Rationale and protocol for a prospective cohort study of respiratory viral infections in patients admitted from emergency departments of community hospitals: Effect of respiratory Virus infection on EmeRgencY admission (EVERY) study.

INTRODUCTION: Respiratory syncytial virus (RSV) is a causative virus for the common cold worldwide and can result in hospitalisations and even death in patients with high-risk conditions and older adults. However, the relationship between RSV or other incidental respiratory infections and acute exacerbations of underlying conditions has not been well investigated. The primary objective of this study is to estimate RSV prevalence, risk factors for adverse outcomes or hospitalisation and their effect on the hospital course of patients with acute respiratory symptoms admitted from emergency departments. Furthermore, we evaluate the prevalence of other respiratory viruses associated with respiratory symptoms. METHODS AND ANALYSIS: We are conducting a multicentre prospective cohort study in Japan. We plan to enrol 3000 consecutive patients admitted from emergency departments with acute respiratory symptoms or signs from 1 July 2023 to 30 June 2024. A nasopharyngeal swab is obtained within 24 hours of admission and the prevalence of RSV and other respiratory viruses is measured using the FilmArray Respiratory 2.1 panel. Paired serum samples are collected from patients with suspected lower respiratory infections to measure RSV antibodies at admission and 30 days later. Information on patients' hospital course is retrieved from the electronic medical records at discharge, death or 30 days after admission. Furthermore, information on readmission to the hospital and all-cause mortality is collected 180 days after admission. We assess the differences in clinical outcomes between patients with RSV or other respiratory viruses and those without, adjusting for baseline characteristics. Clinical outcomes include in-hospital mortality, length of hospital stay, disease progression, laboratory tests and management of respiratory symptoms or underlying conditions. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review boards of participating hospitals. Our study reports will be published in academic journals as well as international meetings. TRIAL REGISTRATION NUMBER: NCT05913700.

Serum levels of club cell secretory protein (Clara) and short- and long-term exposure to particulate air pollution in adolescents.

BACKGROUND: Studies in populations have shown that particulate air pollution is associated with changes in lung function in adolescents. OBJECTIVE: We investigated the effect of short- and long-term exposure to particulate matter (PM10) on the pulmonary health of adolescents, using serum lung club cell secretory protein (Clara) (CC16) as a biomarker for respiratory epithelium integrity. METHODS: We measured serum CC16 in 825 adolescents (57% girls, mean age: 15 years). Short-term and long-term exposure to ambient PM10 was estimated for each participant's home address using a kriging interpolation method. To explore the association between PM10 and serum CC16 we applied restricted cubic splines with 5 knots located at the 5th, 25th, 50th, 75th and 95th percentiles of the PM10 distribution. The explorative analyses showed a change in the slope of this association, after which a change-point analysis was performed. RESULTS: After adjustment for potential covariates, the analysis showed strong associations between PM10 concentrations, averaged over the week preceding the clinical examination, and serum CC16 levels. Each 5 µg/m(3) increase in mean PM10 concentration in the week before the clinical examination was associated with a substantial increase of 0.52 µg/l (95% confidence interval: 0.31 to 0.73; p<0.0001) in serum CC16 levels. The association appears nonlinear with a flattening out of the slope at mean week PM10 levels above 37 µg/m(3). There was no evidence of an association between long-term exposure to PM10 and serum CC16 concentrations. CONCLUSIONS: Our findings suggest that short-term exposure to particulate air pollution may compromise the integrity of the lung epithelium and lead to increased epithelial barrier permeability in the lungs of adolescents, even at low concentrations.

Associations of urinary cadmium with age and urinary proteins: further evidence of physiological variations unrelated to metal accumulation and toxicity.

BACKGROUND: The current risk assessment for environmental cadmium (Cd) largely relies on the assumption that urinary Cd (U-Cd) is a reliable biomarker of the Cd body burden. Recent studies have questioned the validity of this assumption. OBJECTIVES: We studied the lifetime trend of U-Cd as a function of diuresis, gender, smoking status, and protein tubular reabsorption. We also analyzed the associations between U-Cd and urinary proteins. METHODS: Cd, retinol-binding protein, and albumin were measured in the urine of six cohorts of the general population of Belgium, with a mean age ranging from 5.7 to 88.1 years (n = 1,567). Variations of U-Cd with age were modeled using natural cubic splines. RESULTS: In both genders, U-Cd decreased to a minimum (~ 0.20 µg/L) at the end of adolescence, then increased until 60-70 years of age (~ 0.60 µg/L in never-smokers) before leveling off or decreasing. When U-Cd was expressed in micrograms per gram of creatinine, these variations were amplified (minimum, 0.15 µg/g creatinine; maximum, 0.70 µg/g creatinine) and much higher U-Cd values were observed in women. We observed no difference in U-Cd levels between never-smokers and former smokers, and the difference with current smokers did not increase over time. Lifetime curves of U-Cd were higher with increasing urinary retinol-binding protein or albumin, a consequence of the coexcretion of Cd with proteins. CONCLUSIONS: At low Cd exposure levels, U-Cd and age are associated through nonlinear and nonmonotonic relationships that appear to be driven mainly by recent Cd intake and physiological variations in the excretion of creatinine and proteins.

Interactions between domestic water hardness, infant swimming and atopy in the development of childhood eczema.

AIM: Recent studies suggest that domestic water hardness and swimming in chlorinated pools may increase the prevalence of childhood eczema. The combined influence of these two factors as well as their interaction with atopic status has not been investigated. METHODS: We conducted a cross-sectional study on 358 children aged 5-6 years (54% of boys) in 30 kindergarten schools. Parents completed a questionnaire about the child's health, chlorinated pool attendance and potential confounders. Data about tap water quality were provided by water companies. Atopy was defined as a sensitization to at least one aeroallergen or as a medication for allergy. The effect of water hardness and infant swimming practice were assessed by multivariate logistic models. In addition, the effects of these risk factors combined with atopy were evaluated using two measures of biological interaction: the attributable proportion of interaction (AP) and the synergy index (S). AP>0 and S>1 indicate biological interaction between the two risk factors. RESULTS: Water hardness was linearly associated to the prevalence of eczema whereas the relationship of eczema with infant swimming was not linear. We observed a biological interaction between hard water (>150 mg/L CaCO(3)L(-1)) and atopic status that increases the prevalence of eczema with an odds ratio (OR) of 3.30 and a 95% confidence interval (CI) of 1.34-8.15 (AP, 0.41; 95% CI 0.15-0.66 and S, 2.4; 95% CI 0.96-6.01). Infant swimming practice combined with atopy also increased the prevalence of eczema (OR, 2.72; 95% CI 1.29-5.74) although none of the interaction measures was significant. However, when water hardness and infant swimming were combined, there was no further increase of the eczema prevalence due to some form of antagonistic interaction between these two factors (AP, -0.56; 95% CI -1.12 to -0.01 and S, 0.54; 95% CI 0.33-0.87). CONCLUSIONS: Our study shows that exposure to hard water and infant swimming interact with atopic status to increase the prevalence of childhood eczema. A breaching of the epidermal barrier by detergents or salts in hard water and by chlorine-based oxidants in swimming pool water might explain these interactions.

Associations between proteins and heavy metals in urine at low environmental exposures: evidence of reverse causality.

Heavy metals can cause renal effects on vulnerable populations but it is uncertain whether these metals still pose health risks at the low exposure levels now prevailing in most industrialized countries. In a cross-sectional study performed on 736 adolescents, we assessed the associations between the concentrations of cadmium and lead in blood and urine and the urinary concentrations of albumin and of low-molecular-weight (LMW) proteins, retinol-binding protein (RBP) and ß(2)-microglobulin. Multiple regression analyses were tested using urinary markers normalized to urinary creatinine or specific gravity. Median metal concentrations were in blood (µg/L): lead, 15.1, cadmium, 0.18 and in urine (µg/g creatinine): cadmium, 0.09 and lead, 0.82. Multivariate analyses revealed significant associations in urine between RBP and cadmium as well as between ß(2)-microglobulin and lead whereas no associations were seen with metals in blood. These associations were completely abolished in subjects with increased urinary albumin, which may be explained by the competitive inhibition of LMW protein reabsorption by albumin. Given the evidence that cadmium and lead circulate mainly bound to LMW proteins, these associations observed at low exposure might simply reflect the interindividual variations in the renal uptake of proteins sharing the same affinity for tubular binding sites.

The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and beta 2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers.

OBJECTIVE: To evaluate the threshold value of urinary cadmium (CdU) for renal dysfunction on the basis of relationships unconfounded by protein degradation, diuresis and the renal effects associated with chronic smoking. Methods We studied 599 workers (451 men, mean age 45.4 years) who were employed in four nickel-cadmium battery plants for 18.8 years on average. After adjustment for covariates by multiple regression, the CdU threshold values for increased concentrations of retinol-binding protein (RBPU) and b(2)-microglobulin (b(2)-mU) were assessed by logistic regression and benchmark dose analyses using as referents workers with CdU<1 µg/g creatinine. Results Relationships between urinary proteins and CdU (µg/g creatinine) were influenced by sex, age, diuresis and especially smoking. When considering all workers, odds for abnormal RBPU and b(2)-mU were significantly increased from CdU of 6-10 and >10, respectively. The benchmark dose (BMD5) and the benchmark dose lower limit (BMDL5) for a 5% excess in the background prevalence of abnormal RBPU and b(2)-mU were estimated at 5.1/3.0 and 9.6/5.9. When excluding ever smokers, odds for abnormal RBPU and b(2)-mU were both increased only among workers with CdU>10 (OR, 21.8, 95% CI, 6.4-74.4 and OR, 15.1, 95% CI, 3.6-63.1, respectively). In never smokers, these BMD5/BMDL5 of CdU were estimated at 12.6/6.6 and 12.2/5.5 while in ever smokers they were 6.2/4.9 and 4.3/3.5. Conclusions On the basis of associations undistorted by smoking and adjusted for covariates, the BMDL5 of CdU for low-molecular-weight proteinuria induced by occupational exposure to Cd can be reliably estimated between 5.5 and 6.6 µg/g creatinine.