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.).

Impact of COVID-19 on gestational diabetes pregnancy outcomes in the UK: A multicentre retrospective cohort study.

OBJECTIVE: To determine the impact of implementing emergency care pathway(s) for screening, diagnosing and managing women with gestational diabetes (GDM) during COVID-19. DESIGN: Retrospective multicentre cohort. SETTING: Nine National Health Service (NHS) Hospital Trusts/Health boards in England and Scotland. POPULATION: 4915 women with GDM pre-pandemic (1 April 2018 to 31 March 2020), and 3467 women with GDM during the pandemic (1 May 2020 to 31 March 2021). METHODS: We examined clinical outcomes for women with GDM prior to and during the pandemic following changes in screening methods, diagnostic testing, glucose thresholds and introduction of virtual care for monitoring of antenatal glycaemia. MAIN OUTCOME MEASURES: Intervention at birth, perinatal mortality, large-for-gestational-age infants and neonatal unit admission. RESULTS: The new diagnostic criteria more often identified GDM women who were multiparous, had higher body mass index (BMI) and greater deprivation, and less frequently had previous GDM (all p < 0.05). During COVID, these women had no differences in the key outcome measures. Of the women, 3% were identified with pre-existing diabetes at antenatal booking. Where OGTT continued during COVID, but virtual care was introduced, outcomes were also similar pre- and during the pandemic. CONCLUSIONS: Using HbA1c and fasting glucose identified a higher risk GDM population during the pandemic but this had minimal impact on pregnancy outcomes. The high prevalence of undiagnosed pre-existing diabetes suggests that women with GDM risk factors should be offered HbA1c screening in early pregnancy.

Femoral Arterial Doppler Use During Active Cardiopulmonary Resuscitation.

STUDY OBJECTIVE: This study explored femoral arterial Doppler during active cardiopulmonary resuscitation (CPR) to identify and characterize the resumptions of cardiac activity without stopping CPR. METHODS: This was a proof-of-concept study exploring arterial Doppler during cardiac arrest. Patients in cardiac arrest undergoing active CPR were prospectively enrolled. Arterial Doppler of the common femoral artery was recorded during CPR and during pauses in CPR. CPR-induced arterial tracings and native cardiac-induced tracings were analyzed for rate and peak systolic velocity. Cardiac activity on echocardiogram during pause in CPR was classified as "absent," "disorganized," or "organized." Descriptive data and survival are presented as mean and 95% confidence intervals (CI), as well as sensitivity and specificity of Doppler during active CPR in detecting native cardiac pulsations. RESULTS: Sixteen patients with 48 paired Doppler recordings during active CPR, pause in CPR, and associated echocardiogram were enrolled. Native cardiac-induced tracings were visible during 39.6% of pauses in CPR (19 of 48) and during 18.8% of the periods of active CPR (9 of 48). Arterial pulsations were more frequently visualized with organized contractions by echocardiogram (10 of 14, 71%) than disorganized contractions (9 of 22, 41%). Arterial Doppler was 100% specific and 50% sensitive in detecting organized cardiac activity during active CPR. Patients with visible native cardiac pulsations during active CPR demonstrated 0% mortality compared with 67% mortality without visible arterial pulsations. CONCLUSION: Arterial Doppler tracings may identify the resumption of native cardiac activity during active CPR; however, more research is needed.

Corrosion inhibition in acidic environments: key interfacial insights with photoelectron spectroscopy.

In many engineering scenarios, surface-active organic species are added to acidic solutions to inhibit the corrosion of metallic components. Given suitable selection, such corrosion inhibitors are highly effective, preventing significant degradation even in highly aggressive environments. Nevertheless, there are still considerable gaps in fundamental knowledge of corrosion inhibitor functionality, severely restricting rational development. Here, we demonstrate the capability of X-ray photoelectron spectroscopy (XPS), supported by ab initio modelling, for revealing key details of inhibited substrates. Attention is focussed on the corrosion inhibition of carbon steel through the addition of an exemplar imidazoline-based corrosion inhibitor (OMID) to aqueous solutions of both HCl and H2SO4. Most notably, it is demonstrated that interfacial chemistry varies with the identity of the acid. High resolution Fe 2p, O 1s, N 1s, and Cl 2p XPS spectra, acquired from well-inhibited carbon steel in 1 M HCl, show that there are two different singly protonated OMID species bound directly to the metallic carbon steel substrate. In sharp contrast, in 0.01 M H2SO4, OMID adsorbs onto an ultra-thin surface film, composed primarily of a ferric sulfate (Fe2(SO4)3)-like phase. Such insight is essential to efforts to develop a mechanistic description of corrosion inhibitor functionality, as well as knowledge-based identification of next generation corrosion inhibitors.

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.

A Multicenter, Prospective Study Comparing Subxiphoid and Parasternal Views During Brief Echocardiography: Effect on Image Quality, Acquisition Time, and Visualized Anatomy.

BACKGROUND: Recent literature has suggested echocardiography (echo) may prolong pauses in chest compressions during cardiac arrest. OBJECTVES: We sought to determine the impact of the sonographic approach (subxiphoid [SX] vs. parasternal long [PSL]) on time to image completion, image quality, and visualization of cardiac anatomy during echo, as performed during Advanced Cardiac Life Support. METHODS: This was a multicenter, randomized controlled trial conducted at 29 emergency departments (EDs) assessing the time to image acquisition and image quality between SX and PSL views for echo. Patients were enrolled in the ED and imaged in a simulated cardiac arrest scenario. Clinicians experienced in echo performed both SX and PSL views, first view in random order. Image quality and time to image acquisition were recorded. Echos were evaluated for identification of cardiac landmarks. Data are presented as percentages or medians with interquartile ranges (IQRs). RESULTS: We obtained 6247 echo images, comprising 3124 SX views and 3123 PSL. Overall time to image acquisition was 9.0 s (IQR 6.7-14.1 s). Image acquisition was shorter using PSL (8.8 s, IQR 6.5-13.5 s) compared with SX (9.3 s, IQR 6.7-15.0 s). The image quality was better with the PSL view (3.86 vs. 3.54; p < 0.0001), twice as many SX images scoring in the worst quality category compared with PSL (8.6% vs. 3.7%). Imaging of the pericardium, cardiac chambers, and other anatomic landmarks was superior with PSL imaging. CONCLUSIONS: Echo was performed in < 10 s in > 50% of patients using either imaging technique. Imaging using PSL demonstrated improved image quality and improved identification of cardiac landmarks.

The association of polypharmacy and high-risk drug classes with adverse health outcomes in the Scottish population with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to map the number of prescribed drugs over age, sex and area-based socioeconomic deprivation, and to examine the association between the number of drugs and particular high-risk drug classes with adverse health outcomes among a national cohort of individuals with type 1 diabetes. METHODS: Utilising linked healthcare records from the population-based diabetes register of Scotland, we identified 28,245 individuals with a diagnosis of type 1 diabetes on 1 January 2017. For this population, we obtained information on health status, predominantly reflecting diabetes-related complications, and information on the total number of drugs and particular high-risk drug classes prescribed. We then studied the association of these baseline-level features with hospital admissions for falls, diabetic ketoacidosis (DKA), and hypoglycaemia or death within the subsequent year using multivariate Cox proportional hazards models. RESULTS: Not considering insulin and treatment for hypoglycaemia, the mean number of prescribed drugs was 4.00 (SD 4.35). The proportion of individuals being prescribed five or more drugs at baseline consistently increased with age (proportion [95% CI]: 0-19 years 2.04% [1.60, 2.49]; 40-49 years 28.50% [27.08, 29.93]; 80+ years 76.04% [67.73, 84.84]). Controlling for age, sex, area-based socioeconomic deprivation and health status, each additional drug at baseline was associated with an increase in the hazard for hospitalisation for falls, hypoglycaemia and death but not for DKA admissions (HR [95% CI]: falls 1.03 [1.01, 1.06]; DKA 1.01 [1.00, 1.03]; hypoglycaemia 1.05 [1.02, 1.07]; death 1.04 [1.02, 1.06]). We found a number of drug classes to be associated with an increased hazard of one or more of these adverse health outcomes, including antithrombotic/anticoagulant agents, corticosteroids, opioids, antiepileptics, antipsychotics, hypnotics and sedatives, and antidepressants. CONCLUSIONS: Polypharmacy is common among the Scottish population with type 1 diabetes and is strongly patterned by sociodemographic factors. The number of prescribed drugs and the prescription of particular high-risk drug classes are strong markers of an increased risk of adverse health outcomes, including acute complications of diabetes.

Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with type 1 diabetes: a nationwide observational study in Scotland.

AIMS/HYPOTHESIS: Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. METHODS: We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. RESULTS: HbA1c decreased after CSII initiation, with a median within-person change of -5.5 mmol/mol (IQR -12.0, 0.0) (-0.5% [IQR -1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median -21.0 mmol/mol (-30.0, -11.0) (-1.9% [-2.7, -1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: -19.0 mmol/mol (-27.6, -6.5) (-1.7% [-2.5, -0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). CONCLUSIONS/INTERPRETATION: CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control.

Epidemiology of type 2 diabetes remission in Scotland in 2019: A cross-sectional population-based study.

BACKGROUND: Clinical pathways are changing to incorporate support and appropriate follow-up for people to achieve remission of type 2 diabetes, but there is limited understanding of the prevalence of remission in current practice or patient characteristics associated with remission. METHODS AND FINDINGS: We carried out a cross-sectional study estimating the prevalence of remission of type 2 diabetes in all adults in Scotland aged ≥30 years diagnosed with type 2 diabetes and alive on December 31, 2019. Remission of type 2 diabetes was assessed between January 1, 2019 and December 31, 2019. We defined remission as all HbA1c values <48 mmol/mol in the absence of glucose-lowering therapy (GLT) for a continuous duration of ≥365 days before the date of the last recorded HbA1c in 2019. Multivariable logistic regression in complete and multiply imputed datasets was used to examine characteristics associated with remission. Our cohort consisted of 162,316 individuals, all of whom had at least 1 HbA1c ≥48 mmol/mol (6.5%) at or after diagnosis of diabetes and at least 1 HbA1c recorded in 2019 (78.5% of the eligible population). Over half (56%) of our cohort was aged 65 years or over in 2019, and 64% had had type 2 diabetes for at least 6 years. Our cohort was predominantly of white ethnicity (74%), and ethnicity data were missing for 19% of the cohort. Median body mass index (BMI) at diagnosis was 32.3 kg/m2. A total of 7,710 people (4.8% [95% confidence interval [CI] 4.7 to 4.9]) were in remission of type 2 diabetes. Factors associated with remission were older age (odds ratio [OR] 1.48 [95% CI 1.34 to 1.62] P < 0.001) for people aged ≥75 years compared to 45 to 54 year group), HbA1c <48 mmol/mol at diagnosis (OR 1.31 [95% CI 1.24 to 1.39] P < 0.001) compared to 48 to 52 mmol/mol), no previous history of GLT (OR 14.6 [95% CI 13.7 to 15.5] P < 0.001), weight loss from diagnosis to 2019 (OR 4.45 [95% CI 3.89 to 5.10] P < 0.001) for ≥15 kg of weight loss compared to 0 to 4.9 kg weight gain), and previous bariatric surgery (OR 11.9 [95% CI 9.41 to 15.1] P < 0.001). Limitations of the study include the use of a limited subset of possible definitions of remission of type 2 diabetes, missing data, and inability to identify self-funded bariatric surgery. CONCLUSIONS: In this study, we found that 4.8% of people with type 2 diabetes who had at least 1 HbA1c ≥48 mmol/mol (6.5%) after diagnosis of diabetes and had at least 1 HbA1c recorded in 2019 had evidence of type 2 diabetes remission. Guidelines are required for management and follow-up of this group and may differ depending on whether weight loss and remission of diabetes were intentional or unintentional. Our findings can be used to evaluate the impact of future initiatives on the prevalence of type 2 diabetes remission.

The Predialysis Serum Sodium Level Modifies the Effect of Hemodialysis Frequency on Left-Ventricular Mass: The Frequent Hemodialysis Network Trials.

INTRODUCTION: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. METHODS: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated sodium-adjusted fluid load (TIFL), and extracellular fluid volume estimated by bioelectrical impedance analysis. RESULTS: In 197 enrolled subjects in the FHN Daily Trial, the treatment effect of frequent HD on ∆LVM was modified by SNa. When the FHN Daily Trial participants are divided into lower and higher predialysis SNa groups (less and greater than 138 mEq/L), the LVM reduction in the lower group was substantially higher (-28.0 [95% CI -40.5 to -15.4] g) than in the higher predialysis SNa group (-2.0 [95% CI -15.5 to 11.5] g). Accounting for GNa, TIFL also showed more pronounced effects among patients with higher GNa or higher TIFL. Results in the Nocturnal Trial were similar in direction and magnitude but did not reach statistical significance. DISCUSSION/CONCLUSION: In the FHN Daily Trial, the favorable effects of frequent HD on left-ventricular hypertrophy were more pronounced among patients with lower predialysis SNa and higher GNa and TIFL. Whether these metrics can be used to identify patients most likely to benefit from frequent HD or other dialytic or nondialytic interventions remains to be determined. Prospective, adequately powered studies studying the effect of GNa reduction on mortality and hospitalization are needed.

Time trends in deaths before age 50 years in people with type 1 diabetes: a nationwide analysis from Scotland 2004-2017.

AIMS/HYPOTHESIS: We aimed to examine whether crude mortality and mortality relative to the general population below 50 years of age have improved in recent years in those with type 1 diabetes. METHODS: Individuals with type 1 diabetes aged below 50 and at least 1 year old at any time between 2004 and 2017 in Scotland were identified using the national register. Death data were obtained by linkage to Scottish national death registrations. Indirect age standardisation was used to calculate sex-specific standardised mortality ratios (SMRs). Poisson regression was used to test for calendar-time effects as incidence rate ratios (IRRs). RESULTS: There were 1138 deaths in 251,143 person-years among 27,935 people with type 1 diabetes. There was a significant decline in mortality rate over time (IRR for calendar year 0.983 [95% CI 0.967, 0.998], p = 0.03), but the SMR remained approximately stable at 3.1 and 3.6 in men and 4.09 and 4.16 in women for 2004 and 2017, respectively. Diabetic ketoacidosis or coma (DKAoC) accounted for 22% of deaths and the rate did not decline significantly (IRR 0.975 [95% CI 0.94, 1.011], p = 0.168); 79.3% of DKAoC deaths occurred out of hospital. Circulatory diseases accounted for 27% of deaths and did decline significantly (IRR 0.946 [95% CI 0.914, 0.979], p = 0.002). CONCLUSIONS/INTERPRETATION: Absolute mortality has fallen, but the relative impact of type 1 diabetes on mortality below 50 years has not improved. There is scope to improve prevention of premature circulatory diseases and DKAoC and to develop more effective strategies for enabling people with type 1 diabetes to avoid clinically significant hyper- or hypoglycaemia. Graphical abstract.

Factors associated with stillbirth in women with diabetes.

AIMS/HYPOTHESIS: Stillbirth risk is increased in pregnancy complicated by diabetes. Fear of stillbirth has major influence on obstetric management, particularly timing of delivery. We analysed population-level data from Scotland to describe timing of stillbirths in women with diabetes and associated risk factors. METHODS: A retrospective cohort of singleton deliveries to mothers with type 1 (n = 3778) and type 2 diabetes (n = 1614) from 1 April 1998 to 30 June 2016 was analysed using linked routine care datasets. Maternal and fetal characteristics, HbA1c data and delivery timing were compared between stillborn and liveborn groups. RESULTS: Stillbirth rates were 16.1 (95% CI 12.4, 20.8) and 22.9 (95% CI 16.4, 31.8) per 1000 births in women with type 1 (n = 61) and type 2 diabetes (n = 37), respectively. In women with type 1 diabetes, higher HbA1c before pregnancy (OR 1.03 [95% CI 1.01, 1.04]; p = 0.0003) and in later pregnancy (OR 1.06 [95% CI 1.04, 1.08]; p < 0.0001) were associated with stillbirth, while in women with type 2 diabetes, higher maternal BMI (OR 1.07 [95% CI 1.01, 1.14]; p = 0.02) and pre-pregnancy HbA1c (OR 1.02 [95% CI 1.00, 1.04]; p = 0.016) were associated with stillbirth. Risk was highest in infants with birthweights <10th centile (sixfold higher born to women with type 1 diabetes [n = 5 stillbirths, 67 livebirths]; threefold higher for women with type 2 diabetes [n = 4 stillbirths, 78 livebirths]) compared with those in the 10th-90th centile (n = 20 stillbirths, 1685 livebirths). Risk was twofold higher in infants with birthweights >95th centile born to women with type 2 diabetes (n = 15 stillbirths, 402 livebirths). A high proportion of stillborn infants were male among mothers with type 2 diabetes (81.1% vs 50.5% livebirths, p = 0.0002). A third of stillbirths occurred at term, with highest rates in the 38th week (7.0 [95% CI 3.7, 12.9] per 1000 ongoing pregnancies) among mothers with type 1 diabetes and in the 39th week (9.3 [95% CI 2.4, 29.2]) for type 2 diabetes. CONCLUSIONS/INTERPRETATION: Maternal blood glucose levels and BMI are important modifiable risk factors for stillbirth in diabetes. Babies at extremes of weight centiles are at most risk. Many stillbirths occur at term and could potentially be prevented by change in routine care and delivery policies.

Consequences of being overweight or obese during pregnancy on diabetes in the offspring: a record linkage study in Aberdeen, Scotland.

AIMS/HYPOTHESIS: Maternal obesity in pregnancy is associated with cardiovascular disease and mortality rate in the offspring. We aimed to determine whether maternal obesity is also associated with increased incidence of type 2 and type 1 diabetes in the offspring, independently of maternal diabetes as a candidate mechanistic pathway. METHODS: Birth records of 118,201 children from 1950 to 2011 in the Aberdeen Maternity and Neonatal Databank were linked to Scottish Care Information-Diabetes, the national register for diagnosed diabetes in Scotland, to identify incident and prevalent type 1 and type 2 diabetes up to 1 January 2012. Maternal BMI was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on offspring outcomes was tested using time-to-event analysis with Cox proportional hazards regression to compare outcomes in offspring of mothers in underweight, overweight or obese categories of BMI, compared with offspring of women with normal BMI. RESULTS: Offspring of obese (BMI ≥30 kg/m2) and overweight (BMI 25-29.9 kg/m2) mothers had an increased hazard of type 2 diabetes compared with mothers with normal BMI, after adjustment for gestation when weight was measured, maternal history of diabetes before pregnancy, maternal history of hypertension, age at delivery, parity, socioeconomic status, and sex of the offspring: HR 3.48 (95% CI 2.33, 5.06) and HR 1.39 (1.06, 1.83), respectively. CONCLUSIONS/INTERPRETATION: Maternal obesity is associated with increased incidence of type 2 diabetes in the offspring. Evidence-based strategies that reduce obesity among women of reproductive age and that might reduce the incidence of diabetes in their offspring are urgently required.

Glycaemic control trends in people with type 1 diabetes in Scotland 2004-2016.

AIMS/HYPOTHESIS: The aim of this work was to examine whether glycaemic control has improved in those with type 1 diabetes in Scotland between 2004 and 2016, and whether any trends differed by sociodemographic factors. METHODS: We analysed records from 30,717 people with type 1 diabetes, registered anytime between 2004 and 2016 in the national diabetes database, which contained repeated measures of HbA1c. An additive mixed regression model was used to estimate calendar time and other effects on HbA1c. RESULTS: Overall, median (IQR) HbA1c decreased from 72 (21) mmol/mol [8.7 (4.1)%] in 2004 to 68 (21) mmol/mol (8.4 [4.1]%) in 2016. However, all of the improvement across the period occurred in the latter 4 years: the regression model showed that the only period of significant change in HbA1c was 2012-2016 where there was a fall of 3 (95% CI 1.82, 3.43) mmol/mol. The largest reductions in HbA1c in this period were seen in children, from 69 (16) mmol/mol (8.5 [3.6]%) to 63 (14) mmol/mol (7.9 [3.4]%), and adolescents, from 75 (25) mmol/mol (9.0 [4.4]%) to 70 (23) mmol/mol (8.6 [4.3]%). Socioeconomic status (according to Scottish Index of Multiple Deprivation) affected the HbA1c values: from the regression model, the 20% of people living in the most-deprived areas had HbA1c levels on average 8.0 (95% CI 7.4, 8.9) mmol/mol higher than those of the 20% of people living in the least-deprived areas. However this difference did not change significantly over time. From the regression model HbA1c was on average 1.7 (95% CI 1.6, 1.8) mmol/mol higher in women than in men. This sex difference did not narrow over time. CONCLUSIONS/INTERPRETATION: In this high-income country, we identified a modest but important improvement in HbA1c since 2012 that was most marked in children and adolescents. These changes coincided with national initiatives to reduce HbA1c including an expansion of pump therapy. However, in most people, overall glycaemic control remains far from target levels and further improvement is badly needed, particularly in those from more-deprived areas.

Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes.

BACKGROUND: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. METHODS: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. RESULTS: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. CONCLUSIONS: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.

Technique Failure in a Multicenter Canadian Home Hemodialysis Cohort.

RATIONALE & OBJECTIVE: Increasing uptake of home hemodialysis (HD) has led to interest in characteristics that predict discontinuation of home HD therapy for reasons other than death or transplantation. Recent reports of practice pattern variability led to the hypothesis that there are patient- and center-specific factors that influence these discontinuations. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident home HD patients at 7 centers in Canada between 2000 and 2010. PREDICTOR: Treatment center, case-mix, and process-of-care variables. OUTCOMES: Technique failure (defined as discontinuation of home HD therapy for any reason other than training failure, death, or transplantation) and mortality. ANALYTICAL APPROACH: Regression modeling of technique failure using Cox proportional hazard models adjusting for treatment center and modifiable and nonmodifiable patient-level variables, censored for death and transplantation. RESULTS: The cohort consisted of 579 patients. Mean age was 49.9±14.1 years, 74% were of European ancestry, median dialysis vintage was 1.9 (IQR, 0.6-5.2) years, and 68% used an arteriovenous access. Mean duration of dialysis was 31.2±12.6 hours per week. Unadjusted 1- and 2-year technique survival and overall survival were 90% and 83% and 94% and 87%, respectively. Treating center was a strong predictor of technique failure and mortality, with HRs ranging from 0.37 to 5.11 for technique failure (1 of 6 centers with P<0.05 relative to the reference) and 0.17 to 8.73 for mortality (3 of 6 centers with P<0.05 relative to the reference). With baseline adjustment for center, only older age and more than 3 treatments per week remained significant predictors of technique failure, while no individual-level variables remained as significant predictors of survival. LIMITATIONS: Limited statistical power. CONCLUSIONS: Home HD treating centers may influence technique failure and patient mortality independent of case-mix. The relationship between processes of care and patient outcomes requires further investigation.

Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD.

BACKGROUND: Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

Diabetes and pregnancy: national trends over a 15 year period.

AIMS/HYPOTHESIS: We aimed to examine time trends in national perinatal outcomes in pregnancies complicated by pre-existing type 1 or type 2 diabetes. METHODS: We analysed episode-level data on all obstetric inpatient delivery events (live or stillbirth) between 1 April 1998 and 31 March 2013 (n = 813,921) using the Scottish Morbidity Record (SMR02). Pregnancies to mothers with type 1 (n = 3229) and type 2 (n = 1452) diabetes were identified from the national diabetes database (Scottish Care Information-Diabetes), and perinatal outcomes were compared among women with type 1 diabetes, type 2 diabetes and those without diabetes. RESULTS: The number of pregnancies complicated by diabetes increased significantly, by 44% in type 1 diabetes and 90% in type 2 diabetes, across the 15 years examined, to rates of 1 in 210 and 1 in 504 deliveries, respectively. Compared with women without diabetes, delivery occurred 2.6 weeks earlier (type 1 diabetes 36.7 ± 2.3 weeks) and 2 weeks earlier (type 2 diabetes 37.3 ± 2.4 weeks), respectively, showing significant reductions for both type 1 (from 36.7 weeks to 36.4 weeks, p = 0.03) and type 2 (from 38.0 weeks to 37.2 weeks, p < 0.001) diabetes across the time period. The proportions of preterm delivery were markedly increased in women with diabetes (35.3% type 1 diabetes, 21.8% type 2 diabetes, 6.1% without diabetes; p < 0.0001), and these proportions increased with time for both groups (p < 0.005). Proportions of elective Caesarean sections (29.4% type 1 diabetes, 30.5% type 2 diabetes, 9.6% without diabetes) and emergency Caesarean sections (38.3% type 1 diabetes, 29.1% type 2 diabetes, 14.6% without diabetes) were greatly increased in women with diabetes and increased over time except for stable rates of emergency Caesarean section in type 1 diabetes. Gestational age-, sex- and parity-adjusted z score for birthweight (1.33 ± 1.34; p < 0.001) were higher in type 1 diabetes and increased over time from 1.22 to 1.47 (p < 0.001). Birthweight was also increased in type 2 diabetes (0.94 ± 1.34; p < 0.001) but did not alter with time. There were 65 perinatal deaths in offspring of mothers with type 1 diabetes and 39 to mothers with type 2 diabetes, representing perinatal mortality rates of 20.1 (95% CI 14.7, 24.3) and 26.9 (16.7, 32.9) per 1000 births, respectively, and rates 3.1 and 4.2 times, respectively, those observed in the non-diabetic population (p < 0.001). Stillbirth rates in type 1 and type 2 diabetes were 4.0-fold and 5.1-fold that in the non-diabetic population (p < 0.001). Perinatal mortality and stillbirth rates showed no significant fall over time despite small falls in the rates for the non-diabetic population. CONCLUSIONS/INTERPRETATION: Women with diabetes are receiving increased intervention in pregnancy (earlier delivery, increased Caesarean section rates), but despite this, higher birthweights are being recorded. Improvements in rates of stillbirth seen in the general population are not being reflected in changes in stillbirth or perinatal mortality in our population with diabetes.

Effect of non-surgical weight management on weight and glycaemic control in people with type 2 diabetes: A comparison of interventional and non-interventional outcomes at 3 years.

AIMS: To examine the long-term effectiveness of lifestyle weight management interventions, recommended in clinical guidelines for patients with type 2 diabetes mellitus (T2DM) and obesity. MATERIALS AND METHODS: Electronic health records were used to follow 23 208 patients with T2DM and obesity in Glasgow, UK, for up to 3 years between 2005 and 2014. Patients were stratified by referral to and attendance at a lifestyle weight management intervention, and by attainment of a target weight loss of ≥5 kg over 7 to 9 sessions ("successful completers"). Outcomes were change in weight, glycated haemoglobin (HbA1c) and diabetes medications. RESULTS: A total of 3471 potentially eligible patients were referred to the service, and fewer than half of these attended (n = 1537). Of those who attended 7 to 9 sessions, >40% successfully completed and achieved 5-kg weight loss (334/808). Successful completers maintained greater weight loss (change at 3 years -8.03 kg; 95% confidence interval [CI] -9.44 to -6.62) than the non-completers (-3.26 kg; 95% CI -4.01 to -2.51; P < .001) and those not referred to the service (-1.00 kg; 95% CI -1.15 to -0.85; P < .001). Successful completers were the only patient group who did not increase their use of diabetes medication and insulin over 3 years. In adjusted models, successful completers had a clinically significant reduction in HbA1c (-3.7 mmol/mol; 95% CI -5.82 to -1.51) after 3 years; P ≤ .001) compared with non-completers and unsuccessful completers. CONCLUSIONS: A real-life structured weight management intervention in patients with diabetes can reduce weight in the medium term, result in improved glycaemic control with fewer medications, and may be more effective than pharmacological alternatives. Challenges include getting a higher proportion of patients referred to and engaged with interventions.

In-center hemodialysis education: Challenges and innovations in training of fellows in nephrology.

The in-center dialysis unit and practice of dialysis, in the current multi-team approach, requires knowledge and skills in all the domains including medical expert, communicator, collaborator, scholar, health advocate, and leader. We are tasked as a community, to embrace and incentivize new innovations and technology to address these needs for our post graduate trainees. These innovations must address the basic principles of dialysis, quality improvement, technical and procedural skills as well as leadership and administration skills. The teaching methods and innovations must also be challenged to demonstrate the translation into adoption and improvements in practice to demonstrate success. This article will review the current state of the training curriculum in Nephrology for in-center hemodialysis and address some of the recent innovations.