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Background: A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. Methods: Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight < 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach. Results: When the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1–5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated. Conclusions: Vulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals. [ABSTRACT FROM AUTHOR]

Male sex, birthweight, gestational age, maternal eczema, maternal hay fever, paternal eczema and family history of atopy were all positively correlated with eczema. In the replication "gene-environment" analyses, a family history of eczema was analysed using as a potential modifier of the effect of water hardness on eczema (FLG data were not available). Water hardness is not correlated with infant eczema overall in a naturally soft water area. [Extracted from the article]

Aims: We aimed to assess ethnic differences in inflammatory markers and their relationships with insulin sensitivity and regional adiposity between white European and black African men. Methods: A total of 53 white European and 53 black African men underwent assessment of inflammatory markers alongside Dixon‐magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue and intrahepatic lipid. A hyperinsulinaemic‐euglycaemic clamp was used to measure whole‐body and adipose tissue insulin sensitivity. To assess ethnic differences in relationships, the statistical significance of an interaction term between adipokines and ethnic group was tested in multivariable regression models. Results: The black African men exhibited significantly lower adiponectin and tumour necrosis factor‐α (TNF‐α) and greater interleukin‐10 (IL‐10) compared to white European men (all p < 0.05). There were no statistically significant ethnic differences in leptin, resistin, IL‐6, interferon‐γ, IL‐13, IL‐1β, IL‐8 and vascular endothelial growth factor. Several relationships differed significantly by ethnicity such that they were stronger in white European than black African men including IL‐6 with visceral adipose tissue; adiponectin with subcutaneous adipose tissue; leptin with intrahepatic lipid; adiponectin, IL‐6 and TNF‐α with whole‐body insulin sensitivity and TNF‐α with adipose tissue insulin sensitivity (all pinteraction <0.05). Leptin significantly predicted whole‐body insulin sensitivity in white European (R2 = 0.51) and black African (R2 = 0.29) men; however, adiponectin was a statistically significant predictor in only white European men (R2 = 0.22). Conclusions: While adiponectin is lower in black African men, its insulin sensitising effects may be greater in white men suggesting that the role of adipokines in the development of type 2 diabetes may differ by ethnicity. [ABSTRACT FROM AUTHOR]

Background: Hard domestic water has been reported to worsen atopic eczema (AE) and may contribute to its development in early life. Objective: To review the literature on the relationship between the effect of water hardness (high calcium carbonate; CaCO3) on (a) the risk of developing AE, (b) the treatment of existing AE and (c) skin barrier function in human and animal studies. Design , data sources and eligibility criteria: We systematically searched databases (MEDLINE, Embase, Cochrane CENTRAL, GREAT and Web of Science) from inception until 30/6/2020. Human and animal observational and experimental studies were included. The primary outcomes were risk of AE and skin barrier function. Studies were meta‐analysed using a random effects model. Evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results: Sixteen studies were included. Pooled observational data from seven studies on 385,901 participants identified increased odds of AE in children exposed to harder versus softer water (odds ratio 1.28, 95% CI 1.09, 1.50; GRADE certainty: very low). Two mechanistic studies in humans reported higher deposition of the detergent sodium lauryl sulphate in those exposed to harder versus softer water. Two randomized controlled trials comparing water softeners with standard care did not show a significant difference in objective AE severity with softened water (standardized mean difference 0.06 standard deviations higher, 95% CI 0.16 lower to 0.27 higher; GRADE certainty: moderate). Conclusions & Clinical Relevance: There was a positive association between living in a hard water (range: 76 to > 350 mg/L CaCO3) area and AE in children. There is no evidence that domestic water softeners improve objective disease severity in established AE. There may be a role of water hardness in the initiation of skin inflammation in early life, but there is a need for further longitudinal and interventional studies. [ABSTRACT FROM AUTHOR]

Aim: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. Methods: Twenty‐three BA and twenty‐three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic‐euglycaemic clamp with stable glucose isotope infusion to measure whole‐body and hepatic‐specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). Results: BA men had higher glucose‐stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L−1 × min, P =.017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m−2 body surface area min −1, P <.001) compared with WE men. There were no ethnic differences in beta‐cell insulin secretion or beta‐cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole‐body insulin sensitivity (r = 0.691, P =.001) and inversely correlated with IHL (r = −0.674, P =.001). These associations were not found in BA men. Conclusions: While normally glucose‐tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin. [ABSTRACT FROM AUTHOR]

Objectives: Selective dorsal rhizotomy (SDR) has gained interest as an intervention to reduce spasticity and pain, and improve quality of life and mobility in children with cerebral palsy mainly affecting the legs (diplegia). We evaluated the cost-effectiveness of SDR in England. Methods: Cost-effectiveness was quantified with respect to Gross Motor Function Measure (GMFM-66) and the pain dimension of the Cerebral Palsy Quality of Life questionnaire for Children (CPQOL-Child). Data on outcomes following SDR over two years were drawn from a national evaluation in England which included 137 children, mean age 6.6 years at surgery. The incremental impact of SDR on GMFM-66 was determined through comparison with data from a historic Canadian cohort not undergoing SDR. Another single centre provided data on hospital care over ten years for 15 children undergoing SDR at a mean age of 7.0 years, and a comparable cohort managed without SDR. The incremental impact of SDR on pain was determined using a before and after comparison using data from the national evaluation. Missing data were imputed using multiple imputation. Incremental costs of SDR were determined as the difference in costs over 5 years for the patients undergoing SDR and those managed without SDR. Uncertainty was quantified using bootstrapping and reported as the cost-effectiveness acceptability curve. Results: In the base case, the incremental cost-effectiveness ratios (ICERs) for SDR are £1,382 and £903 with respect to a unit improvement in GMFM-66 and the pain dimension of CPQOL-Child, respectively. Inclusion of data to 10 years indicates SDR is cheaper than management without SDR. Incremental costs and ICERs for SDR rose in sensitivity analysis applying an alternative regression model to cost data. Conclusions: Data on outcomes from a large observational study of SDR and long-term cost data on children who did and did not receive SDR indicates SDR is cost-effective. [ABSTRACT FROM AUTHOR]

We previously demonstrated corticosteroid administration on the neonatal intensive care unit was associated with reduced lung function at 11 to 14 years of age in children born very prematurely. The objective of this observational study was to assess if lung function remained impaired at 16 to 19 years of age in those who had received postnatal corticosteroids and whether the trajectory of lung function with increasing age differed between those who had and had not received corticosteroids. One hundred and fifty-nine children born prior to 29 weeks of gestational age had comprehensive lung function measurements; 49 had received postnatal dexamethasone. Lung function outcomes were compared between those who had and had not received postnatal dexamethasone after adjustment for neonatal factors. Forced expiratory flow at 75%, 50%, 25% and 25–75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes (total lung capacity and residual volume) were assessed. The majority of results were significantly lower in those who received dexamethasone (between 0.61 to 0.78 standard deviations). Lung function reduced as the number of courses of dexamethasone increased. Between 11 and 14 years and 16 to 19 years, lung function improved in the unexposed group, but forced expiratory flow at 75% of the expired vital capacity and forced expiratory volume in one second deteriorated in those who had received postnatal corticosteroids (p = 0.0006). These results suggest that prematurely born young people who received postnatal corticosteroids may be at risk of premature onset of chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Objectives: In men of black west African (BAM) and white European (WEM) ethnicity, we aimed to (1) compare adipose tissue, peripheral and hepatic insulin sensitivity and (2) investigate associations between ectopic fat and insulin sensitivity by ethnicity. Design and methods: In overweight BAM (n = 21) and WEM (n = 23) with normal glucose tolerance, we performed a two-step hyperinsulinaemic-euglycaemic clamp with infusion of [6,6 ²H2]-glucose and [²H5]-glycerol to measure whole body, peripheral, hepatic and adipose tissue insulin sensitivity (lipolysis). Visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular (IMCL) lipids were measured using MRI and spectroscopy. Associations between insulin sensitivity and ectopic fat were assessed using Pearson's correlation coefficient by ethnicity and regression analysis. Results: There were no ethnic differences in whole body or tissue-specific insulin sensitivity (all P > 0.05). Suppression of lipolysis was inversely associated with VAT and IHL in WEM but not BAM (VAT: WEM r = -0.68, P < 0.01; BAM r = 0.07, P = 0.79. IHL: WEM r = -0.52, P = 0.01; BAM r = -0.12, P = 0.63). IMCL was inversely associated with skeletal muscle insulin sensitivity in WEM but not BAM (WEM r = -0.56, P < 0.01; BAM r = -0.09, P = 0.75) and IHL was inversely associated with hepatic insulin sensitivity in WEM but not BAM (WEM r = -0.53, P = 0.02; BAM r = -0.13, P = 0.62). Conclusions: Ectopic fat deposition may play a lesser role in reducing insulin sensitivity in men of black African ethnicity and may not be driven by lipolysis. Resistance to storing VAT, IHL and IMCL may enable men of black African ethnicity to maintain comparable insulin sensitivity to white Europeans. [ABSTRACT FROM AUTHOR]

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D <5 years. They underwent magnetic resonance imaging to quantify IHL, a hyperinsulinemic euglycaemic clamp with [6,6 2H2] glucose infusion to assess hepatic insulin sensitivity and a hyperglycaemic clamp to assess insulin clearance. BWA men had lower IHL than WE men (3.7 [5.3] vs 6.6 [10.6]%, P = 0.03). IHL was inversely associated with basal hepatic insulin sensitivity in WE but not BWA men (BWA: r = −0.01, P = 0.96; WE: r = −0.72, P = 0.006) with a significant interaction by ethnicity (Pinteraction = 0.05); however, IHL was not associated with % suppression of endogenous glucose production by insulin in either ethnicity. IHL showed a trend to an association with insulin clearance in BWA only (BWA: r = −0.42, P = 0.09; WE: r = −0.14, P = 0.58). The lack of association between IHL and hepatic insulin sensitivity in BWA men indicates IHL may play a lesser detrimental role in T2D in BWA men. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes is more prevalent in black African than white European populations although, paradoxically, black African individuals present with lower levels of visceral fat, which has a known association with insulin resistance. Insulin resistance occurs at a tissue-specific level; however, no study has simultaneously compared whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men. We hypothesised that, in those with early type 2 diabetes, black (West) African men (BAM) have greater hepatic and adipose tissue insulin sensitivity, compared with white European men (WEM), because of their reduced visceral fat. Methods: Eighteen BAM and 15 WEM with type 2 diabetes underwent a two-stage hyperinsulinaemic–euglycaemic clamp with stable glucose and glycerol isotope tracers to assess tissue-specific insulin sensitivity and a magnetic resonance imaging scan to assess body composition. Results: We found no ethnic differences in whole body, skeletal muscle, hepatic or adipose tissue insulin sensitivity between BAM and WEM. This finding occurred in the presence of lower visceral fat in BAM (3.72 vs 5.68 kg [mean difference −1.96, 95% CI −3.30, 0.62]; p = 0.01). There was an association between skeletal muscle and adipose tissue insulin sensitivity in WEM that was not present in BAM (r = 0.78, p < 0.01 vs r = 0.25 p = 0.37). Conclusions/interpretation: Our data suggest that in type 2 diabetes there are no ethnic differences in whole body, skeletal muscle, hepatic and adipose tissue insulin sensitivity between black and white men, despite differences in visceral adipose tissue, and that impaired lipolysis may not be contributing to skeletal muscle insulin resistance in men of black African ethnicity. [ABSTRACT FROM AUTHOR]

Our aim was to compare the work of breathing (WOB) during synchronised nasal intermittent positive pressure ventilation (SNIPPV) and heated humidified high flow nasal cannula (HHHFNC) when used as post-extubation support in preterm infants. A randomised crossover study was undertaken of nine infants with a median gestational age of 27 (range 24-31) weeks and post-natal age of 7 (range 2-50) days. Infants were randomised to either SNIPPV or HHHFNC immediately following extubation. They were studied for 2 h on one mode and then switched to the other modality and studied for a further 2-h period. The work of breathing, assessed by measuring the pressure time product of the diaphragm (PTPdi), and thoracoabdominal asynchrony (TAA) were determined at the end of each 2-h period. The infants' inspired oxygen requirement, oxygen saturation, heart rate and respiratory rate were also recorded. The median PTPdi was lower on SNIPPV than on HHHFNC (232 (range 130-352) versus 365 (range 136-449) cmH2O s/min, p = 0.0077), and there was less thoracoabdominal asynchrony (13.4 (range 8.5-41.6) versus 36.1 (range 4.3-50.4) degrees, p = 0.038).Conclusion: In prematurely born infants, SNIPPV compared to HHHFNC post-extubation reduced the work of breathing and thoracoabdominal asynchrony. What is Known: • The work of breathing and extubation failure are not significantly different in prematurely-born infants supported by HHHFNC or nCPAP. • SNIPPV reduces inspiratory effort and increases tidal volume and carbon dioxide exchange compared to nCPAP in prematurely born infants. What is New: • SNIPPV, as compared to HHHFNC, reduced the work of breathing in prematurely-born infants studied post-extubation. • SNIPPV, as compared to HHHFNC, reduced thoracoabdominal asynchrony in prematurely born infants studied post-extubation. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23–28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25–75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up. [ABSTRACT FROM AUTHOR]

Aim: To test the hypothesis that men of black (West) African ethnicity (black African men [BAM]) with early type 2 diabetes (T2D) would have greater insulin secretory deficits compared with white European men (WEM), following prediabetic hypersecretion. Methods: In 19 BAM and 15 WEM, matched for age, body mass index and duration of diabetes, we assessed and modelled insulin secretory responses to hyperglycaemia stimulated intravenously (hyperglycaemic clamp) and orally (meal tolerance test). Results: With similar post‐challenge glucose responses, BAM had lower second‐phase C‐peptide responses to intravenous glucose (BAM 70.6 vs WEM 115.1 nmol/L/min [ratio of geometric mean 0.55, 95% confidence interval {CI} 0.37, 0.83]; P = .006) and to oral glucose (BAM 65.4 vs WEM 88.5 nmol/L/min [mean difference −23.2, 95% CI −40.0, −6.3]; P = .009). Peripheral insulin response in BAM to oral glucose was preserved (BAM 47.4 vs WEM 59.4 nmol/L/min [ratio of geometric mean 0.89, 95% CI 0.59, 1.35]; P = .566), with relative reductions in insulin clearance (BAM 506.2 vs WEM 630.1 mL/m2 BSA/min [mean difference −123.9, 95% CI −270.5, 22.6]; P = .095), associated with enhanced incretin responses (gastric inhibitory polypeptide incremental area under the curve: BAM 46.8 vs WEM 33.9 μg/L/min [mean difference 12.9, 95% CI 2.1, 23.7]; P = .021). Conclusions: In early T2D, BAM had significantly lower insulin secretory responses to intravenous and oral stimulation than WEM. Lower insulin clearance, potentially driven by increased incretin responses, may act to preserve peripheral insulin concentrations. Tailoring early management strategies to reflect distinct ethnic‐specific pathophysiology may improve outcomes in this high‐risk population. [ABSTRACT FROM AUTHOR]

Importance: Surgical treatment can bring seizure remission in people with focal epilepsy but requires careful selection of candidates.Objectives: To determine which preoperative factors are associated with postoperative seizure outcome.Design: We audited seizure outcome of 693 adults who had resective epilepsy surgery between 1990 and 2010 and used survival analysis to detect preoperatively identifiable risk factors of poor seizure outcome.Results: Seven factors were significantly associated with increased probability of recurrence of seizures with impaired awareness postsurgery: MRI findings (eg, HR adjusted for other variables in the model 2.5; 95% CI 1.6 to 3.8 for normal MRI compared with hippocampal sclerosis), a history of secondarily generalised convulsive seizures (2.3; 95% CI 1.7 to 3.0 for these seizures in the previous year vs never), psychiatric history (1.3; 95% CI 1.1 to 1.7), learning disability (1.8; 95% CI 1.2 to 2.6) and extratemporal (vs temporal) surgery (1.4; 95% CI 1.02, 2.04). People with an older onset of epilepsy had a higher probability of seizure recurrence (1.01; 95% CI 1.00, 1.02) as did those who had used more antiepileptic drugs (1.05; 95% CI 1.01 to 1.09). Combinations of variables associated with seizure recurrence gave overall low probabilities of 5-year seizure freedom (eg, a normal MRI and convulsive seizures in the previous year has a probability of seizure freedom at 5 years of approximately 0.19).Conclusions and Relevance: Readily identified clinical features and investigations are associated with reduced probability of good outcome and need consideration when planning presurgical evaluation. [ABSTRACT FROM AUTHOR]

Importance: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. Objective: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. Materials and methods: The study included 412 infants born at 23–28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. Results: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). Conclusions: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities. [ABSTRACT FROM AUTHOR]

Background: The analysis of perinatal outcomes often involves datasets with some multiple births. These are datasets mostly formed of independent observations and a limited number of clusters of size two (twins) and maybe of size three or more. This non-independence needs to be accounted for in the statistical analysis. Using simulated data based on a dataset of preterm infants we have previously investigated the performance of several approaches to the analysis of continuous outcomes in the presence of some clusters of size two. Mixed models have been developed for binomial outcomes but very little is known about their reliability when only a limited number of small clusters are present.Methods: Using simulated data based on a dataset of preterm infants we investigated the performance of several approaches to the analysis of binomial outcomes in the presence of some clusters of size two. Logistic models, several methods of estimation for the logistic random intercept models and generalised estimating equations were compared.Results: The presence of even a small percentage of twins means that a logistic regression model will underestimate all parameters but a logistic random intercept model fails to estimate the correlation between siblings if the percentage of twins is too small and will provide similar estimates to logistic regression. The method which seems to provide the best balance between estimation of the standard error and the parameter for any percentage of twins is the generalised estimating equations.Conclusions: This study has shown that the number of covariates or the level two variance do not necessarily affect the performance of the various methods used to analyse datasets containing twins but when the percentage of small clusters is too small, mixed models cannot capture the dependence between siblings. [ABSTRACT FROM AUTHOR]

Background: Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation.Objective: This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial.Methods: Eligible older adults who were not vitamin D-deficient [serum 25(OH)D ≥12 ng/mL] were randomly assigned in a modified 2 × 2 factorial design to 1 of 4 groups: daily 1000 IU cholecalciferol, 1200 mg Ca as carbonate, both, or placebo. Women could elect 2-group (calcium ± cholecalciferol) random assignment. In secondary analyses, we used multivariable models to assess factors associated with serum 25(OH)D concentrations in all enrollees (n = 2753) and with relative changes in serum 25(OH)D after 1 y cholecalciferol supplementation among those randomly assigned (n = 2187).Results: In multivariable models, 8 factors accounted for 50% of the variability of proportional change in serum 25(OH)D after cholecalciferol supplementation. Larger increases were associated with being female (34.5% compared with 20.5%; P < 0.001) and with lower baseline serum 25(OH)D (P < 0.0001), optimal adherence to study pill intake (P = 0.0002), wearing long pants and sleeves during sun exposure (P = 0.0002), moderate activity level (P = 0.01), use of extra vitamin D-containing supplements during the trial (P = 0.03), and seasons of blood draw (P ≤ 0.002). Several genetic polymorphisms were associated with baseline serum 25(OH)D and/or serum response, but these did not substantially increase the models' R2 values. Other factors, including body mass index, were associated with serum 25(OH)D at baseline but not with its response to supplemental cholecalciferol.Conclusions: The factors that most affected changes in serum 25(OH)D concentrations in response to cholecalciferol supplementation included sex, baseline serum 25(OH)D, supplement intake adherence, skin-covering clothes, physical activity, and season. Genetic factors did not play a major role. This trial was registered at www.clinicaltrials.gov as NCT00153816. [ABSTRACT FROM AUTHOR]

Objective: The tension-time index of the diaphragm (TTdi) is a composite assessment of the load on and the capacity of the diaphragm. TTmus is a non-invasive tension-time index of the respiratory muscles. Our aim was to determine whether TTdi or TTmus predicted extubation outcome and performed better than respiratory muscle strength (Pimax, Pdimax), respiratory drive (P0.1) and work of breathing (transdiaphragmatic pressure-time product (PTPdi)) or routinely available clinical data.Design: Prospective study.Setting: Tertiary neonatal intensive care unit.Patients: Sixty infants, median gestation age 35 (range 23-42) weeks and postnatal age of 55 (range 1-115) days.Interventions: Airway occlusions were performed to measure Pimax, Pdimax and P0.1. TTdi and PTPdi were derived from measurements of transdiaphragmatic pressure. TTmus was derived from airway pressure measurements. Measurements were made within 6 h of extubation.Main Outcome Measures: Extubation failure defined as reintubation within 48 h of extubation.Results: Twelve infants failed extubation. The infants who failed extubation were significantly more immature (medians 25 vs 37 weeks) and of greater postnatal age (23 vs 5 days) and had higher TTdi (0.15 vs 0.04) and TTmus (0.17 vs 0.08). TTdi and TTmus were only significantly better predictors than the peak inflation pressure immediately prior to extubation and did not perform significantly better than gestational age or birth weight.Conclusions: Assessment of TTdi and TTmus cannot be recommended for use in routine clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To determine whether continuous positive airway pressure (CPAP) compared with heated humidified, high-flow nasal cannula (HHFNC) in infants with evolving or established bronchopulmonary dysplasia (BPD) reduced the work of breathing (WOB) and thoracoabdominal asynchrony (TAA) and improved oxygen saturation (SaO2).Design: Randomised crossover study.Setting: Tertiary neonatal unit.Patients: 20 infants (median gestational age of 27.6 weeks (range 24.6-31.9 weeks)) were studied at a median postnatal age of 30.9 weeks (range 28.1-39.1 weeks).Interventions: Infants were studied on 2 consecutive days. On the first study day, they were randomised to either CPAP or HHFNC each for 2 h, the order being reversed on the second day.Main Outcome Measures: The WOB was assessed by measuring the pressure time product of the diaphragm (PTPdi). PTPdi, TAA and SaO2 were assessed during the final 5 min of each 2 h period and the results on the two study days were meaned.Results: There were no significant differences in the results on CPAP versus HHFNC: mean PTPdi 226 (range 126-294) versus 224 cm H2O/s/min (95% CI for difference: -27 to 22; p=0.85) (range 170-318) (p=0.82), mean TAA 13.4° (range 4.51°-23.32°) versus 14.01° (range 4.25°-23.86°) (95% CI for difference: -3.9 to 2.8: p=0.73) (p=0.63) and mean SaO2 95% (range 93%-100%) versus 95% (94%-99%), (95% CI for difference -1.8 to 0.5; p=0.25) (p=0.45).Conclusion: In infants with evolving or established BPD, CPAP compared with HHFNC offered no significant advantage with regard to the WOB, degree of asynchrony or oxygen saturation. [ABSTRACT FROM AUTHOR]

Objectives: We investigated long-term (to 25 years) seizure prognosis and survival in people with newly diagnosed epilepsy in the community. We explored whether prognosis is different in those with epilepsy (>2 unprovoked seizures) and those with a single seizure at presentation.Methods: This is a prospective observational cohort study of people with newly diagnosed seizures. We investigated seizure outcome and survival in people presenting with a single seizure and in those presenting with >2 seizures (epilepsy).Results: 695 people (median follow-up 23.6 years) had unprovoked epileptic seizures. For seizure analysis we excluded 38 people with missing data leaving 657 (309 male, and 249 aged <18 years). Seizures recurred in 67%. The 354 people with epilepsy were only slightly more likely to have further seizure recurrence than the 302 people with a single seizure at presentation (HR 1.32, 95% CI 1.09 to 1.59). In 327 people with complete follow-up, 268 (82%, 95% CI 77% to 86%) were in terminal remission; (80%, (95% CI 73% to 85%) in those with epilepsy at presentation). Premature mortality was increased in people with epilepsy (standardised mortality ratio 1.67; 95% CI 1.40 to 1.99) and those with a single seizure at presentation (standardised mortality ratio 2.65; 95% CI 2.23 to 3.15). It is also high in those with early remission.Conclusions: People with epilepsy and with single seizures at presentation in the community generally have good prognosis for seizure control with prolonged follow-up. The risk of premature mortality is significantly increased in both groups. [ABSTRACT FROM AUTHOR]

Background: Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability.Methods: We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666).Results: Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF.Conclusions: There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention.Trial Registration: ClinicalTrials.gov: NCT00153816 . Registered September 2005. [ABSTRACT FROM AUTHOR]

Background: Dichotomisation of continuous data has statistical drawbacks such as loss of power but may be useful in epidemiological research to define high risk individuals. Methods: We extend a methodology for the presentation of comparison of proportions derived from a comparison of means for a continuous outcome to reflect the relationship between a continuous outcome and covariates in a linear (mixed) model without losing statistical power. The so called "distributional method" is described and using perinatal data for illustration, results from the distributional method are compared to those of logistic regression and to quantile regression for three different outcomes. Results: Estimates obtained using the distributional method for the comparison of proportions are consistently more precise than those obtained using logistic regression. For one of the three outcomes the estimates obtained from the distributional method and from logistic regression disagreed highlighting that the relationships between outcome and covariate differ conceptually between the two models. Conclusion: When an outcome follows the required condition of distribution shift between exposure groups, the results of a linear regression model can be followed by the corresponding comparison of proportions at risk. This dual approach provides more precise estimates than logistic regression thus avoiding the drawback of the usual dichotomisation of continuous outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Infants of smoking (S) and substance misusing (SM) mothers have an increased risk of sudden infant death syndrome. The aim of this study was to test the hypothesis that infants of SM or S mothers compared with infants of non-SM, non-smoking mothers (controls) would have a poorer ventilatory response to hypoxia, which was particularly marked in the SM infants.Design: Physiological study.Setting: Tertiary perinatal centre.Patients: 21 SM; 21 S and 19 control infants. Infants were assessed before maternity/neonatal unit discharge.Interventions: Maternal and infant urine samples were tested for cotinine, cannabinoids, opiates, amphetamines, methadone, cocaine and benzodiazepines.Main Outcome Measures: During quiet sleep, the infants were switched from breathing room air to 15% oxygen and changes in minute volume were assessed.Results: The SM infants had a greater mean increase (p=0.028, p=0.034, respectively) and a greater magnitude of decline (p<0.001, p=0.018, respectively) in minute volume than the S infants and the controls. The rate of decline in minute volume was greater in the SM infants (p=0.008) and the S infants (p=0.011) compared with the controls.Conclusions: Antenatal substance misuse and smoking affect the infant's ventilatory response to a hypoxic challenge. [ABSTRACT FROM AUTHOR]

Unlabelled: During proportional assist ventilation (PAV), the applied pressure is servo-controlled based on continuous input from the infant's breathing. In addition, elastic and resistive unloading can be employed to compensate for the abnormalities in the infant's lung mechanics. The aim of this study was to test the hypothesis that in very prematurely born infants remaining ventilated beyond the first week, PAV compared to assist control ventilation (ACV) would be associated with superior oxygenation. A randomised crossover study was undertaken. Infants were studied for 4 hours each on PAV and ACV in random order; at the end of each 4-h period, the oxygenation index (OI) was calculated. Eight infants, median gestational age of 25 (range 24-33) weeks, were studied at a median of 19 (range 10-105) days. It had been intended to study 18 infants but as all the infants had superior oxygenation on PAV (p = 0.0039), the study was terminated after recruitment of eight infants. The median inspired oxygen concentration (p = 0.049), mean airway pressure (p = 0.012) and OI (p = 0.012) were all lower on PAV.Conclusion: These results suggest that PAV compared to ACV is advantageous in improving oxygenation for prematurely born infants with evolving or established BPD.What Is Known: During proportional assist ventilation (PAV), the applied pressure is servo controlled throughout each spontaneous breath. Elastic and resistive unloading can compensate for the infant's abnormalities in lung mechanics.What Is New: In a randomised crossover study, infants with evolving/established BPD were studied on PAV and ACV each for 4 h. The oxygenation index was significantly lower on PAV in all infants studied. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the benefits of universal newborn hearing screening (UNHS) seen at age 8 years persist through the second decade.Design: Prospective cohort study of a population sample of children with permanent childhood hearing impairment (PCHI) followed up for 17 years since birth in periods with (or without) UNHS.Setting: Birth cohort of 100 000 in southern England.Participants: 114 teenagers aged 13-19 years, 76 with PCHI and 38 with normal hearing. All had previously their reading assessed aged 6-10 years.Interventions: Birth in periods with and without UNHS; confirmation of PCHI before and after age 9 months.Main Outcome Measure: Reading comprehension ability. Regression modelling took account of severity of hearing loss, non-verbal ability, maternal education and main language.Results: Confirmation of PCHI by age 9 months was associated with significantly higher mean z-scores for reading comprehension (adjusted mean difference 1.17, 95% CI 0.36 to 1.97) although birth during periods with UNHS was not (adjusted mean difference 0.15, 95% CI -0.75 to 1.06). The gap between the reading comprehension z-scores of teenagers with early compared with late confirmed PCHI had widened at an adjusted mean rate of 0.06 per year (95% CI -0.02 to 0.13) during the 9.2-year mean interval since the previous assessment.Conclusions: The benefit to reading comprehension of confirmation of PCHI by age 9 months increases during the teenage years. This strengthens the case for UNHS programmes that lead to early confirmation of permanent hearing loss.Trial Registration Number: ISRCTN03307358. [ABSTRACT FROM AUTHOR]

Objective: To assess the effectiveness of models of antenatal care designed to prevent and reduce preterm birth (PTB) in pregnant women. Methods: We conducted a search of seven electronic databases and reference lists of retrieved studies to identify trials from inception up to July 2014 where pregnant women, regardless of risk factors for pregnancy complications, were randomly allocated to receive an alternative model of antenatal care or routine care. We pooled risks of PTB to determine the effect of alternative care models in all pregnant women. We also assessed secondary maternal and infant outcomes, women's satisfaction and economic outcomes. Results: 15 trials involving 22 437 women were included. Pregnant women in alternative care models were less likely to experience PTB (risk ratio 0.84, 95% CI 0.74 to 0.96). The subgroup of women randomised to midwife-led continuity models of antenatal care were less likely to experience PTB (0.78, 0.66 to 0.91) but there was no significant difference between this group and women allocated to specialised care (0.92, 0.76 to 1.12) (interaction test for subgroup differences p=0.20). Overall low-risk women in alternative care models were less likely to have PTB (0.74, 0.59 to 0.93), but this effect was not significantly different from that in mixed-risk populations (0.91, 0.79 to 1.05) (subgroup p=0.13). Conclusions: Alternative models of antenatal care for all pregnant women are effective in reducing PTB compared with routine care, but no firm conclusions could be drawn regarding the relative benefits of the two models. Future research should evaluate the impact of antenatal care models which include more recent interventions and predictive tests, and which also offer continuity of care by midwives throughout pregnancy. PROSPERO registration number: CRD42014007116. [ABSTRACT FROM AUTHOR]

A retrospective cohort analysis of survival after keratinocyte cancer (KC) was conducted using data from a large, population-based case-control study of KC in New Hampshire. The original study collected detailed information during personal interviews between 1993 and 2002 from individuals with squamous (SCC) and basal (BCC) cell carcinoma, and controls identified through the Department of Transportation, frequency-matched on age and sex. Participants without a history of non-skin cancer at enrolment were followed as a retrospective cohort to assess survival after either SCC or BCC, or a reference date for controls. Through 2009, cancers were identified from the New Hampshire State Cancer Registry and self-report; death information was obtained from state death certificate files and the National Death Index. There were significant differences in survival between those with SCC, BCC and controls ( p = 0.040), with significantly greater risk of mortality after SCC compared to controls (adjusted hazard ratio [HR] 1.25; 95% confidence interval 1.01-1.54). Mortality after BCC was not significantly altered (HR 0.96; 95% CI 0.77-1.19). The excess mortality after SCC persisted after adjustment for numerous personal risk factors including time-varying non-skin cancer occurrence, age, sex and smoking. Survival from the date of the intervening cancer, however, did not vary (HR for SCC 0.98; 95% CI 0.70-1.38). Mortality also remained elevated when individuals with subsequent melanoma were excluded (HR for SCC 1.30; 95% CI 1.05-1.61). Increased mortality after SCC cannot be explained by the occurrence of intervening cancers, but may reflect a more general predisposition to life threatening illness that merits further investigation. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia is common in older adults and less treated, but little is known about correlates of untreated hypercholesterolemia. Using a standard interview method we examined a random sample of 7,572 participants aged ≥60 years in a community-based household survey across 7 provinces of China during 2007–2012, and documented 328 cases of hypercholesterolemia from self-reported doctor diagnosis. Compared to participants with normal cholesterol, older adults with hypercholesterolemia had higher socioeconomic position and larger body mass index. In patients with hypercholesterolemia, 209 were not treated using lipid-lowering medications (63.7%, 95% confidence interval (CI) 58.5%–68.9%). Untreated hypercholesterolemia was significantly associated with female sex (adjusted odds ratio 2.13, 95%CI 1.17–3.89), current smoking (3.48, 1.44–8.44), heavy alcohol drinking (3.13,1.11–8.84), chronic bronchitis (2.37,1.14–4.90) and high level of meat consumptions (2.85,1.22–6.65). Although having coronary heart disease exposed participants for treatment, half of participants with coronary heart disease did not receive lipid-lowering medications. Among hypercholesterolemia participants with stroke, hypertension or diabetes, more than half of them did not receive lipid-lowering medications. The high proportion of untreated hypercholesterolemia in older, high-risk Chinese adults needs to be mitigated through multi-faceted primary and secondary prevention strategies to increase population opportunities of treating hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is a commonly used outcome for randomized neonatal trials. Objectives: The aim of the present study was to determine whether a diagnosis of BPD or respiratory morbidity (RM1 or RM2) at 12 months corrected age better predicted subsequent RM in extremely low gestational age infants (23-28 weeks of gestation). Methods: Initial analysis was undertaken in a development cohort of 76 infants who underwent pulmonary function tests (PFTs) at 12 months corrected age. Parents completed infant respiratory diaries 2 weeks before the PFTs. Analysis was then undertaken in a validation cohort of 227 infants whose parents completed a 4-week respiratory diary when their infant was 12 months corrected age. BPD at 28 days (BPD28d) and 36 weeks post-menstrual age (BPD36w), RM1 (≥3 days and/or nights of cough, wheeze, and/or medicine use) and RM2 (≥4 days and/or nights of cough, wheeze, and/or respiratory medicine use) each week for 2 weeks at 12 months corrected age were assessed with regard to prediction of respiratory outcomes at 24 months documented by respiratory health questionnaires. Results: BPD28d and BPD36w were not significantly associated with any respiratory outcome. Areas under the receiver operating characteristic curves were significantly better for either definition of RM than BPD28d or BPD36w for all outcomes. Conclusions: RM documented by parental completed diaries at 12 months corrected age better predicted respiratory outcome at 24 months corrected age than BPD regardless of diagnostic criteria. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Dichotomisation of continuous outcomes has been rightly criticised by statisticians because of the loss of information incurred. However to communicate a comparison of risks, dichotomised outcomes may be necessary. Peacock et al. developed a distributional approach to the dichotomisation of normally distributed outcomes allowing the presentation of a comparison of proportions with a measure of precision which reflects the comparison of means. Many common health outcomes are skewed so that the distributional method for the dichotomisation of continuous outcomes may not apply. Methods: We present a methodology to obtain dichotomised outcomes for skewed variables illustrated with data from several observational studies. We also report the results of a simulation study which tests the robustness of the method to deviation from normality and assess the validity of the newly developed method. Results: The review showed that the pattern of dichotomisation was varying between outcomes. Birthweight, Blood pressure and BMI can either be transformed to normal so that normal distributional estimates for a comparison of proportions can be obtained or better, the skew-normal method can be used. For gestational age, no satisfactory transformation is available and only the skew-normal method is reliable. The normal distributional method is reliable also when there are small deviations from normality. Conclusions: The distributional method with its applicability for common skewed data allows researchers to provide both continuous and dichotomised estimates without losing information or precision. This will have the effect of providing a practical understanding of the difference in means in terms of proportions. [ABSTRACT FROM AUTHOR]

Objective To test the hypothesis that in very prematurely born infants remaining ventilated beyond the first week, proportional assist ventilation (PAV) compared with assist control ventilation (ACV) would be associated with reduced work of breathing, increased respiratory muscle strength and less ventilator-infant asynchrony which would be associated with improved oxygenation. Design Randomised crossover study. Setting Tertiary neonatal unit. Patients 12 infants with a median gestational age of 25 (range 24-26) weeks were studied at a median of 43 (range 8-86) days. Interventions Infants were studied for 1 h each on PAV and ACV in random order. Main outcome measures At the end of each hour, the work of breathing (assessed by measuring the diaphragmatic pressure time product), thoracoabdominal asynchrony and respiratory muscle strength (maximal inspiratory pressure, maximal expiratory pressure (Pemax) and maximal transdiaphragmatic pressure (Pdimax)) were assessed. Blood gas analysis was performed and the oxygenation index (OI) calculated. Results After 1 h on PAV compared with 1 h on ACV, the median OI (5.55 (range 5-11) vs 10.10 (range 7-16), p=0.002) and PTP levels were lower (217 (range 59-556) cm H2O.s/min vs 309 (range 55-544) cm H2O. s/min, p=0.005), while Pdimax (44.26 (range 21-66) cm H2O vs 37.9 (range 19-45) cm H2O, p=0.002) and Pemax (25.6 (range 6.5-42) cm H2O vs 15.9 (range 3-35) cm H2O levels p=0.010) were higher. Conclusions These results suggest that PAV compared with ACV may have physiological advantages for prematurely born infants who remain ventilated after the first week after birth. [ABSTRACT FROM AUTHOR]

Background We identified child-related determinants of health-related quality of life (HRQoL) in children aged 8–14 years who were treated for 2 common types of pediatric brain tumors. Methods Questionnaire measures of HRQoL and psychometric assessments were completed by 110 children on 3 occasions over 24 months. Of these 110, 72 were within 3 years of diagnosis of a cerebellar tumor (37 standard-risk medulloblastoma, 35 low-grade cerebellar astrocytoma), and 38 were in a nontumor group. HRQoL, executive function, health status, and behavioral difficulties were also assessed by parents and teachers as appropriate. Regression modeling was used to relate HRQoL z scores to age, sex, socioeconomic status, and 5 domains of functioning: Cognition, Emotion, Social, Motor and Sensory, and Behavior. Results HRQoL z scores were significantly lower after astrocytoma than those in the nontumor group and significantly lower again in the medulloblastoma group, both by self-report and by parent-report. In regression modeling, significant child-related predictors of poorer HRQoL z scores by self-report were poorer cognitive and emotional function (both z scores) and greater age (years) at enrollment (B = 0.038, 0.098, 0.136, respectively). By parent-report, poorer cognitive, emotional and motor or sensory function (z score) were predictive of lower subsequent HRQoL of the child (B = 0.043, 0.112, 0.019, respectively), while age at enrollment was not. Conclusions Early screening of cognitive and emotional function in this age group, which are potentially amenable to change, could identify those at risk of poor HRQoL and provide a rational basis for interventions to improve HRQoL. [ABSTRACT FROM PUBLISHER]

Background There is a need for cost-effective weight management interventions that primary care can deliver to reduce the morbidity caused by obesity. Automated web-based interventions might provide a solution, but evidence suggests that they may be ineffective without additional human support. The main aim of this study was to carry out a feasibility trial of a web-based weight management intervention in primary care, comparing different levels of nurse support, to determine the optimal combination of web-based and personal support to be tested in a full trial. Methods This was an individually randomised four arm parallel non-blinded trial, recruiting obese patients in primary care. Following online registration, patients were randomly allocated by the automated intervention to either usual care, the web-based intervention only, or the web-based intervention with either basic nurse support (3 sessions in 3 months) or regular nurse support (7 sessions in 6 months). The main outcome measure (intended as the primary outcome for the main trial) was weight loss in kg at 12 months. As this was a feasibility trial no statistical analyses were carried out, but we present means, confidence intervals and effect sizes for weight loss in each group, uptake and retention, and completion of intervention components and outcome measures. Results All randomised patients were included in the weight loss analyses (using Last Observation Carried Forward). At 12 months mean weight loss was: usual care group (n = 43) 2.44 kg; web-based only group (n = 45) 2.30 kg; basic nurse support group (n = 44) 4.31 kg; regular nurse support group (n = 47) 2.50 kg. Intervention effect sizes compared with usual care were: d = 0.01 web-based; d = 0.34 basic nurse support; d = 0.02 regular nurse support. Two practices deviated from protocol by providing considerable weight management support to their usual care patients. Conclusions This study demonstrated the feasibility of delivering a web-based weight management intervention supported by practice nurses in primary care, and suggests that the combination of the web-based intervention with basic nurse support could provide an effective solution to weight management support in a primary care context. Trial registration Current Controlled Trials ISRCTN31685626. [ABSTRACT FROM AUTHOR]

Objectives To test the hypothesis that the ventilatory response to a carbon dioxide (CO2) challenge would be lower in the prone compared to the supine position in prematurely born infants studied post-term. To determine whether there were postural-related differences in respiratory drive, respiratory muscle strength, thoracoabdominal synchrony and/or lung volume. Design Prospective cohort study. Setting Tertiary neonatal unit. Patients Eighteen infants (median gestational age 31 (range 22-32) weeks) were studied at a median of 5 (range 2-11) weeks post-term. Interventions The ventilatory responses to three added carbon dioxide (CO2) levels (0% baseline, 2% and 4%) were assessed in the prone and supine positions. Main outcome measures The airway pressure change after the first 100 ms of an occluded inspiration (P0.1) (respiratory drive) and the maximum inspiratory pressure during crying with an occluded airway (Pimax) (respiratory muscle strength) were measured. The P0.1/ Pimax ratio at each CO2 level and slope of the P0.1/ Pimax response were calculated. Results The mean P0.1 (p<0.05) and P0.1/Pimax (p<0.05) were higher and the functional residual capacity ( p=0.031) lower in the supine compared to the prone position. The mean P0.1 and P0.1/Pimax increased independently of position as the percentage CO2 increased (p<0.001). There was no tendency for the differences in P0.1 and P0.1/Pimax between the prone and supine position to vary by CO2 level. Conclusions Convalescent, prematurely born infants studied post-term have a reduced respiratory drive, but not a lower ventilatory response to a CO2 challenge, in the prone compared to the supine position. [ABSTRACT FROM AUTHOR]

Background: Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). Methods: A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3-5 of CKD. Results: Of 73 children aged 5-18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. Conclusions: In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients. Methods/design Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibodypositive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes. Discussion We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer. Trial registration Current Controlled Trials ISRCTN46157828. [ABSTRACT FROM AUTHOR]

In a trial substudy of 1000 IU vitamin D3 supplementation, 759 participants completed daily health diaries for up to 17 months. Supplementation provided no significant reduction in upper respiratory tract infections, colds, or influenza-like illness during winter or overall.Background. Randomized controlled trials testing the association between vitamin D status and upper respiratory tract infection (URTI) have given mixed results. During a multicenter, randomized controlled trial of colorectal adenoma chemoprevention, we tested whether 1000 IU/day vitamin D3 supplementation reduced winter episodes and duration of URTI and its composite syndromes, influenza-like illness (ILI; fever and ≥2 of sore throat, cough, muscle ache, or headache) and colds (no fever, and ≥2 of runny nose, nasal congestion, sneezing, sore throat, cough, swollen or tender neck glands).Methods. The 2259 trial participants were aged 45–75, in good health, had a history of colorectal adenoma, and had a serum 25-hydroxyvitamin D level ≥12 ng/mL. They were randomized to vitamin D3 (1000 IU/day), calcium (1200 mg/day), both, or placebo. Of these, 759 participants completed daily symptom diaries. Secondary data included semiannual surveys of all participants.Results. Among those who completed symptom diaries, supplementation did not significantly reduce winter episodes of URTI (rate ratio [RR], 0.93; 95% confidence interval [CI], .79–1.09) including colds (RR, 0.93; 95% CI, .78–1.10) or ILI (RR, 0.95; 95% CI, .62–1.46), nor did it reduce winter days of illness (RR, 1.13; 95% CI, .90–1.43). There was no significant benefit according to adherence, influenza vaccination, body mass index, or baseline vitamin D status. Semiannual surveys of all participants (N = 2228) identified no benefit of supplementation on ILI (odds ratio [OR], 1.14; 95% CI, .84–1.54) or colds (OR, 1.03; 95% CI, .87–1.23).Conclusions. Supplementation with 1000 IU/day vitamin D3 did not significantly reduce the incidence or duration of URTI in adults with a baseline serum 25-hydroxyvitamin D level ≥12 ng/mL. [ABSTRACT FROM AUTHOR]

Background: During volume-targeted ventilation (VTV), a constant volume is delivered with each ventilator inflation. Objectives: To determine whether VTV compared to pressure-limited ventilation (PLV) reduced the time to reach weaning criteria in prematurely born infants with acute respiratory distress, and if any difference was explained by better respiratory muscle strength and/or a lower work of breathing (WOB). Methods: Infants of <34 weeks of gestational age ventilated for <24 h in the first week after birth were randomised to receive either VTV or PLV. The primary outcome was the time to achieve pre-specified weaning criteria. Respiratory muscle strength was assessed by the measurement of the maximum inflation and expiratory pressures, and the WOB assessed by the transdiaphragmatic pressure time product. Other outcomes reported are the duration of ventilation, occurrence of patent ductus arteriosus, pneumothorax, intraventricular haemorrhage, periventricular leukomalacia and episodes of hypocarbia. Results: Forty infants, median gestational age 27 (range 23-33) weeks, were recruited. The time taken to achieve weaning criteria was similar in the two groups [median 14 h (VTV) vs. 23 h (PLV)]. There were no significant differences between the groups with regard to respiratory muscle strength, WOB or other outcomes, except that fewer of the VTV compared to the PLV group had episodes of hypocarbia (8 vs. 19; p < 0.001). Conclusion: In prematurely born infants with acute respiratory failure, use of VTV did not reduce the time to reach weaning criteria, but was associated with a reduction in episodes of hypocarbia. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The long-term outcome of chronic epilepsy remains largely unknown, despite a long historical experience. We report the lifelong course of epilepsy of an historical cohort of 235 subjects who were in residential care at the Chalfont Centre for Epilepsy: 122 had comprehensive post-mortem examination. The populations admitted as resident to the centre over time followed the evolution of society’s perception of epilepsy. ‘Early residents’ (before 1972) were admitted for sheltered employment, escaping stigmatization, whereas ‘later’ residents with more severe epilepsies were admitted for care. Subjects admitted before 1972 were similar to subjects followed nowadays as outpatients, whereas patients admitted later with a higher burden of disabilities are often those in residential care. This long follow-up allowed exploration of a wide spectrum of epilepsies, affecting both subjects who were otherwise healthy and those with co-morbidities. Age at death showed a bimodal distribution with an early peak of mortality between 45–50 years old, whilst the remainder had life expectancy comparable to the general population. As a group, subjects who had post-mortem examination were not significantly different from patients who did not have post-mortem examination, but post-mortem examination provided data that were otherwise unavailable. For those who had post-mortem examination, sudden unexpected death in epilepsy (SUDEP, 18% of all deaths) did not fully explain the early mortality, to which co-morbidities contributed. High seizure frequency was a significant independent predictor of early death even after excluding SUDEP (e.g. reduction in years of life for those who had >4 seizures/month compared with those who had <1 seizure/month: 13 years; 95% confidence interval: 6–19; overall P = 0.0006). Those who survived to older age increasingly went into spontaneous remission lasting until death (in the whole cohort, 38/166, 23% of those who died in or after sixth decade). In subjects who had post-mortem examination, older age (odds ratio = 1.13; 95% confidence interval: 1.06–1.20) and presence of neuropathologically confirmed degenerative changes (that were not the cause of epilepsy) (odds ratio 7.14; 1.95–26.2) were independent predictors of terminal remission. Epilepsy may cause premature death indirectly through co-morbid conditions. Terminal remission occurs even without prior remissions; ageing may improve epilepsy drug responsiveness although unknown factors related to the natural history may also play a role. [ABSTRACT FROM PUBLISHER]

Background: Patients with fibrotic interstitial lung disease have symptom control and quality of life (QoL) needs. This review aims to evaluate the evidence for the use of interventions in improving dyspnoea, other symptoms and QoL. Methods: Eleven databases, relevant websites and key journals were hand-searched. Studies were assessed and data extracted independently by two researchers using standardised proformas. Meta-analyses were performed where possible with 95% CI. Results: 34 papers with 19 interventions in 3635 patients were included. Meta-analyses showed no significant effect of interferon ?-1b or sildenafil on 6-minute walking distance (6MWD) or dyspnoea. Pulmonary rehabilitation and pirfenidone had a positive effect on 6MWD (mean difference (95% CI) 27.4 (4.1 to 50.7)) and 24.0 (4.3 to 43.7), respectively), and pulmonary rehabilitation had a mixed effect on dyspnoea. Both pulmonary rehabilitation and sildenafil showed a trend towards significance in improving QoL. There was weak evidence for the improvement of 6MWD using oxygen; dyspnoea using prednisolone, diamorphine, D-pencillamine and colchicine; cough using interferon α and thalidomide; anxiety using diamorphine; fatigue using pulmonary rehabilitation; and QoL using thalidomide and doxycycline. A wide range of outcome scales was used and there were no studies with economic evaluation. Conclusions: There is strong evidence for the use of pulmonary rehabilitation and pirfenidone to improve 6MWD and moderate evidence for the use of sildenafil and pulmonary rehabilitation to improve QoL. Future recommendations for research would include careful consideration of the dichotomy of radical and palliative treatments when deciding on how symptom and QoL outcome measures are used and data presented. [ABSTRACT FROM AUTHOR]