Search

Objective: To examine major congenital anomaly (CA) risks in children of mothers with coeliac disease (CD) compared with mothers without CD.Design: Population-based cohort study.Setting: Linked maternal-child medical records from a large primary care database from the UK.Population: A total of 562,332 live singletons of mothers with and without CD in 1990-2013.Methods: We calculated the absolute major CA risks in children whose mothers had CD, and whether this was diagnosed or undiagnosed before childbirth. Logistic regression with a generalised estimating equation was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) for CAs associated with CD.Main Outcome Measures: Fourteen system-specific major CA groups classified according to the European Surveillance of Congenital Anomalies and neural tube defects (NTDs).Results: Major CA risk in 1880 children of mothers with CD was 293 per 10,000 liveborn singletons, similar to the risk in those without CD (282; aOR 0.98, 95% CI 0.74-1.30). The risk was slightly higher in 971 children, whose mothers were undiagnosed (350; aOR 1.14, 95% CI 0.79-1.64), than in 909 children whose mothers were diagnosed (231; aOR 0.80, 95% CI 0.52-1.24). There was a three-fold increase in nervous system anomalies in the children of mothers with undiagnosed CD (aOR 2.98, 95% CI 1.06-8.33, based on five exposed cases and one had an NTD), and these women were all diagnosed with CD at least 4 years after their children were born.Conclusions: There was no statistically significant increase in risk of major CAs in children of mothers with coeliac disease overall, compared with the general population. [ABSTRACT FROM AUTHOR]

Introduction: Low-density lipoprotein cholesterol (LDL-C) is among the most important modifiable risk factors for cardiovascular disease. In very high-risk patients, the European Society of Cardiology/European Atherosclerosis Society guidelines recommend attaining LDL-C < 55 mg/dL. In the German cohort of the observational HEYMANS study, we aimed to describe the clinical characteristics and LDL-C control among patients initiating evolocumab., Methods: Data was collected between 09/2016 and 05/2021 for ≤ 6 months before (retrospectively) and ≤ 30 months after evolocumab initiation (prospectively). Patient characteristics, lipid-lowering therapy (LLT), lipid values, evolocumab use, and safety were collected., Results: Of 380 enrolled patients, 93% received evolocumab in secondary prevention and 69% had a history of statin intolerance. At study baseline, 49% did not receive any statins and LDL-C was very high (145 mg/dL). Use of evolocumab decreased LDL-C by a median of 53% within 3 months and remained stable thereafter, despite mainly unchanged background LLT. Overall, 59% attained an LDL-C level < 55 mg/dL (69% with, 49% without LLT). Persistence to evolocumab was 90.6% in months 1-12 and 93.5% in months 13-30. Adverse drug reactions were reported in 8% of patients., Conclusion: Data from the German HEYMANS cohort corroborate previous reports on evolocumab effectiveness and safety in clinical practice. Evolocumab initiation was associated with a rapid and sustained LDL-C reduction. Persistence with evolocumab was high. Our finding that patients receiving an evolocumab/LLT combination are more likely to attain the LDL-C goal than those receiving evolocumab alone corroborates previous data showing the importance of using highly intensive therapy. Graphical abstract available for this article., Trial Registration: ClinicalTrials.gov Identifier NCT02770131 (registration date 27 April 2016)., (© 2024. The Author(s).)

Background: This real-world study examined clinical characteristics and dyslipidemia management among patients initiating evolocumab across 12 European countries. Austrian data are reported., Methods: Data of consenting adults were collected for ≤ 6 months prior to evolocumab initiation (baseline) and ≤ 30 months post-initiation. Patient characteristics, lipid lowering therapy (LLT, i.e. statin and/or ezetimibe) and lipid values were collected from medical records., Results: In Austria, 363 patients were enrolled. At baseline, 52% of patients initiated evolocumab without background LLT; the median (Q1, Q3) initial low-density lipoprotein cholesterol (LDL-C) level was 142 (111, 187) mg/dL. Within 3 months of evolocumab treatment, median LDL‑C decreased by 59% to 58 (37, 91) mg/dL. This reduction was maintained over time, despite consistently infrequent use of background LLT. LDL-C < 55 mg/dL was attained by 65% of patients (76% with, 55% without background LLT). Evolocumab persistence was ≥ 90% at month 12 and month 30., Conclusion: In Austria, patients were initiated on evolocumab at LDL‑C levels almost 3‑times higher than the guideline-recommended clinical goal (< 55 mg/dL). Persistence with evolocumab was very high. Evolocumab led to a rapid and sustained LDL‑C reduction with 65% attaining the LDL‑C goal. Patients using evolocumab in combination with statins and/or ezetimibe were more likely to attain their LDL‑C goal and thus decrease cardiovascular risk., (© 2023. The Author(s).)

Background: Low-density lipoprotein cholesterol (LDL-C) is used to guide lipid-lowering therapy after a myocardial infarction (MI). Lack of LDL-C testing represents a missed opportunity for optimizing therapy and reducing cardiovascular risk., Objectives: The purpose of this study was to estimate the proportion of Medicare beneficiaries who had their LDL-C measured within 90 days following MI hospital discharge., Methods: We conducted a retrospective cohort study of Medicare beneficiaries ≥66 years of age with an MI hospitalization between 2016 and 2020. The primary analysis used data from all beneficiaries with fee-for-service coverage and pharmacy benefits (532,767 MI hospitalizations). In secondary analyses, we used data from a 5% random sample of beneficiaries with fee-for-service coverage without pharmacy benefits (10,394 MI hospitalizations), and from beneficiaries with Medicare Advantage (176,268 MI hospitalizations). The proportion of beneficiaries who had their LDL-C measured following MI hospital discharge was estimated accounting for the competing risk of death., Results: In the primary analysis (mean age 76.9 years, 84.4% non-Hispanic White), 29.9% of beneficiaries had their LDL-C measured within 90 days following MI hospital discharge. Among Hispanic, Asian, non-Hispanic White, and non-Hispanic Black beneficiaries, the 90-day postdischarge LDL-C testing was 33.8%, 32.5%, 30.0%, and 26.0%, respectively. Postdischarge LDL-C testing within 90 days was highest in the Middle Atlantic (36.4%) and lowest in the West North Central (23.4%) U.S. regions. In secondary analyses, the 90-day postdischarge LDL-C testing was 26.9% among beneficiaries with fee-for-service coverage without pharmacy benefits, and 28.6% among beneficiaries with Medicare Advantage coverage., Conclusions: LDL-C testing following MI hospital discharge among Medicare beneficiaries was low., Competing Interests: The design and conduct of the study, interpretation of the results, and preparation of the manuscript were supported through a research grant from 10.13039/100002429Amgen, Inc. Dr Colantonio has received research support from Amgen Inc. Dr Jones, Dr Dhalwani, Ms Shannon, and Dr Kalich are employees and stockholders of Amgen Inc. Dr Muntner has received research support and consulting fees from Amgen Inc. Dr Rosenson has received research grants to his institution from Amgen, Arrowhead, Eli Lilly, NIH, Novartis and Regeneron; consulting fees from Amgen, CRISPER Therapeutics Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, UltraGenyx, and Verve; non-promotional honoraria from Kowa; royalties from Wolters Kluwer (UpToDate); stock holding in MediMergent, LLC; and patent applications on: Methods and systems for biocellular marker detection and diagnosis using a microfluidic profiling device (EFS ID: 32278349, Application No. PCT/US2019/026364, provisional); compositions and methods relating to the identification and treatment of immunothrombotic conditions (New International Application No. PCT/US2021/63104926), and Quantification of Lp(a) vs non-Lp(a) apoB concentration: development of a novel validated equation. (Application No. PCT/US2021/63248837). Dr Bittner has received research grants to her institution from Sanofi and Regeneron (ODYSSEY OUTCOMES trial, Steering Committee member), Esperion (CLEAR OUTCOMES trial, National Coordinator), Dalcor (DalGene trial, National Coordinator), Astra Zeneca (STRENGTH trial, National Coordinator), Novartis (ORION trial, Site PI), Amgen (Industry Collaboration between the UAB School of Public Health and Amgen, co-Investigator); and has received payments as Senior Guest Editor for Circulation (American Heart Association, ongoing), Editor in Chief of the American College of Cardiology Self-Assessment Program (ACCSAP, American College of Cardiology, ongoing), Advisory Board member (Pfizer, concluded at the end of 2021), and Data Safety Monitoring Board member (Verve Therapeutics, ongoing). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: LDL-C testing following MI hospital discharge among Medicare beneficiaries was low. There were disparities in LDL-C testing following MI hospital discharge by race/ethnicity (lower in Black vs White beneficiaries), geographic region of residence (highest in the Middle Atlantic and lowest in the West North Central U.S. regions), and type of Medicare program (lower in beneficiaries without vs with pharmacy benefits). TRANSLATIONAL OUTLOOK: Increasing the use of LDL-C testing among Medicare beneficiaries following an MI may lead to guideline-recommended lipid-lowering therapy and a reduction of the risk for recurrent cardiovascular events., (© 2024 The Authors.)

Purpose: We examined clinical characteristics and low-density lipoprotein cholesterol (LDL-C) lowering in patients initiating evolocumab in real-world practice in a Central and Eastern European (CEE) cohort from the pan-European HEYMANS study. Methods: Patients from Bulgaria, Czech Republic, and Slovakia were enrolled at initiation of evolocumab (baseline) as per local reimbursement criteria. Demographic/clinical characteristics, lipid-lowering therapy (LLT) and lipid values were collected from medical records for ≤6 months before baseline and ≤30 months after evolocumab initiation. Results: Overall, 333 patients were followed over a mean (SD) duration of 25.1 (7.5) months. At initiation of evolocumab, LDL-C levels were markedly elevated in all three countries, with a median (Q1, Q3) LDL-C of 5.2 (4.0, 6.6) mmol/L in Bulgaria, 4.5 (3.8, 5.8) mmol/L in the Czech Republic, and 4.7 (4.0, 5.6) mmol/L in Slovakia. Within the first three months of evolocumab treatment, LDL-C levels were reduced by a median of 61% in Bulgaria, 64% in the Czech Republic, and 53% in Slovakia. LDL-C levels remained low throughout the remaining period of observation. The 2019 ESC/EAS guideline-recommended risk-based LDL-C goals were attained by 46% of patients in Bulgaria, 59% in the Czech Republic, and 43% of patients in Slovakia. LDL-C goal attainment was higher in patients receiving a statin ± ezetimibe-based background therapy (Bulgaria: 55%, Czech Republic: 71%, Slovakia: 51%) compared to those receiving evolocumab alone (Bulgaria: 19%, Czech Republic: 49%, Slovakia: 34%). Conclusion: In the HEYMANS CEE cohort, patients initiated on evolocumab had baseline LDL-C levels approximately three-fold higher than guideline-recommended thresholds for PCSK9i initiation. Risk-based LDL-C goal attainment was highest in patients receiving high-intensity combination therapy. Lowering the LDL-C reimbursement threshold for PCSK9i initiation would allow more patients to receive combination therapy, thus improving LDL-C goal attainment. Trial registration: ClinicalTrials.gov (NCT02770131; registration date: 27 April 2016).

Objectives: This review aims to summarize key methods for estimating years of life lost (YLL), highlighting their differences and how they can be implemented in current software, and applies them in a real-world example., Study Design and Setting: We investigated the common YLL methods: (1) Years of potential life lost (YPLL); (2) Global Burden of Disease (GBD) approach; (3) Life tables; (4) Poisson regression; and (5) Flexible parametric Royston-Parmar regression. We used data from UK Biobank and multimorbidity as our example., Results: For the YPLL and GBD method, the analytical procedures allow only to quantify the average YLL within each group (with and without multimorbidity) and, from them, their difference; conversely, for the other methods both the remaining life expectancy within each group and the YLL could be estimated. At 65 years, the YLL in those with vs. without multimorbidity was 1.8, 1.2, and 2.7 years using the life tables approach and the Poisson, and Royston-Parmar regression, respectively; corresponding values were -0.73 and -0.05 years for YPLL and using the GBD approach., Conclusion: While deciding among different methods to estimate YLL, researchers should consider the purpose of the research, the type of available data, and the flexibility of the model., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Whether a healthy lifestyle impacts longevity in the presence of multimorbidity is unclear. We investigated the associations between healthy lifestyle and life expectancy in people with and without multimorbidity., Methods and Findings: A total of 480,940 middle-aged adults (median age of 58 years [range 38-73], 46% male, 95% white) were analysed in the UK Biobank; this longitudinal study collected data between 2006 and 2010, and participants were followed up until 2016. We extracted 36 chronic conditions and defined multimorbidity as 2 or more conditions. Four lifestyle factors, based on national guidelines, were used: leisure-time physical activity, smoking, diet, and alcohol consumption. A combined weighted score was developed and grouped participants into 4 categories: very unhealthy, unhealthy, healthy, and very healthy. Survival models were applied to predict life expectancy, adjusting for ethnicity, working status, deprivation, body mass index, and sedentary time. A total of 93,746 (19.5%) participants had multimorbidity. During a mean follow-up of 7 (range 2-9) years, 11,006 deaths occurred. At 45 years, in men with multimorbidity an unhealthy score was associated with a gain of 1.5 (95% confidence interval [CI] -0.3 to 3.3; P = 0.102) additional life years compared to very unhealthy score, though the association was not significant, whilst a healthy score was significantly associated with a gain of 4.5 (3.3 to 5.7; P < 0.001) life years and a very healthy score with 6.3 (5.0 to 7.7; P < 0.001) years. Corresponding estimates in women were 3.5 (95% CI 0.7 to 6.3; P = 0.016), 6.4 (4.8 to 7.9; P < 0.001), and 7.6 (6.0 to 9.2; P < 0.001) years. Results were consistent in those without multimorbidity and in several sensitivity analyses. For individual lifestyle factors, no current smoking was associated with the largest survival benefit. The main limitations were that we could not explore the consistency of our results using a more restrictive definition of multimorbidity including only cardiometabolic conditions, and participants were not representative of the UK as a whole., Conclusions: In this analysis of data from the UK Biobank, we found that regardless of the presence of multimorbidity, engaging in a healthier lifestyle was associated with up to 6.3 years longer life for men and 7.6 years for women; however, not all lifestyle risk factors equally correlated with life expectancy, with smoking being significantly worse than others., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests. FZ is funded with an unrestricted educational grant from the NIHR CLAHRC East Midlands to the University of Leicester. KK has acted as a consultant and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Servier, and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim, and Merck Sharp & Dohme. KK has received funds for research and honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp & Dohme, and Novo Nordisk. MJD has acted as consultant, advisory board member, and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen; an advisory board member for Servier and Gilead Sciences Ltd; and as a speaker for NAPP, Mitsubishi Tanabe Pharma Corporation, and Takeda Pharmaceuticals International Inc. TY has received funding from the Leicester NIHR Leicester BRC. All other authors have declared that no competing interests exist.

Aim: To compare the efficacy and tolerability of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes., Materials and Methods: Electronic databases were searched from inception to 24 April 2019 for randomized controlled trials reporting change in glycated haemoglobin (HbA1c) at approximately 24 and/or 52 weeks for SGLT-2is and/or GLP-1RAs (classified as short- and long-acting). Bayesian network meta-analyses were conducted to compare within and between SGLT-2i and GLP-1RA classes for cardiometabolic efficacy and adverse events (PROSPERO registration number: CRD42018091306)., Results: Sixty-four trials (53 trials of 24 weeks; seven trials of 52 weeks; four trials of both 24 and 52 weeks), comprising 31 384 participants were identified. Compared with placebo, all treatments improved HbA1c. Long-acting GLP-1RAs reduced HbA1c compared with short-acting GLP-1RAs and SGLT-2is, with semaglutide showing greater reduction compared with placebo [24 weeks: -1.49% (95% credible interval: -1.76, -1.22); 52 weeks: -1.38% (-2.05, -0.71)] and all other treatments. Long-acting GLP-1RAs showed benefits in body weight and waist circumference reduction, while SGLT-2is reduced blood pressure. SGLT-2is showed increased risk of genital infection in comparison with long-acting GLP-1RAs [odds ratio (95% credible interval): 5.26 (1.45, 25.00)], while GLP-1RAs showed increased risk of diarrhoea in comparison with SGLT-2is [short-acting GLP-1RAs: 1.65 (1.09, 2.49); long-acting GLP-1RAs: 2.23 (1.51, 3.28)]. No other differences were found between SGLT-2is and GLP-1RAs in adverse events., Conclusion: Long-acting GLP-1RAs showed superiority in reducing HbA1c levels, body weight and waist circumference. SGLT-2is showed reductions in blood pressure levels. This review provides essential evidence to guide treatment recommendations in the management of type 2 diabetes., (© 2020 John Wiley & Sons Ltd.)

Rationale & Objective: Previous studies of inflammation and anemia management in hemodialysis (HD) patients may be biased due to patient differences. We used a self-matched longitudinal design to test whether new inflammation, defined as an acute increase in C-reactive protein (CRP) level, reduces hemoglobin response to erythropoiesis-stimulating agent (ESA) treatment., Study Design: Self-matched longitudinal design., Setting & Participants: 3,568 new inflammation events, defined as CRP level > 10 mg/L following a 3-month period with CRP level ≤ 5 mg/L, were identified from 12,389 HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018) in 10 countries in which CRP is routinely measured., Predictor: "After" (vs "before") observing a high CRP level., Outcomes: Within-patient changes in hemoglobin level, ESA dose, and ESA hyporesponsiveness (hemoglobin < 10 g/dL and ESA dose > 6,000 [Japan] or >8,000 [Europe] U/wk)., Analytical Approach: Linear mixed models and modified Poisson regression., Results: Comparing before with after periods, mean hemoglobin level decreased from 11.2 to 10.9 g/dL (adjusted mean change, -0.26 g/dL), while mean ESA dose increased from 6,320 to 6,960 U/wk (adjusted relative change, 8.4%). The prevalence of ESA hyporesponsiveness increased from 7.6% to 12.3%. Both the unadjusted and adjusted prevalence ratios of ESA hyporesponsiveness were 1.68 (95% CI, 1.48-1.91). These associations were consistent in sensitivity analyses varying CRP thresholds and were stronger when the CRP level increase was sustained over the 3-month after period., Limitations: Residual confounding by unmeasured time-varying risk factors for ESA hyporesponsiveness., Conclusions: In the 3 months after HD patients experienced an increase in CRP levels, hemoglobin levels declined quickly, ESA doses increased, and the prevalence of ESA hyporesponsiveness increased appreciably. Routine CRP measurement could identify inflammation as a cause of worsened anemia. In turn, these findings speak to a potentially important role for anemia therapies that are less susceptible to the effects of inflammation., (© 2020 The Authors.)

Background: Whether and to what extent leisure-time physical activity at the recommended levels of 150-min moderate activity is associated with survival in people with cardiometabolic multimorbidity and depression is unknown., Methods: UK Biobank participants were classified into groups: (i) no disease; (ii) diabetes; (iii) cardiovascular disease (CVD); (iv) depression; (v) diabetes and CVD; (vi) diabetes and depression; (vii) CVD and depression; (viii) diabetes, CVD and depression. Leisure-time physical activity was categorized as active (meeting recommendations) or inactive. Survival models were applied to estimate life expectancy., Results: A total of 480 940 participants were included (median age, 58 years; 46% men; 95% white), of whom 74% with cardiometabolic multimorbidity and depression were inactive. During a mean follow-up of 7 years, 11 006 deaths occurred. At age of 45 years, being physically active was associated with 2.34 (95% confidence interval: 0.93, 3.54) additional years of life compared with being inactive in participants with diabetes; corresponding estimates were 2.28 (1.40, 3.16) for CVD; 2.15 (0.05, 4.26) for diabetes and CVD; and 1.58 (1.27, 1.89) for no disease. Participants with a combination of diabetes, CVD and depression, being active was associated with 6.81 (-1.50, 15.31) additional years compared with being inactive; corresponding estimates were 3.07 (-2.46, 8.59) for diabetes and depression; 2.34 (-1.24, 5.91) for CVD and depression; and 0.80 (-0.46, 2.05) for depression. A similar pattern was found at 65 years., Conclusions: Meeting the recommended level of physical activity was associated with a longer life expectancy in people with cardiometabolic multimorbidity but not in those with depression., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background: Multimorbidity is an emerging public health priority. Physical activity (PA) is recommended as one of the main lifestyle behaviours, yet the benefits of PA for people with multimorbidity are unclear. We assessed the benefits of PA on mortality and life expectancy in people with and without multimorbidity., Methods: Using the UK Biobank dataset, we extracted data on 36 chronic conditions and defined multimorbidity as (a) 2 or more conditions, (b) 2 or more conditions combined with self-reported overall health, and (c) 2 or more top-10 most common comorbidities. Leisure-time PA (LTPA) and total PA (TPA) were measured by questionnaire and categorised as low (< 600 metabolic equivalent (MET)-min/week), moderate (600 to < 3000 MET-min/week), and high (≥ 3000 MET-min/week), while objectively assessed PA was assessed by wrist-worn accelerometer and categorised as low (4 min/day), moderate (10 min/day), and high (22 min/day) walking at brisk pace. Survival models were applied to calculate adjusted hazard ratios (HRs) and predict life expectancy differences., Results: 491,939 individuals (96,622 with 2 or more conditions) had a median follow-up of 7.0 (IQR 6.3-7.6) years. Compared to low LTPA, for participants with multimorbidity, HR for mortality was 0.75 (95% CI 0.70-0.80) and 0.65 (0.56-0.75) in moderate and high LTPA groups, respectively. This finding was consistent when using TPA measures. Using objective PA, HRs were 0.49 (0.29-0.80) and 0.29 (0.13-0.61) in the moderate and high PA groups, respectively. These findings were similar for participants without multimorbidity. In participants with multimorbidity, at the age of 45 years, moderate and high LTPA were associated with an average of 3.12 (95% CI 2.53, 3.71) and 3.55 (2.34, 4.77) additional life years, respectively, compared to low LTPA; in participants without multimorbidity, corresponding figures were 1.95 (1.59, 2.31) and 1.85 (1.19, 2.50). Similar results were found with TPA. For objective PA, moderate and high levels were associated with 3.60 (- 0.60, 7.79) and 5.32 (- 0.47, 11.11) life years gained compared to low PA for those with multimorbidity and 3.88 (1.79, 6.00) and 4.51 (2.15, 6.88) life years gained in those without. Results were consistent when using other definitions of multimorbidity., Conclusions: There was an inverse dose-response association between PA and mortality. A moderate exercise is associated with a longer life expectancy, also in individuals with multimorbidity.

Background: Bariatric surgery reduces cardiovascular events and mortality risk in obese individuals. However, it is unclear whether diabetes modifies this effect. This study examined mortality, cardiovascular, and cancer risk following bariatric surgery in adults with and without pre-existing diabetes., Methods: Using mortality-linked Hospital Episodes Statistics (2006-14) from England, the risk of death, myocardial infarction, stroke, unstable angina, heart failure, and cancer following bariatric surgery was examined; the risk of death in people undergoing surgery was also compared with mortality rates of the general population., Results: Of the 35 887 people undergoing bariatric surgery, 9175 (25.6%) had pre-existing diabetes. During a mean follow-up of 5.3 years, 801 people died, of whom 293 (36.6%) had pre-existing diabetes. The risk of all-cause mortality was 26% higher in people with than without diabetes (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.08-1.46), whereas the risk of cancer was 21% higher (aHR 1.21; 95% CI 1.14-1.77). The risk of cardiovascular events was higher for patients with than without diabetes (aHRs [95% CIs] 2.08 [1.42-3.05], 1.80 [1.29-2.52], 1.61 [1.18-2.19], and 1.42 [1.14-1.77] for myocardial infarction, unstable angina, stroke, and heart failure, respectively). Compared with the general population, the age-standardized mortality rate ratio was 1.70 (1.52-1.91) and 1.35 (1.23-1.48) in people with and without pre-existing diabetes, respectively., Conclusions: For patients with pre-existing diabetes, the risk of death, cardiovascular events, and cancer after bariatric surgery was higher than for those without diabetes, whose mortality risk after surgery remains 35% higher than that of the general population., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Introduction: We aimed to compare risk of stillbirth between maternal smokers and those prescribed nicotine replacement therapy (NRT) during pregnancy., Aims and Methods: We conducted a cross-sectional analysis on a pregnancy cohort of 220,630 singleton pregnancies ending in live or stillbirth between 2001 and 2012 from The Health Improvement Network UK general practice database. Women were categorized into three groups: NRT (prescribed during pregnancy or 1 month before conception); smokers; and controls (nonsmokers without a pregnancy NRT prescription). We calculated Odds ratios (OR) and corresponding 95% confidence intervals (CI) for stillbirth in the NRT group and smokers compared to controls., Results: A total of 805 pregnancies ended in stillbirth (3.6/1000 births). Absolute risks of stillbirth in NRT and smoker groups were both 5/1000 births compared with 3.5/1000 births in the control group. Compared with the control group, the adjusted odds of stillbirth in the NRT group was not statistically significant (OR = 1.35, 95% CI 0.91 to 2.00), although it was similar in magnitude to that in the smokers group (OR = 1.41, 95% CI 1.13 to 1.77)., Conclusions: We found no evidence of a statistically significant association between being prescribed NRT during pregnancy and odds of stillbirth compared with nonsmoking women. Although our study had much larger numbers than any previously, an even larger study with biochemically validated smoking outcome data and close monitoring of NRT use throughout pregnancy is required to exclude effects on findings of potential exposure misclassification., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Background and Aims: To investigate the association of body mass index with all-cause, cardiovascular and cancer mortality in individuals with and without diabetes., Methods and Results: We used data on 490,852 participants from the UK Biobank, with linkage to national mortality data between 2006 and 2016. Using Cox regression, we calculated hazard ratios (HRs) and 95% confidence intervals (95%CI) for all-cause, cardiovascular and cancer mortality within body mass index categories in people with and without diabetes adjusting for potential confounders. 24,789 (5.0%) participants reported having diabetes at baseline. Over a median follow-up of 6.9 years, 13,896 participants died, of which 1800 had diabetes. Compared with normal body mass index (18.5-24.9 kg/m 2 ), mortality risk in the overweight group (25.0-29.9 kg/m 2 ) was 33% lower in people with diabetes (HR 0.67, 95%CI 0.62-0.73) and 12% lower in participants without (HR 0.88, 95%CI 0.85-0.90). For class I obesity (30.0-34.9 kg/m 2 ), mortality risk was 35% lower in participants with diabetes (HR 0.65, 95%CI 0.59-0.71) and 5% lower in participants without (HR 0.95, 95%CI 0.91-0.99). For class III obesity (≥40 kg/m 2 ), there was a 10% non-significant lower mortality risk compared to normal body mass index in people with diabetes (HR 0.90, 95%CI 0.77-1.05); in contrast, the risk was 29% higher in people without diabetes (HR 1.29, 95%CI 1.13-1.45). Similar patterns were observed for cardiovascular mortality but not for cancer mortality., Conclusion: The impact of obesity on the risk of mortality was dependent on the presence of diabetes: for the same level of obesity, mortality risk was higher in people without diabetes compared to those with diabetes., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are two classes of glucose-lowering drugs gaining popularity in the treatment of type 2 diabetes mellitus (T2DM). Current guidelines suggest patient-centred approaches when deciding between available hyperglycaemia drugs with no indication to which specific drug should be administered. Despite systematic reviews and meta-analyses being conducted within SGLT-2is and GLP-1RAs, differences across these classes of drugs have not been investigated. Therefore, this systematic review and network meta-analysis (NMA) will aim to compare the efficacy and safety profiles across and within SGLT-2is and GLP-1RAs., Methods: PubMed, the Cochrane Central Register of Controlled Trials and ISI Web of Science will be searched from inception for published randomised controlled trials conducted in patients with T2DM, with at least two arms consisting of SGLT-2is, GLP-1RAs or control/placebo. Title and abstracts will be screened by two independent reviewers with conflicts resolved by a third. Data will be extracted by the primary researcher, a random sample will be checked by an independent reviewer. Risk of bias will be assessed using the Cochrane Risk of Bias Tool and overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.Study characteristics, participants baseline characteristics, mean change in cardiometabolic outcomes and number of adverse events will be extracted for each study. Primary outcome will be the mean change in glycated haemoglobin (HbA 1c ) (%, mmol/mol). Initial random-effects pairwise meta-analysis will be conducted for each unique treatment comparison where heterogeneity will be assessed. A Bayesian NMA approach will be adopted where random-effects generalised linear models will be fitted in WinBUGS. Sensitivity analysis will be conducted to assess choices of prior distributions and length of burn-in and sample., Ethics and Dissemination: Ethics approval is not required for this study. Results from this study will be published in a peer-review journal., Prospero Registration Number: CRD42018091306., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality., Methods: We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes-related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time., Results: Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000-2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia-related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000-2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person-years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA., Conclusions/interpretation: Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia., Data Availability: Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1.

Objective: To assess the prevalence, disease clusters, and patterns of multimorbidity using a novel 2-stage approach in middle-aged and older adults from the United Kingdom., Patients and Methods: Data on 36 chronic conditions from 502,643 participants aged 40 to 69 years with baseline measurements between March 13, 2006, and October 1, 2010, from the UK Biobank were extracted. We combined cluster analysis and association rule mining to assess patterns of multimorbidity overall and by age, sex, and ethnicity. A maximum of 3 clusters and 30 disease patterns were mined. Comparisons were made using lift as the main measure of association., Results: Ninety-five thousand seven hundred-ten participants (19%) had 2 or more chronic conditions. The first cluster included only myocardial infarction and angina (lift=13.3), indicating that the likelihood of co-occurrence of these conditions is 13 times higher than in isolation. The second cluster consisted of 26 conditions, including cardiovascular, musculoskeletal, respiratory, and neurodegenerative diseases. The strongest association was found between heart failure and atrial fibrillation (lift=23.6). Diabetes was at the center of this cluster with strong associations with heart failure, chronic kidney disease, liver failure, and stroke (lift>2). The third cluster contained 8 highly prevalent conditions, including cancer, hypertension, asthma, and depression, and the strongest association was observed between anxiety and depression (lift=5.0)., Conclusion: Conditions such as diabetes, hypertension, and asthma are the epicenter of disease clusters for multimorbidity. A more integrative multidisciplinary approach focusing on better management and prevention of these conditions may help prevent other conditions in the clusters., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Aims: To assess the evidence supporting the choice of third-line agents in adults with inadequately controlled type 2 diabetes., Materials and Methods: We searched randomized controlled trials (RCTs) published between January 2000 and July 2017 that reported data on cardiometabolic outcomes and hypoglycaemia for glucose-lowering agents added to metformin-based dual treatments. Data were stratified by background therapy and RCT duration, and synthesized, when possible, with network meta-analyses., Results: A total of 43 RCTs (16 590 participants) were included, with metformin combined with: sulphonylureas (SUs) in 20 RCTs; thiazolidinediones (TZDs) in 10; basal or rapid-acting insulin in 6; dipeptidyl peptidase-4 (DPP-4) inhibitors in 3; glucagon-like peptide-1 receptor agonists (GLP-1RAs) in 2; and sodium-glucose co-transporter-2 (SGLT-2) inhibitors in 2. When added to metformin and SUs, after 24 to 36 weeks, rapid-acting insulin resulted in the largest reduction in glycated haemoglobin (HbA1c; 1.6% vs placebo), followed by GLP-1RAs (1.0%), basal insulin (0.8%) and SGLT-2 inhibitors (0.7%), with no difference between GLP-1RAs and SGLT-2 inhibitors; body weight increased with insulin treatment (~3 kg vs placebo), while the greatest reduction was observed for SGLT-2 inhibitors compared with all other therapies. Limited data for hypoglycaemia indicated a similar risk for SGLT-2 inhibitors and GLP-1RAs. Results for third-line agents added to metformin and TZDs were comparable, showing similar HbA1c reduction and risk of hypoglycaemia between SGLT-2 inhibitors and GLP-1RAs, and a slightly greater reduction in body weight with SGLT-2 inhibitors vs GLP-1RAs. Data for 52 to 54 weeks were more limited: added to metformin and a SU, TZDs, GLP-1RAs or SGLT-2 inhibitors reduced HbA1c to a similar extent but had different effects on body weight (7 kg and 5 kg more with TZDs vs SGLT-2 inhibitors and GLP-1RAs, respectively; 2 kg less when comparing SGLT-2 inhibitors with GLP-1RAs). Formal analyses could not be performed for any other dual therapy failure combinations because of the small number of available RCTs., Conclusions: Moderate-quality evidence supports the choice of a third-line agent only in patients on metformin combined with a SU or a TZD, with SGLT-2 inhibitors performing generally better than other drugs. In suggesting third-line agents, future guidelines should recognize the widely differing evidence on the various dual therapy failures., (© 2017 John Wiley & Sons Ltd.)

Aims: To quantify the association of self-reported walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality., Methods and Results: A total of 230 670 women and 190 057 men free from prevalent cancer and cardiovascular disease were included from UK Biobank. Usual walking pace was self-defined as slow, steady/average or brisk. Handgrip strength was assessed by dynamometer. Cox-proportional hazard models were adjusted for social deprivation, ethnicity, employment, medications, alcohol use, diet, physical activity, and television viewing time. Interaction terms investigated whether age, body mass index (BMI), and smoking status modified associations. Over 6.3 years, there were 8598 deaths, 1654 from cardiovascular disease and 4850 from cancer. Associations of walking pace with mortality were modified by BMI. In women, the hazard ratio (HR) for all-cause mortality in slow compared with fast walkers were 2.16 [95% confidence interval (CI): 1.68-2.77] and 1.31 (1.08-1.60) in the bottom and top BMI tertiles, respectively; corresponding HRs for men were 2.01 (1.68-2.41) and 1.41 (1.20-1.66). Hazard ratios for cardiovascular mortality remained above 1.7 across all categories of BMI in men and women, with modest heterogeneity in men. Handgrip strength was associated with cardiovascular mortality in men only (HR tertile 1 vs. tertile 3 = 1.38; 1.18-1.62), without differences across BMI categories, while associations with all-cause mortality were only seen in men with low BMI. Associations for walking pace and handgrip strength with cancer mortality were less consistent., Conclusion: A simple self-reported measure of slow walking pace could aid risk stratification for all-cause and cardiovascular mortality within the general population., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

Aims: To validate the Leicester Self-Assessment score using a representative English dataset for detecting prevalent non-diabetic hyperglycaemia or undiagnosed Type 2 diabetes (defined as HbA 1c ≥6.0%) and for identifying those who may go on to develop Type 2 diabetes within 10 years., Methods: Data were taken from the English Longitudinal Study of Ageing, a nationally representative dataset of people aged ≥50 years. The area under the receiver-operator curve and performance metrics for the score at the recommended score threshold (≥16), were calculated for the outcomes of HbA 1c ≥42 mmol/mol (6.0%) at baseline and self-reported Type 2 diabetes within 10 years in those aged 50-75 years at baseline., Results: A total of 3203 individuals had a baseline HbA 1c measurement, of whom 247 (7.7%) had an HbA 1c concentration ≥42 mmol/mol (6.0%). The area under the receiver-operator curve was 69.4% (95% CI 66.0-72.9) for baseline HbA 1c ≥42 mmol/mol. A total of 3550 individuals had diabetes status recorded at 10 years, of whom 324 (9.1%) were diagnosed with Type 2 diabetes within this time; the area under the receiver-operator curve for this outcome was 74.9% (95% CI 72.4-77.5). The score threshold of ≥16 had a sensitivity of 89.2% (95% CI 85.3-92.4) and a specificity of 42.3% (95% CI 40.5-44.0) for Type 2 diabetes within 10 years., Conclusions: The Leicester Self-Assessment score is validated for use across England to identify people with non-diabetic hyperglycaemia or undiagnosed Type 2 diabetes. Those with a high score are at high risk of developing diabetes in the future., (© 2017 Diabetes UK.)

Objectives: Assess the longitudinal association between polypharmacy and falls and examine the differences in this association by different thresholds for polypharmacy definitions in a nationally representative sample of adults aged over 60 years from England., Design: Longitudinal cohort study., Setting: The English Longitudinal Study of Ageing waves 6 and 7., Participants: 5213 adults aged 60 or older., Main Outcome Measures: Rates, incidence rate ratio (IRR) and 95% CI for falls in people with and without polypharmacy., Results: A total of 5213 participants contributed 10 502 person-years of follow-up, with a median follow-up of 2.02 years (IQR 1.9-2.1 years). Of the 1611 participants with polypharmacy, 569 reported at least one fall within the past 2 years (rate: 175 per 1000 person-years, 95% CI 161 to 190), and of the 3602 participants without polypharmacy 875 reported at least one fall (rate: 121 per 1000 person-years, 95% CI 113 to 129). The rate of falls was 21% higher in people with polypharmacy compared with people without polypharmacy (adjusted IRR 1.21, 95% CI 1.11 to 1.31). Using ≥4 drugs threshold the rate of falls was 18% higher in people with polypharmacy compared with people without (adjusted IRR 1.18, 95% CI 1.08 to 1.28), whereas using ≥10 drugs threshold polypharmacy was associated with a 50% higher rate of falls (adjusted IRR 1.50, 95% CI 1.34 to 1.67)., Conclusions: We found almost one-third of the total population using five or more drugs, which was significantly associated with 21% increased rate of falls over a 2-year period. Further exploration of the effects of these complex drug combinations in the real world with a detailed standardised assessment of polypharmacy is greatly required along with pragmatic studies in primary care, which will help inform whether the threshold for a detailed medication review should be lowered., Competing Interests: Competing interests: KK has acted as a consultant and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim and Merck Sharp & Dohme. KK has received funds for research, honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp & Dohme and Novo Nordisk. MJD has acted as consultant, advisory board member and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Janssen, and as a speaker for Mitsubishi Tanabe Pharma Corporation. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis and Lilly., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: To evaluate risk factors for hospital admissions for hypoglycaemia and compare length of hospitalization, inpatient mortality and hospital readmission between hypoglycaemia- and non-hypoglycaemia-related admissions., Materials and Methods: We used all admissions for hypoglycaemia in individuals with diabetes to English NHS hospital trusts between 2005 and 2014 (101 475 case admissions) and 3 random admissions per case in individuals with diabetes without hypoglycaemia (304 425 control admissions). Risk factors and differences in the 3 outcomes were estimated with logistic and negative binomial regressions., Results: A U-shaped relationship between age and risk of admission for hypoglycaemia was observed until the age of 85 years; compared to the nadir at 60 years, the risk was progressively higher in younger and older patients and steadily declined after 85 years. Social deprivation (positively) and comorbidities (negatively) were associated with the risk of admission for hypoglycaemia. Compared to Caucasians, other ethnic groups had lower (Bangladeshi, Pakistani, Indians) or higher (Caribbean) risk of admission for hypoglycaemia. Length of hospitalization was 26% shorter while risk of rehospitalization was 65% higher in individuals admitted for hypoglycaemia. Compared to admissions for hypoglycaemia, risk of inpatient mortality was 50% lower for unstable angina but higher for acute myocardial infarction (3 times), acute renal failure (5 times) or pneumonia (8 times)., Conclusions: Among hospital-admitted individuals with diabetes, age, social deprivation, comorbidities and ethnicity are associated with higher frequency of hospitalization for hypoglycaemia. Admission for hypoglycaemia is associated with a greater risk of readmission, a shorter length of hospitalisation and a generally lower inpatient mortality compared to admissions for other medical conditions. These results could help in identifying at-risk groups to reduce the burden of hospitalization for hypoglycaemia., (© 2017 John Wiley & Sons Ltd.)

Aims/hypothesis: Hospital admissions for hypoglycaemia represent a significant burden on individuals with diabetes and have a substantial economic impact on healthcare systems. To date, no prognostic models have been developed to predict outcomes following admission for hypoglycaemia. We aimed to develop and validate prediction models to estimate risk of inpatient death, 24 h discharge and one month readmission in people admitted to hospital for hypoglycaemia., Methods: We used the Hospital Episode Statistics database, which includes data on all hospital admission to National Health Service hospital trusts in England, to extract admissions for hypoglycaemia between 2010 and 2014. We developed, internally and temporally validated, and compared two prognostic risk models for each outcome. The first model included age, sex, ethnicity, region, social deprivation and Charlson score ('base' model). In the second model, we added to the 'base' model the 20 most common medical conditions and applied a stepwise backward selection of variables ('disease' model). We used C-index and calibration plots to assess model performance and developed a calculator to estimate probabilities of outcomes according to individual characteristics., Results: In derivation samples, 296 out of 11,136 admissions resulted in inpatient death, 1789/33,825 in one month readmission and 8396/33,803 in 24 h discharge. Corresponding values for validation samples were: 296/10,976, 1207/22,112 and 5363/22,107. The two models had similar discrimination. In derivation samples, C-indices for the base and disease models, respectively, were: 0.77 (95% CI 0.75, 0.80) and 0.78 (0.75, 0.80) for death, 0.57 (0.56, 0.59) and 0.57 (0.56, 0.58) for one month readmission, and 0.68 (0.67, 0.69) and 0.69 (0.68, 0.69) for 24 h discharge. Corresponding values in validation samples were: 0.74 (0.71, 0.76) and 0.74 (0.72, 0.77), 0.55 (0.54, 0.57) and 0.55 (0.53, 0.56), and 0.66 (0.65, 0.67) and 0.67 (0.66, 0.68). In both derivation and validation samples, calibration plots showed good agreement for the three outcomes. We developed a calculator of probabilities for inpatient death and 24 h discharge given the low performance of one month readmission models., Conclusions/interpretation: This simple and pragmatic tool to predict in-hospital death and 24 h discharge has the potential to reduce mortality and improve discharge in people admitted for hypoglycaemia.

Background: Evidence on the role of lifestyle factors in relation to multimorbidity, especially in elderly populations, is scarce. We assessed the association between five lifestyle factors and incident multimorbidity (presence of ≥2 chronic conditions) in an English cohort aged ≥50 years., Methods: We used data from waves 4, 5, and 6 of the English Longitudinal Study of Ageing. Data on smoking, alcohol consumption, physical activity, fruit and vegetable consumption, and body mass index were extracted and combined to generate a sum of unhealthy lifestyle factors for each individual. We examined whether these lifestyle factors individually or in combination predicted multimorbidity during the subsequent wave. We used marginal structural Cox proportional hazard models, adjusted for both time-constant and time-varying factors., Results: A total of 5,476 participants contributed 232,749 person-months of follow-up during which 1,156 cases of incident multimorbidity were recorded. Physical inactivity increased the risk of multimorbidity by 33% (adjusted hazard ratio [aHR]: 1.33, 95% confidence interval [CI]: 1.03-1.73). The risk was about two to three times higher when inactivity was combined with obesity (aHR: 2.87, 95% CI: 1.55-5.31) or smoking (aHR: 2.35, 95% CI: 1.36-4.08) and about four times when combined with both (aHR: 3.98, 95% CI: 1.02-17.00). Any combination of 2, 3, and 4 or more unhealthy lifestyle factors significantly increased the multimorbidity hazard, compared with none, from 42% to 116%., Conclusion: This study provides evidence of a temporal association between combinations of different unhealthy lifestyle factors with multimorbidity. Population level interventions should include reinforcing positive lifestyle changes in the population to reduce the risk of developing multimorbidity., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus., Methods: We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis., Results: We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31-35 kg/m 2 and 28-31 kg/m 2 (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m 2 )., Conclusions/interpretation: In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.

Objective: To compare risks of adverse perinatal outcomes between assisted reproductive technology (ART) and naturally conceived singleton births using a dual design approach., Design: Discordant-sibling and conventional cross-sectional general population comparison., Setting: Not applicable., Patient(s): All singleton live births, conceived naturally or via ART., Intervention(s): None., Main Outcome Measure(s): Birth weight, gestational age, low birth weight, preterm delivery, small for gestational age (SGA), low Apgar score., Result(s): A total of 32,762 (0.8%) of 3,896,242 singleton live births in the three states were conceived via ART. In 6,458 sibling pairs, ART-conceived singletons were 33 g lighter (adjusted β = -33.40, 95% confidence interval [CI], -48.60, -18.21) and born half a day sooner (β = -0.58, 95% CI, -1.02, -0.14) than singletons conceived naturally. The absolute risk of low birth weight and preterm birth was 6.8% and 9.7%, respectively, in the ART group and 4.9% and 7.9%, respectively, in the non-ART group. The odds of low birth weight were 33% higher (adjusted odds ratio [aOR] = 1.33; 95% CI, 1.13, 1.56) and 20% higher for preterm birth (aOR = 1.20; 95% CI, 1.07, 1.34). The odds of SGA and low Apgar score were not significantly different in both groups (aOR = 1.22; 95% CI, 0.88, 1.68; and aOR = 0.75; 95% CI, 0.54, 1.05, respectively). Results of conventional analyses were similar, although the magnitude of risk was higher for preterm birth (aOR, 1.51; 95% CI 1.46, 1.56)., Conclusion(s): Despite some inflated risks in the general population comparison, ART remained associated with an increased likelihood of low birth weight and preterm birth when underlying maternal factors were kept constant using discordant-sibling comparison., (Copyright © 2016 American Society for Reproductive Medicine. All rights reserved.)

Background: Studies in the USA and Canada have reported increasing or stable rates of hospital admissions for hypoglycaemia. Some data from small studies are available for other countries. We aimed to gather information about long-term trends in hospital admission for hypoglycaemia and subsequent outcomes in England to help widen understanding for the global burden of hospitalisation for hypoglycaemia., Methods: We collected data for all hospital admissions listing hypoglycaemia as primary reason of admission between Jan 1, 2005, and Dec 31, 2014, using the Hospital Episode Statistics database, which contains details of all admissions to English National Health Service (NHS) hospital trusts. We calculated trends in crude and adjusted (for age, sex, ethnic group, social deprivation, and Charlson comorbidity score) admissions for hypoglycaemia; in admissions for hypoglycaemia per total hospital admissions and per diabetes prevalence in England; and in length of stay, in-hospital mortality, and 1 month readmissions for hypoglycaemia., Findings: 79 172 people had 101 475 admissions for hypoglycaemia between 2005 and 2014, of which 72 568 (72%) occurred in people aged 60 years or older. 13 924 (18%) people had more than one admission for hypoglycaemia during the study period. The number of admissions increased steadily from 7868 in 2005, to 11 756 in 2010 (49% increase) and then remained more stable until 2014 (10 977; 39% increase from baseline, range across English regions 11-89%); the trend was similar after adjustment for risk factors, with a rate ratio of 1·53 (95% CI 1·29-1·81) for 2014 versus 2005. Admissions for hypoglycaemia per 100 000 total hospital admissions increased from 63·6 to 78·9 between 2005-06 and 2010-11 (24% increase), and then fell to 72·3 per 100 000 in 2013-14 (14% overall increase). Accounting for diabetes prevalence data, rates declined from 4·64 to 3·86 admissions per 1000 person-years with diabetes between 2010-11 and 2013-14. We were unable to compare prevalence rates with data prior to 2010, as the populations were not comparable; data were available for all individuals prior to 2010 but only for those aged 17 years or older after 2010. With some differences across regions, from 2005 to 2014, the adjusted proportion of admissions to receive same-day discharge increased by 43·8% (from 18·9 to 27·1 same-day discharges per 100 admissions); in-hospital mortality decreased by 46·3% (from 4·2 to 2·3 deaths per 100 admissions); and 1 month readmissions decreased by 63·0% (from 48·1 to 17·8 per 100 readmissions)., Interpretation: Over 10 years, hospital admissions in England for hypoglycaemia increased by 39% in absolute terms and by 14% considering the general increase in hospitalisation; however, accounting for diabetes prevalence, there was a reduction of admission rates. Hospital length of stay, mortality, and 1 month readmissions decreased progressively and consistently during the study period. Given the continuous rise of diabetes prevalence, ageing population, and costs associated with hypoglycaemia, individual and national initiatives should be implemented to reduce the burden of hospital admissions for hypoglycaemia., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Multimorbidity has become one of the main challenges in the recent years for patients, health care providers and the health care systems globally. However, literature describing the burden of multimorbidity in the elderly population, especially longitudinal trends is very limited. Physical activity is recommended as one of the main lifestyle changes in the prevention and management of multiple chronic diseases worldwide; however, the evidence on its association with multimorbidity remains inconclusive. Therefore, we aimed to assess the longitudinal trends of multimorbidity and the association between multimorbidity and physical activity in a nationally representative cohort of the English population aged ≥50 years between 2002 and 2013., Methods: We used data on 15,688 core participants from six waves of the English Longitudinal Study of Ageing, with complete information on physical activity. Self-reported physical activity was categorised as inactive, mild, moderate and vigorous levels of physical activity. We calculated the number of morbidities and the prevalence of multimorbidity (more than 2 chronic conditions) between 2002 and 2013 overall and by levels of self-reported physical activity. We estimated the odds ratio (OR) and 95% confidence intervals (CI) for multimorbidity by each category of physical activity, adjusting for potential confounders., Results: There was a progressive decrease over time in the proportion of participants without any chronic conditions (33.9% in 2002/2003 vs. 26.8% in 2012/2013). In contrast, the prevalence of multimorbidity steadily increased over time (31.7% in 2002/2003 vs. 43.1% in 2012/2013). Compared to the physically inactive group, the OR for multimorbidity was 0.84 (95% CI 0.78 to 0.91) in mild, 0.61 (95% CI 0.56 to 0.66) in moderate and 0.45 (95% CI 0.41 to 0.49) in the vigorous physical activity group., Conclusion: This study demonstrated an inverse dose-response association between levels of physical activity and multimorbidity, however, given the increasing prevalence of multimorbidity over time, there is a need to explore causal associations between physical activity and multimorbidity and its impact as a primary prevention strategy to prevent the occurrence of chronic conditions later in life and reduce the burden of multimorbidity.

Objective: To examine major congenital anomaly (CA) risks in children of mothers with coeliac disease (CD) compared with mothers without CD., Design: Population-based cohort study., Setting: Linked maternal-child medical records from a large primary care database from the UK., Population: A total of 562,332 live singletons of mothers with and without CD in 1990-2013., Methods: We calculated the absolute major CA risks in children whose mothers had CD, and whether this was diagnosed or undiagnosed before childbirth. Logistic regression with a generalised estimating equation was used to estimate adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) for CAs associated with CD., Main Outcome Measures: Fourteen system-specific major CA groups classified according to the European Surveillance of Congenital Anomalies and neural tube defects (NTDs)., Results: Major CA risk in 1880 children of mothers with CD was 293 per 10,000 liveborn singletons, similar to the risk in those without CD (282; aOR 0.98, 95% CI 0.74-1.30). The risk was slightly higher in 971 children, whose mothers were undiagnosed (350; aOR 1.14, 95% CI 0.79-1.64), than in 909 children whose mothers were diagnosed (231; aOR 0.80, 95% CI 0.52-1.24). There was a three-fold increase in nervous system anomalies in the children of mothers with undiagnosed CD (aOR 2.98, 95% CI 1.06-8.33, based on five exposed cases and one had an NTD), and these women were all diagnosed with CD at least 4 years after their children were born., Conclusions: There was no statistically significant increase in risk of major CAs in children of mothers with coeliac disease overall, compared with the general population., (© 2014 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: We aimed to assess the potential usefulness of primary care data in the UK for estimating smoking prevalence in pregnancy by comparing the primary care data estimates with those obtained from other data sources., Methods: In The Health Improvement Network (THIN) primary care database, we identified pregnant smokers using smoking information recorded during pregnancy. Where this information was missing, we used smoking information recorded prior to pregnancy. We compared annual smoking prevalence from 2000 to 2012 in THIN with measures from the Infant Feeding Survey (IFS), Smoking At Time of Delivery (SATOD), Child Health Systems Programme (CHSP) and Scottish Morbidity Record (SMR)., Results: Smoking estimates from THIN data converged with estimates from other sources after 2004, though still do not agree completely. For example, in 2012 smoking prevalence at booking was 11.6% in THIN using data recorded only during pregnancy, compared with 19.6% in SMR data. However, the use of smoking data recorded up to 27 months before conception increased the THIN prevalence to 20.3%, improving the comparability., Conclusions: Under-recording of smoking status during pregnancy results in unreliable prevalence estimates from primary care data and needs improvement. However, in the absence of gestational smoking data, the inclusion of pre-conception smoking records may increase the utility of primary care data. One strategy to improve gestational smoking status recording in primary care could be the inclusion of pregnancy in the Quality and Outcome's Framework as a condition for which smoking status and smoking cessation advice must be recorded electronically in patient records., (© The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health.)

Background and Objectives: Nicotine replacement therapy (NRT) is now being used as a smoking cessation aid during pregnancy, although little is known about fetal safety. We assessed the relationship between early pregnancy exposure to NRT or smoking with major congenital anomalies (MCA) in offspring., Methods: We studied 192,498 children born in the United Kingdom between 2001 and 2012 with linked mother-child primary care records. The absolute risks of MCAs in the NRT group (women prescribed NRT during the first trimester or 1 month before conception [and therefore likely consumed during the first trimester]) and odds ratios (ORs) and 99% confidence intervals (CIs) were compared with those of women who smoked during pregnancy and with a control group (women who neither smoked nor were prescribed NRT); logistic regression models adjusted for maternal morbidities that increase MCA risk were used for analysis., Results: MCA prevalence was 288 per 10,000 live births (5535 children with ≥ 1 MCA). Maternal morbidities were most common in the NRT group (35%) followed by smokers (27%) and the control group (20%). Compared with the control group, adjusted ORs for MCAs in the NRT group and smokers were 1.12 (99% CI: 0.84-1.48) and 1.05 (99% CI: 0.89-1.23), respectively. The OR comparing the NRT group directly with smokers was 1.07 (99% CI: 0.78-1.47). There were no statistically significant associations between maternal NRT and system-specific anomalies except for respiratory anomalies (OR: 4.65 [99% CI: 1.76-12.25]; absolute risk difference: 3 per 1000 births), which was based on 10 exposed cases., Conclusions: For most system-specific MCAs, we found no statistically significant increased risks associated with maternal NRT prescribed during pregnancy, except for respiratory anomalies. Although this study is the largest published to date, NRT use in pregnancy remains rare; thus, the statistical power was limited. Higher morbidities in those women prescribed NRT may also be an explanatory factor. Nevertheless, absolute MCA risks were similar between women who smoked and those prescribed NRT during pregnancy., (Copyright © 2015 by the American Academy of Pediatrics.)

Background & Aims: Studies have associated infertility with celiac disease. However, these included small numbers of women attending infertility specialist services and subsequently screened for celiac disease, and therefore may not have been representative of the general population. We performed a large population-based study of infertility and celiac disease in women from the United Kingdom., Methods: We identified 2,426,225 women with prospective UK primary care records between 1990 and 2013 during their child-bearing years from The Health Improvement Network database. We estimated age-specific rates of new clinically recorded fertility problems among women with and without diagnosed celiac disease. Rates were stratified by whether celiac disease was diagnosed before the fertility problem or afterward and compared with rates in women without celiac disease using Poisson regression, adjusting for sociodemographics, comorbidities, and calendar time., Results: Age-specific rates of new clinically recorded fertility problems in 6506 women with celiac disease were similar to the rates in women without celiac disease (incidence rate ratio, 1.12; 95% confidence interval, 0.88-1.42 among women age 25-29 years). Rates of infertility among women without celiac disease were similar to those of women with celiac disease before and after diagnosis. However, rates were 41% higher among women diagnosed with celiac disease when they were 25-29 years old, compared with women in the same age group without celiac disease (incidence rate ratio, 1.41; 95% confidence interval, 1.03-1.92)., Conclusions: Women with celiac disease do not have a greater likelihood of clinically recorded fertility problems than women without celiac disease, either before or after diagnosis, except for higher reports of fertility problems between 25-39 years if diagnosed with CD. These findings should assure most women with celiac disease that they do not have an increased risk for fertility problems., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Evidence-based information about adverse birth outcomes and pregnancy complications is crucial when counseling women with celiac disease (CD); however, limited population-based data on such risks exist. We estimated these for pregnant women with CD diagnosed before and after delivery., Methods: We included all singleton pregnancies between 1997 and 2012 using linked primary care data from the Clinical Practice Research Datalink and secondary care Hospital Episode Statistics data. Risks of pregnancy complications (antepartum and postpartum hemorrhage, pre-eclampsia, and mode of delivery) and adverse birth outcomes (preterm birth, stillbirth, and low birth weight) were compared between pregnancies of women with and without CD using logistic/multinomial regression. Risks were stratified on the basis of whether women were diagnosed or yet undiagnosed before delivery., Results: Of 363,930 pregnancies resulting in a live birth or stillbirth, 892 (0.25%) were among women with CD. Diagnosed CD was not associated with an increased risk of pregnancy complications or adverse birth outcomes compared with women without CD. However, the risk of postpartum hemorrhage and assisted delivery was slightly higher among pregnant women with diagnosed CD (adjusted odds ratio (aOR)=1.34). We found no increased risk of any pregnancy complication among those with undiagnosed CD. We only observed a 1% absolute excess risk of preterm birth and low birth weight among undiagnosed CD mothers corresponding to aOR=1.24 (95% confidence interval (CI)=0.82-1.87) and aOR=1.36 (95% CI=0.83-2.24), respectively., Conclusions: Whether diagnosed or undiagnosed during pregnancy, CD is not associated with a major increased risk of pregnancy complications and adverse birth outcomes. These findings are reassuring to both women and clinicians.

Background: Licensing arrangements for nicotine replacement therapy (NRT) in the UK were broadened in 2005 to allow prescribing to pregnant smokers. However, estimates of NRT prescribing in pregnant females in the UK are currently lacking., Aim: To assess trends in NRT prescribing around pregnancy, and variation in prescribing by maternal characteristics., Design and Setting: Population-based descriptive study using pregnancy data from The Health Improvement Network primary care database, 2001-2012., Method: NRT prescriptions were identified during pregnancy and in the 9 months before and after. Annual prescribing prevalence was calculated. Logistic regression was used to assess females' likelihood of receiving prescriptions by maternal characteristics., Results: Of 388 142 pregnancies studied, NRT was prescribed in 7551 for an average duration of 2 weeks. The prescribing prevalence of NRT increased from 0.03% (0.7% in smokers) in 2001 to 2.6% (11.4% in smokers) in 2005, after which it remained stable. Prescribing prevalence of NRT before and after pregnancy was half the prevalence during pregnancy. The odds of prescribing NRT during pregnancy in smokers increased with socioeconomic deprivation (OR = 1.29, 95% CI = 1.15 to 1.45 in the most compared with the least deprived group). Prescribing was 33% higher in pregnant smokers with asthma (OR = 1.33, 95% CI = 1.22 to 1.45) and mental illness (OR = 1.33, 95% CI = 1.23 to 1.44) compared with smokers without these diagnoses., Conclusion: NRT prescribing is higher during pregnancy compared with before and after, and is higher in smokers from more socioeconomically deprived groups, those with asthma or those diagnosed mental illness., (© British Journal of General Practice 2014.)

Objectives: To report the methods used to assemble a contemporary pregnancy cohort for investigating influences on smoking behaviour before, during and after pregnancy and to report characteristics of women recruited., Design: Longitudinal cohort survey., Setting: Two maternity hospitals, Nottingham, England., Participants: 3265 women who attended antenatal ultrasound scan clinics were offered cohort enrolment; those who were 8-26 weeks pregnant and were currently smoking or had recently stopped smoking were eligible. Cohort enrollment took place between August 2011 and August 2012., Primary and Secondary Outcome Measures: Prevalence of smoking at cohort entry and at two follow-up time points (34-36 weeks gestation and 3 months postnatally); response rate, participants' sociodemographic characteristics., Results: 1101 (33.7%, 95% CI 32.1% to 35.4%) women were eligible for inclusion in the cohort, and of these 850 (77.2%, 95% CI 74.6% to 79.6%) were recruited. Within the cohort, 57.4% (N=488, 95% CI 54.1% to 60.7%) reported to be current smokers. Current smokers were significantly younger than ex-smokers (p<0.05), more likely to have no formal qualifications and to not be in current paid employment compared to recent ex-smokers (p<0.001)., Conclusions: This contemporary cohort, which seeks very detailed information on smoking in pregnancy and its determinants, includes women with comparable sociodemographic characteristics to those in other UK cross-sectional studies and cohorts. This suggests that future analyses using this cohort and aimed at understanding smoking behaviour in pregnancy may produce findings that are broadly generalisable., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)