An integrated primary care-based programme of PRE-Pregnancy cARE to improve pregnancy outcomes in women with type 2 Diabetes (The PREPARED study): protocol for a multi-method study of implementation, system adaptation and performance

Background: The number of women of childbearing age with Type 2 diabetes(T2DM) is increasing, and they now account for > 50% of pregnancies in women with pre-existing diabetes. Diabetes pregnancies without adequate pre-pregnancy care have higher risk for poor outcomes (miscarriages, birth-defects, stillbirths) and are associated with increased complications (caesarean deliveries, macrosomic babies, neonatal intensive-care admissions). The risks and costs of these pregnancies can be reduced with pregnancy preparation (HbA1c, ≤ 6.5%, 5 mg folic acid and stopping potentially harmful medicines). However, 90% of women with T2DM, most of whom are based in primary care, are not adequately prepared for pregnancy. This study will evaluate a programme of primary care-based interventions (decision-support systems; pre-pregnancy care-pathways; pregnancy-awareness resources; professional training; and performance monitoring) to improve pregnancy preparation in women with T2DM. Methods: The study aims to optimise the programme interventions and estimate their impact on pregnancy preparation, pre-pregnancy care uptake and pregnancy outcomes. To evaluate this multimodal intervention, we will use a multi-method research design following Complex Adaptive Systems (CAS) theory, refining the interventions iteratively during the study. Thirty GP practices with ≥ 25 women with T2DM of reproductive age (18–45 years) from two South London boroughs will be exposed to the intervention. This will provide > 750 women with an estimated pregnancy incidence of 80–100 to study. The research involves: a clinical audit of processes and outcomes; a process evaluation informing intervention feasibility, implementation, and behaviour change; and a cost-consequences analysis informing future economic evaluation. Performance data will be collected via audits of GP systems, hospital antenatal clinics and pregnancy outcomes. Following CAS theory, we will use repeated measurements to monitor intervention impact on pregnancy preparation markers at 4-monthly intervals over 18-months. We will use performance and feasibility data to optimise intervention effects iteratively. The target performance for the intervention is a 30% increase in the proportion of women meeting pre-pregnancy care criteria. Discussion: The primary output will be development of an integrated programme of interventions to improve pregnancy preparation, pre-pregnancy care uptake, and reduce adverse pregnancy outcomes in women with T2DM. We will also develop an implementation plan to support the introduction of the interventions across the NHS

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research

Oceanographic processes and products around the Iberian margin: a new multidisciplinary approach

Our understanding of the role of bottom currents and associated oceanographic processes (e.g., overflows, barotropic tidal currents) including intermittent processes (e.g., vertical eddies, deep sea storms, horizontal vortices, internal waves and tsunamis) is rapidly evolving. Many deep-water processes remain poorly understood due to limited direct observations, but may generate significant depositional and erosional features on both short- and long-term time scales. This paper describes these oceanographic processes and examines their potential role in the sedimentary features around the Iberian margin. The paper explores the implications of the processes studied, given their secondary role relative to other factors such as mass-transport and turbiditic processes. An integrated interpretation of these oceanographic processes requires an understanding of contourites, sea-floor features, their spatial and temporal evolution, and the near-bottom flows that form them. Given their complex, three-dimensional and temporally-variable nature, integration of these processes into sedimentary, oceanographic and climatological frameworks will require a multidisciplinary approach that includes Geology, Physical Oceanography, Paleoceanography and Benthic Biology. This approach will synthesize oceanographic data, seafloor morphology, sediments and seismic images to improve our knowledge of permanent and intermittent processes around Iberia, and evaluate their conceptual and regional role in the sedimentary evolution of the margin.Department of Earth Sciences, University of Gothenburg. SueciaDepartment of Geoscience, University of Bremen. AlemaniaDepartment of Earth Sciences, Royal Holloway University, Reino UnidoCentro Andaluz de Ciencia y Tecnología Marinas, EspañaInstituto de Ciencias del Mar, EspañaInstituto Geológico y Minero de España, EspañaInstitut für Meereskunde, Universität Hamburg, AlemaniaFacultade de Ciencias do Mar, Universidad de de Vigo, EspañaIstituto Nazionale di Oceanografia e di Geofisica Sperimentale, ItaliaVankgroep Geologie en Bodemwetenschappen, Universiteit Gent, BélgicaCentro oceanográfico de Gijón, Instituto Español de Oceanografía, EspañaCentro oceanográfico de Santander, Instituto Español de Oceanografía, EspañaInstituto de Ciencias Marinas de Andalucía, EspañaInstituto Español de Oceanografía, EspañaChevron Upstream Europe, Chevron North Sea Limited, Reino UnidoMarine Sedimentation Systems Group, Center for Marine Environmental Sciences, University of Bremen. AlemaniaSchool of Coastal and Marine Systems Sciences, Coastal Carolina University, Estados UnidosCentro oceanográfico de Cádiz, Instituto Español de Oceanografía, EspañaGrupo de Oceanografía Física, Universidad de Málaga, EspañaInstitute of Petroleum Engineering, Heriot-Watt Univ.ersity, Reino UnidoShell International Exploration & Production, Países Bajo

The effect of thiazolidinediones on lipoprotein metabolism: A double blind randomised placebo controlled trial using stable isotopes to investigate the effect of pioglitazone, rosiglitazone and placebo on lipoprotein(apolipoprotein B100, VLDL, IDL and LDL) metabolism.

+/- 0.82) with well controlled diabetes (mean HbAlc7.02% +/- 0.15), and lipids (mean total cholesterol 4.91mmol/l +/- 0.17, mean HDL cholesterol 1.21mmol/l +/- 0.06, median triglyceride 1.61 mmol/1 [1.22, 1.97]) at baseline. Following treatment there was a significant reduction in HbAlc in the rosiglitazone (-0.48%, p < 0.05) and the pioglitazone group (-0.71%, p < 0.05), a significant reduction in free fatty acids in both active treatment groups but no change in any other lipid variable. There was a significant reduction in VLDL apo B absolute secretion rate in the rosiglitazone group (-2.19nig/kg/day, p = 0.017) but no change in catabolic rate in any group and no change in IDL or LDL metabolism. These results were not as expected and reasons for this are discussed

The effect of thiazolidinediones on lipoprotein metabolism: A double blind randomised placebo controlled trial using stable isotopes to investigate the effect of pioglitazone, rosiglitazone and placebo on lipoprotein(apolipoprotein B100, VLDL, IDL and LDL) metabolism.

+/- 0.82) with well controlled diabetes (mean HbAlc7.02% +/- 0.15), and lipids (mean total cholesterol 4.91mmol/l +/- 0.17, mean HDL cholesterol 1.21mmol/l +/- 0.06, median triglyceride 1.61 mmol/1 [1.22, 1.97]) at baseline. Following treatment there was a significant reduction in HbAlc in the rosiglitazone (-0.48%, p < 0.05) and the pioglitazone group (-0.71%, p < 0.05), a significant reduction in free fatty acids in both active treatment groups but no change in any other lipid variable. There was a significant reduction in VLDL apo B absolute secretion rate in the rosiglitazone group (-2.19nig/kg/day, p = 0.017) but no change in catabolic rate in any group and no change in IDL or LDL metabolism. These results were not as expected and reasons for this are discussed

Nonmetabolic Complications of Continuous Subcutaneous Insulin Infusion:A Patient Survey

Background: Little is known about the frequencies and types of nonmetabolic complications occurring in type 1 diabetes patients being treated by modern insulin pump therapy (continuous subcutaneous insulin infusion [CSII]), when recorded by standardized questionnaire rather than clinical experience. Subjects and Methods: A self-report questionnaire was completed by successive subjects with type 1 diabetes attending an insulin pump clinic, and those with a duration of CSII of ≥6 months were selected for analysis (n=92). Questions included pump manufacturer, insulin, infusion set type and duration of use, frequency of infusion set and site problems, pump malfunctions, and patient-related problems such as weight change since starting CSII. Results: Median (range) duration of CSII was 3.3 (0.5–32.0) years, and mean±SD duration of infusion set use was 3.2±0.7 (range 2–6) days. The commonest infusion set problems were kinking (64.1% of subjects) and blockage (54.3%). Blockage was associated with >3 days of use of infusion sets plus lispro insulin in the pump (relative risk [95% confidence interval], 1.71 [1.03–2.85]; P=0.07). The commonest infusion site problem was lipohypertrophy (26.1%), which occurred more often in those with long duration of CSII (4.8 [2.38–9.45] vs. 3.0 [1.50–4.25] years; P=0.01). Pump malfunction had occurred in 48% of subjects (43% in the first year of CSII), with “no delivery,” keypad, and battery problems commonly occurring. Although some patients reported weight gain (34%) and some weight loss (15%) on CSII, most patients (51%) reported no change in weight. Conclusions: Pump, infusion set, and infusion site problems remain common with CSII, even with contemporary technology

Diabetes technology including automated insulin delivery systems to manage hyperglycemia in a failing pancreatic graft: Case series of people with type 1 diabetes and a pancreas kidney or pancreas‐only transplant

Abstract We share our experience of using continuous subcutaneous insulin infusion (CSII) therapy and diabetes technology in six people (5 men) with type 1 diabetes (mean duration 36 years), who developed hyperglycemia post‐simultaneous kidney/pancreas (n = 5) or pancreas only (n = 1) transplant. All were on immunosuppression and multiple daily injections of insulin prior to CSII. Four people were started on automated insulin delivery, and two people on CSII and intermittently scanned continuous glucose monitoring. With diabetes technology, the median time in range glucose improved from 37% (24–49%) to 56.6% (48–62%), and similarly, glycated hemoglobin fell from 72.7 mmol/mol (72–79 mmol/mol) to 64 mmol/mol (42–67 mmol/mol; P < 0.05 for both) with no concomitant increase in hypoglycemia. Use of diabetes technology improved glycemic parameters in people with type 1 diabetes with failing pancreatic graft function. Early use of such technology should be considered to improve diabetes control in this complex cohort