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ObjectiveTo determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma.DesignCross-sectional observational study.SettingThe primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry.ParticipantsOptimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)—severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control).Main outcome measuresPrevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group.Results748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified.ConclusionsOral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.

To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders. Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies. Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little. The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.

Maternal Age at Birth and Childhood Type 1 Diabetes: A Pooled Analysis of 30 Observational Studies Chris R. Cardwell 1 , Lars C. Stene 2 , 3 , Geir Joner 4 , Max K. Bulsara 5 , Ondrej Cinek 6 , Joachim Rosenbauer 7 , Johnny Ludvigsson 8 , Mireia Jané 9 , Jannet Svensson 10 , Michael J. Goldacre 11 , Thomas Waldhoer 12 , Przemysława Jarosz-Chobot 13 , Suely G.A. Gimeno 14 , Lee-Ming Chuang 15 , Roger C. Parslow 16 , Emma J.K. Wadsworth 17 , Amanda Chetwynd 18 , Paolo Pozzilli 19 , Girts Brigis 20 , Brone Urbonaitė 21 , Sandra Šipetić 22 , Edith Schober 23 , Gabriele Devoti 24 , Constantin Ionescu-Tirgoviste 25 , Carine E. de Beaufort 26 , Denka Stoyanov 27 , Karsten Buschard 28 and Chris C. Patterson 1 1 Centre for Public Health, Queen's University Belfast, Belfast, U.K.; 2 Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; 3 Oslo Research Centre, Oslo University Hospital, Oslo, Norway; 4 Institute of Health Management and Health Economics, University of Oslo, Oslo, Norway; 5 Institute of Health and Rehabilitation Research, University of Notre Dame, Freemantle, Australia; 6 The 2nd Medical School, Charles University, Prague, Czech Republic; 7 Institute of Biometrics and Epidemiology, German Diabetes Centre, Leibniz Institute at Dusseldorf University, Dusseldorf, Germany; 8 Department of Paediatrics and Diabetes Research Centre, Linkoping University, Linkoping, Sweden; 9 Public Health Division, Department of Health, Barcelona, Spain; 10 Pediatric Department, Glostrup University Hospital, Glostrup, Denmark; 11 Department of Public Health, Oxford University, Oxford, U.K.; 12 Department of Epidemiology, Medical University of Vienna, Vienna, Austria; 13 Department of Pediatric Endocrinology and Diabetes, Medical University of Silesia, Katowice, Poland; 14 Preventive Medicine Department, Federal University of Sao Paulo, Sao Paulo, Brazil; 15 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 16 Paediatric Epidemiology Group, University of Leeds, Leeds, U.K.; 17 Centre for Occupational and Health Psychology, Cardiff University, Cardiff, U.K.; 18 Mathematics & Statistics Department, Lancaster University, Lancaster, U.K.; 19 University Campus Bio-Medico, Rome, Italy; 20 Department of Public Health and Epidemiology, Riga Stradins University, Riga, Latvia; 21 Institute of Endocrinology, Kaunas University of Medicine, Kaunas, Lithuania; 22 Institute of Epidemiology, School of Medicine, Belgrade University, Belgrade, Serbia; 23 Department of Paediatrics, Medical University of Vienna, Vienna, Austria; 24 Department of Social Sciences and Communication, University of Lecce, Lecce, Italy; 25 Nutrition and Metabolic Diseases Clinic, “N. Paulescu” Institute of Diabetes, Bucharest, Romania; 26 Clinique Pediatrique, Luxembourg, Luxembourg; 27 Children's Diabetic Centre, Sofia, Bulgaria; 28 Bartholin Instituttet, Rigshospitalet, Copenhagen, Denmark. Corresponding author: Chris Cardwell, c.cardwell{at}qub.ac.uk . Abstract OBJECTIVE The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders. RESEARCH DESIGN AND METHODS Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies. RESULTS Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2–9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age ( P = 0.006), but there was heterogeneity among studies (heterogeneity I 2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. CONCLUSIONS There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received August 6, 2009. Accepted October 23, 2009. © 2010 by the American Diabetes Association.

Severe refractory asthma poses a substantial burden in terms of healthcare costs but relatively little is known about the factors which drive these costs. This study uses data from the British Thoracic Society Difficult Asthma Registry (n=596) to estimate direct healthcare treatment costs from an National Health Service perspective and examines factors that explain variations in costs. Annual mean treatment costs among severe refractory asthma patients were £2912 (SD £2212) to £4217 (SD £2449). Significant predictors of costs were FEV1% predicted, location of care, maintenance oral corticosteroid treatment and body mass index. Treating individuals with severe refractory asthma presents a substantial cost to the health service.

A Meta-Analysis of the Association Between Childhood Type 1 Diabetes and Atopic Disease Chris R. Cardwell , MSC 1 , Mike D. Shields , MD 2 , Dennis J. Carson , MB 2 and Chris C. Patterson , PHD 1 1 Department of Epidemiology & Public Health, Queen’s University of Belfast, Belfast, Northern Ireland, U.K 2 Department of Child Health, Queen’s University of Belfast, Belfast, Northern Ireland, U.K Address correspondence and reprint requests to Chris Cardwell, Department of Epidemiology & Public Health, The Queen’s University of Belfast, Grosvenor Road, Belfast BT12 6BJ, U.K. E-mail: c.cardwell{at}qub.ac.uk Abstract OBJECTIVE —To review the published literature and perform a meta-analysis summarizing the evidence in support of an inverse association between type 1 diabetes and the atopic disorders: asthma, eczema, and allergic rhinitis in children. RESEARCH DESIGN AND METHODS —MEDLINE, Web of Science, and PubMed were searched to identify relevant studies. These were assessed on quality criteria, and odds ratios (ORs) and 95% CIs were calculated for each study from the reported prevalences of atopy in children with diabetes and in control children. Meta-analysis was then used to derive a combined OR and test for heterogeneity in findings between studies. RESULTS —Twenty-five studies were identified. Heterogeneity in the findings from different studies was evident but was considerably reduced when the asthma and rhinitis analyses were restricted to those studies judged to be of adequate design. The meta-analysis revealed an inverse association between asthma and type 1 diabetes, but the finding only attained significance when analysis was restricted to the studies of adequate design (OR 0.82, 95% CI 0.68–0.99). In this subset an association of similar magnitude was observed between eczema and type 1 diabetes (0.82, 0.62–1.10) although this failed to attain statistical significance, and heterogeneity between studies was still present. There was little evidence of an association between rhinitis and type 1 diabetes (0.97, 0.82–1.16) in this subset of studies. CONCLUSIONS —Our analysis suggests that there is a small but significant reduction in the prevalence of asthma in children with type 1 diabetes, but the findings for the other atopic diseases are less conclusive. Th1, T helper type 1 Th2, T helper type 2 Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted June 16, 2003. Received April 17, 2003. DIABETES CARE

Aims/hypothesis The aim of this study was to investigate the association between routine vaccinations and the risk of childhood type 1 diabetes mellitus by systematically reviewing the published literature and performing meta-analyses where possible. Methods A comprehensive literature search was performed of MEDLINE and EMBASE to identify all studies that compared vaccination rates in children who subsequently developed type 1 diabetes mellitus and in control children. ORs and 95% CIs were obtained from published reports or derived from individual patient data and then combined using a random effects meta-analysis. Results In total, 23 studies investigating 16 vaccinations met the inclusion criteria. Eleven of these contributed to meta-analyses which included data from between 359 and 11,828 childhood diabetes cases. Overall, there was no evidence to suggest an association between any of the childhood vaccinations investigated and type 1 diabetes mellitus. The pooled ORs ranged from 0.58 (95% CI 0.24, 1.40) for the measles, mumps and rubella (MMR) vaccination in five studies up to 1.04 (95% CI 0.94, 1.14) for the haemophilus influenza B (HiB) vaccination in 11 studies. Significant heterogeneity was present in most of the pooled analyses, but was markedly reduced when analyses were restricted to study reports with high methodology quality scores. Neither this restriction by quality nor the original authors’ adjustments for potential confounding made a substantial difference to the pooled ORs. Conclusions/interpretation This study provides no evidence of an association between routine vaccinations and childhood type 1 diabetes.

Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.

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

ObjectivesAfter 20 years of data collection, pregnancy registers have informed prescribing practice. Various populations show trends for a reduction in valproate prescribing, which is associated with an increased risk of anatomical teratogenesis and neurodevelopmental effects in those exposed in utero. Our aim was to determine if any shifts in prescribing trends have occurred in the UK and Ireland Epilepsy and Pregnancy Register cohort and to assess if there had been any change in the overall major congenital malformation (MCM) rate over time.MethodsThe UK and Ireland Epilepsy and Pregnancy Register, a prospective, observational, registration and follow-up study established in 1996, was used to determine the changes in antiepileptic drugs (AEDs) utilised during pregnancy and the MCM rate between 1996 and 2016. Linear regression analysis was used to assess changes in AED utilisation, and Poisson regression was used for the analysis of trends in the MCM rates.ResultsOutcome data for 9247 pregnancies showed a stable percentage of monotherapy to polytherapy prescribing habits over time. After Bonferroni correction, statistically significant (p<0.003) changes were found in monotherapy prescribing with increases in lamotrigine and levetiracetam and decreases in valproate and carbamazepine use. Between 1996 and 2016, the total MCM rate showed a 2.1% reduction per year (incidence risk ratio 0.979 (95% CIs 0.956 to 1.002) but Poisson regression analysis showed that this was not statistically significant p=0.08).ConclusionSignificant changes are seen in the prescribing habits in this cohort over 20 years, but a statistically significant change in the MCM rate was not detected. This work should be replicated on a larger scale to determine if significant changes are occurring in the MCM rate, which would allow a robust economic estimate of the benefits of improvements in prescribing practice and the personal effect of such changes.

Background The main underlying risk factors associated with coronary heart disease (CHD) are modifiable and oxidative injury and systemic inflammatory damage represent key aetiological factors associated with the development and progression of CHD and premature mortality. Objective To examine associations of plasma antioxidant status with all-cause mortality and fatal or non-fatal cardiovascular events. Design The PRIME study prospectively evaluated 9709 men aged 50–59 years between 1991 and 1993 in Northern Ireland and France who were free of CHD at recruitment and followed annually for deaths and cardiovascular events for 10 years. Serum concentrations of vitamin C, retinol, two forms of vitamin E (α- and γ-tocopherol) and six carotenoids were quantified by high-performance liquid chromatography. Baseline conventional risk factors were considered, as well as socioeconomic differences and lifestyle behaviours including diet, smoking habit, physical activity, and alcohol consumption through Cox regression analyses. Results At 10 years, there were 538 deaths from any cause and 440 fatal or non-fatal cardiovascular events. After adjustment for country, age, systolic blood pressure, diabetes, body mass index, cholesterol, high density lipoprotein cholesterol, triglycerides, height, total physical activity, alcohol consumption and smoking habit, higher levels of all antioxidants were associated with significantly lower risk of all-cause mortality, with the exception of γ-tocopherol. Only retinol was significantly associated with decreased risk of cardiovascular events in a fully adjusted model. Conclusions Low antioxidant levels contribute to the gradient of all-cause mortality and cardiovascular incidence independent of lifestyle behaviours and traditional cardiovascular and socioeconomic risk factors.