Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Heterozygous glucokinase (GCK) mutations cause mild, fasting hyperglycaemia from birth. Although patients are usually asymptomatic and have glycaemia within target ranges, some are put on pharmacological treatment. We aimed to investigate how many patients are on pharmacological treatment and the impact of treatment on glycaemic control.European Community’s Seventh Framework ProgrammeNIHR Exeter Clinical Research FacilityWellcome Trus

South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people.

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

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Higher Incidence but Similar Outcomes from Bloodstream Infections in People with Type 2 Diabetes Mellitus: A Retrospective Case-Controlled Analysis

Aims: People with type 2 diabetes mellitus are more susceptible to infections. This study aimed to compare the microbiology, incidence and clinical outcome of bloodstream infections (BSIs) in people with type 2 diabetes and matched controls amongst a cohort of hospital inpatients in the United Kingdom. Methods: A retrospective analysis was conducted on all positive blood cultures obtained over a one-year period, identifying inpatients with type 2 diabetes and BSIs (n = 151). Matched controls were collated from the same cohort. Admission data were obtained from clinical coding. Patient outcomes were analysed in terms of 90-day mortality, length of stay (LOS) and admission rate to high or intensive dependency units (HDU/ICU). Microbial culture and clinical source of infection were compared between groups. Results: Patients with type 2 diabetes comprised 10.6% of admissions but 21.1% (n = 151) of analysed BSIs (OR: 2.27, p < .001). Similar 90-day mortality rates were seen between people with type 2 diabetes (D) and controls (C) (D: 23/151, C: 28/151, p = .54). Mean LOS was also similar (D: 19.8 days, C: 21.1 days p = .62). In both groups, Escherichia coli was the most commonly isolated organism (D: 64/173, C: 55/171) and the urinary tract the most common identified primary site of BSI (D: 47/151, C: 45/151). Conclusions: Whilst inpatients with type 2 diabetes have increased odds of experiencing BSIs, our single-centre study suggests a diagnosis of type 2 diabetes does not necessarily confer a worse outcome

泌尿器科紀要 第40巻 (1994年) 物件索引

This is the final version of the article. Available from Springer Verlag via the DOI in this record.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(-1) day(-1) 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 HbA1c 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 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 HbA1c (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.This research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility, the Wellcome Trust and the European Research Council. FMA is a European Research Council Advanced Investigator and holds a Royal Society/Wolfson Merit Award. SE is a Wellcome Trust Senior Investigator. ATH is a Wellcome Trust Senior Investigator and a NIHR Senior Investigator

Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing.

This is the final version. Available from Springer via the DOI in this record. Data availability Individual-level data used in this study are not freely available to protect the identity of research participants. Information for researchers and protocols for the study and submissions to the Genetic Beta Cell Research Bank are available online (https://www.diabetesge nes.org/current-research/gck-mody-nipt/ and https://www.diabetesge nes.org/current-research/genetic-beta-cell-research-bank/). Requests for additional data specifically related to this work are available to researchers through managed open collaboration. Requests will be considered after liaising with the relevant study and ethics committees, and should be made in writing to the corresponding author, AT HattersleyAIMS/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.Wellcome TrustWellcome TrustNational Institute for Health Research (NIHR