Management of pregnancy in women with monogenic diabetes due to mutations in GCK, HNF1A and HNF4A genes.

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive ß-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

Postoperative mortality and complications in patients with and without pre-operative SARS-CoV-2 infection: a service evaluation of 24 million linked records using OpenSAFELY.

Surgical decision-making after SARS-CoV-2 infection is influenced by the presence of comorbidity, infection severity and whether the surgical problem is time-sensitive. Contemporary surgical policy to delay surgery is informed by highly heterogeneous country-specific guidance. We evaluated surgical provision in England during the COVID-19 pandemic to assess real-world practice and whether deferral remains necessary. Using the OpenSAFELY platform, we adapted the COVIDSurg protocol for a service evaluation of surgical procedures that took place within the English NHS from 17 March 2018 to 17 March 2022. We assessed whether hospitals adhered to guidance not to operate on patients within 7 weeks of an indication of SARS-CoV-2 infection. Additional outcomes were postoperative all-cause mortality (30 days, 6 months) and complications (pulmonary, cardiac, cerebrovascular). The exposure was the interval between the most recent indication of SARS-CoV-2 infection and subsequent surgery. In any 6-month window, < 3% of surgical procedures were conducted within 7 weeks of an indication of SARS-CoV-2 infection. Mortality for surgery conducted within 2 weeks of a positive test in the era since widespread SARS-CoV-2 vaccine availability was 1.1%, declining to 0.3% by 4 weeks. Compared with the COVIDSurg study cohort, outcomes for patients in the English NHS cohort were better during the COVIDSurg data collection period and the pandemic era before vaccines became available. Clinicians within the English NHS followed national guidance by operating on very few patients within 7 weeks of a positive indication of SARS-CoV-2 infection. In England, surgical patients' overall risk following an indication of SARS-CoV-2 infection is lower than previously thought.

Subpolar North Atlantic western boundary density anomalies and the Meridional Overturning Circulation.

Changes in the Atlantic Meridional Overturning Circulation, which have the potential to drive societally-important climate impacts, have traditionally been linked to the strength of deep water formation in the subpolar North Atlantic. Yet there is neither clear observational evidence nor agreement among models about how changes in deep water formation influence overturning. Here, we use data from a trans-basin mooring array (OSNAP-Overturning in the Subpolar North Atlantic Program) to show that winter convection during 2014-2018 in the interior basin had minimal impact on density changes in the deep western boundary currents in the subpolar basins. Contrary to previous modeling studies, we find no discernable relationship between western boundary changes and subpolar overturning variability over the observational time scales. Our results require a reconsideration of the notion of deep western boundary changes representing overturning characteristics, with implications for constraining the source of overturning variability within and downstream of the subpolar region.

A sea change in our view of overturning in the subpolar North Atlantic.

To provide an observational basis for the Intergovernmental Panel on Climate Change projections of a slowing Atlantic meridional overturning circulation (MOC) in the 21st century, the Overturning in the Subpolar North Atlantic Program (OSNAP) observing system was launched in the summer of 2014. The first 21-month record reveals a highly variable overturning circulation responsible for the majority of the heat and freshwater transport across the OSNAP line. In a departure from the prevailing view that changes in deep water formation in the Labrador Sea dominate MOC variability, these results suggest that the conversion of warm, salty, shallow Atlantic waters into colder, fresher, deep waters that move southward in the Irminger and Iceland basins is largely responsible for overturning and its variability in the subpolar basin.

Subpolar North Atlantic Overturning and Gyre-Scale Circulation in the Summers of 2014 and 2016.

The Atlantic Meridional Overturning Circulation (AMOC) is a key component of the global climate system through its transport of heat and freshwater. The subpolar North Atlantic (SPNA) is a region where the AMOC is actively developed and shaped though mixing and water mass transformation and where large amounts of heat are released to the atmosphere. Two hydrographic transbasin sections in the summers of 2014 and 2016 provide highly spatially resolved views of the SPNA velocity and property fields on a line from Canada to Greenland to Scotland. Estimates of the AMOC, isopycnal (gyre-scale) transport, and heat and freshwater transport are derived from the observations. The overturning circulation, the maximum in northward transport integrated from the surface to seafloor and computed in density space, has a high range, with 20.6 ± 4.7 Sv in June-July 2014 and 10.6 ± 4.3 Sv in May-August 2016. In contrast, the isopycnal (gyre-scale) circulation was lowest in summer 2014: 41.3 ± 8.2 Sv compared to 58.6 ± 7.4 Sv in 2016. The heat transport (0.39 ± 0.08 PW in summer 2014, positive is northward) was highest for the section with the highest AMOC, and the freshwater transport was largest in summer 2016 when the isopycnal circulation was high (-0.25 ± 0.08 Sv). Up to 65% of the heat and freshwater transport was carried by the isopycnal circulation, with isopycnal property transport highest in the western Labrador Sea and the eastern basins (Iceland Basin to Scotland).

Prolonged episodes of hypoglycaemia in HNF4A-MODY mutation carriers with IGT. Evidence of persistent hyperinsulinism into early adulthood.

AIMS: HNF4A is an established cause of maturity onset diabetes of the young (MODY). Congenital hyperinsulinism can also be associated with mutations in the HNF4A gene. A dual phenotype is observed in HNF4A-MODY with hyperinsulinaemic hypoglycaemia in the neonatal period progressing to diabetes in adulthood. The nature and timing of the transition remain poorly defined. We performed an observational study to establish changes in glycaemia and insulin secretion over a 6-year period. We investigated glycaemic variability and hypoglycaemia in HNF4A-MODY using a continuous glucose monitoring system (CGMS). METHODS: An OGTT with measurement of glucose, insulin and C-peptide was performed in HNF4A participants with diabetes mellitus (DM) (n = 14), HNF4A-IGT (n = 7) and age- and BMI-matched MODY negative family members (n = 10). Serial assessment was performed in the HNF4A-IGT cohort. In a subset of HNF4A-MODY mutation carriers (n = 10), CGMS was applied over a 72-h period. RESULTS: There was no deterioration in glycaemic control in the HNF4A-IGT cohort. The fasting glucose-to-insulin ratio was significantly lower in the HNF4A-IGT cohort when compared to the normal control group (0.13 vs. 0.24, p = 0.03). CGMS profiling demonstrated prolonged periods of hypoglycaemia in the HNF4A-IGT group when compared to the HNF4A-DM group (432 vs. 138 min p = 0.04). CONCLUSIONS: In a young adult HNF4A-IGT cohort, we demonstrate preserved glucose, insulin and C-peptide secretory responses to oral glucose. Utilising CGMS, prolonged periods of hypoglycaemia are evident despite a median age of 21 years. We propose a prolonged hyperinsulinaemic phase into adulthood is responsible for the notable hypoglycaemic episodes.

Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort.

AIMS: HNF1A gene mutations are the most common cause of maturity-onset diabetes of the young (MODY) in the UK. Persons with HNF1A-MODY display sensitivity to sulphonylurea therapy; however, the long-term efficacy is not established. There is limited literature as to the prevalence of micro- and macrovascular complications in this unique cohort. The aim of this study was to determine the natural progression and clinical management of HNF1A-MODY diabetes in a dedicated MODY clinic. METHODS: Sixty patients with HNF1A-MODY and a cohort of 60 BMI-, age-, ethnicity- and diabetes duration-matched patients with Type 1 diabetes mellitus participated in the study. All patients were phenotyped in detail. Clinical follow-up of the HNF1A-MODY cohort occurred on a bi-annual basis. RESULTS: Following a genetic diagnosis of MODY, the majority of the cohort treated with sulphonylurea therapy remained insulin independent at 84-month follow-up (80%). The HbA1c in the HNF1A-MODY group treated with sulphonylurea therapy alone improved significantly over the study period [from 49 (44-63) mmol/mol, 6.6 (6.2-7.9)% to 41 (31-50) mmol/mol, 5.9 (5-6.7)%; P = 0.003]. The rate of retinopathy was significantly lower than that noted in the Type 1 diabetes mellitus group (13.6 vs. 50%; P = 0.0001).There was also a lower rate of microalbuminuria and cardiovascular disease in the HNF1A-MODY group compared with the Type 1 diabetes mellitus group. CONCLUSIONS: This study demonstrates that the majority of patients with HNF1A-MODY can be maintained successfully on sulphonylurea therapy with good glycaemic control. We note a significantly lower rate of micro- and macrovascular complications than reported previously. The use of appropriate therapy at early stages of the disorder may decrease the incidence of complications.

Differential association of insulin resistance with cognitive and somatic symptoms of depression.

AIM: To examine the associations of depressive symptoms with insulin resistance, evaluating somatic and cognitive depressive symptoms separately. METHODS: A total of 328 individuals (mean age 60 years) referred for exercise stress testing, taking part in the Mechanisms and Outcomes of Silent Myocardial Ischemia study, completed the Beck Depression Inventory II. A fasting venous blood sample was collected for assessments of insulin and glucose level; the HOMA-IR (homeostatic model assessment of insulin resistance) was calculated. In principal component analysis, Beck Depression Inventory II items were forced to load onto two components (somatic and cognitive depressive symptoms). Adjusting for age, sex, BMI, medication use, smoking, physical activity, diabetes and cardiovascular disease, general linear model analyses were conducted to examine the associations between the components and log HOMA-IR . RESULTS: Principal component analysis showed that nine items loaded onto a cognitive depressive symptoms component and 10 items loaded onto a somatic depressive symptoms component. When examined separately, both components were significantly associated with log HOMA-IR however, when including both components simultaneously in the model, only somatic depressive symptoms remained significantly associated with log HOMA-IR. Back-transformed, a one-unit change in somatic depressive symptoms was associated with a 1.07 (95% CI 1.002, 1.14) change in HOMA-IR and a one-unit change in cognitive depressive symptoms was associated with a 1.03 (95% CI 0.97, 1.14) change in HOMA-IR. CONCLUSION: Somatic depressive symptoms seem to be more strongly associated with insulin resistance than do cognitive depressive symptoms. Monitoring somatic depressive symptoms may be more appropriate than monitoring cognitive depressive symptoms among depressed individuals with high insulin resistance.

Identification of circulating microRNAs in HNF1A-MODY carriers.

AIMS/HYPOTHESIS: HNF1A-MODY is a monogenic form of diabetes caused by mutations in the HNF1A gene. Here we identify, for the first time, HNF1A-MODY-associated microRNAs (miRNAs) that can be detected in the serum of HNF1A-MODY carriers. METHODS: An miRNA array was carried out in rat INS-1 insulinoma cells inducibly expressing the common human Pro291fsinsC-HNF1A frame shift mutation. Differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of miRNAs in the serum of HNF1A-MODY carriers (n = 31), MODY-negative family members (n = 10) and individuals with type 2 diabetes mellitus (n = 17) was quantified by absolute real-time PCR analysis. RESULTS: Inducible expression of Pro291fsinsC-HNF1A in INS-1 cells caused a significant upregulation of three miRNAs (miR-103, miR-224, miR-292-3p). The differential expression of two miRNAs (miR-103 and miR-224) was validated in vitro. Strongly elevated levels of miR-103 and miR-224 could be detected in the serum of HNF1A-MODY carriers compared with MODY-negative family controls. Serum levels of miR-103 distinguished HNF1A-MODY carriers from HbA1c-matched individuals with type 2 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers.

An evaluation of four CT-MRI co-registration techniques for radiotherapy treatment planning of prone rectal cancer patients.

OBJECTIVES: MRI is the preferred staging modality for rectal carcinoma patients. This work assesses the CT-MRI co-registration accuracy of four commercial rigid-body techniques for external beam radiotherapy treatment planning for patients treated in the prone position without fiducial markers. METHODS: 17 patients with biopsy-proven rectal carcinoma were scanned with CT and MRI in the prone position without the use of fiducial markers. A reference co-registration was performed by consensus of a radiologist and two physicists. This was compared with two automated and two manual techniques on two separate treatment planning systems. Accuracy and reproducibility were analysed using a measure of target registration error (TRE) that was based on the average distance of the mis-registration between vertices of the clinically relevant gross tumour volume as delineated on the CT image. RESULTS: An automated technique achieved the greatest accuracy, with a TRE of 2.3 mm. Both automated techniques demonstrated perfect reproducibility and were significantly faster than their manual counterparts. There was a significant difference in TRE between registrations performed on the two planning systems, but there were no significant differences between the manual and automated techniques. CONCLUSION: For patients with rectal cancer, MRI acquired in the prone treatment position without fiducial markers can be accurately registered with planning CT. An automated registration technique offered a fast and accurate solution with associated uncertainties within acceptable treatment planning limits.

Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications.

AIM: The prevalence of hepatocyte nuclear factor (HNF)-1A and HNF4A mutations, and the clinical implications following the genetic diagnosis of maturity-onset diabetes of the young (MODY) in the Irish population, remain unknown. The aim of this study was to establish the occurrence of HNF1A and HNF4A mutations in subjects classified clinically as MODY to identify novel mutations, and to determine the phenotypic features and response to therapy. METHODS: A total of 36 unrelated index cases with a clinical diagnosis of MODY were analyzed for HNF1A/HNF4A mutations. OGTT was performed to determine the degree of glucose tolerance and insulin secretory response. Also, 38 relatives underwent OGTT and were tested for the relevant known mutations. HNF1A-/HNF4A-MODY subjects were compared with nine HNF1A mutation-negative relatives and 20 type 2 diabetic (T2DM) patients. RESULTS: Seven different HNF1A mutations were identified in 11/36 (30.5%) index cases, two of which were novel (S352fsdelG and F426X), as well as two novel HNF4A mutations (M1? and R290C; 6%). Family screening revealed 20 subjects with HNF1A and seven with HNF4A mutations. Only 51.6% of HNF1A mutation carriers were diagnosed with diabetes by age 25 years; 11 of the mutation carriers were overweight and four were obese. Insulin secretory response to glucose was significantly lower in HNF1A-MODY subjects than in T2DM patients and HNF1A mutation-negative relatives (P=0.01). Therapeutic changes occurred in 48% of mutation carriers following genetic diagnosis. CONCLUSION: There was an HNF1A-MODY pick-up rate of 30.5% and an HNF4A-MODY pick-up rate of 6% in Irish MODY families. Genetically confirmed MODY has significant therapeutic implications.

Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics.

Venous thromboembolism (VTE) is a clinically important complication for both hospitalised and ambulatory cancer patients. In the current study, the frequency, demographics and risk (according to tumour site) of VTE were examined among patients seen at outpatient DVT (deep-vein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed with cancer, for an overall rate of cancer-associated VTE of 13.6% in this outpatient population. Patients with cancer-associated VTE were significantly older than cancer-free VTE cases (66.4 +/- 12.7 vs. 58.8 +/- 18.5 years; p<0.0001). The frequency of cancer-associated VTE peaked earlier among females than males, occurring in the sixth (137/639, 21.4% vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs. 197/1096, 18%; p=0.036). VTE was described most frequently in common cancers - breast, prostate, colorectal and lung (56.1% of cases). The risk of VTE varied widely across 17 cancer types. Calculating odds ratios (OR) to assess the effect size of cancer type on VTE risk, the highest odds were observed for patients with pancreatic cancer (OR 9.65, 95% confidence interval [CI] (5.51-16.91). Tumours of the head and neck had higher odds than previously reported (OR 8.24, 95% CI 5.06-13.42). Reduced risk estimates were observed for skin cancers (melanoma and non-melanoma: OR 0.89, 95% CI 0.42-1.87; OR 0.74, 95% CI, 0.32-1.69, respectively). We conclude that outpatients have a similar rate of cancer-associated VTE as VTE patient populations previously reported, that cancer-associated VTE occurs in an older age group and earlier in females and that outpatients exhibit distinct tumour site-specific risk from that described among hospitalised cancer patients.

Modeling trophoblast differentiation using equine chorionic girdle vesicles.

The chorionic girdle of the equine conceptus is comprised of specialized trophoblast cells which, at day 36-38 of equine pregnancy, gain an invasive phenotype and invade the endometrium to form endometrial cups. Studies of equine endometrial cups remain difficult to perform because of the invasive techniques required to obtain cup tissue and because sampling requires termination of the pregnancy. In this study we developed a system to model trophoblast differentiation and trophoblast-immune interactions in vitro and in vivo. We utilized a method of culturing chorionic girdle pieces in serum-free medium to promote spontaneous formation of vesicle structures enriched for terminally differentiated binucleate cells that secreted equine chorionic gonadotrophin (eCG). Immunohistochemical staining and scanning electron microscopy showed that the cells of the vesicles closely resembled the outer layers of chorionic girdle immediately prior to invasion. Chorionic girdle vesicles were harvested after 72h in culture and ectopically transplanted via injection into the vulvar mucosa of recipient mares. At 7, 14, 21 and 28days after transplantation, biopsies of the injection sites were obtained. Immunohistochemical labeling of cryostat sections of the biopsies with a panel of monoclonal antibodies to horse trophoblast molecules demonstrated survival, differentiation, and presence of trophoblast cells for at least 21days. Serial sections of the biopsies labeled with antibodies to the equine lymphocyte surface markers CD4 and CD8, together with lymphocyte microcytotoxicity assays, revealed that the recipients mounted both cellular and humoral antibody immune responses to the transplanted trophoblast cells. This new method for culturing equine chorionic girdle trophoblast cells, and for transplanting trophoblast vesicles to ectopic sites, should allow identification of key aspects of trophoblast differentiation and the interactions that occur between invasive trophoblast and the maternal immune system.

Experience applying the UK meticillin-resistant Staphylococcus aureus (MRSA) guidelines in a tertiary referral hospital in the United Arab Emirates 1999-2002: same guidelines, different cultures.

Meticillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial pathogen worldwide. There are few reports concerning MRSA in the United Arab Emirates (UAE). We report our experience with MRSA in a 400-bed tertiary referral hospital in the UAE, which followed the UK MRSA guidelines. MRSA data were reviewed to include demographic and clinical data on all new MRSA cases; a review of the ward environment including number of single rooms, sinks, toilets and bathrooms, frequency of cleaning; cultural observations; and number of infection control personnel per beds. MRSA was an uncommon pathogen. There were 90 new MRSA cases from 1999 to 2002 including two clusters of MRSA. While the procedures followed were the same as those in the UK, there were differences in the hospital environment compared with the UK and in cultural aspects of the patients' behaviour. At least 70% of inpatients were in single rooms with ensuite bathrooms. It was rare for more than two patients to share a toilet or bathroom. There were fewer than recommended infection control personnel and no antibiotic restriction policy in the hospital. Cleaners were on the wards for >100 h per week and were available 24 h per day for rapid response. We conclude that there are many factors that influence the management and control of MRSA, including cultural and social behaviour.

The role of ischaemia and pain in the blood pressure response to exercise stress testing in patients with coronary heart disease.

Silent myocardial ischaemia is a common phenomenon in patients with coronary heart disease. However, very little is known about the underlying mechanisms of silent ischaemia. One potential pathway that may contribute to this absence of pain is increased blood pressure. The main aim of the current study was to assess the associations among blood pressure, pain and ischaemia in patients undergoing a standard exercise stress test. We hypothesized that patients who experienced chest pain during exercise would have lower baseline and peak blood pressures compared to those who did not experience chest pain. A total of 1,355 patients (418 women) who underwent a single-photon emission computed tomography treadmill exercise stress test and had not experienced a cardiac event in the past 2 weeks participated in the current study. Myocardial perfusion defects were assessed at rest and during the stress challenge. Systolic blood pressure (SBP), diastolic blood pressure, heart rate (HR) and rate pressure product (RPP) were assessed during rest and at peak exercise. There were no main effects of either pain or ischaemia on the baseline cardiovascular variables. Peak exercise data revealed main effects of pain on SBP, RPP and HR, and main effects of ischaemia on SBP and RPP, controlling for age, sex, baseline level, medication status and cardiac history. These findings suggest that acute rather than chronic increases in blood pressure may be one mechanism to explain the phenomena of silent myocardial ischaemia in cardiac patients, and may potentially provide a target for future treatment strategies.

Short communication: A method for verified access when using soft copy display.

Soft copy display is a rapidly developing area. To date, most soft copy systems can be classed by their application, e.g. review or reporting. With technology convergence this distinction is becoming less defined by the hardware and more defined by the software functionality. Although it is accepted that routine quality assurance should be conducted on soft copy monitors, this would be logistically difficult to achieve if any monitor within a hospital could be used for image review or reporting. This work proposes a simple psychophysical check to ensure optimal display performance before viewing software can be run. This is in the form of a challenge/response code constructed from letters just above the threshold of detection. This verified login would act as a portal to launching the image viewing software. The developed system was tested on three different types of monitor and five observers. Results indicate that the verified login was able to control access for displays below the optimal settings but was not as sensitive for adjustments above the optimum. However it is believed this is still of value as the lower presentation will compress the display gamma curve and reduce detail contrast. It also provides a minimum level of audit and quality control that might otherwise be missing.