Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

Asthma and decreased lung function in children exposed to perfluoroalkyl and polyfluoroalkyl substances (PFAS): An updated meta-analysis unveiling research gaps.

BACKGROUND AND OBJECTIVE: Associations between exposure to per- and polyfluoroalkyl substances (PFAS) and pediatric asthma and reduced lung function in children are mixed and inconclusive. The study objective was to examine the extant research on exposure to PFAS and the diagnosis of asthma or decreased lung function in children <17 years of age to highlight what is known and to identify research gaps for future investigations. METHODS: The present review was registered on the PROSPER database (CRD42023407172). We systematically searched several bibliographic databases (Scopus, Embase, Web of Science (core Collection), Medline, and CINAHL) along with grey literature sources in January 2023 to find relevant studies before this date. The National Toxicology Program's Office of Health Assessment and Translation (NTP OHAT) tool was applied to assess the risk of bias (RoB) assessment. We used a random-effects meta-analysis to assess the associations. From 12 observational epidemiological studies (out of 513) explored for qualitative analyses, 4 studies were included in quantitative analyses. RESULTS: The meta-analysis revealed a significant association between exposures to perfluorooctanoate (PFOA) with the prevalence of children's asthma [Odds Ratios (OR) = 1.162 (95% CI: 1.004-1.321)] whereas the association for perfluorooctane sulfonate (PFOS) was not statistically significant [OR = 1.03 (95%CI: 0.806-1.265]. The narrative synthesis results of the four included studies that examined the effects of PFAS exposure on lung function did not demonstrate significant associations between exposure to PFAS and decreased lung function. The RoB for most included studies was assessed as probably low without serious limitations. However, two studies were at high risk of biases. CONCLUSION: Our findings suggest that children who are exposed to PFOA are at a higher risk of developing asthma as well as the association between exposure to PFOS with impaired lung function. Large longitudinal studies with homogeneous PFAS exposures and standardized outcome measures are needed to ascertain these outcomes with improved certainty as well as toxicological studies to investigate the underlying mechanisms.

Oximetry and carbon dioxide screening for ventilatory requirements in children with spinal muscular atrophy type 1-3.

INTRODUCTION: Despite disease modifying treatments (DMT), assisted ventilation is commonly required in children with Spinal Muscular Atrophy (SMA). Guidelines suggest screening with oximetry and transcutaneous carbon dioxide (TcCO2) for sleep disordered breathing (SDB). AIM: To determine the utility of pulse oximetry and TcCO2 as a screen for SDB and the need for Non-Invasive Ventilation (NIV) in children with SMA type 1-3. METHODS: A prospective cohort study was conducted in Queensland, Australia. Full diagnostic PSG was completed in DMT naïve children with SMA. Pulse oximetry and TcCO2 were extracted from PSG. Apnoea-hypopnoea indices (AHI) criteria were applied to PSG results to define the need for NIV. Abnormal was defined as: ≤3 months of age [mo] AHI≥10 events/hour; >3mo AHI ≥5 events/hour. Receiver operating characteristic curves were calculated for abnormal PSG and pulse oximetry/TcCO2 variables, and diagnostic statistics were calculated. RESULTS: Forty-seven untreated children with SMA were recruited (type 1 n = 13; 2 n = 21; 3 n = 13) ranging from 0.2 to 18.8 years old (median 4.9 years). Oxygen desaturation index ≥4 % (ODI4) ≥20events/hour had sensitivity 82.6 % (95 % CI 61.2-95.0) and specificity of 58.3 % (95 % CI 36.6-77.9). TcCO2 alone and combinations of oximetry/TcCO2 had low diagnostic ability. The same methodology was applied to 36 children who were treated (type 1 n = 7; type 2 n = 17; type n = 12) and oximetry±TcCO2 had low diagnostic ability. CONCLUSION: ODI4 ≥20events/hour can predict the need for NIV in untreated children with SMA. TcCO2 monitoring does not improve the PPV. If normal however, children may still require a diagnostic PSG. Neither oximetry nor TcCO2 monitoring were useful screening tests in the children treated with DMT.

Association of Maternal Air Pollution Exposure and Infant Lung Function Is Modified by Genetic Propensity to Oxidative Stress.

BACKGROUND AND OBJECTIVE: The association between air pollution and poor respiratory health outcomes is well established. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. This study investigated maternal exposure to air pollution during pregnancy and oxidative stress (OS), inflammation, and infant lung function at 4 weeks of age. METHODS: Data from the Barwon Infant Study were available for 314 infants. The exposure to NO2 and PM2.5 were estimated. Infant lung function (4 weeks) was measured by multiple-breath washout. Glycoprotein acetyls (GlycA) (36 weeks prenatal), cord blood, and OS biomarkers were measured in maternal urine (28 weeks). A genetic pathway score for OS (gPFSox) was calculated. Linear regression was used and potential modification by the OS genotype was tested. RESULTS: There was no relationship between maternal exposure to air pollution and infant lung function, or with GlycA or OS during pregnancy. We found an association in children with a genetic propensity to OS between NO2 and a lower functional residual capacity (FRC) (ß = -5.3 mls, 95% CI (-9.3, -1.3), p = 0.01) and lung clearance index (LCI) score (ß = 0.46 turnovers, (95% CI 0.10, 0.82), p = 0.01). CONCLUSION: High prenatal exposure to ambient NO2 is associated with a lower FRC and a higher LCI score in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.

Assessment of bronchodilator response in preschoolers: A systematic review.

BACKGROUND: Several techniques can be used to assess bronchodilator response (BDR) in preschool-aged children, including spirometry, respiratory oscillometry, the interrupter technique, and specific airway resistance. However, there has not been a systematic comparison of BDR thresholds across studies yet. METHODS: A systematic review was performed on all studies up to May 2023 measuring a bronchodilator effect in children 2-6 years old using one of these techniques (PROSPERO CRD42021264659). Studies were identified using MEDLINE, Cochrane, EMBASE, CINAHL via EBSCO, Web of Science databases, and reference lists of relevant manuscripts. RESULTS: Of 1224 screened studies, 43 were included. Over 85% were from predominantly European ancestry populations, and only 22 studies (51.2%) calculated a BDR cutoff based on a healthy control group. Five studies included triplicate testing with a placebo to account for the within-subject intrasession repeatability. A relative BDR was most consistently reported by the included studies (95%) but varied widely across all techniques. Various statistical methods were used to define a BDR, with six studies using receiver operating characteristic analyses to measure the discriminative power to distinguish healthy from wheezy and asthmatic children. CONCLUSION: A BDR in 2- to 6-year-olds cannot be universally defined based on the reviewed literature due to inconsistent methodology and cutoff calculations. Further studies incorporating robust methods using either distribution-based or clinical anchor-based approaches to define BDR are required.

Hormonal, liver, and renal function associated with electronic waste (e-waste) exposure in Dhaka, Bangladesh.

Electronic waste (e-waste) contains numerous metals and organic pollutants that have detrimental impacts on human health. We studied 199 e-waste recycling workers and 104 non-exposed workers; analyzed blood, urine, and hair samples to measure heavy metals, hormonal, liver, and renal function. We used quantile regression models to evaluate the impact of Pb, Cd, and Hg on hormonal, liver and renal function, and the role of DNA oxidative damage in mediating the relationship between exposures and outcomes. Exposed workers had higher blood lead (Pb) (median 11.89 vs 3.63 µg/dL), similar blood cadmium (Cd) (1.04 vs 0.99 µg/L) and lower total mercury (Hg) in hair (0.38 vs 0.57 ppm) than non-exposed group. Exposed workers also had elevated median concentrations of total triiodothyronine (TT3), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urinary albumin, albumin creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were significantly higher than non-exposed group (p≤0.05). Sex hormones including luteinizing hormone, follicle stimulating hormone, estrogen, progesterone and testosterone concentrations were not significantly different between exposed and non-exposed (all p≥0.05). The median concentration of ALT was 4.00 (95% CI: 0.23, 7.77), urinary albumin was 0.09 (95% CI: 0.06, 0.12) and ACR was 1.31 (95% CI: 0.57, 2.05) units higher in the exposed group compared to non-exposed group. Pb was associated with a 3.67 unit increase in the ALP (95% CI: 1.53, 5.80), 0.01 unit increase in urinary albumin (95% CI: 0.002, 0.01), and 0.07 unit increase in ACR (95% CI: 0.01, 0.13). However, no hormonal, renal, and hepatic parameters were associated with Cd or Hg. Oxidative DNA damage did not mediate exposure-outcome relationships (p≥0.05). Our data indicate e-waste exposure impairs liver and renal functions secondary to elevated Pb levels. Continuous monitoring, longitudinal studies to evaluate the dose-response relationship and effective control measure are required to protect workers from e-waste exposure.

Determinants of lung function development from birth to age 5 years: an interrupted time series analysis of a South African birth cohort.

BACKGROUND: Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to school age in a South African birth cohort. METHODS: We prospectively followed children enrolled in a population-based cohort from birth (between March 5, 2012 and March 31, 2015) to age 5 years with annual lung function assessment. Data on multiple early-life exposures, including LRTI, were collected. The effect of early-life risk factors on lung function development from birth to age 5 years was assessed using the Generalised Additive Models for Location, Scale and Shape and Interrupted Time Series approach. FINDINGS: 966 children (475 [49·2%] female, 491 [50·8%] male) had lung function measured with oscillometry, tidal flow volume loops, and multiple breath washout. LRTI occurred in 484 (50·1%) children, with a median of 2·0 LRTI episodes (IQR 1·0-3·0) per child. LRTI was independently associated with altered lung function, as evidenced by lower compliance (0·959 [95% CI 0·941-0·978]), higher resistance (1·028 [1·016-1·041]), and higher respiratory rate (1·018 [1·063-1·029]) over 5 years. Additional impact on lung function parameters occurred with each subsequent LRTI. Respiratory syncytial virus (RSV) LRTI was associated with lower expiratory flow ratio (0·97 [0·95-0·99]) compared with non-RSV LRTI. Maternal factors including allergy, smoking, and HIV infection were also associated with altered lung development, as was preterm birth, low birthweight, female sex, and coming from a less wealthy household. INTERPRETATION: Public health interventions targeting LRTI prevention, with RSV a priority, are vital, particularly in low-income and middle-income settings. FUNDING: UK Medical Research Council Grant, The Wellcome Trust, The Bill & Melinda Gates Foundation, US National Institutes of Health Human Heredity and Health in Africa, South African Medical Research Council, Hungarian Scientific Research Fund, and European Respiratory Society.

Longitudinal tracking of intrabreath respiratory impedance in preschool children.

BACKGROUND: Longitudinal measurements of intrabreath respiratory impedance (Zrs) in preschool-aged children may be able to distinguish abnormal lung function trajectories in children with a history of wheezing compared to healthy ones. METHODS: Children from a prospective, longitudinal community-based cohort performed annual intrabreath oscillometry (IB-OSC) measurements from age 3- to 7-years. IB-OSC was performed using a single 10 Hz sinusoid while clinically asymptomatic. Linear mixed-effects models were developed to explore the effects of wheezing phenotypes, growth, and sex on seven IB-OSC outcome variables over time: resistance at end-expiration (ReE), resistance at end-inspiration (ReI), the tidal change in resistance (∆R=ReE-ReI), reactance at end-expiration (XeE), reactance at end-inspiration (XeI), the tidal change in reactance (∆X=XeE-XeI), and ∆X normalized by tidal volume (∆X/VT). RESULTS: Eighty-five children produced 374 acceptable IB-OSC measurements. Subjects were classified into one of three wheeze groups: never (n = 36), transient (n = 34), or persistent (n = 15). After adjusting for height, children with persistent wheezing, compared to those who never wheezed, had +0.814 hPa s L-1 ReE (95% confidence interval [CI] +0.178 to +1.451, p = 0.015), -0.792 hPa s L-1 XeE (95% CI -1.203 to -0.381, p = 0.003), -0.538 hPa s L-1 ∆X (95% CI -0.834 to -0.242, p = 0.007) and -1.672 hPa s L-2 ∆X/VT (95% CI -2.567 to -0.777, p < 0.001). Increasing height had a significant effect on all IB-OSC resistance and reactance variables when adjusted for the effect of preschool wheezing. CONCLUSIONS: IB-OSC is feasible for tracking lung function growth in preschool-aged children and may allow abnormal lung function to be identified early in asymptomatic preschoolers with a history of persistent wheezing.

Azithromycin reduces bronchial wall thickening in infants with cystic fibrosis.

BACKGROUND: COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis. METHOD: Inspiratory and expiratory CTs at 12 and 36 months were analysed. BA-analysis measures BA-diameters: bronchial outer wall (Bout), bronchial inner wall (Bin), artery (A), and bronchial wall thickness (Bwt) and computes BA-ratios: Bout/A and Bin/A for bronchial widening, Bwt/A and Bwa/Boa (bronchial wall area/bronchial outer area) for bronchial wall thickening. Low attenuation regions (LAR) were analysed using an automatic method. Mixed-effect model was used to compare BA-outcomes at 36 months between treatment groups. RESULTS: 228 CTs (59 placebo; 66 azithromycin) were analysed. The azithromycin group had lower Bwa/Boa (p = 0.0034) and higher Bin/A (p = 0.001) relative to placebo. Bout/A (p = 0.0088) was higher because of a reduction in artery diameters which correlated to a reduction in LAR. CONCLUSION: Azithromycin-treated infants with CF show a reduction in bronchial wall thickness and possibly a positive effect on lung perfusion.

Changes in urinary glutathione sulfonamide (GSA) levels between admission and discharge of patients with cystic fibrosis.

There is an urgent need to develop sensitive, non-invasive biomarkers that can track airway inflammatory activity for patients with cystic fibrosis (CF). Urinary glutathione sulfonamide (GSA) levels correlate well with GSA levels in BAL samples and other markers of neutrophilic inflammation, suggesting that this biomarker may be suitable for tracking disease activity in this population. We recruited 102 children (median 11.5 years-old) and 64 adults (median 32.5 years-old) who were admitted to hospital for management of an acute pulmonary exacerbation and/or eradication of infectious agents such as Pseudomonas aeruginosa or Staphylococcus aureus. Our aim was to explore how urinary GSA levels changed across admission timepoints. Urine samples were collected at admission and discharge, and GSA measured by liquid chromatography with mass spectrometry. Paired admission-discharge results were compared using Wilcoxon signed-rank test. Paired admission-discharge samples were available for 53 children and 60 adults. A statistically significant difference was observed between admission-discharge for children and adults. Spearman's correlation analysis identified a correlation between urinary GSA levels and sex and S. aureus infection for children only. Our preliminary findings suggest that urinary GSA is responsive to the resolution of an acute pulmonary exacerbation and therefore warrants further studies in this population.

In utero smoking exposure induces changes to lung clearance index and modifies risk of wheeze in infants.

BACKGROUND: Fetal exposure to tobacco smoking throughout pregnancy is associated with wheezing in infancy. We investigated the influence of in utero smoking exposure on lung ventilation homogeneity and the relationship between lung ventilation inhomogeneity at 7 weeks of age and wheezing in the first year of life. METHODS: Maternal smoking was defined as self-reported smoking of tobacco or validated by exhaled (e)CO > 6 ppm. Lung function data from healthy infants (age 5-9 weeks) born to asthmatic mothers and parent-reported respiratory questionnaire data aged 12 months were collected in the Breathing for Life Trial (BLT) birth cohort. Tidal breathing analysis and SF6-based Multiple Breath Washout testing were performed in quiet sleep. Descriptive statistics and regression analysis were used to assess associations. RESULTS: Data were collected on 423 participants. Infants born to women who self-reported smoking during pregnancy (n = 42) had higher lung clearance index (LCI) than those born to nonsmoking mothers (7.90 vs. 7.64; p = .030). Adjusted regression analyzes revealed interactions between self-reported smoking and LCI (RR: 1.98, 95% CI: 1.07-3.63, 0.028, for each unit increase in LCI) and between eCO > 6 ppm and LCI (RR: 2.25, 95% CI: 1.13-4.50, 0.022) for the risk of wheeze in the first year of life. CONCLUSION: In utero tobacco smoke exposure induces lung ventilation inhomogeneities. Furthermore, an interaction between smoke exposure and lung ventilation inhomogeneities increases the risk of having a wheeze in the first year of life.

Updates in Air Pollution: Current Research and Future Challenges.

Background: The United Nations has declared that humans have a right to clean air. Despite this, many deaths and disability-adjusted life years are attributed to air pollution exposure each year. We face both challenges to air quality and opportunities to improve, but several areas need to be addressed with urgency. Objective: This paper summarises the recent research presented at the Pacific Basin Consortium for Environment and Health Symposium and focuses on three key areas of air pollution that are important to human health and require more research. Findings and conclusion: Indoor spaces are commonly places of exposure to poor air quality and are difficult to monitor and regulate. Global climate change risks worsening air quality in a bi-directional fashion. The rising use of electric vehicles may offer opportunities to improve air quality, but it also presents new challenges. Government policies and initiatives could lead to improved air and environmental justice. Several populations, such as older people and children, face increased harm from air pollution and should become priority groups for action.

CFTR is required for zinc-mediated antibacterial defense in human macrophages.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and E. coli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against E. coli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.

Blood lead, cadmium and hair mercury concentrations and association with soil, dust and occupational factors in e-waste recycling workers in Bangladesh.

BACKGROUND: Electronic waste (e-waste) recycling activities release toxic metals, which pose substantial hazard to the environment and human health. We evaluated metal concentrations in biological and environmental samples, and examined the associations between biological lead (Pb), cadmium (Cd), and mercury (Hg) with soil and dust metals, and other possible determinants, among populations exposed and non-exposed to e-waste in Bangladesh. METHODS: A total of 199 e-waste workers and 104 non-exposed individuals were recruited. We measured blood Pb (BPb) and Cd (BCd) concentrations and total Hg (THg) from hair samples. Data were collected on occupational, and behavioral factors. We fitted an elastic net regression (ENET) to model the relationship between a set of influencing factors and metals as outcome variables while controlling for potential covariates. RESULTS: The median concentrations of BPb (11.89 µg/dL) and BCd (1.04 µg/L) among exposed workers were higher than those of non-exposed workers (BPb: 3.63 µg/dL and BCd: 0.83 µg/L respectively). A 100 ppm increment in soil Pb level was associated with an increase in ln-Pb (transformed) in blood (ß = 0.002; 95% CI = 0.00, 0.02). Similarly, ln-BCd level increased (ß = 0.02; 95% CI = 0.001, 0.07) with every ppm increase in dust Cd level. The number of years worked in e-waste activities was associated with elevated ln-BPb (ß = 0.01; 95% CI = 0.01, 0.02) and ln-BCd levels (ß = 0.003; 95% CI = 0.00, 0.05). Smoking significantly contributed to elevated levels of ln-BCd (ß = 0.46; 95% CI = 0.43, 0.73). An increment of 100 kg of e-waste handling per week led to an increase in ln-BPb levels (ß = 0.002; 95% CI = 0.00, 0.01), while respondents knowledge about adverse impact on e-waste reduced the ln-BPb level (ß = -0.14; 95% CI = -0.31, -0.03). Fish consumption frequency had a positive association with THg in hair. CONCLUSIONS: Our data show the need for workplace controls to reduce exposure to Pb and Cd with a broader view of exposure source taken.

Association of antenatal and early childhood air pollution and greenspace exposures with respiratory pathogen upper airway acquisitions and respiratory health outcomes.

The association of air pollution and greenspace with respiratory pathogen acquisition and respiratory health was investigated in a community-based birth-cohort of 158 Australian children. Weekly nasal swabs and daily symptom-diaries were collected for 2-years, with annual reviews from ages 3-7-years. Annual exposure to fine-particulate-matter (PM2.5), nitrogen-dioxide (NO2), and normalised-difference-vegetation-index (NDVI) was estimated for pregnancy and the first 2-years-of-life. We examined rhinovirus, any respiratory virus, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae detections in the first 3-months-of-life, age at initial pathogen detection, wheezing in the first 2-years, and asthma at ages 5-7-years. Our findings suggest that higher NDVI was associated with fewer viral and M. catarrhalis detections in the first 3-months, while increased PM2.5 and NO2 were linked to earlier symptomatic rhinovirus and H. influenzae detections, respectively. However, no associations were observed with wheezing or asthma. Early-life exposure to air pollution and greenspace may influence early-life respiratory pathogen acquisition and illness. .

Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.

BACKGROUND: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. METHODS: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. RESULTS: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected; however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM d'd not restore endocytosis in CF, another essential feature of M2 macrophages. CONCLUSIONS: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.

Indoor air pollution is associated with respiratory symptoms in children in urban Vietnam.

Exposure to indoor air pollution (IAP) is a leading environmental risk for respiratory diseases. We investigated the relationship between respiratory symptoms and polluting indoor activities such as smoking, cooking and contact with pets among children in Ho Chi Minh City (HCMC), Vietnam. A cross-sectional survey applied a multistage sampling method in 24 randomly selected secondary schools across the city. Approximately 15,000 students completed self-administrated questionnaires on risk factors and respiratory health outcomes within the preceding 12 months. Data were analyzed using a multivariable logistic regression model with robust standard errors. Wheeze was the most common respiratory symptom (39.5 %) reported, followed by sneezing and runny nose (28.3 %). A small percentage of students self-reported asthma (8.6 %). Approximately 56 % of participants lived with family members who smoked. A positive association between exposure to indoor secondhand smoke and respiratory symptoms was observed, with adjusted odds ratios (aOR) of 1.41 (95 % CI: 1.25-1.60, p < 0.001) for wheezing and 1.64 (95 % CI: 1.43-1.87, p < 0.001) for sneezing and runny nose, respectively. Using an open stove fuelled by coal, wood, or kerosene for cooking was associated with wheeze (aOR: 1.36, CI 95 %: 1.10-1.68, p = 0.01) and sneezing and runny nose (aOR: 1.36, CI 95 %: 1.09-1.69, p = 0.01). In the present study, IAP was associated with adverse health outcomes, as evidenced by an increase in respiratory symptoms reported within the previous 12 months.

Bronchiolitis hospital admission in infancy is associated with later preschool ventilation inhomogeneity.

BACKGROUND: Rhinovirus (RV) positive bronchiolitis episodes in infancy confer a higher risk to develop asthma in later childhood with associated lung function impairments. We aimed to investigate the association between the type of virus causing a bronchiolitis hospitalization episode and lung ventilation inhomogeneities at preschool age. METHODS: Infants hospitalized with a clinical diagnosis of moderate (ward admission) or severe (pediatric intensive care ward admission) bronchiolitis were prospectively followed-up at preschool age to assess nitrogen (N2 ) multiple breath washout (MBW). Lung clearance index (LCI), functional residual capacity (FRC), and concentration normalized phase III slope analysis (SnIII ) indices were reported from ≥2 technically acceptable trials. Differences between groups were calculated using logistic and linear regression and adjusted for confounders (sex, age at bronchiolitis admission, height at visit, maternal asthma, and doctor-diagnosed asthma, including interaction terms between the latter three). An interaction term was included in a regression model to test for an interaction between RV bronchiolitis severity and MBW parameters at preschool age. RESULTS: One hundred and thirty-nine subjects attended preschool follow-up, of which 84 out of 103 (82%) performing MBW had technically acceptable data. Children with a history of RV positive bronchiolitis (n = 39) had increased LCI (adjusted ß-coefficient [aß] = 0.33, 95% confidence interval [CI] 0.02-0.65, p = 0.040) and conductive airways ventilation inhomogeneity [Scond ] (aß = 0.016, CI 0.004-0.028, p = 0.011) when compared with those with a RV negative bronchiolitis history (n = 45). In addition, we found a statistical interaction between RV bronchiolitis and bronchiolitis severity strengthening the association with LCI (aß = 0.93, CI 0.20-1.58, p = 0.006). CONCLUSION: Children with a history of hospital admission for RV positive bronchiolitis in infancy might be at a higher risk of lung ventilation inhomogeneities at preschool age, arising from the peripheral conducting airways.

Exposure to endocrine-disrupting plasticisers and lung function in children and adolescents: A systematic review and meta-analysis.

Exposure to endocrine-disrupting plasticisers (EDPs), such as phthalates and bisphenols, has been associated with reduced lung function in children and adolescents. However, the existing literature yields conflicting results. This systematic review and meta-analysis aimed to assess the epidemiologic evidence investigating the association between EDP exposure and lung function in children and adolescents. A comprehensive search of five databases identified 25 relevant studies. We employed a random-effects meta-analysis on spirometry measures. The effect size of interest was the change in lung function in standard deviation (SD) units resulting from a two-fold increase in exposure levels. We found that certain phthalates marginally reduced lung function in children. Forced expiratory volume in 1 s (FEV1) was reduced by a two-fold increase in mono-benzyl phthalate (MBzP) (ß = -0.025 SD, 95%CI: 0.042, -0.008), mono-ethyl-oxo-hexyl phthalate (MEOHP) (ß = -0.035 SD, 95%CI: 0.057, -0.014) and mono-carboxy-nonyl phthalate (MCNP) (ß = -0.024 SD, 95%CI: 0.05, -0.003). Forced vital capacity (FVC) was decreased by a two-fold increase in MBzP (ß = -0.022 SD, 95%CI: 0.036, -0.008) and MEOHP (ß = -0.035 SD, 95%CI: 0.057, -0.014) levels. A two-fold increase in MCNP levels was associated with lower FEV1/FVC (ß = -0.023 SD, 95%CI: 0.045, -0.001). Furthermore, a two-fold increase in MEOHP levels reduced forced mid-expiratory flow (FEF25-75) (ß = -0.030 SD, 95%CI: 0.055, -0.005) and peak expiratory flow (PEF) (ß = -0.056 SD, 95%CI: 0.098, -0.014). Notably, associations were more pronounced in males. Given the potential for reverse causation bias, the association between childhood exposure to EDPs and lung function remains uncertain. Overall, our meta-analysis showed small reductions in lung function with higher phthalate exposure. However, future studies are warranted in younger age groups.