exercise and using CGM trend arrows to adjust insulin dose and timing improves TIR.

General population screening for childhood type 1 diabetes: is it time for a UK strategy?

Type 1 diabetes (T1D) is a chronic autoimmune disease of childhood affecting 1:500 children aged under 15 years, with around 25% presenting with life-threatening diabetic ketoacidosis (DKA). While first-degree relatives have the highest risk of T1D, more than 85% of children who develop T1D do not have a family history. Despite public health awareness campaigns, DKA rates have not fallen over the last decade. T1D has a long prodrome, and it is now possible to identify children who go on to develop T1D with a high degree of certainty. The reasons for identifying children presymptomatically include prevention of DKA and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression. Research studies of population-based screening strategies include using islet autoantibodies alone or in combination with genetic risk factors, both of which can be measured from a capillary sample. If found during screening, the presence of two or more islet autoantibodies has a high positive predictive value for future T1D in childhood (under 18 years), offering an opportunity for DKA prevention. However, a single time-point test will not identify all children who go on to develop T1D, and so combining with genetic risk factors for T1D may be an alternative approach. Here we discuss the pros and cons of T1D screening in the UK, the different strategies available, the knowledge gaps and why a T1D screening strategy is needed.

WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism.

INTRODUCTION: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence. OBJECTIVE: This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period. METHODS: We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from eight families. RESULTS: All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes, encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. CONCLUSION: Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.

DYNAMIC: Dynamic glucose management strategies delivered through a structured education program improves time in range in a socioeconomically deprived cohort of children and young people with type 1 diabetes with a history of hypoglycemia.

OBJECTIVES: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM). DESIGN AND METHODS: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award-winning diabetes educators' websites, and CGM user feedback. Step 3: Program effectiveness was assessed at six months by change in time below range (TBR) (<3.9mmol/L), time in range (TIR) (3.9-10.0mmol/L), time above range level 2 (TAR2) (>13.9mmol/L), severe hypoglycemia and HbA1c using a paired T-test. A DynamicGM score was developed to assess proactive glucose management. Factors predicting TBR and TIR were assessed using regression analysis. RESULTS: Dexcom G6 was chosen for integrated CGM (iCGM) status and highest composite score (29/30). Progressive DynamicGM strategies were taught through five sessions delivered over two months. Fifty CYP (23 male) with a mean (±SD) age and diabetes duration of 10.2 (±4.8) and 5.2 (±3.7) years respectively, who completed the education program were prospectively evaluated. Evaluation at six months showed a significant reduction in TBR (10.4% to 2.1%, p<.001), TAR2 (14.1% to 7.3%, p<.001), HbA1c [7.4 to 7.1% (57.7 to 53.8 mmol/mol), p<.001] and severe hypoglycemic episodes (10 to 1, p<.05); TIR increased (47.4% to 57.0%, p<.001). Number of Dexcom followers (p<.05) predicted reduction in TBR and DynamicGM score (p<.001) predicted increased TIR. CONCLUSION: Teaching DynamicGM strategies successfully improves TIR and reduces hypoglycemia.