Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study

Neonatal diabetes presents <6 months of life but delays in recognition result in presentation with life-threatening hyperglycaemia/diabetic ketoacidosis. Early identification and rapid genetic diagnosis is crucial and ensures correct treatment/management. Adding 'glucose' to newborn bloodspot screening (NBS) could aid prompt detection but requires evidence of parental acceptance. Objectives: Increase understanding of parental experience of presentation/recognition of neonatal diabetes and perceptions of glucose testing within NBS. Setting: UK families confirmed with a genetic diagnosis of neonatal diabetes, November 2014-2018, were invited to participate. Participants: In-depth qualitative interviews were conducted with 10 parents of 14 children. 8 had transient neonatal diabetes: KCNJ11 (n=5), ABCC8 (n=1), 6q24 (n=2), 6 had permanent neonatal diabetes: KCNJ11 (n=4), INS (n=1), homozygous GCK (n=1). Primary and secondary outcome measures: Interviews audio recorded, transcribed and subjected to thematic content analysis. Results: 3 key themes emerged:Babies were extremely ill at hospital admission, with extended stays in intensive care required.Identification of diabetes was not 'standardised' and perceived a 'chance' finding.Adding glucose to NBS was universally considered extremely positive. Conclusions: Diagnosis of neonatal diabetes is frequently delayed, resulting in critically ill presentation with prolonged intensive care support, additional healthcare costs and familial distress. Potential to detect hyperglycaemia earlier was universally endorsed by parents with no negative consequences identified. Although further study including a larger number of individuals is needed to confirm our findings this study provides the first evidence of acceptability of glucose testing fulfilling Wilson-Jungner criteria for implementation within the NBS programme.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.MS is a National Institute for Health Research (NIHR) 70@70 Senior Nurse and Midwife Research Leaderpublished version, accepted version, submitted versio

Major surgery induces acute changes in measured DNA methylation associated with immune response pathways

Surgery is an invasive procedure evoking acute inflammatory and immune responses that can influence risk for postoperative complications including cognitive dysfunction and delirium. Although the specific mechanisms driving these responses have not been well-characterized, they are hypothesized to involve the epigenetic regulation of gene expression. We quantified genome-wide levels of DNA methylation in peripheral blood mononuclear cells (PBMCs) longitudinally collected from a cohort of elderly patients undergoing major surgery, comparing samples collected at baseline to those collected immediately post-operatively and at discharge from hospital. We identified acute changes in measured DNA methylation at sites annotated to immune system genes, paralleling changes in serum-levels of markers including C-reactive protein (CRP) and Interleukin 6 (IL-6) measured in the same individuals. Many of the observed changes in measured DNA methylation were consistent across different types of major surgery, although there was notable heterogeneity between surgery types at certain loci. The acute changes in measured DNA methylation induced by surgery are relatively stable in the post-operative period, generally persisting until discharge from hospital. Our results highlight the dramatic alterations in gene regulation induced by invasive surgery, primarily reflecting upregulation of the immune system in response to trauma, wound healing and anaesthesia.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Medical Research Council (Grant MR/M008924/1), the Sasakawa Foundation (Butterfield Awards B108) and the UK National Institute for Health Research (NIHR) Exeter Clinical Research Facility (Exeter CRF).Published version, Accepted version, Submitted versio

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.Objective: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as Type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating Type 1 from non-Type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. Research Design and Methods: We studied patients diagnosed ≤30y, currently <50y, in two UK regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised 3 stages: 1) Assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) If UCPCR≥0.2nmol/mmol, measurement of GAD and IA2 islet autoantibodies; 3) If negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. Results: 1407 patients participated (1365 no known genetic cause, 34 monogenic diabetes, 8 cystic-fibrosis-related diabetes). 386/1365(28%) had UCPCR≥0.2nmol/mmol. 216/386(56%) of these patients were negative for GAD and IA2 and underwent molecular genetic testing. 17 new cases of monogenic diabetes were diagnosed (8 common MODY (Sanger sequencing), 9 rarer causes (next generation sequencing)) in addition to the 34 known cases (estimated prevalence of 3.6% (51/1407) (95%CI: 2.7-4.7%)). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. Conclusions: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed ≤30y.This study was funded by the Department of Health and Wellcome Trust Health Innovation Challenge Award (HICF-1009-041; WT-091985). ATH and SE are Wellcome Trust Senior Investigators. ATH is an NIHR Senior Investigator. BS, ATH, MH, SE, and BK are core members of the NIHR Exeter Clinical Research Facility. EP is a Wellcome Trust New Investigator. TM is supported by NIHR CSO Fellowship. JP is partly funded by the NIHR Collaboration for Leadership in Applied Health Research and Care for the South West (PenCLAHRC)

Patterns of postmeal insulin secretion in individuals with sulfonylurea- treated KCNJ11 neonatal diabetes show predominance of non- KATP- channel pathways

Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-KATP-channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Effect of perchlorate and thiocyanate exposure on thyroid function of pregnant women from South-West England: a cohort study

This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Assessing newborn body composition using principal components analysis: differences in the determinants of fat and skeletal size

BACKGROUND: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. METHODS: Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. RESULTS: Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). CONCLUSION: Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression

Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis

Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight