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Effective integration of research within healthcare organisations is recognised to improve outcomes. A research strategy within a hospital Trust in South West England was revised, following the launch of a national Chief Nursing Officer (CNO) strategy that promotes research engagement and activity. The aim was to develop, implement and evaluate this revised strategic plan for research. High-level engagement within the organisation was established and previous initiatives evaluated. A 6-year plan with 2-year targets was defined and evaluated at year end. The four pillars of the CNO strategy were central to the revised strategy, underpinned by digital innovation. Evaluation of the earlier strategy indicated excellent engagement with the Chief Nurse Research Fellow initiative and the Clinical Academic Network. The 'Embedding Research In Care' (ERIC) unit was reconfigured to an ERIC model, which aided question generation and project development. Year one objectives were achieved within the revised plan. Implementing a research strategy within an organisation requires a cultural shift and a long-term vision is required with measurable objectives. The team demonstrated significant progress through high-level leadership, mentoring and cross-professional collaboration. [ABSTRACT FROM AUTHOR]

Biological soil crusts represent a rich habitat for diverse and complex eukaryotic microbial communities. A unique but extremely common habitat is the urban sidewalk and its cracks that collect detritus. While these habitats are ubiquitous across the globe, little to no work has been conducted to characterize protists found there. Amoeboid protists are major predators of bacteria and other microbial eukaryotes in these microhabitats and therefore play a substantial ecological role. From sidewalk crack soil crusts, we have isolated three naked amoebae with finely tapered subpseudopodia, and a simple life cycle consisting of a trophic amoeba and a cyst stage. Using a holistic approach including light, electron, and fluorescence microscopy as well as phylogenetics using the ribosomal small subunit rRNA gene and phylogenomics using 230 nuclear genes, we find that these amoeboid organisms fail to match any previously described eukaryote genus. However, we determined the amoebae belong to the amoebozoan lineage Variosea based on phylogenetics. The molecular analyses place our isolates in two novel genera forming a grade at the base of the variosean group Protosteliida. These three novel varioseans among two novel genera and species are herein named "Kanabo kenzan" and "Parakanabo toge." [ABSTRACT FROM AUTHOR]

The incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)‐treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea‐treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0‐240 minutes) for total GLP‐1 and GIP were compared between groups, using non‐parametric statistical methods. Post‐meal GLP‐1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate‐sensitive potassium channel‐independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management. Methods: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021. Results: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3–8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18–24), with 23/25 (92%) reported before 28 weeks. Conclusions/interpretation: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies. [ABSTRACT FROM AUTHOR]

Aims: To identify strategies used by registered nurses and non‐registered nursing care staff in overcoming barriers when providing fundamental nursing care for non‐invasively ventilated inpatients with COVID‐19. Design: Online survey with open‐ended questions to collect qualitative data. Methods: In August 2020, we asked UK‐based nursing staff to describe any strategies they employed to overcome barriers to delivering care in 15 fundamental nursing care categories when providing care to non‐invasively ventilated patients with COVID‐19. We analysed data using Framework Analysis. Results: A total of 1062 nurses consented to participate in our survey. We derived four themes. 1) Communication behaviours included adapting verbal and non‐verbal communication with patients, using information technology to enable patients' significant others to communicate with staff and patients, and establishing clear information‐sharing methods with other staff. 2) Organizing care required clustering interventions, carefully managing supplies, encouraging patient self‐care and using 'runners' and interdisciplinary input. 3) Addressing patients' well‐being and values required spending time with patients, acting in loco familiae, providing access to psychological and spiritual support, obtaining information about patients' wishes early on and providing privacy and comforting/meaningful items. 4) Management and leadership behaviours included training, timely provision of pandemic information, psychological support, team huddles and facilitating regular breaks. Conclusions: Our respondents identified multiple strategies in four main areas of clinical practice. Management and leadership are crucial to both fundamental care delivery and the well‐being of nurses during pandemics. Grouping strategies into these areas of action may assist nurses and leaders to prepare for pandemic nursing. Impact As these strategies are unlikely to be exclusive to the COVID‐19 pandemic, their global dissemination may improve patient experience and help nurses deliver fundamental care when planning pandemic nursing. However, their effectiveness is unknown. Therefore, we are currently evaluating these strategies in a cluster randomized controlled trial. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of U.K. cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY, including education initiatives (Genetic Diabetes Nurse [GDN] project), the MODY probability calculator, and targeted next-generation sequencing (tNGS). We examined how the estimated prevalence of MODY and other forms of monogenic diabetes diagnosed outside the neonatal period has changed over time and how the initiatives have impacted case finding.Research Design and Methods: U.K. referrals for genetic testing for monogenic diabetes diagnosed >1 year of age from 1 January 1996 to 31 December 2019 were examined. Positive test rates were compared for referrals reporting GDN involvement/MODY calculator use with those that did not.Results: A diagnosis of monogenic diabetes was confirmed in 3,860 individuals, more than threefold higher than 2009 (1 January 1996 to 28 February 2009, n = 1,177). Median age at diagnosis in probands was 21 years. GDN involvement was reported in 21% of referrals; these referrals had a higher positive test rate than those without GDN involvement (32% vs. 23%, P < 0.001). MODY calculator usage was indicated in 74% of eligible referrals since 2014; these referrals had a higher positive test rate than those not using the calculator (33% vs. 25%, P = 0.001). Four hundred ten (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 because of increased case finding).Conclusions: Since 2009, referral rates and case diagnosis have increased threefold. This is likely to be the consequence of tNGS, GDN education, and use of the MODY calculator. [ABSTRACT FROM AUTHOR]

Background: Research active hospitals have better patient outcomes and improvements in healthcare are associated with greater staff engagement in research. However, barriers to research activity include inadequate knowledge/training and perceptions that research is a specialist activity. Nursing is an academic discipline but the infrastructure supporting nursing research worldwide is variable and sustaining clinical academic careers remains challenging. The National Institute of Health Research 70@70 Senior Nurse Research Leader programme provides dedicated time to increase clinical academic opportunities and foster a research culture across England; we describe initiatives developed by one National Institute of Health Research 70@70 leader to increase clinical staff engagement in research. Aim: The purpose of this work was to develop initiatives to facilitate clinical research opportunities and bridge the gap between clinical care and research. Methods: New strategies were developed in one health service to increase clinical staff engagement in research activity. This included: (a) Chief Nurse Research Fellows: clinical staff undertaking bespoke research training to identify local clinical research priorities, (b) an exemplar nurse-led Embedding Research In Care unit to pioneer innovation, evaluation and research participation supported by a research facilitator and (c) a Clinical Academic Network for nursing, midwifery and allied healthcare professionals to aid collaborative working. Results: The first cohort of Chief Nurse Research Fellows have successfully completed a bespoke training programme and, with mentoring, developed projects to tackle clinical problems. The Embedding Research In Care unit initiative was configured and the first Embedding Research In Care unit has been awarded. A Clinical Academic Network group of 25+ nurses, midwives and allied health professionals was established and provides peer support and mentoring. Conclusions: This multi-faceted approach has successfully supported research training/engagement, enabled career development and identified nurses/midwives with potential to undertake clinical academic careers. A range of strategies, such as those described in this paper, are required to successfully bridge the gap between clinical care and research and provide additional opportunities for clinical staff to become engaged in a research active career. [ABSTRACT FROM AUTHOR]

Aim: This systematic review identifies, appraises and synthesizes the evidence on the provision of fundamental nursing care to hospitalized patients with a highly infectious virus and the effectiveness of adaptations to overcome barriers to care. Design: Systematic review. Data Sources: In July 2020, we searched Medline, PsycINFO (OvidSP), CINAHL (EBSCOhost), BNI (ProQuest), WHO COVID‐19 Database (https://search.bvsalud.org/) MedRxiv (https://www.medrxiv.org/), bioRxiv (https://www.biorxiv.org/) and also Google Scholar, TRIP database and NICE Evidence, forwards citation searching and reference checking of included papers, from 2016 onwards. Review Methods: We included quantitative and qualitative research reporting (i) the views, perceptions and experiences of patients who have received fundamental nursing care whilst in hospital with COVID‐19, MERS, SARS, H1N1 or EVD or (ii) the views, perceptions and experiences of professional nurses and non‐professionally registered care workers who have provided that care. We included review articles, commentaries, protocols and guidance documents. One reviewer performed data extraction and quality appraisal and was checked by another person. Results: Of 3086 references, we included 64 articles; 19 empirical research and 45 review articles, commentaries, protocols and guidance documents spanning five pandemics. Four main themes (and 11 sub‐themes) were identified. Barriers to delivering fundamental care were wearing personal protective equipment, adequate staffing, infection control procedures and emotional challenges of care. These barriers were addressed by multiple adaptations to communication, organization of care, staff support and leadership. Conclusion: To prepare for continuation of the COVID‐19 pandemic and future pandemics, evaluative studies of adaptations to fundamental healthcare delivery must be prioritized to enable evidence‐based care to be provided in future. Impact: Our review identifies the barriers nurses experience in providing fundamental care during a pandemic, highlights potential adaptations that address barriers and ensure positive healthcare experiences and draws attention to the need for evaluative research on fundamental care practices during pandemics. [ABSTRACT FROM AUTHOR]

Background: Patient experience of nursing care is associated with safety, care quality, treatment outcomes, costs and service use. Effective nursing care includes meeting patients' fundamental physical, relational and psychosocial needs, which may be compromised by the challenges of SARS-CoV-2. No evidence-based nursing guidelines exist for patients with SARS-CoV-2. We report work to develop such a guideline. Our aim was to identify views and experiences of nursing staff on necessary nursing care for inpatients with SARS-CoV-2 (not invasively ventilated) that is omitted or delayed (missed care) and any barriers to this care. Methods: We conducted an online mixed methods survey structured according to the Fundamentals of Care Framework. We recruited a convenience sample of UK-based nursing staff who had nursed inpatients with SARS-CoV-2 not invasively ventilated. We asked respondents to rate how well they were able to meet the needs of SARS-CoV-2 patients, compared to non-SARS-CoV-2 patients, in 15 care categories; select from a list of barriers to care; and describe examples of missed care and barriers to care. We analysed quantitative data descriptively and qualitative data using Framework Analysis, integrating data in side-by-side comparison tables. Results: Of 1062 respondents, the majority rated mobility, talking and listening, non-verbal communication, communicating with significant others, and emotional wellbeing as worse for patients with SARS-CoV-2. Eight barriers were ranked within the top five in at least one of the three care areas. These were (in rank order): wearing Personal Protective Equipment, the severity of patients' conditions, inability to take items in and out of isolation rooms without donning and doffing Personal Protective Equipment, lack of time to spend with patients, lack of presence from specialised services e.g. physiotherapists, lack of knowledge about SARS-CoV-2, insufficient stock, and reluctance to spend time with patients for fear of catching SARS-CoV-2. Conclusions: Our respondents identified nursing care areas likely to be missed for patients with SARS-CoV-2, and barriers to delivering care. We are currently evaluating a guideline of nursing strategies to address these barriers, which are unlikely to be exclusive to this pandemic or the environments represented by our respondents. Our results should, therefore, be incorporated into global pandemic planning. [ABSTRACT FROM AUTHOR]

Objective: ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM.Research Design and Methods: We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.Results: Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1-13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).Conclusions: Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment. [ABSTRACT FROM AUTHOR]

Objectives To evaluate and compare the lifetime costs associated with strategies to identify individuals with monogenic diabetes and change their treatment to more appropriate therapy. Design A decision analytical model from the perspective of the National Health Service (NHS) in England and Wales was developed and analysed. The model was informed by the literature, routinely collected data and a clinical study conducted in parallel with the modelling. Setting Secondary care in the UK. Participants Simulations based on characteristics of patients diagnosed with diabetes <30 years old. Interventions Four test-treatment strategies to identify individuals with monogenic diabetes in a prevalent cohort of diabetics diagnosed under the age of 30 years were modelled: clinician-based genetic test referral, targeted genetic testing based on clinical prediction models, targeted genetic testing based on biomarkers, and blanket genetic testing. The results of the test-treatment strategies were compared with a strategy of no genetic testing. Primary and secondary outcome measures Discounted lifetime costs, proportion of cases of monogenic diabetes identified. Results Based on current evidence, strategies using clinical characteristics or biomarkers were estimated to save approximately £100–£200 per person with diabetes over a lifetime compared with no testing. Sensitivity analyses indicated that the prevalence of monogenic diabetes, the uptake of testing, and the frequency of home blood glucose monitoring had the largest impact on the results (ranging from savings of £400–£50 per person), but did not change the overall findings. The model is limited by many model inputs being based on very few individuals, and some long-term data informed by clinical opinion. Conclusions Costs to the NHS could be saved with targeted genetic testing based on clinical characteristics or biomarkers. More research should focus on the economic case for the use of such strategies closer to the time of diabetes diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE Identifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population. RESEARCH DESIGN AND METHODS Swedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing. RESULTS The minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment. CONCLUSIONS At diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin. [ABSTRACT FROM AUTHOR]

Renal teams focus predominantly on renal replacement therapy and physical symptom management, rather than psychological issues, such as mental health, body image or self-esteem. This study aims to increase understanding of how renal nurses feel about discussing sexual issues with patients undergoing haemodialysis [ABSTRACT FROM AUTHOR]

Objective: Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to KCNJ11 mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of KCNJ11 mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with KCNJ11 PNDM compared with adults with INS PNDM.Research Design and Methods: Adults with PNDM due to KCNJ11 mutations (n = 8) or INS mutations (n = 4) underwent a neurological examination and completed standardized neuropsychological tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to Z scores using normative data, and outcomes were compared between groups.Results: In individuals with KCNJ11 mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. KCNJ11 mutations were also associated with impaired attention, working memory, and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ KCNJ11 vs. INS mutations 76 vs. 111, respectively; P = 0.02). However, no structural brain abnormalities were noted on MRI. The severity of these features was related to the specific mutation, and they were absent in individuals with INS mutations.Conclusions: KCNJ11 PNDM is associated with specific CNS features that are not due to long-standing diabetes, persist into adulthood despite sulfonylurea therapy, and represent the major burden from KCNJ11 mutations. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.Methods: This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.Results: A total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m2) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.Conclusions/interpretation: In participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA1c. [ABSTRACT FROM AUTHOR]

Objective Bisphenol A (BPA) has been associated with adverse human health outcomes and exposure to this compound is near-ubiquitous in the Western world. We aimed to examine whether self-moderation of BPA exposure is possible by altering diet in a real-world setting. Design An Engaged Research dietary intervention study designed, implemented and analysed by healthy teenagers from six schools and undertaken in their own homes. Participants A total of 94 students aged between 17 and 19 years from schools in the South West of the UK provided diet diaries and urine samples for analysis. Intervention Researcher participants designed a set of literature-informed guidelines for the reduction of dietary BPA to be followed for 7 days. Main outcome measures Creatinine-adjusted urinary BPA levels were taken before and after the intervention. Information on packaging and food/drink ingested was used to calculate a BPA risk score for anticipated exposure. A qualitative analysis was carried out to identify themes addressing long-term sustainability of the diet. Results BPA was detected in urine of 86% of participants at baseline at a median value of 1.22 ng/mL (IQR 1.99). No effect of the intervention diet on BPA levels was identified overall (P=0.25), but there was a positive association in those participants who showed a drop in urinary BPA concentration postintervention and their initial BPA level (P=0.003). Qualitative analysis identified themes around feelings of lifestyle restriction and the inadequacy of current labelling practices. Conclusions We found no evidence in this self-administered intervention study that it was possible to moderate BPA exposure by diet in a real-world setting. Furthermore, our study participants indicated that they would be unlikely to sustain such a diet long term, due to the difficulty in identifying BPA-free foods. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The majority of infants with neonatal diabetes mellitus present with severe ketoacidosis at a median of 6 weeks. The treatment is very challenging and can result in severe neurological sequelae or death. The genetic defects that cause neonatal diabetes are present from birth. We aimed to assess if neonatal diabetes could be diagnosed earlier by measuring glucose in a dried blood spot collected on day 5 of life. Methods: In this retrospective case-control study we retrieved blood spot cards from 11 infants with genetically confirmed neonatal diabetes (median age of diagnosis 6 [range 2-112] days). For each case we also obtained one ( n = 5) or two ( n = 6) control blood spot cards collected on the same day. Glucose was measured on case and control blood spot cards. We established a normal range for random glucose at day 5 of life in 687 non-diabetic neonates. Results: All 11 neonates with diabetes had hyperglycaemia present on day 5 of life, with blood glucose levels ranging from 10.2 mmol/l to >30 mmol/l (normal range 3.2-6.0 mmol/l). In six of these neonates the diagnosis of diabetes was made after screening at day 5, with the latest diagnosis made at 16 weeks. Conclusions/interpretation: Neonatal diabetes can be detected on day 5 of life, preceding conventional diagnosis in most cases. Earlier diagnosis by systematic screening could lead to prompt genetic diagnosis and targeted treatment, thereby avoiding the most severe sequelae of hyperglycaemia in neonates. [ABSTRACT FROM AUTHOR]

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 x 10-4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 x 10-5) and Finnish (n = 80, odds ratio = 22, P = 1 x 10-6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. [ABSTRACT FROM AUTHOR]

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 at age 30 years or younger, currently younger than 50 years, in two U.K. regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised three stages: 1) assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) if UCPCR was ≥0.2 nmol/mmol, measurement of GAD and IA2 islet autoantibodies; and 3) if negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes.Results: A total of 1,407 patients participated (1,365 with no known genetic cause, 34 with monogenic diabetes, and 8 with cystic fibrosis-related diabetes). A total of 386 out of 1,365 (28%) patients had a UCPCR ≥0.2 nmol/mmol, and 216 out of 386 (56%) were negative for GAD and IA2 and underwent molecular genetic testing. Seventeen new cases of monogenic diabetes were diagnosed (8 common Maturity Onset Diabetes of the Young [Sanger sequencing] and 9 rarer causes [next-generation sequencing]) in addition to the 34 known cases (estimated prevalence of 3.6% [51/1,407] [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 at age 30 years or younger. [ABSTRACT FROM AUTHOR]

Objective: Monogenic diabetes is rare but is an important diagnosis in pediatric diabetes clinics. These patients are often not identified as this relies on the recognition of key clinical features by an alert clinician. Biomarkers (islet autoantibodies and C-peptide) can assist in the exclusion of patients with type 1 diabetes and allow systematic testing that does not rely on clinical recognition. Our study aimed to establish the prevalence of monogenic diabetes in U.K. pediatric clinics using a systematic approach of biomarker screening and targeted genetic testing.Research Design and Methods: We studied 808 patients (79.5% of the eligible population) <20 years of age with diabetes who were attending six pediatric clinics in South West England and Tayside, Scotland. Endogenous insulin production was measured using the urinary C-peptide creatinine ratio (UCPCR). C-peptide-positive patients (UCPCR ≥0.2 nmol/mmol) underwent islet autoantibody (GAD and IA2) testing, with patients who were autoantibody negative undergoing genetic testing for all 29 identified causes of monogenic diabetes.Results: A total of 2.5% of patients (20 of 808 patients) (95% CI 1.6-3.9%) had monogenic diabetes (8 GCK, 5 HNF1A, 4 HNF4A, 1 HNF1B, 1 ABCC8, 1 INSR). The majority (17 of 20 patients) were managed without insulin treatment. A similar proportion of the population had type 2 diabetes (3.3%, 27 of 808 patients).Conclusions: This large systematic study confirms a prevalence of 2.5% of patients with monogenic diabetes who were <20 years of age in six U.K. clinics. This figure suggests that ∼50% of the estimated 875 U.K. pediatric patients with monogenic diabetes have still not received a genetic diagnosis. This biomarker screening pathway is a practical approach that can be used to identify pediatric patients who are most appropriate for genetic testing. [ABSTRACT FROM AUTHOR]

HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. [ABSTRACT FROM AUTHOR]

Distinguishing patients with monogenic diabetes from those with type 1 diabetes (T1D) is important for correct diagnosis, treatment, and selection of patients for gene discovery studies. We assessed whether a T1D genetic risk score (T1D-GRS) generated from T1D-associated common genetic variants provides a novel way to discriminate monogenic diabetes from T1D. The T1D-GRS was highly discriminative of proven maturity-onset diabetes of young (MODY) (n = 805) and T1D (n = 1,963) (receiver operating characteristic area under the curve 0.87). A T1D-GRS of >0.280 (>50th T1D centile) was indicative of T1D (94% specificity, 50% sensitivity). We then analyzed the T1D-GRS of 242 white European patients with neonatal diabetes (NDM) who had been tested for all known NDM genes. Monogenic NDM was confirmed in 90, 59, and 8% of patients with GRS <5th T1D centile, 50-75th T1D centile, and >75th T1D centile, respectively. Applying a GRS 50th T1D centile cutoff in 48 NDM patients with no known genetic cause identified those most likely to have a novel monogenic etiology by highlighting patients with probable early-onset T1D (GRS >50th T1D centile) who were diagnosed later and had less syndromic presentation but additional autoimmune features compared with those with proven monogenic NDM. The T1D-GRS is a novel tool to improve the use of biomarkers in the discrimination of monogenic diabetes from T1D. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in KCNJ11 (which encodes the inwardly rectifying potassium channel Kir6.2). Methods: We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to KCNJ11 mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg day glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in Xenopus oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer. Results: In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas ( p = 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years, p = 0.032). There was no difference in pre-transfer HbA ( p = 0.87), weight-for-age z scores (SD score; p = 0.12) or sex ( p = 0.17). Conclusions/interpretation: Transfer from insulin is successful for most KCNJ11 patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months. [ABSTRACT FROM AUTHOR]

Background: Differentiating between type 1 and type 2 diabetes is fundamental to ensuring appropriate management of patients, but can be challenging, especially when treating with insulin. The 2010 UK Practical Classification Guidelines for Diabetes were developed to help make the differentiation.Aim: To assess diagnostic accuracy of the UK guidelines against 'gold standard' definitions of type 1 and type 2 diabetes based on measured C-peptide levels.Design and Setting: In total, 601 adults with insulin-treated diabetes and diabetes duration ≥5 years were recruited in Devon, Northamptonshire, and Leicestershire.Method: Baseline information and home urine sample were collected. Urinary C-peptide creatinine ratio (UCPCR) measures endogenous insulin production. Gold standard type 1 diabetes was defined as continuous insulin treatment within 3 years of diagnosis and absolute insulin deficiency (UCPCR<0.2 nmol/mmol ≥5 years post-diagnosis); all others classed as having type 2 diabetes. Diagnostic performance of the clinical criteria was assessed and other criteria explored using receiver operating characteristic (ROC) curves.Results: UK guidelines correctly classified 86% of participants. Most misclassifications occurred in patients classed as having type 1 diabetes who had significant endogenous insulin levels (57 out of 601; 9%); most in those diagnosed ≥35 years and treated with insulin from diagnosis, where 37 out of 66 (56%) were misclassified. Time to insulin and age at diagnosis performed best in predicting long-term endogenous insulin production (ROC AUC = 0.904 and 0.871); BMI was a less strong predictor of diabetes type (AUC = 0.824).Conclusion: Current UK guidelines provide a pragmatic clinical approach to classification reflecting long-term endogenous insulin production; caution is needed in older patients commencing insulin from diagnosis, where misclassification rates are increased. [ABSTRACT FROM AUTHOR]

Glucokinase--maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ~1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10-60%): persistent incidental childhood hyperglycemia (10-60%) and gestational diabetes mellitus (1-2%). GCK-MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4-8.3 mmol/L, HbA1c range 5.8-7.6% [40-60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C-peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR ≥0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment. [ABSTRACT FROM AUTHOR]

Genetics in health care is shifting, and responsibilities of genetic and nongenetic specialists are changing, requiring new guidance on how to adapt health care to advances in genetic services. This paper explores facilitators and barriers in the process of implementation of innovations in genetic health care. Furthermore, lessons learnt for optimizing development of new genetic services are summarized. Barriers and facilitators in transition processes were identified using mixed methods, including an online open-ended questionnaire among professionals and an international expert meeting. A multi-case study approach was used to explore recent experiences with innovations in genetic services in different phases of implementation. Barriers encountered in transitions in genetic service provision include the following: lack of genetic knowledge and skills among nongenetic health care providers, resistance to new divisions of responsibilities, and a need for more close collaboration and communication between geneticists and nongeneticists. Facilitating factors include the following: statutory registration of genetic specialists, availability of essential staff and equipment, and existence of registries and guidelines. Other challenges are experienced in the establishment of the appropriate legal and financial structures. A set of points to consider for genetic innovation processes is proposed, addressing, e.g., transition management and cooperation and communication strategies. [ABSTRACT FROM AUTHOR]

Background 11 patients were referred to our Molecular Genetics Department at the Royal Devon and Exeter Hospital between 2000-2012 with a physician's diagnosis of remitting diabetes. Our aim was to identify patients with remitting diabetes whose clinical presentation is not explained by any known aetiology of diabetes. Methods We obtained longitudinal clinical data on all 11 patients from the hospital records. All patients were aged between 0.5 and 35 years at diagnosis. We applied clinical criteria derived from the literature to establish 1) definite diabetes, 2) diabetes initially severe-requiring treatment with insulin, 3) remission of diabetes, and 4) exclusion of known causes of remitting diabetes. Results 10 out of 11 patients had an alternative explanation for their remission or a clear diagnosis was not identified. We identified a single patient with idiopathic remitting diabetes using these criteria. The patient was a white Caucasian female diagnosed aged 15 with symptoms of diabetes, laboratory glucose of 21.2 mmol/L and HbA1c 134 mmol/mol. Her BMI was 23.6 kg/m2. She was treated with basal bolus insulin but discontinued two years after diagnosis due to hypoglycaemia. 13 years post diagnosis, she had a normal oral glucose tolerance test during pregnancy (fasting glucose 4.5 mmol/L, 2 hr glucose 4.8 mmol/L) and an HbA1c of 30 mmol/mol. This patient does not appear to have Type 1 or Type 2 diabetes, and furthermore does not fit into current classifications of diabetes. Conclusions Idiopathic remitting diabetes is rare but does exist. Strict clinical criteria are important to ensure patients have a robust clinical diagnosis. Identification of more patients with idiopathic remitting diabetes will enable further study of the clinical course of this syndrome. Applying these strict criteria will allow the identification of patients with remitting diabetes to assess its aetiology. [ABSTRACT FROM AUTHOR]

Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype. [ABSTRACT FROM AUTHOR]

Diabetes specialist nurses are ideally placed to identify patients with monogenic diabetes but may lack knowledge of the key features and fail to recognise potential cases. Once the diagnosis of diabetes has been made this may not be revisited and may be assumed to be correct. However, increasing knowledge and awareness of monogenic diabetes will allow health care professionals to question the diagnosis of their patients where appropriate and lead to greater recognition and correct treatment of monogenic diabetes. Maturity onset diabetes of the young (MODY) is typically detected in individuals diagnosed with diabetes before the age of 25 years who also have a parent with diabetes. They are non-insulin dependent but are often mistaken to have type 1 diabetes and are insulin treated. Patients meeting these criteria should be considered for further investigation to ensure their diagnosis is correct. Neonatal diabetes can also be caused by a single genetic change, and patients diagnosed with diabetes within the first six months of life should be referred for genetic testing whatever their current age. This paper highlights three useful means of aiding differential diagnosis: urinary C-peptide creatinine ratio (UCPCR), pancreatic autoantibodies, and use of the online MODY probability calculator. Case studies are used to illustrate the key diagnostic features of MODY and indicate how awareness of family history and other features raised suspicion of an alternative cause of diabetes in these families. Treatment change following a positive molecular genetic diagnosis is also described. [ABSTRACT FROM AUTHOR]

The HNF1αp291fsinsC truncation is the most common mutation associated with maturity-onset diabetes of the young 3 (MODY3). Although shown to impair HNF1α signaling, the mechanism by which HNF1αp291fsinsC causes MODY3 is not fully understood. Here we use MODY3 patient and CRISPR/Cas9-engineered human induced pluripotent stem cells (hiPSCs) grown as 3D organoids to investigate how HNF1αp291fsinsC affects hiPSC differentiation during pancreatic development. HNF1αp291fsinsC hiPSCs shows reduced pancreatic progenitor and β cell differentiation. Mechanistically, HNF1αp291fsinsC interacts with HNF1β and inhibits its function, and disrupting this interaction partially rescues HNF1β-dependent transcription. HNF1β overexpression in the HNF1αp291fsinsC patient organoid line increases PDX1+ progenitors, while HNF1β overexpression in the HNF1αp291fsinsC patient iPSC line partially rescues β cell differentiation. Our study highlights the capability of pancreas progenitor-derived organoids to model disease in vitro. Additionally, it uncovers an HNF1β-mediated mechanism linked to HNF1α truncation that affects progenitor differentiation and could explain the clinical heterogeneity observed in MODY3 patients. [Display omitted] • MODY3 patient and CRISPR/Cas9 HNF1αp291fsinsC mutated iPSC lines are generated • Mutant iPSCs show deficient pancreatic progenitor and β cell differentiation • Mutant truncated HNF1α protein binds wild-type HNF1β protein to hinder its function • HNF1β overexpression in MODY3 iPSC line partially rescues β cell differentiation Cujba et al. use human MODY3 patient and CRISPR/Cas9 edited iPSC lines to show that the HNF1αp291fsinsC mutation results in the expression of a mutant truncated HNF1α protein that interacts with wild-type HNF1β protein and inhibits its function, impairing pancreatic progenitor and β cell differentiation. [ABSTRACT FROM AUTHOR]

Monogenic diabetes is poorly recognised but identification is important as many people may be successfully managed with sulphonylureas rather than insulin (Pearson et al, 2000; Stride and Hattersley, 2002; Pearson et al, 2003; Shepherd et al, 2003; Hattersley, 2005). Ensuring the correct diagnosis also allows appropriate follow up and counselling of family members (Shepherd et al, 2010). The Genetic Diabetes Nurse (GDN) project was set up in 2002 to increase awareness of monogenic diabetes (Dudding et al, 2005; Shepherd et al, 2005) and prior to the appointment of a GDN for Sussex in 2005, only one person had a confirmed diagnosis of monogenic diabetes in the Brighton and Hove area. This paper describes how training a GDN improved care through the identification of 54 people with monogenic diabetes and the establishment of a specialist clinic. [ABSTRACT FROM AUTHOR]

Aims: HaemoglobinA1c (HbA1c) is recommended for diabetes diagnosis but fasting plasma glucose (FPG) has been useful for identifying patients with glucokinase (GCK) mutations which cause lifelong persistent fasting hyperglycaemia. We aimed to derive age-related HbA1c reference ranges for these patients to determine how well HbA1c can discriminate patients with a GCK mutation from unaffected family members and young-onset type 1 (T1D) and type 2 diabetes (T2D) and to investigate the proportion of GCK mutation carriers diagnosed with diabetes using HbA1c and/or FPG diagnostic criteria. Methods: Individuals with inactivating GCK mutations (n = 129), familial controls (n = 100), T1D (n = 278) and T2D (n = 319) aged ≥18years were recruited. Receiver Operating Characteristic (ROC) analysis determined effectiveness of HbA1c and FPG to discriminate between groups. Results: HbA1c reference ranges in subjects with GCK mutations were: 38–56 mmol/mol (5.6–7.3%) if aged ≤40years; 41–60 mmol/mol (5.9–7.6%) if >40years. All patients (123/123) with a GCK mutation were above the lower limit of the HbA1c age-appropriate reference ranges. 69% (31/99) of controls were below these lower limits. HbA1c was also effective in discriminating those with a GCK mutation from those with T1D/T2D. Using the upper limit of the age-appropriate reference ranges to discriminate those with a mutation from those with T1D/T2D correctly identified 97% of subjects with a mutation. The majority (438/597 (73%)) with other types of young-onset diabetes had an HbA1c above the upper limit of the age-appropriate GCK reference range. HbA1c ≥48 mmol/mol classified more people with GCK mutations as having diabetes than FPG ≥7 mmol/l (68% vs. 48%, p = 0.0009). Conclusions: Current HbA1c diagnostic criteria increase diabetes diagnosis in patients with a GCK mutation. We have derived age-related HbA1c reference ranges that can be used for discriminating hyperglycaemia likely to be caused by a GCK mutation and aid identification of probands and family members for genetic testing. [ABSTRACT FROM AUTHOR]

Although type 1 diabetes accounts for most cases of diabetes presenting in childhood, skills and knowledge enabling paediatric teams to confidently identify other forms of diabetes are clearly required. Ensuring correct diagnosis by recognising cases of "non-type 1" diabetes in children and young people is crucial as it has implications for treatment and follow up. This article highlights three cases of diabetes presenting in children with features suggesting potential monogenic causes of diabetes. The cases include hepatocyte nuclear factor 1-alpha maturity onset diabetes of the young (MODY), glucokinase MODY and KCNJ11 neonatal diabetes. The implications of the correct diagnosis are also discussed. [ABSTRACT FROM AUTHOR]

We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency. [ABSTRACT FROM AUTHOR]

Misdiagnosis of monogenic diabetes is common and can lead to years of unnecessary insulin treatment. Aids to diagnosis are available and can differentiate between maturity onset diabetes of the young and type 1 diabetes; however, these are seldom used routinely in clinical practice. This article provides details of these aids and illustrates their use in ensuring the correct diagnosis in a case study, highlighting their importance in terms of both appropriate treatment and follow-up of family members. [ABSTRACT FROM AUTHOR]

Background: Urinary C-peptide creatinine ratio (UCPCR) is a non-invasive and convenient way of assessing endogenous insulin production. Adjusting for urine creatinine levels allows for differences in urine concentration. Creatinine excretion is known to be higher in men due to gender differences in muscle mass. We investigated the impact of gender on UCPCR. Methods: One hundred and seventy-six subjects underwent a mixed meal tolerance test (MMTT). We looked at the relationship between UCPCR on urine C-peptide and creatinine excretion rates using timed post-meal urine samples. A further 415 subjects had two-hour post-meal UCPCR measurements in order to derive gender-specific percentiles for different diabetes subgroups and controls. Results: UCPCR was 1.48-fold higher in women (n = 78) than men (n = 98), median (interquartile range [IQR]): 1.88 (0.49-3.49) men versus 2.88 (1.58-4.91) nmol μmol-1 women, P = 0.01. This reflects a gender difference in creatinine excretion rates (11.5 [8.3-13.7] men versus 8.2 [5.6-9.1] women mmol min-1 P, 0.001). C-peptide excretion rate was similar in men and women (19.8 [5.2-37.0] versus 22.1 [7.4-40.5] pmol min-1, P = 0.7). UCPCR was higher in women in all subgroups defined by diabetes classification and treatment, except long-term type 1 diabetes in whom C-peptide secretion was minimal. Conclusions: Gender affects UCPCR, with higher values found in women. This results from lower urine creatinine reflecting gender differences in muscle mass. This necessitates gender-specific ranges for accurate interpretation of UCPCR results. [ABSTRACT FROM AUTHOR]

The authors report an adolescent who was found to have diabetes on routine blood testing. The initial diagnosis was type 2 diabetes because she was obese, did not have type 1 diabetes antibodies and both parents had diabetes. Highly sensitive C-reactive protein (hsCRP) was low in the proband and her father (≤0.1 mg/l) indicating that type 2 diabetes was unlikely, and that hepatocyte nuclear factor 1-α-maturity onset diabetes of the young (HNF1A-MODY) was the most likely diagnosis. Following a genetic diagnosis of HNF1A-MODY in the proband and her father, both patients were treated with gliclazide, with improvement in HbA1c. This case highlights the challenges of making a correct diagnosis of MODY in young onset diabetes. The authors report the first case where hsCRP, an easily available biomarker, has been used on an individual level to determine appropriate genetic testing of MODY in a family whose main differential diagnosis was familial type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on the reassessment of diabetic-diagnosed patients who are under 25 years old. It explores four cases that can help determine possible monogenic diabetes, involving the hepatocyte nuclear factor 1 alpha (HNF1A), glucokinase maturity onset diabetes of the young (MODY), and HNF 1 beta (HNF1B). Meanwhile, it suggests that patients diagnosed under the age of 25 years and who have diabetic patients still need assessment in order to assure the type and cause of their diabetes. INSETS: Case Study 1;Case Study 2;Case Study 3;Case Study 4

Objective: Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes.Research Design and Methods: Adults with diabetes for ≥ 5 years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes.Results: UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98-2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥ 0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98-2.90] vs. 2.47 nmol/mmol [1.4-4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64).Conclusions: UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years' duration, UCPCR could be used to determine whether genetic testing is indicated. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS--Adults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY In = 23], glucokinase MODY [n = 20], type 1 diabetes In = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS--UCPCR was lower in type i diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98-2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98-2.90] vs. 2.47 nmol/mmol [1.4-4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64). CONCLUSIONS--UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years' duration, UCPCR could be used to determine whether genetic testing is indicated. [ABSTRACT FROM AUTHOR]