Right ventricular dysfunction in patients with COVID-19 pneumonitis whose lungs are mechanically ventilated: a multicentre prospective cohort study.

Cardiovascular complications due to COVID-19, such as right ventricular dysfunction, are common. The combination of acute respiratory distress syndrome, invasive mechanical ventilation, thromboembolic disease and direct myocardial injury creates conditions where right ventricular dysfunction is likely to occur. We undertook a prospective, multicentre cohort study in 10 Scottish intensive care units of patients with COVID-19 pneumonitis whose lungs were mechanically ventilated. Right ventricular dysfunction was defined as the presence of severe right ventricular dilation and interventricular septal flattening. To explore the role of myocardial injury, high-sensitivity troponin and N-terminal pro B-type natriuretic peptide plasma levels were measured in all patients. We recruited 121 patients and 118 (98%) underwent imaging. It was possible to determine the primary outcome in 112 (91%). Severe right ventricular dilation was present in 31 (28%), with interventricular septal flattening present in nine (8%). Right ventricular dysfunction (the combination of these two parameters) was present in seven (6%, 95%CI 3-13%). Thirty-day mortality was 86% in those with right ventricular dysfunction as compared with 45% in those without (p = 0.051). Patients with right ventricular dysfunction were more likely to have: pulmonary thromboembolism (p < 0.001); higher plateau airway pressure (p = 0.048); lower dynamic compliance (p = 0.031); higher plasma N-terminal pro B-type natriuretic peptide levels (p = 0.006); and raised plasma troponin levels (p = 0.048). Our results demonstrate a prevalence of right ventricular dysfunction of 6%, which was associated with increased mortality (86%). Associations were also observed between right ventricular dysfunction and aetiological domains of: acute respiratory distress syndrome; ventilation; thromboembolic disease; and direct myocardial injury, implying a complex multifactorial pathophysiology.

Longitudinal analysis of the effect of water hardness on atopic eczema: evidence for gene-environment interaction.

BACKGROUND: Several studies have identified an association between water hardness and atopic eczema (AE); however, there is a paucity of longitudinal data in early life. OBJECTIVES: To examine whether water hardness is associated with an increased risk of AE and skin barrier dysfunction in infants and to assess effect modification by filaggrin (FLG) loss-of-function variants. METHODS: We performed a longitudinal analysis of data from infants in the Enquiring About Tolerance (EAT) study, who were enrolled at 3 months and followed up until 36 months of age. RESULTS: Of 1303 infants enrolled in the EAT study, 91·3% (n = 1189) attended the final clinic visit and 94·0% (n = 1225) of participants' families completed the 36-month questionnaire. In total, 761 (58·4%) developed AE by 36 months. There was no overall association between exposure to harder (> 257 mg L-1 CaCO3 ) vs. softer (≤ 257 mg L-1 CaCO3 ) water: adjusted hazard ratio (HR) 1·07, 95% confidence interval (CI) 0·92-1·24. However, there was an increased incidence of AE in infants with FLG mutations exposed to hard water (adjusted HR 2·72, 95% CI 2·03-3·66), and statistically significant interactions between hard water plus FLG and both risk of AE (HR 1·80, 95% CI 1·17-2·78) and transepidermal water loss (0·0081 g m-2 h-1 per mg L-1 CaCO3 , 95% CI 0·00028-0·016). CONCLUSIONS: There is evidence of an interaction between water hardness and FLG mutations in the development of infantile AE.

Voluntary monitoring systems for pig health and welfare in the UK: Comparative analysis of prevalence and temporal patterns of selected non-respiratory post mortem conditions.

Collection of abattoir data related to public health is common worldwide. Standardised on-going programmes that collect information from abattoirs that inform producers about the presence and frequency of disease that are important to them rather than public health hazards are less common. The three voluntary pig health schemes, implemented in the United Kingdom, are integrated systems which capture information on different macroscopic disease conditions detected in slaughtered pigs. Many of these conditions have been associated with a reduction in performance traits and consequent increases in production costs. The schemes are the Wholesome Pigs Scotland in Scotland, the British Pig Health Scheme in England and Wales and the Pig Regen Ltd. health and welfare checks in Northern Ireland. In this study, four post mortem conditions (pericarditis, milk spots, papular dermatitis and tail damage) were surveyed and analysed over a ten and half year period, with the aim to compare the prevalence, monthly variations, and yearly trends between schemes. Liver milk spot was the most frequently recorded condition while tail damage was the least frequently observed condition. The prevalence of papular dermatitis was relatively low compared to liver milk spot and pericarditis in the three schemes. A general decreasing trend was observed for milk spots and papular dermatitis for all three schemes. The prevalence of pericarditis increased in Northern Ireland and England and Wales; while Scotland in recent years showed a decreasing trend. An increasing trend of tail damage was depicted in Scotland and Northern Ireland until 2013/2014 followed by a decline in recent years compared to that of England and Wales with a decreasing trend over the full study period. Monthly effects were more evident for milk spots and papular dermatitis. Similarity of the modus operandi of the schemes made the comparison of temporal variations and patterns in gross pathology between countries possible over time, especially between countries with similar pig production profile. This study of temporal patterns enables early detection of prevalence increases and alerts industry and researchers to investigate the reasons behind such changes. These schemes are, therefore, valuable assets for endemic disease surveillance, early warning for emerging disease and also for monitoring of welfare outcomes.

Automated arteriole and venule classification using deep learning for retinal images from the UK Biobank cohort.

The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully-connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image.

Cochlear implantation in Malawi: report of the first four cases.

OBJECTIVE: This paper reports on the first four cochlear implant cases in Malawi. CASE REPORTS: Three patients were deafened from infectious diseases and one from an unknown cause. They all had post-lingual deafness. Six months after the last implant, they are all progressing well. CONCLUSION: Despite significant practical difficulties, it has proved possible, with the right support, to carry out cochlear implantation in one of the world's poorest countries. The project has also raised awareness of deafness in Malawi and highlighted significant public health issues relating to the aetiology of deafness in developing countries.

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose.

This corrects the article DOI: 10.1038/cdd.2015.26.

Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium.

BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.

Improving paranasal sinus computed tomography reporting prior to functional endoscopic sinus surgery - an ENT-UK panel perspective.

BACKGROUND: Functional endoscopic sinus surgery is recognised to have a significant complication profile (e.g. blindness, cerebrospinal fluid leak and intracranial sepsis). Pre-operative computed tomography imaging is considered mandatory for surgical planning to reduce intra-operative risk. A radiological report is the 'gold standard' in image interpretation; however, because of a lack of otolaryngological or radiological guidance, its contents may be variable. By surveying practising otolaryngologists, this study aimed to provide some guidance which may be used by radiologists to produce more surgically relevant radiological reports. METHOD: A prospective questionnaire was distributed to the ENT-UK panel. RESULTS: A total of 117 consultant members of the panel completed the survey. Twenty-nine per cent indicated that they were uncomfortable interpreting all areas of the computed tomography scan. Greatest importance was given to areas including the ethmoid roof (dehiscence, asymmetry and angle), lamina papyracea (dehiscence) and sphenoid sinus (carotid canal dehiscence and optic nerve relationships). CONCLUSION: Functional endoscopic sinus surgery is commonly performed by non-subspecialist rhinologists. The information obtained from this study can be used by radiologists to improve report relevance, particularly for the generalist ENT surgeon. This contributes to improving patient safety and helps avoid medicolegal litigation when complications arise.

Distinguishing the associations between daily mortality and hospital admissions and nitrogen dioxide from those of particulate matter: a systematic review and meta-analysis.

OBJECTIVES: To quantitatively assess time-series studies of daily nitrogen dioxide (NO2) and mortality and hospital admissions which also controlled for particulate matter (PM) to determine whether or to what extent the NO2 associations are independent of PM. DESIGN: A systematic review and meta-analysis. METHODS: Time-series studies-published in peer-reviewed journals worldwide, up to May 2011-that reported both single-pollutant and two-pollutant model estimates for NO2 and PM were ascertained from bibliographic databases (PubMed, EMBASE and Web of Science) and reviews. Random-effects summary estimates were calculated globally and stratified by different geographical regions, and effect modification was investigated. OUTCOME MEASURES: Mortality and hospital admissions for various cardiovascular or respiratory diseases in different age groups in the general population. RESULTS: 60 eligible studies were identified, and meta-analysis was conducted on 23 outcomes. Two-pollutant model study estimates generally showed that the NO2 associations were independent of PM mass. For all-cause mortality, a 10 µg/m(3) increase in 24-hour NO2 was associated with a 0.78% (95% CI 0.47% to 1.09%) increase in the risk of death, which reduced to 0.60% (0.33% to 0.87%) after control for PM. Heterogeneity between geographical region-specific estimates was removed by control for PM (I(2) from 66.9% to 0%). Estimates of PM and daily mortality assembled from the same studies were greatly attenuated after control for NO2: from 0.51% (0.29% to 0.74%) to 0.18% (-0.11% to 0.47%) per 10 µg/m(3) PM10 and 0.74% (0.34% to 1.14%) to 0.54% (-0.25% to 1.34%) for PM2.5. CONCLUSIONS: The association between short-term exposure to NO2 and adverse health outcomes is largely independent of PM mass. Further studies should attempt to investigate whether this is a generic PM effect or whether it is modified by the source and physicochemical characteristics of PM. This finding strengthens the argument for NO2 having a causal role in health effects.

Automated retinal image quality assessment on the UK Biobank dataset for epidemiological studies.

Morphological changes in the retinal vascular network are associated with future risk of many systemic and vascular diseases. However, uncertainty over the presence and nature of some of these associations exists. Analysis of data from large population based studies will help to resolve these uncertainties. The QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) retinal image analysis system allows automated processing of large numbers of retinal images. However, an image quality assessment module is needed to achieve full automation. In this paper, we propose such an algorithm, which uses the segmented vessel map to determine the suitability of retinal images for use in the creation of vessel morphometric data suitable for epidemiological studies. This includes an effective 3-dimensional feature set and support vector machine classification. A random subset of 800 retinal images from UK Biobank (a large prospective study of 500,000 middle aged adults; where 68,151 underwent retinal imaging) was used to examine the performance of the image quality algorithm. The algorithm achieved a sensitivity of 95.33% and a specificity of 91.13% for the detection of inadequate images. The strong performance of this image quality algorithm will make rapid automated analysis of vascular morphometry feasible on the entire UK Biobank dataset (and other large retinal datasets), with minimal operator involvement, and at low cost.

Eczema and indoor environment: lessons from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase 2.

BACKGROUND: Numerous studies have reported a positive association between damp housing conditions and asthma, but little is known about indoor environmental exposures in relation to childhood eczema. We aimed to specifically investigate the effect of indoor mould and dampness on eczema risk in the International Study of Asthma and Allergies in Childhood (ISAAC). METHODS: ISAAC Phase 2 is a cross-sectional study of 46 051 children aged 8-12 years from 20 countries. Information on demographics, eczema symptoms, and dampness was gathered with parental questionnaires. Children were examined for eczema and underwent skin prick testing. In a stratified subgroup, dust samples were collected to measure house dust mite exposure. Sex, maternal education, parental allergy, pet ownership, maternal smoking, having an older sibling, bedroom sharing, and cooking with fuels were explored as potential confounders or effect modifiers in logistic regression analysis. FINDINGS: Current residential exposure to dampness and mould was significantly associated with flexural eczema in the previous year, with a stronger association seen in non-affluent than in affluent countries (adjusted odds ratio [OR] 1·96, 95% CI 1·62-2·37, vs 1·34, 1·18-1·51). Dampness and mould in the first year of life was also significantly associated with parent-reported eczema ever (1·94, 1·40-2·68, vs 1·43, 1·28-1·60). However, the association with flexural eczema on examination was not significant (0·93, 0·76-1·13). Risk estimates were similar in children positive and negative on skin prick testing, and were not appreciably altered by the effect modifiers, apart from parental allergic disease (parental allergies OR 1·35, 95% CI 1·18-1·54, vs no parental allergies 1·61, 1·37-1·90). INTERPRETATION: These data suggest an association between damp housing conditions and childhood eczema symptoms, which may be causal. Further work is needed to elucidate possible mechanisms. Modification to home environment to reduce dampness and mould could be harnessed to improve or even prevent this common and debilitating condition. FUNDING: None.

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose.

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions.

Comparison of Respiratory Disease Prevalence among Voluntary Monitoring Systems for Pig Health and Welfare in the UK.

Surveillance of animal diseases provides information essential for the protection of animal health and ultimately public health. The voluntary pig health schemes, implemented in the United Kingdom, are integrated systems which capture information on different macroscopic disease conditions detected in slaughtered pigs. Many of these conditions have been associated with a reduction in performance traits and consequent increases in production costs. The schemes are the Wholesome Pigs Scotland in Scotland, the BPEX Pig Health Scheme in England and Wales and the Pig Regen Ltd. health and welfare checks done in Northern Ireland. This report set out to compare the prevalence of four respiratory conditions (enzootic pneumonia-like lesions, pleurisy, pleuropneumonia lesions and abscesses in the lung) assessed by these three Pig Health Schemes. The seasonal variations and year trends associated with the conditions in each scheme are presented. The paper also highlights the differences in prevalence for each condition across these schemes and areas where further research is needed. A general increase in the prevalence of enzootic pneumonia like lesions was observed in Scotland, England and Wales since 2009, while a general decrease was observed in Northern Ireland over the years of the scheme. Pleurisy prevalence has increased since 2010 in all three schemes, whilst pleuropneumonia has been decreasing. Prevalence of abscesses in the lung has decreased in England, Wales and Northern Ireland but has increased in Scotland. This analysis highlights the value of surveillance schemes based on abattoir pathology monitoring of four respiratory lesions. The outputs at scheme level have significant value as indicators of endemic and emerging disease, and for producers and herd veterinarians in planning and evaluating herd health control programs when comparing individual farm results with national averages.

Factors affecting myringoplasty success.

OBJECTIVE: To identify factors that significantly influence myringoplasty success. METHODS: A retrospective study was performed of all adults and children who underwent myringoplasty from January 2005 to January 2010 in a teaching hospital. Outcome measures were tympanic membrane perforation closure and air-bone gap closure to within 20 dB HL. The factors assessed were the surgeon grade, pre-operative condition of the ipsilateral and contralateral middle ears, perforation site, perforation size, graft material, and whether simultaneous cortical mastoidectomy was performed. Factors with statistically significant effects were determined by logistic regression analysis. RESULTS: In the adult group, the perforation site significantly influenced tympanic membrane closure (p = 0.016): anterior (p = 0.008) and subtotal (p = 0.017) sites had the greatest influence. None of the factors proved to have a significant influence on tympanic membrane closure in the paediatric group. CONCLUSION: There was a significant association between perforation site and tympanic membrane perforation closure in adults. Anterior and subtotal perforations had a significantly reduced closure rate.

Automated retinal vessel recognition and measurements on large datasets.

The characteristics of the retinal vascular network have been prospectively associated with many systemic and vascular diseases. QUARTZ is a fully automated software that has been developed to localize and quantify the morphological characteristics of blood vessels in retinal images for use in epidemiological studies. This software was used to analyse a dataset containing 16,000 retinal images from the EPIC-Norfolk cohort study. The objective of this paper is to both assess the suitability of this dataset for computational analysis and to further evaluate the QUARTZ software.

17q21 gene variation is not associated with asthma in adulthood.

BACKGROUND: 17q21 gene variants are the strongest known genetic determinants for childhood asthma and have been reported to interact with environmental tobacco smoke exposure in childhood. It remains unclear whether individuals with 17q21 risk variants have increased risk of asthma or reduced lung function in adulthood. The aim was to examine the association between the 17q21 region and current adult asthma and lung function, and interaction with active smoking. METHODS: We investigated the single nucleotide polymorphism rs7216389 at the 17q21 locus in 3471 adults from the Health2006 cross-sectional study and in 7008 adults from The British 1958 Birth Cohort and examined the association with current asthma, spirometry measures, and related atopic traits. Analyses were performed for interaction with active smoking. RESULTS: We found no association between rs7216389[T] and asthma when meta-analyzed (OR = 1.02 [0.92-1.13], P = 0.81). The risk variant was associated with reduced FEV1 as compared to normal FEV1 (OR = 1.10 [1.01-1.12], P = 0.033) and with allergic sensitization (OR = 1.10 [1.03-1.17], P = 0.003). Individuals with rs7216389 risk variants smoked as frequently as individuals without risk variants, and there was no evidence that smoking modified the association between rs7216389 and asthma. CONCLUSION: Our study suggests that the 17q21 rs7216389 locus variant does not substantially influence asthma risk in adulthood or susceptibility to detrimental effects of active smoking. This contrasts the findings in children and suggests that this locus is associated with a childhood-specific asthma endotype.

Siblings, asthma, rhinoconjunctivitis and eczema: a worldwide perspective from the International Study of Asthma and Allergies in Childhood.

BACKGROUND: Associations of larger families with lower prevalences of hay fever, eczema and objective markers of allergic sensitization have been found fairly consistently in affluent countries, but little is known about these relationships in less affluent countries. METHODS: Questionnaire data for 210,200 children aged 6-7 years from 31 countries, and 337,226 children aged 13-14 years from 52 countries, were collected by Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC). Associations of disease symptoms and labels of asthma, rhinoconjunctivitis and eczema were analysed by numbers of total, older and younger siblings, using mixed (multi-level) logistic regression models to adjust for individual covariates and at the centre level for region, language and national affluence. RESULTS: In both age groups, inverse trends (P < 0.0001) were observed for reported 'hay fever ever' and 'eczema ever' with increasing numbers of total siblings, and more specifically older siblings. These inverse associations were significantly (P < 0.005) stronger in more affluent countries. In contrast, symptoms of severe asthma and severe eczema were positively associated (P < 0.0001) with total sibship size in both age groups. These associations with disease severity were largely independent of position within the sibship and national GNI per capita. CONCLUSIONS: These global findings on sibship size and childhood asthma, rhinoconjunctivitis and eczema suggest at least two distinct trends. Inverse associations with older siblings (observations which prompted the 'hygiene hypothesis' for allergic disease) are mainly a phenomenon of more affluent countries, whereas greater severity of symptoms in larger families is globally more widespread.

Dampness and moulds in relation to respiratory and allergic symptoms in children: results from Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC Phase Two).

BACKGROUND: Many studies report that damp housing conditions are associated with respiratory symptoms. Less is known about mechanisms and possible effect modifiers. Studies of dampness in relation to allergic sensitization and eczema are scarce. OBJECTIVE: We study the influence of damp housing conditions world-wide on symptoms and objective outcomes. METHODS: Cross-sectional studies of 8-12-year-old children in 20 countries used standardized methodology from Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC). Symptoms of asthma, rhinitis and eczema, plus residential exposure to dampness and moulds, were ascertained by parental questionnaires (n = 46 051). Skin examination, skin prick tests (n = 26 967) and hypertonic saline bronchial challenge (n = 5713) were performed. In subsamples stratified by wheeze (n = 1175), dust was sampled and analysed for house dust mite (HDM) allergens and endotoxin. RESULTS: Current exposure to dampness was more common for wheezy children (pooled odds ratio 1.58, 95% CI 1.40-1.79) and was associated with greater symptom severity among wheezers, irrespective of atopy. A significant (P < 0.01) adverse effect of dampness was also seen for cough and phlegm, rhinitis and reported eczema, but not for examined eczema, nor bronchial hyperresponsiveness. HDM sensitization was more common in damp homes (OR 1.16, 1.03-1.32). HDM-allergen levels were higher in damp homes and were positively associated with HDM-sensitization, but not wheeze. CONCLUSION: A consistent association of dampness with respiratory and other symptoms was found in both affluent and non-affluent countries, among both atopic and non-atopic children. HDM exposure and sensitization may contribute, but the link seems to be related principally to non-atopic mechanisms.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Asthma phenotypes identified by latent class analysis in the ISAAC phase II Spain study.

BACKGROUND: Classification of respiratory symptoms may help to identify different underlying asthma phenotypes reflecting differences in aetiology and prognosis of wheezing disease among children. OBJECTIVE: To determine childhood asthma phenotypes based on respiratory symptoms from a widely used questionnaire to further classify phenotypes in international settings. METHODS: Between 2000 and 2002 cross-sectional studies were performed in four centres in Spain. Parental questionnaires were used to collect information on allergic diseases in more than 4000 children aged 8-12 years. In addition, objective markers for allergic sensitization and bronchial hyperresponsiveness (BHR) were measured. Latent class analyses (LCA) were applied to identify subgroups of children according to respiratory symptoms, and then the association of these groups with relevant clinical features such as concomitant allergic disease symptoms, atopy and BHR was studied. RESULTS: We found seven classes, one corresponding to healthy children, three classes related to wheeze and three other classes mainly related to congestion and coughed-up phlegm. These tentative phenotypes differed in severity of symptoms and also in clinical correlates such as BHR and allergic sensitization. Atopy was more predominant in the 'wheeze phenotypes' whereas concomitant 'allergic' symptoms were most frequent in two of the 'wheeze phenotypes' and one of the 'cough phenotypes'. CONCLUSIONS: LCA on reported symptoms in a cross-sectional survey allowed different subgroups with meaningful clinical correlates to be defined. It remains to be investigated to what extent these groups also have different aetiologies, prognoses and therapeutic needs.