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Background and Aims: Soluble adhesion molecules are associated with cardiovascular disease and increased in individuals with diabetes. This study assesses the impact of diabetes exposure in utero on the abundance of circulating adhesion molecules in cord serum and soluble adhesion molecules released from human umbilical vein endothelial cells (HUVEC) exposed to high glucose concentrations., Methods and Results: Women with and without diabetes were recruited. DM was diagnosed based on the American Diabetes Association criteria. Primary cultures of HUVEC were cultured in 5 mM and 25 mM glucose with 25 mM mannitol osmotic control. The soluble adhesion molecules, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and E-selectin were measured by ELISA in the cord blood serum and conditioned HUVEC media. The mothers with DM were older with higher BMI (p = 0.027 and 0.008, respectively). In a fully adjusted model, VCAM was significantly increased in the cord serum of infants born to mothers with diabetes (p = 0.046), but ICAM and E-selectin were not different. ICAM was also significantly correlated with maternal HbA1c (r 2  = 0.16, p = 0.004) and cord serum non-esterified fatty acids (r 2  = 0.08, p = 0.013). From the HUVEC media, the abundance of adhesion molecules was not different based on DM or high glucose exposure; however, VCAM abundance in the HUVEC supernatant was significantly correlated with ICAM (r 2  = 0.27, p = 0.010) and cord serum c-peptide (R 2  = 0.19, p = 0.043)., Conclusions: Alterations in soluble adhesion molecule abundance in infants exposed to the diabetic milieu of pregnancy may reflect early alterations in vascular function predicting future cardiovascular disease., (Copyright © 2022 The Italian Diabetes Society, 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.)

Objective: Guidelines for asthma management contain a consensus recommendation that inhaled corticosteroid (ICS) dose should not be stepped down in pregnancy. However, this is not consistent with consumer preferences and pharmacological principles to minimize medication exposure during pregnancy. We investigated exacerbations after changes to ICS and long acting beta agonist (LABA) therapy in pregnant women with asthma., Methods: Pregnant women ( n  = 220) were recruited to a randomized controlled trial (RCT) where maintenance treatment was adjusted monthly based on either symptoms (control group), or fractional exhaled nitric oxide (FeNO, to alter ICS) and symptoms (to alter LABA, FeNO group). Exacerbations were monitored prospectively., Results: ICS were used by 137 (62.3%) women at some time during pregnancy. ICS dose remained unchanged in 16 women (11.7%, 95% confidence interval [CI] 7-18%), increased in 37 women (27%, 95%CI 20-35%), decreased in 34 women (24.8%, 95%CI 18%-33%), or both increased and decreased in 50 women (36.5%, 95%CI 29-45%). Exacerbations occurred within 14 days of ICS step-down in 11 women (13%, 95%CI 7.5%-22%). This was not significantly different from exacerbations occurring within 14 days of step-up, in 7 women (8.1%, 95%CI 4%-16%, P  = 0.294). There were no differences between management groups. Exacerbations occurred within 14 days of step-down in 14.7% (95%CI 7%-30%) of women in the control group, and in 12% (95%CI 6%-24%) of women in the FENO group., Conclusions: ICS step-down could be considered when eosinophilic inflammation or symptoms are low, and may be a useful management approach for women, doctors, and midwives wishing to minimize ICS exposure during pregnancy.

Background: There are few reports about reflux esophagitis (RE) as a cause of severe upper gastrointestinal bleeding (UGIB)., Aims: This study aims to evaluate (1) changes in its prevalence over the last three decades and (2) clinical and endoscopic characteristics and 30-day outcomes among RE patients with and without focal esophageal ulcers (EUs) and stigmata of recent hemorrhage (SRH)., Methods: A retrospective study of prospectively collected data of esophagitis patients hospitalized with severe UGIB between 1992 and 2020. Descriptive analysis and statistical comparisons were performed., Results: Of 114 RE patients, the mean age was 61.1 years and 76.3% were males. 38.6% had prior gastroesophageal reflux disease (GERD) symptoms; overall 36% were on acid suppressants. Over three consecutive decades, the prevalence of RE as a cause of severe UGIB increased significantly from 3.8 to 16.7%. 30-day rebleeding and all-cause mortality rates were 11.4% and 6.1%. RE patients with focal EUs and SRH (n = 23) had worse esophagitis than those with diffuse RE (n = 91) (p = 0.012). There were no differences in 30-day outcomes between RE patients with and without EUs and SRH., Conclusions: For patients with severe UGIB caused by RE, (1) the prevalence has increased significantly over the past three decades, (2) the reasons for this increase and preventive strategies warrant further study, (3) most patients lacked GERD symptoms and did not take acid suppressants, and (4) those with focal ulcers and SRH had more severe esophagitis and were treated endoscopically., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Background: Asthma exacerbations during pregnancy are associated with adverse pregnancy outcomes., Objective: The aim of this study was to establish factors associated with asthma exacerbations during pregnancy., Methods: We obtained data from three cohorts of pregnant women with asthma recruited in eastern Australia (2004-2019; n = 1461). Severe exacerbations were defined as episodes of asthma requiring hospitalization, an emergency department visit, or prescription of oral corticosteroids after enrollment. Baseline information on potential risk factors included demographic characteristics, asthma characteristics (eg, lung function, asthma triggers, asthma control, medication use), pregnancy factors (eg, fetal sex, parity, antenatal care type), and other maternal factors (body mass index, smoking status, mental health). Backward stepwise logistic regression and Akaike information criterion were used to determine the best-fitting model., Results: A total of 135 participants experienced a severe exacerbation during pregnancy (9.2%). Medium to high ICS dose was most strongly associated with severe asthma exacerbations (adjusted odds ratio = 3.20; 95% confidence interval, 1.85-5.53). Worse asthma control, possession of a written action plan, and a history of asthma exacerbations in the year preceding pregnancy were associated with an increased rate of exacerbations., Conclusions: Asthma exacerbations before pregnancy and more severe asthma at the beginning of pregnancy were associated with an increased rate of exacerbations during pregnancy. Despite Global Initiative for Asthma step 3 and 4 treatment and optimal management including a written asthma action plan, there is still a significant asthma burden in a group of women at high risk for severe exacerbations in pregnancy., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Adults with obesity exhibit a restrictive pattern, whereas children with obesity exhibit an obstructive pattern. However, the transition process remains unclear. We performed a systematic search for studies reporting on body mass index and pulmonary function in children. The main outcomes were forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and their ratio (FEV 1 /FVC). We compared individuals with overweight or with obesity with individuals with normal weight. Random-effects models were used to calculate pooled estimates. A total of 17 studies were included. Individuals with obesity had a lower FEV 1 /FVC ratio (mean difference [MD] = -3.61%; 95% confidence interval [CI] = -4.58%, -2.64%) and a higher percent-predicted FVC (MD = 3.33%; 95% CI = 0.79%, 5.88%) than those with normal weight. Obesity impaired pulmonary function in the obstructive pattern during childhood to young adulthood, and the maximum obstruction was observed at the age of 16 years in boys and 20 years in girls. The effects attenuated at approximately 30 years and then shifted to the restrictive pattern after 35 years of age in men and 40 years in women. The effects of obesity on pulmonary function change from the obstructive pattern in childhood to the restrictive pattern in adulthood., (© 2021 World Obesity Federation.)

Background: To describe 24-hour fluid administration in emergency department (ED) patients with suspected infection., Methods: A prospective, multicenter, observational study conducted in three Danish hospitals, January 20 to March 2, 2020. We included consecutive adult ED patients with suspected infection (drawing of blood culture and/or intravenous antibiotic administration within 6 hours of admission). Oral and intravenous fluids were registered for 24 hours., Primary Outcome: 24-hour total fluid volume. We used linear regression to investigate patient and disease characteristics' effect on 24-hour fluids and to estimate the proportion of the variance in fluid administration explained by potential predictors., Results: 734 patients had 24-hour fluids available: 387 patients had simple infection, 339 sepsis, eight septic shock. Mean total 24-hour fluid volumes were 3656 mL (standard deviation [SD]:1675), 3762 mL (SD: 1839), and 6080 mL (SD: 3978) for the groups, respectively. Fluid volumes varied markedly. Increasing age (mean difference [MD]: 60-79 years: -470 mL [95% CI: -789, -150], +80 years; -974 mL [95% CI: -1307, -640]), do-not-resuscitate orders (MD: -466 mL [95% CI: -797, -135]), and preexisting atrial fibrillation (MD: -367 mL [95% CI: -661, -72) were associated with less fluid. Systolic blood pressure < 100 mmHg (MD: 1182 mL [95% CI: 820, 1543]), mean arterial pressure < 65 mmHg (MD: 1317 mL [95% CI: 770, 1864]), lactate ≥ 2 mmol/L (MD: 655 mL [95% CI: 306, 1005]), heart rate > 120 min (MD: 566 [95% CI: 169, 962]), low (MD: 1963 mL [95% CI: 813, 3112]) and high temperature (MD: 489 mL [95% CI: 234, 742]), SOFA score > 5 (MD: 1005 mL [95% CI: 501, 510]), and new-onset atrial fibrillation (MD: 498 mL [95% CI: 30, 965]) were associated with more fluid. Clinical variables explained 37% of fluid variation among patients., Conclusions: Patients with simple infection and sepsis received equal fluid volumes. Fluid volumes varied markedly, a variation that was partly explained by clinical characteristics., (© 2021 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: A high fruit and vegetable (F&V) diet reduces asthma exacerbations in adults; this has not been examined in children to date., Objective: To investigate the effect of a 6-month, high F&V diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial., Methods: Children (aged 3-11 years) with asthma, history of exacerbations and usual low F&V intake (≤3 serves/day) were randomized to the intervention (high F&V diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression., Results: 67 children were randomized between September 2015 and July 2018. F&V intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p < 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (X 5 ∆: 0.76 [0.04, 1.48] p = 0.038, X 20 ∆: 0.93 [0.23, 1.64] p = 0.009) and changes in faecal microbiota were observed though there was no difference between groups in systemic inflammation or molecular mechanisms. In the control group, CRP and HDAC enzyme activity increased, while GPR41 expression decreased. No adverse events attributable to the interventions were observed., Conclusion & Clinical Relevance: A high F&V diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma., (© 2021 John Wiley & Sons Ltd.)

Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.

Background: Asthma is the most frequent cause of hospitalisation among children; however, little is known regarding the effects of asthma on immune responses in children., Objective: The present study aimed to evaluate cytokine responses of peripheral blood mononuclear cells (PBMCs), PBMC composition and lung function in children with and without asthma., Methods: Using a case-control design, we compared 48 children with asthma aged 3-11 years with 14 age-matched healthy controls. PBMC composition and cytokine production including interferon (IFN)-γ, interleukin (IL)-1β, IL-5 and lL-6 following stimulation with rhinovirus-1B (RV1B), house dust mite (HDM) and lipopolysaccharide (LPS) were measured. Lung function was assessed using impulse oscillometry and nitrogen multiple breath washout., Results: The frequency of group 2 innate lymphoid cells were significantly higher in asthmatics and PBMCs from asthmatics had deficient IFN-γ production in response to both RV1B and LPS compared with controls (P<0.01). RV1B-induced IL-1β response and HDM-stimulated IL-5 production was higher in asthmatics than controls (P<0.05). In contrast, IL-1β and IL-6 were significantly reduced in response to HDM and LPS in asthmatics compared to controls (P<0.05). Children with asthma also had reduced pulmonary function, indicated by lower respiratory reactance as well as higher area of-reactance and lung clearance index values compared with controls (P<0.05)., Conclusion: Our study indicates that children with asthma have a reduced lung function in concert with impaired immune responses and altered immune cell subsets. Improving our understanding of immune responses to viral and bacterial infection in childhood asthma can help to tailor management of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hosseini, Berthon, Starkey, Collison, McLoughlin, Williams, Nichol, Wark, Jensen, Da Silva Sena, Baines, Mattes and Wood.)

Background: The risk of wheezing is high in infancy and is heightened in infants with a family history of asthma/atopy. The role of breastfeeding in influencing respiratory health for these high-risk infants is unclear., Objectives: To systematically appraise evidence for the association between breastfeeding and wheeze incidences and severity in high-risk infants., Methods: Studies identified through electronic databases and reference lists were eligible if they assessed breastfeeding and respiratory outcomes in infants with a family history of asthma/atopy. The primary outcome was wheeze incidences in the first year of life. Secondary outcomes were wheeze incidences in the first 6 months of life, indicators of wheeze severity (recurrent wheeze, health-care utilization, and medication use), and other wheeze-related outcomes [bronchiolitis, pneumonia, croup, and incidence of lower respiratory tract infection (LRTI)] up to 12 months old. Meta-analyses were conducted where possible., Results: Of 1843 articles screened, 15 observational studies met the inclusion criteria. Breastfeeding was associated with 32% reduced odds of wheezing during the first year of life (ever vs. never: OR, 0.68; 95% CI: 0.53, 0.88; n = 9 studies); this association was even stronger in the first 6 months (OR, 0.45; 95% CI: 0.27, 0.75; n = 5 studies). Breastfeeding for a "longer" versus "shorter" time (approximately longer vs. shorter than 3 months) was associated with 50% reduced odds of wheezing at the age of 6 months (OR, 0.50; 95% CI: 0.39, 0.64; n = 3 studies)., Conclusions: Breastfeeding was associated with reduced odds of wheezing in high-risk infants, with the strongest protection in the first 6 months. More research is needed to understand the impact of breastfeeding intensity on wheezing and to examine additional respiratory outcomes, including wheeze severity. This review was registered at PROSPERO as CRD42019118631., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Spirometry is commonly used to assess and monitor lung function. It may also be a useful tool to monitor maternal health during pregnancy. However, large studies examining lung function across gestation are limited. Also, whether spirometry values follow the same pattern during pregnancy in women with and without asthma is unknown., Objective: To investigate the effect of advancing gestation, and its interaction with asthma, on lung function in a large well-defined cohort of pregnant women., Methods: Data were obtained from prospective cohorts involving women with (n = 770) and without (n = 259) asthma (2004-2017), recruited between 12 and 22 weeks' gestation. Lung function (forced vital capacity [FVC], FEV 1 , FEV 1 :FVC%) was assessed periodically during pregnancy using spirometry. Multilevel mixed-effect regression models were used to assess changes in lung function over gestation., Results: Asthma had a significant effect on baseline lung function (FEV 1 %, -9%; FVC%, -3%; FEV 1 :FVC%, -4%). FVC% decreased with advancing gestation (-0.07%/wk; 95% CI, -0.10 to -0.04]), as did FEV 1 %, but only among those without asthma (women without asthma: -0.14%/wk, 95% CI, -0.22 to -0.06%; compared with women with asthma: 0.02%/wk, 95% CI, -0.01 to 0.06). FEV 1 :FVC% remained relatively stable for women without asthma (0.03%/wk; 95% CI, -0.08 to 0.02), but increased for women with asthma (0.06%/wk; 95% CI, 0.04 to 0.16)., Conclusions: Data suggest that advancing gestation negatively affects FVC% and FEV 1 %. This is consistent with extrapulmonary restriction from advancing pregnancy. Yet, the presence of asthma altered the trajectories of FEV 1 % and FEV 1 :FVC%. Optimal asthma management during pregnancy might have opposed the negative effects of gestation on lung function., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: There is little data and lack of consensus regarding antiplatelet management for intracranial stenting due to underlying intracranial atherosclerosis in the setting of endovascular treatment (EVT). In this DELPHI study, we aimed to assess whether consensus on antiplatelet management in this situation among experienced experts can be achieved, and what this consensus would be., Methods: We used a modified DELPHI approach to address unanswered questions in antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT. An expert-panel (19 neurointerventionalists from 8 countries) answered structured, anonymized on-line questionnaires with iterative feedback-loops. Panel-consensus was defined as agreement ≥ 70% for binary closed-ended questions/≥ 50% for closed-ended questions with > 2 response options., Results: Panel members answered a total of 5 survey rounds. They acknowledged that there is insufficient data for evidence-based recommendations in many aspects of antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT. They believed that antiplatelet management should follow a standardized regimen, irrespective of imaging findings and reperfusion quality. There was no consensus on the timing of antiplatelet-therapy initiation. Aspirin was the preferred antiplatelet agent for the peri-procedural period, and oral Aspirin in combination with a P2Y12 inhibitor was the favored postprocedural regimen., Conclusion: Data on antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT are limited. Panel-members in this study achieved consensus on postprocedural antiplatelet management but did not agree upon a preprocedural and intraprocedural antiplatelet regimen. Further prospective studies to optimize antiplatelet regimens are needed.

Background: Nonadherence is common among pregnant women prescribed inhaled corticosteroids (ICS) for asthma and may have serious consequences for mother and baby. Factors associated with ICS nonadherence have not been determined in this population., Objectives: To determine factors associated with {1} nonadherence to ICS in early-mid pregnancy (cross-sectional) and {2} persistent nonadherence to ICS during pregnancy (longitudinal)., Methods: Data used come from 3 prospective studies (2004-2019) involving women with asthma recruited by 23 weeks' gestation (N = 1614). Demographics, asthma history, and current symptoms were assessed, and spirometry was performed at baseline and throughout pregnancy. Women self-reported current medication use and number of ICS doses missed in the past week. Nonadherence was defined as ≥20% of prescribed dosages missed in the past week (baseline) and on at least 2 occasions during follow-up (persistent). Factors associated with ICS nonadherence were examined using backward stepwise logistic regression., Results: Of 610 (38%) women prescribed ICS at baseline, 236 (39%) were classified as nonadherent. Of 612 (38%) women prescribed ICS during at least 2 follow-up visits, 149 (24%) were classified as persistent nonadherent. Factors associated with nonadherence at baseline were current or ex-smoking, non-Caucasian/non-Indigenous ethnicity, adult diagnosis of asthma, and lower lung function. Factors associated with persistent nonadherence to ICS were lower maternal age, higher parity, and no prescribed ICS at baseline., Conclusion: Young multiparous non-Caucasian/non-Indigenous mothers are at increased risk of being nonadherent to ICS during pregnancy. Strategies to improve ICS nonadherence should address maternal smoking and target women who (re-)initiate ICS use in pregnancy., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The impact of obesity interventions on dietary intake in children and adolescents with overweight or obesity is unclear. This systematic review aimed to investigate the impact of the dietary component of weight management interventions on the change in diet in children and adolescents with overweight or obesity., Methods: Eligible randomised controlled trials (RCTs) published between 1975 and 2020 were identified by a systematic search following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Meta-analyses of eligible study outcomes were performed using statistical software. A multilevel random effects model was used with three significant random effects fitted using restricted maximum likelihood estimation., Results: This review identified 109 RCTs, including 95 that reported at least one statistically significant dietary outcome change and 14 reporting no significant dietary change. Results from the meta-analyses (n = 29 studies) indicated that, compared to control groups, intervention groups achieved significantly greater reductions in mean total energy intake at ≤6 months (-194 kcal day -1 , 95% confidence interval = -275.80 to -112.90 kcal day -1 , P < 0.001) and up to 12 months (-112 kcal day -1 95% confidence interval = -218.92 to -5.83 kcal day -1 ) P = 0.038), increases in fruit and/or vegetable intakes over 2-12 months (n = 34, range +0.6 to +1.5 servings day -1 ) and reductions in consumption of sugar-sweetened beverages (n = 28, range -0.25 to -1.5 servings day -1 ) at 4-24 months follow-up., Conclusions: Obesity interventions with a dietary component have a modest but sustained impact on reducing total energy intake and improving intakes of specific food groups in children and adolescents with overweight or obesity. High quality RCTs that are powered to detect change in diet as a primary outcome are warranted., (© 2020 The British Dietetic Association Ltd.)

Background: Although there is a growing body of literature about the impact of asthma exacerbations during pregnancy on adverse perinatal outcomes, it is still unclear whether asthma exacerbations themselves or asthma severity are the driving factor for negative outcomes. This study aimed to estimate the associations between maternal asthma exacerbations and perinatal outcomes, and whether this differed by asthma treatment regime as a proxy for severity., Methods: We included births of women with asthma in Sweden from July 2006 to November 2013 (n=33 829). Asthma exacerbations were defined as unplanned emergency visits/hospitalisations or a short course of oral corticosteroids. Adjusted odds ratios (aOR) were estimated for the associations between exacerbations during pregnancy and perinatal outcomes (small for gestational age (SGA), preterm birth, birthweight and mode of delivery), stratified by preconception treatment regime., Results: Exacerbations occurred in 1430 (4.2%) pregnancies. Exacerbations were associated with reduced birthweight (aOR 1.45, 95% CI 1.24-1.70), and elective (aOR 1.50, 95% CI 1.25-1.79) and emergency caesarean section (aOR 1.35, 95% CI 1.13-1.61). Multiple exacerbations were associated with a 2.6-fold increased odds of SGA (95% CI 1.38-4.82). Amongst women treated prepregnancy with combination therapy (proxy for moderate-severe asthma), exacerbators were at increased odds of elective (aOR 1.69, 95% CI 1.30-2.2) and emergency (aOR 1.62, 95% CI 1.26-2.08) caesarean section, and SGA (aOR 1.74, 95% CI 1.18-2.57) versus non-exacerbators., Conclusion: Maternal asthma exacerbations increase the risk of SGA and caesarean sections, particularly in women with multiple exacerbations or moderate-severe asthma. Adequate antenatal asthma care is needed to reduce exacerbations and reduce risks of poor outcomes., Competing Interests: Conflict of interest: A.L. Robijn reports a Short-Term Research Fellowship from the European Respiratory Society during the conduct of the study. Conflict of interest: B.K. Brew has nothing to disclose. Conflict of interest: M.E. Jensen has nothing to disclose. Conflict of interest: G. Rejnö has nothing to disclose. Conflict of interest: C. Lundholm has nothing to disclose. Conflict of interest: V.E. Murphy has nothing to disclose. Conflict of interest: C. Almqvist reports grants from the Swedish Research Council, Swedish Heart–Lung Foundation, and Swedish Research Council for Health, Working Life and Welfare (FORTE), during the conduct of the study., (Copyright ©ERS 2020.)

Measurement of vitamin D status has significant use in clinical and research settings, including during pregnancy. We aimed to assess the agreement of total 25-hydroxyvitamin D (25(OH)D) concentration, and its three analytes (25-hydroxyvitamin D 3 (25(OH)D 3 ), 25-hydroxyvitamin D 2 (25(OH)D 2 ) and Epi-25-hydroxyvitamin D 3 (Epi-25(OH)D 3 )), in plasma and serum samples collected during pregnancy, and to examine the proportion of women who change vitamin D status category based on sample type. Matching samples were collected from n = 114 non-fasting women between 12-25 weeks gestation in a clinical trial in Newcastle, Australia. Samples were analysed by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) to quantify total 25(OH)D and its analytes and examined using Bland-Altman plots, Pearson correlation (r), intraclass correlation coefficient and Cohen's Kappa test. Serum total 25(OH)D ranged from 33.8-169.8 nmol/L and plasma ranged from 28.6-211.2 nmol/L. There was a significant difference for total 25(OH)D based on sample type (measurement bias 7.63 nmol/L for serum vs plasma (95% Confidence Interval (CI) 5.36, 9.90, p ≤ 0.001). The mean difference between serum and plasma concentrations was statistically significant for 25(OH)D 3 (7.38 nmol/L; 95% CI 5.28, 9.48, p ≤ 0.001) and Epi-25(OH)D 3 (0.39 nmol/L; 95% CI 0.14, 0.64, p = 0.014). Of 114 participants, 28% were classified as vitamin D deficient (<50 nmol/L) or insufficient (<75 nmol/L) based on plasma sample and 36% based on serum sample. Nineteen (16.7%) participants changed vitamin D status category based on sample type. 25-hydroxyvitamin D quantification using LC-MS/MS methodology differed significantly between serum and plasma, yielding a higher value in plasma; this influenced vitamin D status based on accepted cut-points, which may have implications in clinical and research settings.

Background and Purpose: There are only few data and lack of consensus regarding antiplatelet management for carotid stent placement in the setting of endovascular stroke treatment. We aimed to develop a consensus-based algorithm for antiplatelet management in acute ischemic stroke patients undergoing endovascular treatment and simultaneous emergent carotid stent placement., Materials and Methods: We performed a literature search and a modified Delphi approach used Web-based questionnaires that were sent in several iterations to an international multidisciplinary panel of 19 neurointerventionalists from 7 countries. The first round included open-ended questions and formed the basis for subsequent rounds, in which closed-ended questions were used. Participants continuously received feedback on the results from previous rounds. Consensus was defined as agreement of ≥70% for binary questions and agreement of ≥50% for questions with >2 answer options. The results of the Delphi process were then summarized in a draft manuscript that was circulated among the panel members for feedback., Results: A total of 5 Delphi rounds were performed. Panel members preferred a single intravenous aspirin bolus or, in jurisdictions in which intravenous aspirin is not available, a glycoprotein IIb/IIIa receptor inhibitor as intraprocedural antiplatelet regimen and a combination therapy of oral aspirin and a P2Y12 inhibitor in the postprocedural period. There was no consensus on the role of platelet function testing in the postprocedural period., Conclusions: More and better data on antiplatelet management for carotid stent placement in the setting of endovascular treatment are urgently needed. Panel members preferred intravenous aspirin or, alternatively, a glycoprotein IIb/IIIa receptor inhibitor as an intraprocedural antiplatelet agent, followed by a dual oral regimen of aspirin and a P2Y12 inhibitor in the postprocedural period., (© 2020 by American Journal of Neuroradiology.)

Background and Purpose: There is a paucity of data regarding antiplatelet management strategies in the setting of stent-assisted coiling/flow diversion for ruptured intracranial aneurysms. This study aimed to identify current challenges in antiplatelet management during stent-assisted coiling/flow diversion for ruptured intracranial aneurysms and to outline possible antiplatelet management strategies., Materials and Methods: The modified DELPHI approach with an on-line questionnaire was sent in several iterations to an international, multidisciplinary panel of 15 neurointerventionalists. The first round consisted of open-ended questions, followed by closed-ended questions in the subsequent rounds. Responses were analyzed in an anonymous fashion and summarized in the final manuscript draft. The statement received endorsement from the World Federation of Interventional and Therapeutic Neuroradiology, the Japanese Society for Neuroendovascular Therapy, and the Chinese Neurosurgical Society., Results: Data were collected from December 9, 2019, to March 13, 2020. Panel members achieved consensus that platelet function testing may not be necessary and that antiplatelet management for stent-assisted coiling and flow diversion of ruptured intracranial aneurysms can follow the same principles. Preprocedural placement of a ventricular drain was thought to be beneficial in cases with a high risk of hydrocephalus. A periprocedural dual, intravenous, antiplatelet regimen with aspirin and a glycoprotein IIb/IIIa inhibitor was preferred as a standard approach. The panel agreed that intravenous medication can be converted to oral aspirin and an oral P2Y12 inhibitor within 24 hours after the procedure., Conclusions: More and better data on antiplatelet management of patients with ruptured intracranial aneurysms undergoing stent-assisted coiling or flow diversion are urgently needed. Panel members in this DELPHI consensus study preferred a periprocedural dual-antiplatelet regimen with aspirin and a glycoprotein IIb/IIIa inhibitor., (© 2020 by American Journal of Neuroradiology.)

Low 25-hydroxyvitamin D (25(OH)D) levels are common in pregnancy and associated with adverse maternal/neonatal outcomes. In pregnant women with asthma, this study examined the association of lifestyle- and asthma-related factors on 25(OH)D levels and maternal/neonatal outcomes by vitamin D status. Serum 25(OH)D was measured at 16 and 35 weeks gestation in women with asthma ( n = 103). Body mass index (BMI), gestational weight gain (GWG), smoking status, inhaled corticosteroid (ICS) use, asthma control, airway inflammation, and exacerbations, and maternal/neonatal outcomes were collected. Baseline and change (Δ) in 25(OH)D were modelled separately using backward stepwise regression, adjusted for season and ethnicity. Maternal/neonatal outcomes were compared between low (25(OH)D < 75 nmol/L at both time points) and high (≥75 nmol/L at one or both time points) vitamin D status. Fifty-six percent of women had low vitamin D status. Obesity was significantly associated with lower baseline 25(OH)D (Adj-R 2 = 0.126, p = 0.008); ICS and airway inflammation were not. Excess GWG and season of baseline sample collection were significantly associated with Δ25(OH)D (Adj-R 2 = 0.405, p < 0.0001); asthma-related variables were excluded ( p > 0.2). Preeclampsia was more common in the low (8.6%) vs. high (0%) vitamin D group ( p < 0.05). Obesity and excess GWG may be associated with gestational 25(OH)D levels, highlighting the importance of antenatal weight management.

Introduction: A solid body of preclinical evidence shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the effects of substance use disorder related behaviors. The mechanisms underlying these effects remain elusive. In the present study, we hypothesized that GLP-1R activation modulates dopaminetransporter (DAT) and thus dopamine (DA) homeostasis in striatum. This was evaluated in three different experiments: two preclinical and one clinical., Methods: Rat striatal DA uptake, DA clearance and DAT cell surface expression was assessed following GLP-1 (7-36)-amide exposure in vitro. DA uptake in mice was assesed ex vivo following systemic treatment with the GLP-1R agonist exenatide. In addition, DA uptake was measured in GLP-1R knockout mice and compared with DA-uptake in wild type mice. In healthy humans, changes in DAT availability was assessed during infusion of exenatide measured by single-photon emission computed tomography imaging., Results: In rats, GLP-1 (7-36)-amide increased DA uptake, DA clearance and DAT cell surface expression in striatum. In mice, exenatide did not change striatal DA uptake. In GLP-1R knockout mice, DA uptake was similar to what was measured in wildtype mice. In humans, systemic infusion of exenatide did not result in acute changes in striatal DAT availability., Conclusions: The GLP-1R agonist-induced modulation of striatal DAT activity in vitro in rats could not be replicated ex vivo in mice and in vivo in humans. Therefore, the underlying mechanisms of action for the GLP-1R agonists-induced efficacy in varios addiction-like behavioural models still remain., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of Competing Interest Thank you for considering our manuscript The acceptability and feasibility of implementing a Fractional exhaled Nitric Oxide (FeNO)-based asthma management strategy into antenatal care: the perspective of pregnant women with asthma for publication in Midwifery. We declare no conflict of interests, including financial or personal, that could inappropriately influence this work.

Maternal asthma increases the risk of infant wheeze. Breastfeeding may offer protection but there is limited evidence in this high-risk group. We examined associations between breastfeeding and respiratory outcomes, in infants born to women with asthma. This study was a secondary analysis of two prospective cohorts of pregnant women with asthma, and their infants, conducted between 2007 and 2018. At 6 ± 1 (T1) and 12 ± 1 (T2) months post-partum, mothers reported breastfeeding patterns and infant wheeze (primary outcome), bronchiolitis, and related medication use and healthcare utilization, via a validated questionnaire; a subgroup completed face-to-face interviews. χ 2 tests and logistic regression models, adjusting for confounders, were utilized. Data were complete for 605 participants at T1 and 486 (80%) at T2. Of 605 participants: 89% initiated breastfeeding and 38% breastfed for more than 6 months. Breastfeeding for more than 6 months vs "never" was associated with a reduced adjusted relative risk of infant wheeze at T1 (0.54, 95% confidence interval, 0.30-0.96). Bronchiolitis risk was reduced at T1 and T2 with more tha 6 months of breastfeeding vs "never." Breastfeeding duration of 1 to 3 months, 4 to 6 months, and more than 6 months were associated with a reduced risk of infant healthcare utilization (all P < .05, vs "never"), but not medication use (P > .05). Breastfeeding for more than 6 months was associated with a reduced risk of wheeze, bronchiolitis, and wheeze-related healthcare utilization in infants at risk due to maternal asthma. Notably, breastfeeding for shorter durations was associated with a reduced risk of healthcare utilization compared with none. Larger cohorts are needed to further examine the impact of breastfeeding exposure on respiratory health in infants exposed to maternal asthma., (© 2020 Wiley Periodicals, Inc.)

Background: The use of fractional exhaled nitric oxide (FeNO)-based asthma management during pregnancy can significantly reduce asthma exacerbations in non-smoking pregnant women. The feasibility of implementing this strategy into antenatal care has not been explored., Aims: To examine the feasibility of implementing FeNO-based asthma management into antenatal clinics in New South Wales (NSW) Australia., Materials and Methods: Semi-structured face-to-face interviews with video elicitation were conducted with healthcare professionals (HCPs) providing antenatal care in one of two hospital-based antenatal clinics in NSW, Australia. The video shown demonstrated the use of the FeNO instrument and other aspects of the management strategy, in antenatal care. Interviews were recorded, transcribed and analysed using qualitative content analysis., Results: A total of 20 interviews were conducted with 15 midwives, four obstetricians, and one general practitioner. Two main themes and ten sub-themes arose: Getting a number (sub-themes: engaging, technically easy, objective, predictive, reassuring); and Resourcing (sub-themes: time and timing, systems, staff, education and cost). Comments included: 'It's easy, fast and effective' and 'the main barrier is time'. All HCPs felt capable of facilitating the FeNO-based management strategy, with appropriate education, and were willing to undertake this strategy, saying: '…it would be perfectly acceptable for a midwife or doctor to do it'; also, 'they don't necessarily need to see a physician, it's something that midwives would take on generally…'., Conclusion: Participants in this study considered FeNO-based asthma management for pregnant women to be a feasible addition to antenatal care following appropriate provision of resources and education., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.

The prevalence of obesity in asthmatic children is high and is associated with worse clinical outcomes. We have previously reported that weight loss leads to improvements in lung function and asthma control in obese asthmatic children. The objectives of this secondary analysis were to examine: (1) changes in diet quality and (2) associations between the baseline subject characteristics and the degree of weight loss following the intervention. Twenty-eight obese asthmatic children, aged 8-17 years, completed a 10-week diet-induced weight loss intervention. Dietary intake, nutritional biomarkers, anthropometry, lung function, asthma control, and clinical outcomes were analysed before and after the intervention. Following the intervention, the body mass index (BMI) z-score decreased (Δ = 0.18 ± 0.04; p < 0.001), %energy from protein increased (Δ = 4.3 ± 0.9%; p = 0.002), and sugar intake decreased (Δ = 23.2 ± 9.3 g; p = 0.025). Baseline lung function and physical activity level were inversely associated with Δ% fat mass. The ΔBMI z-score was negatively associated with physical activity duration at baseline. Dietary intervention is effective in achieving acute weight loss in obese asthmatic children, with significant improvements in diet quality and body composition. Lower lung function and physical engagement at baseline were associated with lesser weight loss, highlighting that subjects with these attributes may require greater support to achieve weight loss goals., Competing Interests: The authors declare no conflict of interest.

Purpose: Differentiating between epileptic seizures, convulsive syncope or non-epileptic seizures is a common diagnostic challenge in the acute setting. Plasma-lactate levels have previously been proposed as a tool to aid in differentiating between epileptic and non-epileptic seizures, with lower levels of lactate suggesting a non-epileptic origin. The aim of this study was to investigate levels of lactate in non-epileptic seizures., Methods: Healthy subjects were asked to perform a simulated seizure lasting no more than 5 min. Venous blood samples were taken before and immediately after the simulated seizure and analyzed using an ABL90 FLEX yielding information about lactate, pH, pO 2, pCO 2 , electrolytes and plasma glucose., Results: 8 people participated in the study: 6 men and 2 women aged 27-45. The average pre-simulation lactate was 1.1 mmol/L while the average pH was 7.39. The average post-simulation lactate was 10.2 mmol/L while the average pH was 7.25. This means an average increase in plasma-lactate of 9.1 mmol/L and an average drop of 0.15 in pH., Conclusion: Our data indicate that high rises in lactate levels are not specific for an epileptic origin. Further study of lactate as a marker for epileptic seizures is warrented., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Maternal asthma is associated with perinatal complications and respiratory illness in offspring. Obesity increases asthma exacerbation risk in pregnancy and risk of wheeze in offspring., Objectives: In this secondary analysis of a randomized controlled trial, we investigated the influence of maternal body mass index, gestational weight gain (GWG), and fractional exhaled nitric oxide (F E NO)-based management on asthma exacerbations in pregnancy and offspring wheeze., Methods: A total of 220 women were randomized to asthma treatment adjustment according to symptoms (control group), or F E NO and symptoms (F E NO group). Exacerbations were recorded prospectively. Height and weight were measured at baseline, and in late pregnancy. GWG was categorized according to Institute of Medicine guidelines. A validated parent-completed questionnaire assessed infant wheeze-related outcomes., Results: F E NO-based management was associated with a significantly lower incidence rate ratio for maternal exacerbations in nonobese mothers (0.52, 95% confidence interval [CI], 0.31-0.88, P = .015, n = 129), and women with GWG within recommendations (0.35, 95% CI, 0.12-0.96, P = .042, n = 43), but not for obese mothers (0.59, 95% CI, 0.32-1.08, P = .089, n = 88), or women with excess GWG (0.58, 95% CI, 0.32-1.04, P = .07, n = 104). Recurrent bronchiolitis occurred in 5.3% (n = 1) of infants born to non-overweight mothers, 16.7% (n = 3) of infants of overweight mothers, and 21.7% (n = 5) of infants of obese mothers in the control group. In the F E NO group, 2 infants of obese mothers had recurrent bronchiolitis (7.1%, P = .031)., Conclusions: The benefits of F E NO-based management are attenuated among obese mothers and those with excess GWG, indicating the importance of weight management in contributing to improved asthma management in pregnancy., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D 3 supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations., Methods and Analysis: This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D 3 supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D 3 (3.5 months apart) with 400 IU vitamin D 3 daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety., Ethics and Dissemination: This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines., Trial Registration Number: NCT03365687., Competing Interests: Competing interests: By partnership agreement, Euro-Pharm International Canada Inc. (Montreal, QC Canada), and their representative (Ali Khamessan) donated all vitamin D study preparations. Dr Khamessan is responsible for the formulation of the placebo and high dose vitamin D preparation; however, neither Dr Khamessan, nor Euro-Pharm International Canada Inc., had any input into other aspects of study design, and will have no involvement in analysis or interpretation of results.The authors have no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Studies demonstrate the prescription rate for inhaled corticosteroids (ICS) decreases in early pregnancy, possibly increasing exacerbation risk. This could be related to non-adherence to prescribed asthma medication or medication cessation by the patient or doctor. ICS use during pregnancy has not previously been summarized in a systematic review., Objective: The aim of this systematic review and meta-analysis was to evaluate the use of ICS during pregnancy among asthmatic women, specifically: (1) the prevalence of use, (2) changes of use during pregnancy compared with pre-pregnancy and (3) medication adherence among ICS users., Methods: We systematically searched literature in Embase, MEDLINE, CINAL and Cochrane, using terms related to asthma, pregnancy and medication use. All English articles reporting ICS among pregnant women with asthma were included. Prevalence, changes in ICS use during pregnancy and ICS adherence were pooled using STATA (version 15.0, StataCorp USA)., Results: A total of 4237 references were retrieved in the initial search. Screening and review led to the inclusion of 52 articles for one or more aims (Aim 1: N = 45; Aim 2, N = 13; and Aim 3, N = 5). The pooled prevalence of ICS use during pregnancy was 41% (95%CI 36%-45%); 49% (95%CI 44%-55%) in Europe, 39% (95%CI 32%-47%) in Australia and 34% (95%CI 27%-41%) in North America. In eight prescription databases, ICS prescription rates lowered in the first trimester of pregnancy, compared with pre-pregnancy, increased in the second trimester and decreased in the third trimester. Five studies reported ICS adherence among pregnant women, using four measures of self-reported non-adherence. In two comparable studies, pooled ICS non-adherence was 40% (95%CI 36%-44%)., Conclusions: The prevalence of ICS use among pregnant women with asthma is 41% and varies widely between countries and continents, and prescription rates for ICS change throughout pregnancy. More studies are needed to investigate ICS adherence during pregnancy in women with asthma., (© 2019 John Wiley & Sons Ltd.)

Background: Acute kidney injury after cardiac surgery is common and associated with increased mortality. It is unknown whether an intended higher arterial pressure during cardiopulmonary bypass reduces the incidence of acute and chronic kidney injury., Methods: Patients were randomised either to a control group or a high pressure group (arterial pressure > 60 mmHg). The inclusion criteria were age > 70 years, combined cardiac surgery and serum creatinine < 200 μmol/L. Glomerular filtration rate using the Cr-EDTA clearance method was measured the day before surgery and 4 months postoperatively. The RIFLE criteria were used to define the presence of acute kidney injury. In addition, the ratio between urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and creatinine was measured., Results: Ninety patients were included. Mean age was 76 ± 4 years and 76% were male. Mean arterial pressure was 47 ± 5 mmHg in the control group and 61 ± 4 mmHg in the high pressure group (p < 0.0001). The change in glomerular filtration rate at follow-up was - 9 ± 12 ml/min in the control group and - 5 ± 16 ml/min in the high pressure group (p = 0.288, 95% CI - 13 to 4). According to the RIFLE criteria 38% in the control group and 46% in the high pressure group developed acute kidney injury (p = 0.447). The postoperative urinary NGAL/creatinine ratio was comparable between the groups., Conclusions: An intended increase in arterial pressure during cardiopulmonary bypass to > 60 mmHg did not decrease the incidence of acute or chronic kidney injury after cardiac surgery., Trial Registration: Clinicaltrials.gov, identifier: NCT01408420 . Registered 3rd of August 2011.

Objective: Asthma exacerbations and medication non-adherence are significant clinical problems during pregnancy. While asthma self-management education is effective, the number of education sessions required to maximise asthma management knowledge and inhaler technique and whether improvements persist postpartum, are unknown. This paper describes how asthma knowledge, skills, and inhaled corticosteroid (ICS) use have changed over time., Methods: Data were obtained from 3 cohorts of pregnant women with asthma recruited in Newcastle, Australia between 2004 and 2017 (N = 895). Medication use, adherence, knowledge, and inhaler technique were compared between cohorts. Changes in self-management knowledge/skills and women's perception of medication risk to the fetus were assessed in 685 women with 5 assessments during pregnancy, and 95 women who had a postpartum assessment., Results: At study entry, 41%, 29%, and 38% of participants used ICS in the 2004, 2007, and 2013 cohorts, respectively (p = 0.017), with 40% non-adherence in each cohort. Self-management skills of pregnant women with asthma did not improve between 2004 and 2017 and possession of a written action plan remained low. Maximum improvements were reached by 3 sessions for medications knowledge and one session for inhaler technique, and were maintained postpartum. ICS adherence was maximally improved after one session, but not maintained postpartum. Perceived risk of asthma medications on the fetus was highest for corticosteroid-containing medication; and was significantly reduced following education., Conclusions: There was a high prevalence of non-adherence and poor self-management skills in all cohorts. More awareness of the importance of optimal asthma management during pregnancy is warranted, since no improvements were observed over the past decade.

Background: Vitamin D may influence pregnancy and infant outcomes, especially infant respiratory health. This study aimed to examine vitamin D status in pregnant women with asthma, and whether higher vitamin D levels are associated with fewer adverse respiratory outcomes in their infants., Methods: Pregnant women with asthma, recruited from John Hunter Hospital Newcastle Australia (latitude 33°S), had serum total 25-hydroxyvitamin-D (25(OH)D) measured at 16 and 35 weeks gestation. Infant respiratory outcomes were collected at 12 months by parent-report questionnaire. Mother-infant dyads were grouped by serum 25(OH)D during pregnancy: 25(OH)D < 75 nmol/L (at both time-points) versus 25(OH)D ≥ 75 nmol/L (at one or both time-points)., Results: In 52 pregnant women with asthma, mean serum 25(OH)D levels were 61 (range 26-110) nmol/L at 16 weeks, and 65 (range 32-116) nmol/L at 35 weeks, gestation. Thirty-one (60%) women had 25(OH)D < 75 nmol/L at both time-points; 21 (40%) had 25(OH)D ≥ 75 nmol/L at one or both time-points. Maternal 25(OH)D < 75 nmol/L during pregnancy was associated with a higher proportion of infants with "wheeze ever" at 12 months, compared with 25(OH)D ≥ 75 nmol/L (71 versus 43%, p = .04). Infant acute-care presentations (45 versus 13%, p = .02) and oral corticosteroid use (26 versus 4%, p = .03) due to "asthma/wheezing" were higher in the maternal group with 25(OH)D < 75 nmol/L, versus ≥75 nmol/L., Conclusions: Most pregnant women with asthma had low vitamin D status, which persisted across gestation. Low maternal vitamin D status was associated with greater risk of adverse respiratory outcomes in their infants, a group at high risk of developing childhood asthma.

Background: Recurrent Clostridium difficile infection (rCDI) is becoming increasingly common. Faecal microbiota transplantation (FMT) is effective for rCDI, but the costs of an FMT and hospital cost savings related to FMT are unknown. The aim of this study was to calculate the cost of an FMT and the total hospital costs before and after FMT., Methods: This was an observational single-centre study, carried out in a public teaching hospital. We included all patients referred for rCDI from January 2014 through December 2015 and documented costs related to donor screening, laboratory processing, and clinical FMT application. We calculated patient-related hospital costs 1 year before FMT (pre-FMT) and 1 year after FMT (post-FMT). Sensitivity analyses were applied to assess the robustness of the results., Results: We included 50 consecutive adult patients who had a verified diagnosis of rCDI and were referred for FMT. The average cost of an outpatient FMT procedure if donor faeces were applied by colonoscopy was €3,326 per patient and €2,864 if donor faeces were applied using a nasojejunal tube. The total annual pre-FMT hospital costs per patient were €56,415 (95% confidence interval (CI) 41,133-71,697), and these costs dropped by 42% to €32,816 (22,618-42,014) post-FMT ( p = 0.004). The main cost driver was hospital admissions. Sensitivity analyses demonstrated cost reductions in all scenarios., Conclusions: In a public hospital with an implemented FMT service, the average cost of FMT applied by either colonoscopy or nasojejunal tube was €3,095. Total hospital costs dropped by 42% the first year after FMT. The reduction was mainly caused by reductions in the number of hospital admissions and in length of stay., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Asthma affects 12.7% of pregnancies in Australia. Poorly controlled asthma is associated with increased maternal and infant morbidity and mortality. Optimal antenatal management of asthma during pregnancy has the potential to reduce complications relating to asthma. Evidence-based clinical practice guidelines help to translate health research findings into practice and when implemented can improve health outcomes. National and International guidelines currently provide recommendations for optimal asthma care in pregnancy., Aim: To appraise the existing asthma in pregnancy guidelines with respect to their evidence for recommendations, consistency of recommendations and appropriateness for clinical practice., Method: The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to appraise four English language asthma in pregnancy guidelines, published or updated between 2007 and 2016. The recommendations, range and level of evidence was analysed., Results: Two of the four guidelines scored highly in most domains of the appraisal. Many of the recommendations made in the appraised guidelines were consistent. Due to the lack of randomised controlled trials involving pregnant women with asthma, most recommendations were evidenced by consensus and expert opinion rather than high quality meta-analysis, systematic reviews of randomised controlled trials., Conclusion: The recommended antenatal asthma management was generally consistent among the guidelines but lacked clarity in some areas which then leave them open to interpretation. More randomised controlled trials involving pregnant women with asthma are required to fortify the recommendations made and asthma management guidelines should be included in Australian Antenatal Care Guidelines as they currently are not., (Copyright © 2018 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Background: Few studies have examined dietary intake changes following a weight loss intervention in fathers and the association between father-child dietary intakes. The present study aimed to: (i) evaluate the change in dietary intake in overweight fathers randomised to a family-based lifestyle intervention [Healthy Dads Healthy Kids (HDHK)] versus controls and (ii) investigate whether an association exists between father-child dietary intakes., Methods: A secondary analysis was conducted of father-child baseline and 3-month post-intervention data (n = 93) collected in the HDHK community randomised controlled trial. Intention-to-treat linear mixed models were used to assess dietary changes by group, time (baseline and 3-month) and the group-by-time interaction. Cohens d was used to determine effect sizes., Results: Significant group-by-time effects (all P < 0.05) favouring fathers in the intervention group were identified for total daily energy intake (-1956 kJ, d = 0.74), total sugars (-45 g, d = 0.63), sodium (-414 mg, d = 0.58) and % energy from nutrient-dense, core foods (+10.1%, d = 0.86), fruit (+2.4%, d = 0.71), vegetarian protein sources (+1.2%, d = 0.57), pre-packed snacks (+1.7%, d = 0.58) and sugar-sweetened beverages (-4.1%, d = 0.58). At baseline, positive correlations were observed between father-child intakes for a number of dietary variables, and significant correlations were observed between father-child change scores for % energy carbohydrate (r = 0.35, P = 0.023), % energy from fruit (r = 0.47, P = 0.002), vegetarian protein sources (r = 0.46, P = 0.002) and frequency of consuming meals with vegetables (r = 0.38, P = 0.012)., Conclusions: The HDHK intervention successfully improved some aspects of father's dietary intakes compared to controls. The fathers' eating patterns also correlated with those of their children for several dietary variables. These novel data suggest that fathers can be targeted as agents of dietary change within obesity prevention and treatment programmes., (© 2018 The British Dietetic Association Ltd.)

Introduction: Alcohol dependence is a major public health problem. It is underdiagnosed and undertreated. Even when treated, more than 2/3 of patients in abstinence-oriented treatment will relapse within the first year. Thus, there is an urgent need for efficacious medical treatment of alcohol dependence. Glucagon-like peptide-1 (GLP-1) receptor stimulation has proven to reduce alcohol consumption in preclinical experiments. However, the effect of GLP-1 receptor agonists in humans has to our knowledge, not yet been investigated. METHODS AND ANALYSIS: Design, participants and intervention : The effect of the once-weekly GLP-1-receptor-agonist exenatide will be investigated in a double-blinded, placebo-controlled, randomised clinical trial. 114 outpatients will be recruited and randomised to treatment with either placebo or exenatide once weekly for 26 weeks as a supplement to cognitive-behavioural therapy. The primary endpoint is reduction in number of 'heavy drinking days'. The secondary endpoints include changes in total alcohol consumption, days without consumption, changes in brain activity and function, smoking status, cognition, measures of quality of life and changes in phosphatidylethanol as a biomarker of alcohol consumption from baseline to follow-up at week 26. Status : Currently recruiting patients., Ethics and Dissemination: Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study results will be disseminated by peer-review publications and conference presentations and has the potential to reveal a completely new medical treatment of alcohol dependence., Competing Interests: Competing interests: TV has received lecture fees from Amgen, Astra Zeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Sanofi and Zealand Pharma, and is a member of the Advisory Boards of Astra Zeneca, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck, Sharp & Dohme, Novo Nordisk and Sanofi. AF-J has received an unrestricted grant from Novo Nordisk A/S for another project., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Subarachnoid hemorrhage (SAH) from posterior circulation perforator aneurysms (PCPAs) is rare and its natural history is unknown. Diagnosis may be difficult, acute management is poorly defined, and long-term recurrent SAH rates and clinical outcome data are lacking., Methods: We searched our institution's records for cases of PCPA rupture and analyzed patient demographics, Hunt and Hess (HH) grades, diagnostic imaging, management, and clinical outcomes. We conducted telephone interviews to calculate modified Rankin Scale (mRS) scores., Results: We identified 9 patients (6 male, 3 female) with a ruptured PCPA who presented to the University of Virginia Health System (Charlottesville, VA, USA) between 2010 and 2016. Median and mean ages were 62 and 63 years, respectively. Median HH grade was 3. Seven of nine (78%) PCPAs were angiographically occult on initial imaging and median time to diagnosis was 5 days. Three conservatively managed patients had a mean mRS score of 0.67 (range 0-1) at mean follow-up of 35.3 months. Antifibrinolytic therapy was administered to all conservatively managed patients without thrombotic complication. Six patients receiving endovascular treatment had a mean mRS score of 2.67 (range 0-6) at mean follow-up of 49.2 months. No cases of recurrent SAH were seen in the study., Conclusions: The rarity of PCPA has precluded long-term clinical follow-up until now. Our experience suggests low recurrent SAH rates. Until further studies are performed, conservative management, possibly combined with antifibrinolytic therapy, may be a viable treatment with acceptable long-term outcome., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown., Methods: For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D 3 or vitamin D 2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953., Findings: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; p interaction =0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I 2 =0·0, p=0·56)., Interpretation: Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients., Funding: Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Prebiotic soluble fibers are fermented by beneficial bacteria in the colon to produce short-chain fatty acids (SCFAs), which are proposed to have systemic anti-inflammatory effects., Objective: This review examines the effect of SCFAs, prebiotics, and pre- and probiotic combinations (synbiotics) on systemic inflammation., Design: Relevant English language studies from 1947 to May 2017 were identified with the use of online databases. Studies were considered eligible if they examined the effects of SCFAs, prebiotics, or synbiotics; were delivered orally, intravenously, or per rectum; were on biomarkers of systemic inflammation in humans; and performed meta-analysis where possible., Results: Sixty-eight studies were included. Fourteen of 29 prebiotic studies and 13 of 26 synbiotic studies reported a significant decrease in ≥1 marker of systemic inflammation. Eight studies compared prebiotic and synbiotic supplementation, 2 of which reported a decrease in inflammation with synbiotics only, with 1 reporting a greater anti-inflammatory effect with synbiotics than with prebiotics alone. Meta-analyses indicated that prebiotics reduce C-reactive protein (CRP) [standardized mean difference (SMD): -0.60; 95% CI: -0.98, -0.23], and synbiotics reduce CRP (SMD: -0.40; 95% CI: -0.73, -0.06) and tumor necrosis factor-α (SMD -0.90; 95% CI: -1.50, -0.30)., Conclusions: There is significant heterogeneity of outcomes in studies examining the effect of prebiotics and synbiotics on systemic inflammation. Approximately 50% of included studies reported a decrease in ≥1 inflammatory biomarker. The inconsistency in reported outcomes may be due to heterogeneity in study design, supplement formulation, dosage, duration, and subject population. Nonetheless, meta-analyses provide evidence to support the systemic anti-inflammatory effects of prebiotic and synbiotic supplementation., (© 2017 American Society for Nutrition)

Background: Obesity is a risk factor for exacerbations of asthma, but the mechanisms of this effect in pregnancy are unknown., Objective: This study determined the influence of maternal body mass index, gestational weight gain, eosinophilic inflammation, and systemic macrophage activation on the risk of exacerbations during pregnancy., Methods: Women with asthma (n = 164) participated in the study. Body mass index recorded at baseline (17 weeks gestation) was categorized as healthy weight (18.5-24.9 kg/m 2 ), overweight (25-29.9 kg/m 2 ), or obese (>30 kg/m 2 ). Exacerbations requiring medical intervention were recorded prospectively. Asthma control, medication use, and fractional exhaled nitric oxide were assessed monthly; additional visits occurred during exacerbations. Peripheral blood was collected at baseline for the measurement of eosinophils, soluble CD-163, C-reactive protein, and IL-6., Results: Exacerbations occurred in a higher proportion of overweight (51.1%) and obese (48.4%) women compared with healthy weight women (25%; P = .026). Excess weight gain during pregnancy was not associated with exacerbation risk. Macrophage activation (elevated serum soluble CD-163) was associated with exacerbations requiring oral corticosteroids (P = .043), whereas high peripheral blood eosinophils or fractional exhaled nitric oxide were not associated with exacerbation or oral corticosteroid use., Conclusions: Being overweight or obese confers a greater risk of asthma exacerbation during pregnancy, and may be due to systemic macrophage activation., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

One in 10 pregnant women worldwide has asthma and of these, 10% will have a severe exacerbation requiring oral corticosteroids (OCSs) in pregnancy. This review of recent publications in the field will describe the effects of exacerbation on maternal and neonatal health, the use of asthma medications during pregnancy, and will suggest novel management approaches for asthma in pregnancy. Pregnancy results in unpredictable changes in the disease; therefore, regular monitoring of symptoms is recommended. Uncontrolled asthma is frequently described in cohorts of pregnant women with asthma, and some recent studies show associations with adverse perinatal outcomes, as previously demonstrated with exacerbations. Guidelines for the management of asthma recommend the continued use of inhaled corticosteroids (ICSs) in pregnancy, with budesonide having a particularly good safety profile. Recent data suggest small effects of asthma and/or asthma medication use on congenital malformations; however, there is less data available on the safety of ICS/long-acting β agonist combinations, which are increasingly used for maintenance treatment. Novel management strategies are needed to address the complex needs of pregnant women with asthma. These include medication nonadherence and the presence of numerous comorbidities which can affect asthma, such as rhinitis, cigarette smoking, obesity, and mental health issues. Inflammation-based management has been shown to be effective in reducing exacerbations in pregnancy and may also improve perinatal outcomes. The involvement of a multidisciplinary team and the assessment of comorbidities have potential to improve the health of mothers and their offspring., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

A higher proportion of children with asthma are overweight and obese compared to children without asthma; however, it is unknown whether asthmatic children are at increased risk of weight gain due to modifiable lifestyle factors. Thus, the aim of this cross-sectional study was to compare weight-gain risk factors (sleep, appetite, diet, activity) in an opportunistic sample of children with and without asthma. Non-obese children with ( n = 17; age 10.7 (2.4) years) and without asthma ( n = 17; age 10.8 (2.3) years), referred for overnight polysomnography, underwent measurement of lung function, plasma appetite hormones, dietary intake and food cravings, activity, and daytime sleepiness. Sleep latency (56.6 (25.5) vs. 40.9 (16.9) min, p = 0.042) and plasma triglycerides (1.0 (0.8, 1.2) vs. 0.7 (0.7, 0.8) mmol/L, p = 0.013) were significantly greater in asthmatic versus non-asthmatic children. No group difference was observed in appetite hormones, dietary intake, or activity levels ( p > 0.05). Sleep duration paralleled overall diet quality ( r = 0.36, p = 0.04), whilst daytime sleepiness paralleled plasma lipids ( r = 0.61, p =0.001) and sedentary time ( r = 0.39, p = 0.02). Disturbances in sleep quality and plasma triglycerides were evident in non-obese asthmatic children referred for polysomnography, versus non-asthmatic children. Observed associations between diet quality, sedentary behavior, and metabolic and sleep-related outcomes warrant further investigation, particularly the long-term health implications.

Carotid-cavernous fistulas (CCFs) pose an anatomically and physiologically challenging problem for clinicians. The most common method of treatment for these lesions is transvenous endovascular embolization via the inferior petrosal sinus or the facial vein. When transvenous access is not possible, an alternate approach must be devised. We describe a case example with bilateral Barrow Type B CCFs, which were inaccessible using the traditional transvenous approach. Hence, a direct transorbital approach, performed under fluoroscopic guidance, was employed to successfully obliterate the CCF. At five months follow-up, the patient was recovering without complications. This case delineates the technical aspects of transorbital CCF embolization and demonstrates that this approach is a viable alternative to conventional transvenous methods for appropriately selected CCF cases. We supplement our case example and technical note with a literature review of this approach., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The present study investigated the effects of high- versus low-quality protein supplementation on the regain of exercise performance during recovery from a period of high-intensity resistance training., Methods: In a diet-controlled crossover study, 12 resistance-trained participants performed two identical training periods, with each training period including four sessions of high-intensity resistance exercise during 5 days, while receiving either high- or low-quality protein. Prior to and at 3, 24 and 48 h after the training periods, performance was evaluated in knee extensor and flexor isometric maximal voluntary contraction (MVC), counter-movement jumping height (CMJ), and peak and mean anaerobic power. In addition, prior to and at 48 h after the training periods, performance in time-to-exhaustion at 70 % of VO 2max (TTE) was evaluated., Results: After the intense training periods, decrements in the order of 4-24 % were observed for MVC ext , CMJ, mean anaerobic power, and TTE. In particular for TTE, this decrement in exercise performance did not attain full recovery at 48 h post-exercise. The regain of exercise performance was not dictated by type of protein supplement., Conclusion: The regain of muscle strength as well as anaerobic or aerobic performances were not markedly influenced by the type of protein supplement.

Background and Purpose: While recent literature has described the prevalence of transverse sinus stenosis in patients with idiopathic intracranial hypertension, tinnitus, and refractory headaches, it is unclear what the prevalence is in the general population. This study evaluates the prevalence of venous sinus stenosis and hypoplasia in the general patient population., Materials and Methods: 355 of 600 consecutive patients who underwent CT angiography of the head met the inclusion criteria. The diameters of the dural venous sinuses were recorded. Each study was evaluated by a neuroradiologist for the presence of stenoses. Univariate and multivariate statistical analyses were performed by a statistician., Results: The prevalence of unilateral transverse sinus stenosis or hypoplasia in a sample of patients representing the general population was 33%, the prevalence of bilateral transverse sinus stenosis was 5%, and the prevalence of unilateral stenosis with contralateral hypoplasia was 1%. A multivariate analysis identified arachnoid granulations as a predictor of stenosis (p<0.001). Gender trended toward significance (p=0.094). Race was not a significant predictor of stenosis (p=0.745)., Conclusions: The prevalence of bilateral transverse sinus stenosis in the general population is not trivial. These data may be used as a reference for understanding the mechanistic role of stenoses in idiopathic intracranial hypertension, tinnitus, and refractory headaches., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)