Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity.

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine KrasG12D -p53null , -p53R172H (conformational), and -p53R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53R270H -specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant.

HBM4EU E-waste study: Assessing persistent organic pollutants in blood, silicone wristbands, and settled dust among E-waste recycling workers in Europe.

E-waste recycling is an increasingly important activity that contributes to reducing the burden of end-of-life electronic and electrical apparatus and allows for the EU's transition to a circular economy. This study investigated the exposure levels of selected persistent organic pollutants (POPs) in workers from e-waste recycling facilities across Europe. The concentrations of seven polychlorinated biphenyls (PCBs) and eight polybrominated diphenyl ethers (PBDEs) congeners were measured by GC-MS. Workers were categorized into five groups based on the type of e-waste handled and two control groups. Generalized linear models were used to assess the determinants of exposure levels among workers. POPs levels were also assessed in dust and silicone wristbands (SWB) and compared with serum. Four PCB congeners (CB 118, 138, 153, and 180) were frequently detected in serum regardless of worker's category. With the exception of CB 118, all tested PCBs were significantly higher in workers compared to the control group. Controls working in the same company as occupationally exposed (Within control group), also displayed higher levels of serum CB 180 than non-industrial controls with no known exposures to these chemicals (Outwith controls) (p < 0.05). BDE 209 was the most prevalent POP in settled dust (16 µg/g) and SWB (220 ng/WB). Spearman correlation revealed moderate to strong positive correlations between SWB and dust. Increased age and the number of years smoked cigarettes were key determinants for workers exposure. Estimated daily intake through dust ingestion revealed that ΣPCB was higher for both the 50th (0.03 ng/kg bw/day) and 95th (0.09 ng/kg bw/day) percentile exposure scenarios compared to values reported for the general population. This study is one of the first to address the occupational exposure to PCBs and PBDEs in Europe among e-waste workers through biomonitoring combined with analysis of settled dust and SWB. Our findings suggest that e-waste workers may face elevated PCB exposure and that appropriate exposure assessments are needed to establish effective mitigation strategies.

Configurations of mother-child and father-child attachment relationships as predictors of child language competence: An individual participant data meta-analysis.

An individual participant data meta-analysis was conducted to test pre-registered hypotheses about how the configuration of attachment relationships to mothers and fathers predicts children's language competence. Data from seven studies (published between 1985 and 2014) including 719 children (Mage : 19.84 months; 51% female; 87% White) were included in the linear mixed effects analyses. Mean language competence scores exceeded the population average across children with different attachment configurations. Children with two secure attachment relationships had higher language competence scores compared to those with one or no secure attachment relationships (d = .26). Children with two organized attachment relationships had higher language competence scores compared to those with one organized attachment relationship (d = .23), and this difference was observed in older versus younger children in exploratory analyses. Mother-child and father-child attachment quality did not differentially predict language competence, supporting the comparable importance of attachment to both parents in predicting developmental outcomes.

Mortality burden of cardiovascular disease attributable to ambient PM2.5 exposure in Portugal, 2011 to 2021.

BACKGROUND: Exposure to high levels of environmental air pollution causes several health outcomes and has been associated with increased mortality, premature mortality, and morbidity. Ambient exposure to PM2.5 is currently considered the leading environmental risk factor globally. A causal relationship between exposure to PM2.5 and the contribution of this exposure to cardiovascular morbidity and mortality was already demonstrated by the American Heart Association. METHODS: To estimate the burden of mortality attributable to environmental risk factors, a comparative risk assessment was performed, considering a "top-down" approach. This approach uses an existing estimate of mortality of the disease endpoint by all causes as a starting point. A population attributable fraction was calculated for the exposure to PM2.5the overall burden of IHD and stroke was multiplied by the PAF to determine the burden attributable to this risk factor. The avoidable burden was calculated using the potential impact fraction (PIF) and considering the WHO-AQG 2021 as an alternative scenario. RESULTS: Between 2011 and 2021, the ambient exposure to PM2.5 resulted in a total of 288,862.7 IHD YLL and a total of 420,432.3 stroke YLL in Portugal. This study found a decreasing trend in the mortality burden attributable to PM2.5 exposure, for both males and females and different age-groups. For different regions of Portugal, the same trend was observed in the last years. The mortality burden attributable to long-term exposure to PM2.5 was mainly concentrated in Lisbon Metropolitan Area, North and Centre. Changes in the exposure limits to the WHO recommended value of exposure (WHO-AQG 2021) have a reduction in the mortality burden due to IHD and stroke attributable to PM2.5 exposure, in Portugal. CONCLUSION: Between 2011 and 2021, approximately 22% and 23% of IHD and stroke deaths were attributable to PM2.5 exposure. Nevertheless, the mortality burden attributable to cardiovascular diseases has been decreasing in last years in Portugal. Our findings provide evidence of the impact of air pollution on human health, which are crucial for decision-making, at the national and regional level.

An online qualitative study exploring wants and needs for a cooking programme during pregnancy in the UK and Ireland.

BACKGROUND: Optimal maternal nutrition is associated with better pregnancy and infant outcomes. Culinary nutrition programmes have potential to improve diet quality during pregnancy. Therefore, this research aimed to understand the experiences of cooking and the wants and needs of pregnant women regarding a cooking and food skills programme in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Online focus group discussions with pregnant women and those who had experienced a pregnancy in the UK or ROI were conducted between February and April 2022. Two researchers conducted a thematic analysis. Seven focus groups with ROI participants (n = 24) and six with UK participants (n = 28) were completed. RESULTS: Five themes were generated. These were (1) cooking during pregnancy: barriers, motivators and solutions; (2) food safety, stress and guilt; (3) need for cooking and food skills programmes and desired content; (4) programme structure; (5) barriers and facilitators to programme participation. Overall, there was support for a programme focusing on broad food skills, including planning, food storage, using leftovers and to manage pregnancy-specific physiological symptoms such as food aversions. Participants emphasised the importance of inclusivity for a diverse range of people and lifestyles for programme design and content. CONCLUSIONS: Current findings support the use of digital technologies for culinary nutrition interventions, potentially combined with in-person sessions using a hybrid structure to enable the development of a support network.

Insights into animal septins using recombinant human septin octamers with distinct SEPT9 isoforms.

Septin GTP-binding proteins contribute essential biological functions that range from the establishment of cell polarity to animal tissue morphogenesis. Human septins in cells form hetero-octameric septin complexes containing the ubiquitously expressed SEPT9 subunit (also known as SEPTIN9). Despite the established role of SEPT9 in mammalian development and human pathophysiology, biochemical and biophysical studies have relied on monomeric SEPT9, thus not recapitulating its native assembly into hetero-octameric complexes. We established a protocol that enabled, for the first time, the isolation of recombinant human septin octamers containing distinct SEPT9 isoforms. A combination of biochemical and biophysical assays confirmed the octameric nature of the isolated complexes in solution. Reconstitution studies showed that octamers with either a long or a short SEPT9 isoform form filament assemblies, and can directly bind and cross-link actin filaments, raising the possibility that septin-decorated actin structures in cells reflect direct actin-septin interactions. Recombinant SEPT9-containing octamers will make it possible to design cell-free assays to dissect the complex interactions of septins with cell membranes and the actin and microtubule cytoskeleton.

Frequency-encoded two-photon excited fluorescence microscopy.

Two-photon excited fluorescence (2PEF) microscopy is the most popular non-linear imaging method of biomedical samples. State-of-the art 2PEF microscopes use multiple detectors and spectral filter sets to discriminate different fluorophores based on their distinct emission behavior (emission discrimination). One drawback of 2PEF is that fluorescence photons outside the filter transmission range are inherently lost, thereby reducing the imaging efficiency and speed. Furthermore, emission discrimination of different fluorophores may fail if their emission profiles are too similar. Here, we present an alternative 2PEF method that discriminates fluorophores based on their excitation spectra (excitation discrimination). For excitation we use two lasers of different wavelengths (ω1, ω2) resulting in excitation energies at 2ω1, 2ω2, and the mixing energy ω1+ω2. Both lasers are frequency encoded (FE) by an intensity modulation at distinct frequencies while all 2PEF emission is collected on a single detector. The signal is fed into a lock-in-amplifier and demodulated at various frequencies simultaneously. A customized nonnegative matrix factorization (NNMF) then generates fluorescence images that are free of cross talk. Combining FE-2PEF with multiple detectors has the potential to enable the simultaneous imaging of an unprecedented number of fluorophores.

Evaluation of the Potential Impact of In Silico Humanization on VHH Dynamics.

Camelids have the peculiarity of having classical antibodies composed of heavy and light chains as well as single-chain antibodies. They have lost their light chains and one heavy-chain domain. This evolutionary feature means that their terminal heavy-chain domain, VH, called VHH here, has no partner and forms an independent domain. The VHH is small and easy to express alone; it retains thermodynamic and interaction properties. Consequently, VHHs have garnered significant interest from both biotechnological and pharmaceutical perspectives. However, due to their origin in camelids, they cannot be used directly on humans. A humanization step is needed before a possible use. However, changes, even in the constant parts of the antibodies, can lead to a loss of quality. A dedicated tool, Llamanade, has recently been made available to the scientific community. In a previous paper, we already showed the different types of VHH dynamics. Here, we have selected a representative VHH and tested two humanization hypotheses to accurately assess the potential impact of these changes. This example shows that despite the non-negligible change (1/10th of residues) brought about by humanization, the effect is not drastic, and the humanized VHH retains conformational properties quite similar to those of the camelid VHH.

Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.

The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.

The (scarce and circumscribed) culinary content in food-based dietary guidelines around the world: 1991-2021.

OBJECTIVE: To evaluate the culinary content of key messages contained in food-based dietary guidelines (FBDG) available at the global online repository of the FAO of the UN. DESIGN: Document analysis was conducted in August 2021 with data extraction of key messages explicitly related to cooking present in FBDG. Data were analysed inductively using thematic analysis. SETTING: The FAO's global repository of FBDG. PARTICIPANTS: Not applicable. RESULTS: Just over half (n 39; 53·4 %) of the seventy-three FBDG analysed included at least one key message about cooking. The Latin American and Caribbean FBDG presented the greatest amount and variety of content about cooking in the key messages, whereas the Near East and North America placed less emphasis on cooking. We identified three themes: (i) healthy food preparation (n 35; 61·4 % of the fifty-seven culinary key messages identified); (ii) food hygiene (n 14; 24·6 %) and (iii) the promotion of culinary practices (n 7; 12·3 %). Albania's key message covered two themes (food hygiene and healthy food preparation) (n 1; 1·8 %). CONCLUSION: FBDG are official documents that express recommendations for a healthy diet. As most of these recommendations throughout the world include foods that must be cooked prior to consumption, culinary content should gain more visibility and be presented more broadly in these official documents.

Nanomaterials in Foods and Human Digestion: An Important Layer in the Assessment of Potential Toxic Effects.

The use of nanoparticles (e.g. titanium dioxide) in commercial food products to modify some properties, such as brightness and whiteness, increased in the last years and is nowadays widespread. Despite the inhalation of nanoparticles is already a topic of concern, the potential adverse health effects due to ingestion still present gaps of knowledge. In fact, gastrointestinal tract is the first interface between the body and the external environment and consequently could represent a target organ for compounds present in food, namely nanoparticles, that could exert toxic effects. The in vitro digestion models used to simulate the human digestion may contribute to fill these gaps. The applicability of the in vitro digestion methods is discussed concerning its potential use as a tool for addressing the toxicity of ingested nanomaterials or other food contaminants, mimicking the physiological processes.

Towards Molecular Understanding of the Functional Role of UbiJ-UbiK2 Complex in Ubiquinone Biosynthesis by Multiscale Molecular Modelling Studies.

Ubiquinone (UQ) is a polyisoprenoid lipid found in the membranes of bacteria and eukaryotes. UQ has important roles, notably in respiratory metabolisms which sustain cellular bioenergetics. Most steps of UQ biosynthesis take place in the cytosol of E. coli within a multiprotein complex called the Ubi metabolon, that contains five enzymes and two accessory proteins, UbiJ and UbiK. The SCP2 domain of UbiJ was proposed to bind the hydrophobic polyisoprenoid tail of UQ biosynthetic intermediates in the Ubi metabolon. How the newly synthesised UQ might be released in the membrane is currently unknown. In this paper, we focused on better understanding the role of the UbiJ-UbiK2 heterotrimer forming part of the metabolon. Given the difficulties to gain functional insights using biophysical techniques, we applied a multiscale molecular modelling approach to study the UbiJ-UbiK2 heterotrimer. Our data show that UbiJ-UbiK2 interacts closely with the membrane and suggests possible pathways to enable the release of UQ into the membrane. This study highlights the UbiJ-UbiK2 complex as the likely interface between the membrane and the enzymes of the Ubi metabolon and supports that the heterotrimer is key to the biosynthesis of UQ8 and its release into the membrane of E. coli.

VHH Structural Modelling Approaches: A Critical Review.

VHH, i.e., VH domains of camelid single-chain antibodies, are very promising therapeutic agents due to their significant physicochemical advantages compared to classical mammalian antibodies. The number of experimentally solved VHH structures has significantly improved recently, which is of great help, because it offers the ability to directly work on 3D structures to humanise or improve them. Unfortunately, most VHHs do not have 3D structures. Thus, it is essential to find alternative ways to get structural information. The methods of structure prediction from the primary amino acid sequence appear essential to bypass this limitation. This review presents the most extensive overview of structure prediction methods applied for the 3D modelling of a given VHH sequence (a total of 21). Besides the historical overview, it aims at showing how model software programs have been shaping the structural predictions of VHHs. A brief explanation of each methodology is supplied, and pertinent examples of their usage are provided. Finally, we present a structure prediction case study of a recently solved VHH structure. According to some recent studies and the present analysis, AlphaFold 2 and NanoNet appear to be the best tools to predict a structural model of VHH from its sequence.

"Healthy", "usual" and "convenience" cooking practices patterns: How do they influence children's food consumption?

This study identified adults' cooking practices patterns and tested their associations with children's consumption of ultra-processed foods. Cross-sectional study conducted with 551 adult-child pairs from São Paulo, Brazil. Children's food consumption was collected through dietary recalls. Adults' cooking practices were identified using a questionnaire developed for the Brazilian's context. Principal Component Analysis has been employed to identify cooking patterns and linear regression models (crude and adjusted for sociodemographic variables) have been used to test associations between pattern's scores and contribution of ultra-processed foods to total energy at dinners. Three cooking patterns were identified: "Healthy", "Usual" and "Convenience". The first two patterns reflected behaviors of people who mostly cook "from scratch". Only the Healthy pattern (confidence to cook several meals using fresh foods and natural seasonings; healthier cooking techniques) was inversely associated with ultra-processed food consumption (ß = -4.1; p = 0.002), whereas the Convenience pattern (less frequency and time to cook, using microwave and ready-to-heat meals) was positively associated with (ß = 3.6; p = 0.008). Our results suggest that cooking at home, as an isolated action, is not enough to protect the consumption of ultra-processed foods. To promote healthy eating among children, the adults' cooking practices should be aligned with the preparation of meals made "from scratch", taking into account the healthiness of what is being cooked.

Complications on Percutaneous Hallux Valgus Surgery: A Systematic Review.

Lately there has been a growing interest in the use of percutaneous surgery for the correction of hallux valgus (HV). The purpose of the present study was to systematically review the published data about this topic and establish the efficacy and safety, stressing the complication rates found on this percutaneous technique. A systematic review of the literature available in PubMed was performed. The radiological and clinical outcomes were evaluated as well as complication rates. A total of 16 studies were included and 1157 procedures reported for percutaneous HV on 1246 patients. The mean angle correction of HV deformity improved postoperatively. Reported complications vary among the studies. The highest complication rate was joint stiffness in 18.47% of cases, followed by HV recurrence and shortening of M1, both in 15.2%, material intolerance in 10.1%, osteoarthritic changes in 9.1%, infection in 7.6%, and transfer metatarsalgia in 5.4%. There is a lack of randomized control trials and insufficient comparative case control studies to assess whether one technique is more effective than another or if the percutaneous surgery is recommended rather than open surgery with respect to complications.

Posteroinferior tibiofibular ligament - A cadaveric study.

BACKGROUND: Ankle injuries are one of the most common musculoskeletal disorder. The purpose of this study was to analyze and describe the detailed anatomical arrangement and relationship of posterior ligaments of the ankle, especially de posteroinferior tibiofibular ligament (PITFL) and intermalleolar ligament (IML). Controversy exists in the previous literature regarding their morphology and denomination, as well as the relation with ankle injuries including posterior soft tissue impingement syndrome. METHODS: Seventeen fresh-frozen cadaveric feet were used. The origins, insertions, ligament lengths, orientations with respect to relevant bony landmarks of the PITFL were evaluated. RESULTS: PITFL was present in all anatomical specimens. It was formed by two independent components, the superficial and deep fibers. Their dimensions vary widely between specimens. The IML was located between the deep PITFL and posterior talofibular ligament. The shape varied from a thin fibrous band to a thick cordlike structure. The IML was evident in 82.4% of the ankles. In 28.6% of the cases, the posterior intermalleolar ligament was split into two bundles in the fibular insertion. In 14 ankles, three slips were found. CONCLUSION: Given the frequency of injury and increasing necessity for surgical intervention, a more comprehensive anatomic knowledge of the different ligaments is warranted, provide clinically pertinent quantitative data and improve the treatment of these lesions.

Parents' cooking skills confidence reduce children's consumption of ultra-processed foods.

Ultra-processed foods are industrial formulations requiring little if any preparation before consumption. Their consumption is increasing in many countries and one of the possible determinants is the decrease in home cooking. As parents are key for family meals, we analysed the influence of parents' cooking skills confidence on children's consumption of ultra-processed foods at dinner. This is a cross-sectional study with 657 child-parent pairs from nine private schools in São Paulo, Brazil. Food consumption data were collected using two children's dinner dietary recalls while the Cooking Skills Index was used to collect parents' cooking skills, measuring their confidence in their own skills related to cooking 'from scratch', according to the Dietary Guidelines for the Brazilian Population. Food items were classified according to the NOVA classification system, considering the nature, extension and purpose of food processing. We used linear regression models to test associations between parents' cooking skills confidence and the contribution of ultra-processed foods to total energy intake at dinner, adjusting for socio-demographic variables. Parents' mean age was 38.3 and children's mean age was 7.8. These parents were mostly women, white, married, employed, with full secondary education and per capita household incomes up to ~ USD 320.00/month. They reached an average of 78.8 points (SD 14.8) in the Cooking Skills Index. Children's mean energy intake at dinner was 672.2 kcal (31.3% from ultra-processed foods). The increase in parents' cooking skills confidence was directly associated with decrease in consumption of ultra-processed foods (ß = -0.17; p = 0.007), which remained after adjustment (ß = -0.15; p = 0.026). These findings suggest that parents' cooking skills confidence potentially protect their children against ultra-processed foods, indicating the need for revaluing cooking to promote healthy eating.

Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease.

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.

Exposure to indoor endocrine-disrupting chemicals and childhood asthma and obesity.

BACKGROUND: Indoor air contaminants may act as endocrine-disrupting chemicals (EDCs). However, to what extent these contaminants affect health is poorly known. We aimed to assess the association between EDCs exposure and asthma, respiratory symptoms and obesity in schoolchildren. METHODS: Data from a cross-sectional analysis of 815 participants from 20 schools in Porto, Portugal, were analysed. Symptoms were assessed, asthma was defined on lung function, and airway reversibility and body mass index (BMI) were calculated. The concentrations of 13 volatile organic compounds and 2 aldehydes identified as EDCs were measured in 71 classrooms throughout 1 week. Principal component analysis (PCA) was used to assess the effect of co-exposure. Associations were estimated by regression coefficients using linear and logistic regression models. RESULTS: Increased individual and combined EDCs levels were found in classrooms having more children with asthma and obesity. Higher levels of hexane, styrene, cyclohexanone, butylated hydroxytoluene and 2-butoxyethanol were associated with obesity, and higher levels of cyclohexanone were associated with increased child BMI. Toluene, o-xylene, m/p-xylene and ethylbenzene were significantly associated with nasal obstruction. A positive association was found between PC1 and the risk of obese asthma (OR = 1.43, 95% CI 1.01, 1.98) and between PC2 and overweight (OR = 1.51, 95% CI 1.28, 1.79). PC1 and PC2 were also associated with nasal obstruction, and PC2 was associated with breathing difficulties and lean body mass, although EDCs concentrations were low. CONCLUSIONS: Our findings further support the role of EDCs in asthma and obesity development. Moreover, even low levels of indoor exposure may influence the risk of asthma, respiratory symptoms and obesity.

Setting definitions of childhood asthma in epidemiologic studies.

BACKGROUND: The definitions of childhood asthma differ among epidemiological studies. We aimed to compare the diagnostic accuracy and agreement of previous asthma definitions and to evaluate questionnaire-driven asthma definition patterns. METHODS: Data on 808 participants aged 7-12 years from 20 schools were analyzed. Asthma definitions based on symptoms assessed by questionnaire, parent-reported medical asthma diagnosis, current use of asthma medication, airway reversibility after bronchodilatation, and increased (≥35 ppb) levels of exhaled nitric oxide (eNO) were compared with a gold standard (medical diagnosis of asthma with asthma symptoms in the past 12 months and/or airway reversibility). Concordance was assessed by Cohen's kappa. Data-driven analysis was applied to the questionnaire, and six scores were determined "asthma," "rhinitis," "cough," "non-specific respiratory symptoms," "treated asthma," and "uncontrolled asthma." Tree decisions were built using these scores. RESULTS: Definitions of asthma based on respiratory symptoms, airway reversibility, and parent-reported medical diagnosis had a low sensitivity but high specificity. Agreement between reported and objective measures was poor. Parent-reported medical asthma diagnosis, but not reversibility or eNO, was able to predict questionnaire-driven symptom patterns. Decision trees indicated that those with recent non-specific respiratory symptoms had a higher probability of positive bronchodilation. CONCLUSION: A standardized operational definition of asthma should include a composite score based on reported asthma medical diagnosis, symptoms, and lung function.