The effect of increased fruit and vegetable consumption on blood pressure and lipids: a pooled analysis of six randomised controlled fruit and vegetable intervention trials.

BACKGROUND: Increasing fruit and vegetable (FV) consumption is associated with reduced cardiovascular disease risk in observational studies but with little evidence from randomised controlled trials (RCTs). The impact of concurrent pharmacological therapy is unknown. OBJECTIVE: To pool data from six RCTs to examine the effect of increasing FV intake on blood pressure (BP) and lipid profile, also exploring whether effects differed by medication use. DESIGN: Across trials, dietary intake was assessed by diet diaries or histories, lipids by routine biochemical methods and BP by automated monitors. Linear regression provided an estimate of the change in lipid profile or BP associated with a one portion increase in self-reported daily FV intake, with interaction terms fitted for medication use. RESULTS: The pooled sample included a total of 554 participants (308 males and 246 females). Meta-analysis of regression coefficients revealed no significant change in either systolic or diastolic BP per portion FV increase, although there was significant heterogeneity across trials for systolic BP (I2 = 73%). Neither adjusting for change in body mass index, nor analysis according to use of anti-hypertensive medication altered the relationship. There was no significant change in lipid profile per portion FV increase, although there was a significant reduction in total cholesterol among those not on lipid-lowering therapy (P < 0.05 after Bonferroni correction). CONCLUSION: Pooled analysis of six individual FV trials showed no impact of increasing intake on BP or lipids, but there was a total cholesterol-lowering effect in those not on lipid-lowering therapy.

Clinical management and outcome of head and neck paragangliomas (HNPGLs): A single centre retrospective study.

CONTEXT: Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined. OBJECTIVE: To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities. METHODS: Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023. RESULTS: There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04). CONCLUSION: The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes.

Mothers' experiences of a lifestyle intervention for weight reduction 12 months after gestational diabetes mellitus: Qualitative findings from the PAIGE2 study.

The standardised pooled prevalence of gestational diabetes mellitus (GDM) globally is approximately 14 %, a reflection of increasing rates of obesity in women of childbearing age. Lifestyle interventions to reduce GDM and subsequent type 2 diabetes (T2D) have been deemed a research priority but are challenging to perform and have variable success rates. The PAIGE2 study was a pragmatic lifestyle randomised controlled trial for women with GDM and body mass index ≥25 kg/m2, which began during pregnancy and continued for one year postnatally. The primary outcome was weight loss 12 months postnatally compared with mothers receiving standard maternity care. Qualitative results are presented from end of study focus groups conducted amongst intervention mothers to gather feedback and determine acceptability of the PAIGE2 intervention. In total, 19 mothers participated in five virtual focus groups. Content analysis explored general study experience, longer term changes to lifestyle and suggested improvements of intervention components including monthly phone calls, motivational text messages, Fitbit experience, Slimming World, and study contact timings. Overall, most mothers found the individual PAIGE2 intervention components enjoyable, although opinions differed as to which were the most effective. Several mothers claimed the intervention helped them make long-term changes to their behaviours. A common suggested improvement was the establishment of a local group where mothers could share their experiences. In conclusion, most mothers deemed the intervention acceptable, and felt that with minor enhancements, it could be utilised as an effective tool to support weight loss after pregnancy and reduce future risk of obesity and T2D.

Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes.

BACKGROUND: Hybrid closed-loop insulin therapy has shown promise for management of type 1 diabetes during pregnancy; however, its efficacy is unclear. METHODS: In this multicenter, controlled trial, we randomly assigned pregnant women with type 1 diabetes and a glycated hemoglobin level of at least 6.5% at nine sites in the United Kingdom to receive standard insulin therapy or hybrid closed-loop therapy, with both groups using continuous glucose monitoring. The primary outcome was the percentage of time in the pregnancy-specific target glucose range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]) as measured by continuous glucose monitoring from 16 weeks' gestation until delivery. Analyses were performed according to the intention-to-treat principle. Key secondary outcomes were the percentage of time spent in a hyperglycemic state (glucose level >140 mg per deciliter), overnight time in the target range, the glycated hemoglobin level, and safety events. RESULTS: A total of 124 participants with a mean (±SD) age of 31.1±5.3 years and a mean baseline glycated hemoglobin level of 7.7±1.2% underwent randomization. The mean percentage of time that the maternal glucose level was in the target range was 68.2±10.5% in the closed-loop group and 55.6±12.5% in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% confidence interval [CI], 7.0 to 14.0; P<0.001). Results for the secondary outcomes were consistent with those of the primary outcome; participants in the closed-loop group spent less time in a hyperglycemic state than those in the standard-care group (difference, -10.2 percentage points; 95% CI, -13.8 to -6.6); had more overnight time in the target range (difference, 12.3 percentage points; 95% CI, 8.3 to 16.2), and had lower glycated hemoglobin levels (difference, -0.31 percentage points; 95% CI, -0.50 to -0.12). Little time was spent in a hypoglycemic state. No unanticipated safety problems associated with the use of closed-loop therapy during pregnancy occurred (6 instances of severe hypoglycemia, vs. 5 in the standard-care group; 1 instance of diabetic ketoacidosis in each group; and 12 device-related adverse events in the closed-loop group, 7 related to closed-loop therapy). CONCLUSIONS: Hybrid closed-loop therapy significantly improved maternal glycemic control during pregnancy complicated by type 1 diabetes. (Funded by the Efficacy and Mechanism Evaluation Program; AiDAPT ISRCTN Registry number, ISRCTN56898625.).

A pragmatic lifestyle intervention for overweight and obese women with gestational diabetes mellitus (PAIGE2): A parallel arm, multicenter randomized controlled trial study protocol.

Background: The global epidemic of type 2 diabetes (T2D) and obesity has been translated into pregnancy, with approximately 18% of women being diagnosed worldwide with Gestational Diabetes Mellitus (GDM). Whilst preventive strategies have proven effective in the non-pregnant context, attrition rates are high and there is an urgent need to develop a customized, pragmatic lifestyle intervention for women both during and after pregnancy. Diet and exercise modification, behavioral support, and Commercial Weight Management Organizations have been strongly recommended to aid postpartum weight reduction for mothers with previous GDM, subsequently reducing their risk of developing obesity and T2D. This study, informed by a previous pilot study, aims to determine the effectiveness of a pragmatic pregnancy and postpartum lifestyle modification program for overweight women with previous GDM (PAIGE2) to reduce body weight at 12 months postpartum. Methods/design: This paper summarizes the protocol for the PAIGE2 study, which has been developed based on results from a pilot study (PAIGE). A six center, two parallel arm, 12-month, randomized controlled trial will be conducted across Northern Ireland and the Republic of Ireland (3 centers each), involving 340 women with GDM and body mass index ≥25 kg/m2 recruited during pregnancy. The lifestyle intervention involves a one-hour virtual educational program (to take place at 32-36 weeks gestation). Postpartum, the intervention will include monthly phone calls, weekly motivational text messages, weekly step counts, and referral for three months to a Commercial Weight Management Organization (Slimming World). The control arm will receive usual care as offered by the local maternity hospital. The primary outcome is weight loss at 12 months postpartum. Study visits for anthropometric and clinical measurements, fasting blood samples, questionnaires pertaining to health, wellbeing and physical activity will take place at 6 weeks, 6- and 12-months postpartum. Focus groups will be conducted with intervention mothers' post-intervention to determine the acceptability of the study design including utility of a Commercial Weight Management Organization, feasibility of remote patient contact, family involvement and patient satisfaction. Discussion: The PAIGE2 study will address the gaps in previously conducted research and, if positive, has the potential to have major public health implications for the prevention of future GDM and subsequent T2D. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04579016?term=NCT04579016&draw=2&rank=1, identifier NCT04579016.

The influence of diet and physical activity on bone density of children aged 5-7 years: The Belfast HAPO family study.

OBJECTIVE: Osteoporosis is a global health issue, and modifiable behavioural factors need to be identified in childhood to reduce the risk of osteoporosis in later life. The aim of this study was to investigate the influence of diet and physical activity on bone density of children aged 5-7 years participating in the Belfast Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Family study. DESIGN AND METHODS: Pregnant women were recruited to the Belfast centre of the HAPO study at 24-32 weeks gestation. Offspring were followed up at 5-7 years as part of the Belfast HAPO Family Study. Heel bone mineral density (BMD) and bone mineral apparent density (BMAD) were measured and calculated, respectively. Physical activity in the offspring was measured by accelerometery and dietary intakes were measured using a 4-day food diary. RESULTS: Results from 793 offspring were analysed. Mean age of the offspring ± standard deviation was 6.4 ± 0.5 years. A mean of 48.3 ± 22.4 min each day was spent in moderate to vigorous physical activity (MVPA). Median (interquartile range) dietary calcium and vitamin D intakes were 844 (662-1073) mg/day and 1.7 (1.1-2.5) µg/day, respectively. Neither dietary vitamin D nor calcium intakes were significantly associated with offspring heel BMD or BMAD in multiple regression. However, controlling for confounders, a 30-min greater MVPA was associated with significantly larger heel BMD (0.018 g/cm2 in boys and 0.010 g/cm2 in girls) and BMAD (0.005 g/cm3 in boys and 0.003 g/cm3 in girls). CONCLUSION: Physical activity was associated with better BMD and BMAD in 5-7-year-old children. Dietary calcium and vitamin D were not predictive of BMD and BMAD.

A peer support dietary change intervention for encouraging adoption and maintenance of the Mediterranean diet in a non-Mediterranean population (TEAM-MED): lessons learned and suggested improvements.

Peer support interventions for dietary change may offer cost-effective alternatives to interventions led by health professionals. This process evaluation of a trial to encourage the adoption and maintenance of a Mediterranean diet in a Northern European population at high CVD risk (TEAM-MED) aimed to investigate the feasibility of implementing a group-based peer support intervention for dietary change, positive elements of the intervention and aspects that could be improved. Data on training and support for the peer supporters; intervention fidelity and acceptability; acceptability of data collection processes for the trial and reasons for withdrawal from the trial were considered. Data were collected from observations, questionnaires and interviews, with both peer supporters and trial participants. Peer supporters were recruited and trained to result in successful implementation of the intervention; all intended sessions were run, with the majority of elements included. Peer supporters were complimentary of the training, and positive comments from participants centred around the peer supporters, the intervention materials and the supportive nature of the group sessions. Attendance at the group sessions, however, waned over the intervention, with suggested effects on intervention engagement, enthusiasm and group cohesion. Reduced attendance was reportedly a result of meeting (in)frequency and organisational concerns, but increased social activities and group-based activities may also increase engagement, group cohesion and attendance. The peer support intervention was successfully implemented and tested, but improvements can be suggested and may enhance the successful nature of these types of interventions. Some consideration of personal preferences may also improve outcomes.

Rollout of Closed-Loop Technology to Pregnant Women with Type 1 Diabetes: Healthcare Professionals' Views About Potential Challenges and Solutions.

Aims: To explore healthcare professionals' views about the training and support needed to rollout closed-loop technology to pregnant women with type 1 diabetes. Methods: We interviewed (n = 19) healthcare professionals who supported pregnant women using CamAPS FX closed-loop during the Automated insulin Delivery Amongst Pregnant women with Type 1 diabetes (AiDAPT) trial. Data were analyzed descriptively. An online workshop involving (n = 15) trial team members was used to inform recommendations. Ethics approvals were obtained in conjunction with those for the wider trial. Results: Interviewees expressed enthusiasm for a national rollout of closed-loop, but anticipated various challenges, some specific to use during pregnancy. These included variations in insulin pump and continuous glucose monitoring expertise and difficulties embedding and retaining key skills, due to the relatively small numbers of pregnant women using closed-loop. Inexperienced staff also highlighted difficulties interpreting data downloads. To support rollout, interviewees recommended providing expert initial advice training, delivered by device manufacturers together with online training resources and specific checklists for different systems. They also highlighted a need for 24 h technical support, especially when supporting technology naive women after first transitioning onto closed-loop in early pregnancy. They further recommended providing case-based meetings and mentorship for inexperienced colleagues, including support interpreting data downloads. Interviewees were optimistic that if healthcare professionals received training and support, their long-term workloads could be reduced because closed-loop lessened women's need for glycemic management input, especially in later pregnancy. Conclusions: Interviewees identified challenges and opportunities to rolling-out closed-loop and provided practical suggestions to upskill inexperienced staff supporting pregnant women using closed-loop. A key priority will be to determine how best to develop mentorship services to support inexperienced staff delivering closed-loop. Clinical Trials Registration: NCT04938557.

First-trimester glycaemic markers as predictors of gestational diabetes and its associated adverse outcomes: A prospective cohort study.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with excessive fetal growth in later gestation. Recent data suggest accelerated growth may begin before 28 weeks' gestation when GDM is typically diagnosed. The identification of pregnancies at risk of early fetal growth would enable early intervention. We assessed the use of early pregnancy HbA1c in predicting excessive fetal growth. RESEARCH DESIGN AND METHODS: Women were recruited at antenatal booking from a major maternity unit in the UK. HbA1c was measured at <14 weeks gestation in 1243 women at risk of GDM as defined by UK NICE risk factors of whom 1115 underwent OGTT. Women with previous GDM were excluded. Comprehensive fetal ultrasound was performed at 28 weeks' gestation alongside 75 g OGTT in 976 of these women. GDM was defined using WHO criteria. Pregnancy outcomes were extracted from the regional maternity care database. RESULTS: Two hundred and thirty-six women screened positive for GDM. At diagnosis, GDM pregnancies demonstrated higher adjusted fetal weight percentile than non-GDM pregnancies: (51.8 vs. 46.3, p = 0.008). This was driven by increases in the fetal abdominal circumference percentile in GDM compared with non-GDM pregnancies (55.3 vs. 46.2, p = <0.001). Early pregnancy HbA1c was higher in the GDM versus non-GDM group: (35.7 mmol/mol vs. 32.9 mmol/mol p = <0.01). A threshold for predicting excessive fetal growth was not identified in this cohort. CONCLUSIONS: Accelerated fetal growth is evident prior to the diagnosis of GDM. There remains a need for suitable methods of early identification of pregnancies at high risk for early accelerated fetal growth due to GDM. First-trimester HbA1c was not useful in identifying these pregnancies. NOVELTY STATEMENT: WHAT IS ALREADY KNOWN?: Recent research suggests excessive growth associated with GDM may begin prior to 28 weeks' gestation, when GDM is typically tested for WHAT THIS STUDY HAS FOUND?: Pregnancies affected by GDM are already subject to accelerated fetal growth in comparison to non-GDM pregnancies by way of higher estimated fetal weight and fetal abdominal circumference Neither first-trimester HbA1c nor plasma glucose was useful predictors of these outcomes WHAT ARE THE IMPLICATIONS OF THIS STUDY?: Highlights the emergence of excessive growth prior to detection of GDM Reinforces need for suitable methods of identifying such pregnancies in earlier gestation.

AiDAPT: automated insulin delivery amongst pregnant women with type 1 diabetes: a multicentre randomized controlled trial - study protocol.

BACKGROUND: Pregnant women with type 1 diabetes strive for tight glucose targets (3.5-7.8 mmol/L) to minimise the risks of obstetric and neonatal complications. Despite using diabetes technologies including continuous glucose monitoring (CGM), insulin pumps and contemporary insulin analogues, most women struggle to achieve and maintain the recommended pregnancy glucose targets. This study aims to evaluate whether the use of automated closed-loop insulin delivery improves antenatal glucose levels in pregnant women with type 1 diabetes. METHODS/DESIGN: A multicentre, open label, randomized, controlled trial of pregnant women with type 1 diabetes and a HbA1c of ≥48 mmol/mol (6.5%) at pregnancy confirmation and ≤ 86 mmol/mol (10%) at randomization. Participants who provide written informed consent before 13 weeks 6 days gestation will be entered into a run-in phase to collect 96 h (24 h overnight) of CGM glucose values. Eligible participants will be randomized on a 1:1 basis to CGM (Dexcom G6) with usual insulin delivery (control) or closed-loop (intervention). The closed-loop system includes a model predictive control algorithm (CamAPS FX application), hosted on an android smartphone that communicates wirelessly with the insulin pump (Dana Diabecare RS) and CGM transmitter. Research visits and device training will be provided virtually or face-to-face in conjunction with 4-weekly antenatal clinic visits where possible. Randomization will stratify for clinic site. One hundred twenty-four participants will be recruited. This takes into account 10% attrition and 10% who experience miscarriage or pregnancy loss. Analyses will be performed according to intention to treat. The primary analysis will evaluate the change in the time spent in the target glucose range (3.5-7.8 mmol/l) between the intervention and control group from 16 weeks gestation until delivery. Secondary outcomes include overnight time in target, time above target (> 7.8 mmol/l), standard CGM metrics, HbA1c and psychosocial functioning and health economic measures. Safety outcomes include the number and severity of ketoacidosis, severe hypoglycaemia and adverse device events. DISCUSSION: This will be the largest randomized controlled trial to evaluate the impact of closed-loop insulin delivery during type 1 diabetes pregnancy. TRIAL REGISTRATION: ISRCTN 56898625 Registration Date: 10 April, 2018.

Trial to Encourage Adoption and Maintenance of a MEditerranean Diet (TEAM-MED): a randomised pilot trial of a peer support intervention for dietary behaviour change in adults from a Northern European population at high CVD risk.

Adhering to a Mediterranean diet (MD) is associated with reduced CVD risk. This study aimed to explore methods of increasing MD adoption in a non-Mediterranean population at high risk of CVD, including assessing the feasibility of a developed peer support intervention. The Trial to Encourage Adoption and Maintenance of a MEditerranean Diet was a 12-month pilot parallel group RCT involving individuals aged ≥ 40 year, with low MD adherence, who were overweight, and had an estimated CVD risk ≥ 20 % over ten years. It explored three interventions, a peer support group, a dietician-led support group and a minimal support group to encourage dietary behaviour change and monitored variability in Mediterranean Diet Score (MDS) over time and between the intervention groups, alongside measurement of markers of nutritional status and cardiovascular risk. 118 individuals were assessed for eligibility, and 75 (64 %) were eligible. After 12 months, there was a retention rate of 69 % (peer support group 59 %; DSG 88 %; MSG 63 %). For all participants, increases in MDS were observed over 12 months (P < 0·001), both in original MDS data and when imputed data were used. Improvements in BMI, HbA1c levels, systolic and diastolic blood pressure in the population as a whole. This pilot study has demonstrated that a non-Mediterranean adult population at high CVD risk can make dietary behaviour change over a 12-month period towards an MD. The study also highlights the feasibility of a peer support intervention to encourage MD behaviour change amongst this population group and will inform a definitive trial.

Characteristics of pregnant women with diabetes using injectable glucose-lowering drugs in the EVOLVE study.

AIMS: To examine clinical parameters, glycemic control, folic acid supplementation, and the presence of other chronic diseases during early pregnancy in the EVOLVE study population (women with pre-existing diabetes treated with injectable glucose-lowering drugs). METHODS: Cross-sectional baseline evaluation of EVOLVE: an international, multicenter, non-interventional study investigating the safety of injectable glucose-lowering drugs in pregnant women with pre-existing type 1 (T1D) or type 2 diabetes (T2D). Data were collected at enrollment visit interviews before gestational week 16. RESULTS: In total, 2383 women from 17 mainly European countries were enrolled in the study: 2122 with T1D and 261 with T2D; mean age was 31 and 33 years, and duration of diabetes was 15 and 6 years, respectively. For women with T1D or T2D, 63% and 75%, respectively, received basal and rapid-acting insulin, 36% and 3% rapid-acting insulin only, 0.7% and 14.0% basal insulin only, 0.2% and 5.4% premix insulin, 0.0% and 1.2% injectable glucagon-like peptide-1 receptor agonist treatment without insulin. In women with T1D or T2D, respectively, during early pregnancy, 59% and 62% had HbA1c <7.0% (53 mmol/mol); 16% and 36% reported not taking folic acid before or during early pregnancy. Overall, >40% of women had ≥1 chronic concomitant condition (predominantly thyroid disease or hypertension). Retinopathy was the most commonly reported diabetic complication. The most commonly reported previous pregnancy complication was miscarriage. CONCLUSIONS: Baseline data from this large multinational population of women with pre-existing diabetes indicate that sub-optimal glycemic control, poor pregnancy planning, and chronic concomitant conditions were common in early pregnancy.

Risk of Major Congenital Malformations or Perinatal or Neonatal Death With Insulin Detemir Versus Other Basal Insulins in Pregnant Women With Preexisting Diabetes: The Real-World EVOLVE Study.

OBJECTIVE: To compare the risk of severe adverse pregnancy complications in women with preexisting diabetes. RESEARCH DESIGN AND METHODS: Multinational, prospective cohort study to assess the prevalence of newborns free from major congenital malformations or perinatal or neonatal death (primary end point) following treatment with insulin detemir (detemir) versus other basal insulins. RESULTS: Of 1,457 women included, 727 received detemir and 730 received other basal insulins. The prevalence of newborns free from major congenital malformations or perinatal or neonatal death was similar between detemir (97.0%) and other basal insulins (95.5%) (crude risk difference 0.015 [95% CI -0.01, 0.04]; adjusted risk difference -0.003 [95% CI -0.03, 0.03]). The crude prevalence of one or more congenital malformations (major plus minor) was 9.4% vs. 12.6%, with a similar risk difference before (-0.032 [95% CI -0.064, 0.000]) and after (-0.036 [95% CI -0.081, 0.009]) adjustment for confounders. Crude data showed lower maternal HbA1c during the first trimester (6.5% vs. 6.7% [48 vs. 50 mmol/mol]; estimated mean difference -0.181 [95% CI -0.300, -0.062]) and the second trimester (6.1% vs. 6.3% [43 vs. 45 mmol/mol]; -0.139 [95% CI -0.232, -0.046]) and a lower prevalence of major hypoglycemia (6.0% vs. 9.0%; risk difference -0.030 [95% CI -0.058, -0.002]), preeclampsia (6.4% vs. 10.0%; -0.036 [95% CI -0.064, -0.007]), and stillbirth (0.4% vs. 1.8%; -0.013 [95% CI -0.024, -0.002]) with detemir compared with other basal insulins. However, differences were not significant postadjustment. CONCLUSIONS: Insulin detemir was associated with a similar risk to other basal insulins of major congenital malformations, perinatal or neonatal death, hypoglycemia, preeclampsia, and stillbirth.

FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function.

Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.

Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment.

CONTEXT: Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. OBJECTIVE: To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. DESIGN AND INTERVENTION: FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. SETTINGS AND PARTICIPANTS: Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. MAIN OUTCOME MEASURES: Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. RESULTS: The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. CONCLUSIONS: The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.

Type 1 Diabetes in Pregnancy.

Congenital malformations and perinatal mortality rates remain severalfold higher in pregnant women with type 1 diabetes than in the background population, and still only a minority of women plan their pregnancy. Optimizing glycemic control is the accepted goal, but remains challenging, and must be constantly balanced against the risks of hypoglycemia. Recent advances including Continuous Glucose Monitoring Systems, Continuous Subcutaneous Insulin Infusion, Closed Loop Devices and very Fast Acting Insulin Aspart analogs offer new possibilities to increase glucose time in target in selected, motivated patients, however their relative roles and indication for use require further elucidation. The importance of education cannot be overstated.

Maternal Lipids at 28 Weeks' Gestation and Offspring Adiposity at Age 5 to 7 Years.

Context: Obesity is a global epidemic, and there is a focus on identifying markers of obesity in children with a view to prevention. Objective: We aimed to examine prospectively the association of maternal fasting lipids with adiposity in 5- to 7-year-old offspring in a large observational study. Design: Pregnant women (1612) were recruited to the Belfast center of the Hyperglycemia and Adverse Pregnancy Outcome study in a large tertiary maternity hospital at an average of 28 weeks' gestation. Maternal fasting total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and high-density lipoprotein-cholesterol were estimated at 28 weeks' gestation. Offspring-mother pairs (819) were included in the current study, and adiposity was expressed as body mass index (BMI) z score (1990 British growth standard) and sum of skin-fold (SSF) thicknesses (triceps, subscapular, and suprailiac). Statistical significance was more rigorously defined as P < 0.01 to allow for multiple comparisons. Results: No linear relation was found between maternal lipids and offspring BMI z score or SSFs (P ≥ 0.01) using correlation analysis. With the use of logistic regression, there was no relation between maternal lipids and offspring adiposity controlled for birthweight z score, offspring age, offspring gender, smoking during pregnancy, offspring energy intake and physical activity, maternal BMI during pregnancy, and fasting glucose during pregnancy (P ≥ 0.01). Conclusion: Maternal 28-week gestational fasting lipids are not associated with offspring BMI or subcutaneous adiposity at age 5 to 7 years.

Maternal vitamin D and neonatal anthropometrics and markers of neonatal glycaemia: Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study.

Vitamin D deficiency is a common occurrence globally, and particularly so in pregnancy. There is conflicting evidence regarding the role of vitamin D during pregnancy in non-skeletal health outcomes for both the mother and the neonate. The aim of this study was to investigate the associations of maternal total 25-hydroxy vitamin D (25OHD) with neonatal anthropometrics and markers of neonatal glycaemia in the Belfast centre of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Serological samples (n 1585) were obtained from pregnant women in the Royal Jubilee Maternity Hospital, Belfast, Northern Ireland, between 24 and 32 weeks' gestation as part of the HAPO study. 25OHD concentrations were measured by liquid chromatography tandem-MS. Cord blood and neonatal anthropometric measurements were obtained within 72 h of birth. Statistical analysis was performed. After adjustment for confounders, birth weight standard deviation scores (SDS) and birth length SDS were significantly associated with maternal total 25OHD. A doubling of maternal 25OHD at 28 weeks' gestation was associated with mean birth weight SDS and mean birth length SDS higher by 0·05 and 0·07, respectively (both, P=0·03). There were no significant associations with maternal 25OHD and other measures of neonatal anthropometrics or markers of neonatal glycaemia. In conclusion, maternal total 25OHD during pregnancy was independently associated with several neonatal anthropometric measurements; however, this association was relatively weak.

Postnatal Lifestyle Intervention for Overweight Women With Previous Gestational Diabetes: A Randomized Controlled Trial.

Background: Gestational diabetes mellitus (GDM) is associated with a sevenfold increased lifetime risk of type 2 diabetes. Excessive gestational weight gain and postpartum weight retention are established predictors of long-term obesity. Objective: To determine the impact of a postnatal lifestyle intervention program for overweight women with previous gestational diabetes mellitus (PAIGE). Design: Postnatal overweight women with previous GDM participated in a multicenter randomized controlled trial between June 2013 and December 2014. The intervention comprised a 1-hour educational program, a free 3-month referral to a commercial weight management organization (Slimming World), a pedometer, and structured telephone and text support, in addition to usual care. The control group received usual care only. The primary outcome was weight loss at 6 months. Results: Sixty women were randomized (29 intervention; 31 control) in two centers based on their week of attendance. The intervention group demonstrated significant weight loss at 6 months after randomization compared with the control group: mean ±SD, 3.9 ± 7.0 kg vs 0.7 ±3.8 kg (P = 0.02). Blood glucose levels did not significantly differ. With respect to well-being measures, a bodily pain was significantly reduced in the intervention group (P = 0.007). Conclusions: PAIGE resulted in significantly greater weight loss at 6 months compared with usual care. Such weight loss could prove beneficial in terms of better long-term health and subsequent prevention of type 2 diabetes in overweight women with previous GDM. Future interventions must consider recruitment strategies, timing of the intervention, and inclusion of partners and/or other family members.

Mortality in type 1 diabetes diagnosed in childhood in Northern Ireland during 1989-2012: A population-based cohort study.

OBJECTIVE: To investigate long-term mortality rates and causes of death in individuals diagnosed with type 1 diabetes before the age of 15 years during the period 1989-2012 or known to paediatric diabetes teams in 1989, in Northern Ireland. METHODS: A cohort of 3129 patients from the Northern Ireland Childhood Diabetes Register was linked to death registrations and underlying causes, coded according to ICD-9 or ICD-10. Standardized mortality ratios (SMRs) were calculated as the ratio of observed to expected deaths by sex, attained age, time since diagnosis, calendar period, and cause of death. RESULTS: Subjects were followed to December 31, 2012 giving 39 764 person-years of follow-up (median 12.1 years). In total, 59 subjects had died (1.5 per 1000 person-years) compared with 19.9 deaths expected, an SMR of 296 (95% confidence interval (CI) 229-382). Women had a significantly higher excess risk of mortality than men with SMRs of 535 (95% CI 361-764) and 203 (95% CI 136-291), respectively. Over half of the deaths (56%) were judged to be related or possibly related to diabetes with most of these due to acute (n = 24) or late (n = 6) complications. CONCLUSIONS: Subjects with type 1 diabetes diagnosed less than 15 years of age had 3 times the mortality risk of the general population. Over half of the deaths were related to acute or chronic complications of diabetes.