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Study Objectives: Few studies of middle-aged and older adults have examined the association between age and sleep using objective sleep measures. We examined these associations in adults aged ≥40 years using wrist actigraphy, and investigated whether these associations differed by sex and race. Methods: Participants were 468 cognitively normal adults aged ≥40 years enrolled in the Baltimore Longitudinal Study of Aging who completed wrist actigraphy. We used Generalized Least Squares Models to examine the associations of age with actigraphic sleep parameters, including total sleep time (TST), sleep efficiency, sleep onset latency, and wake after sleep onset (WASO). We conducted interaction and stratification analyses to test whether cross-sectional age-sleep associations were modified by sex and race. Results: In analyses adjusting for sex, body mass index, and individual medical conditions, older age was associated with longer TST from ages 40-70 that plateaued after age 70. Older age also was associated with lower sleep efficiency, longer sleep onset latency, and greater WASO. In men only, after age 70, older age was associated with shorter TST, lower sleep efficiency, longer onset latency, and greater WASO. However, we did not observe any significant interactions of race with age. Conclusions: Older age was associated with longer TST from ages 40 to 70 and with poorer sleep quality after age 40, and these relationships might vary by sex. Future studies with larger sample sizes are needed to investigate mechanisms that may account for sex differences in the observed age-sleep associations.
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Exposure to ozone (O3) has been associated with cardiovascular outcomes in humans, yet the underlying mechanisms of the adverse effect remain poorly understood. We aimed to investigate the association between O3 exposure and glycerophospholipid metabolism in healthy young adults. We quantified plasma concentrations of phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) using a UPLC-MS/MS system. Time-weighted personal exposures were calculated to O3 and co-pollutants over 4 time windows, and we employed orthogonal partial least squares discriminant analysis to discern differences in lipids profiles between high and low O3 exposure. Linear mixed-effects models and mediation analysis were utilized to estimate the associations between O3 exposure, lipids, and cardiovascular physiology indicators. Forty-three healthy adults were included in this study, and the mean (SD) time-weighted personal exposures to O3 was 9.08 (4.06) ppb. With shorter exposure durations, O3 increases were associated with increasing PC and lysoPC levels; whereas at longer exposure times, the opposite relationship was shown. Furthermore, two specific lipids, namely lysoPC a C26:0 and lysoPC a C17:0, showed significantly positive mediating effects on associations of long-term O3 exposure with pulse wave velocity and systolic blood pressure, respectively. Alterations in specific lipids may underlie the cardiovascular effects of O3 exposure.
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Contaminantes Atmosféricos , Ozono , Humanos , Ozono/toxicidad , Masculino , Femenino , Adulto , Contaminantes Atmosféricos/toxicidad , Adulto Joven , Lisofosfatidilcolinas/sangre , Glicerofosfolípidos/sangre , Glicerofosfolípidos/metabolismo , Exposición a Riesgos Ambientales , Fosfatidilcolinas/metabolismo , Fosfatidilcolinas/sangreRESUMEN
BACKGROUND: Colder temperature exposure is a known trigger for pediatric asthma exacerbation. The induction of oxidative stress is a known pathophysiologic pathway for asthma exacerbation. However, the role of oxidative stress in linking colder temperature exposure and worsened pediatric asthma symptoms is poorly understood. METHODS: In a panel study involving 43 children with asthma, aged 5-13 years old, each child was visited 4 times with a 2-week interval. At each visit, nasal fluid, urine, and saliva samples were obtained and measured for biomarkers of oxidative stress in the nasal cavity (nasal malondialdehyde [MDA]), the circulatory system (urinary MDA), and the oral cavity (salivary MDA). Childhood Asthma-Control Test (CACT) was used to assess asthma symptoms. RESULTS: When ambient daily-average temperature ranged from 7 to 18 °C, a 2 °C decrement in personal temperature exposures were significantly associated with higher nasal MDA and urinary MDA concentrations by 47-77% and 6-14%, respectively. We estimated that, of the decrease in child-reported CACT scores (indicating worsened asthma symptoms and asthma control) associated with colder temperature exposure, 14-57% were mediated by nasal MDA. CONCLUSION: These results suggest a plausible pathway that colder temperature exposure worsens pediatric asthma symptoms partly via inducing nasal oxidative stress. IMPACT: The role of oxidative stress in linking colder temperature exposure and worsened asthma symptoms is still poorly understood. Lower temperature exposure in a colder season was associated with higher nasal and systemic oxidative stress in children with asthma. Nasal MDA, a biomarker of nasal oxidative stress, mediated the associations between colder temperature exposures and pediatric asthma symptoms. The results firstly suggest a plausible pathway that colder temperature exposure worsens pediatric asthma symptoms partly via inducing oxidative stress in the nasal cavity.
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Sleep and physical activity, two important health behaviors, are often studied independently using different accelerometer types and body locations. Understanding whether accelerometers designed for monitoring each behavior can provide similar sleep parameter estimates may help determine whether one device can be used to measure both behaviors. Three hundred and thirty one adults (70.7â ±â 13.7 years) from the Baltimore Longitudinal Study of Aging wore the ActiGraph GT9X Link and the Actiwatch 2 simultaneously on the non-dominant wrist for 7.0â ±â 1.6 nights. Total sleep time (TST), wake after sleep onset (WASO), sleep efficiency, number of wake bouts, mean wake bout length, and sleep fragmentation index (SFI) were extracted from ActiGraph using the Cole-Kripke algorithm and from Actiwatch using the software default algorithm. These parameters were compared using paired t-tests, Bland-Altman plots, and Deming regression models. Stratified analyses were performed by age, sex, and body mass index (BMI). Compared to the Actiwatch, the ActiGraph estimated comparable TST and sleep efficiency, but fewer wake bouts, longer WASO, longer wake bout length, and higher SFI (all pâ <â .001). Both devices estimated similar 1-min and 1% differences between participants for TST and SFI (ßâ =â 0.99, 95% CI: 0.95, 1.03, and 0.91, 1.13, respectively), but not for other parameters. These differences varied by age, sex, and/or BMI. The ActiGraph and the Actiwatch provide comparable absolute and relative estimates of TST, but not other parameters. The discrepancies could result from device differences in movement collection and/or sleep scoring algorithms. Further comparison and calibration is required before these devices can be used interchangeably.
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Actigrafía , Muñeca , Humanos , Adulto , Estudios Longitudinales , Sueño , Polisomnografía , Reproducibilidad de los ResultadosRESUMEN
Ambient temperature and relative humidity can affect asthma symptoms. Apparent temperature is a measure of temperature perceived by humans that takes into account the effect of humidity. However, the potential link between personal exposures to apparent temperature and asthma symptoms has not been investigated. We conducted a panel study of 37 asthmatic children, aged 5-11 years, during an early spring season (average daily ambient temperature: 14°C, range: 7-18°C). Asthma symptoms were measured 4 times for each participant with a 2-week interval between consecutive measurements using the Childhood Asthma-Control Test (C-ACT). Average, minimum, and maximum personal apparent temperature exposures, apparent temperature exposure variability (TV), and average ambient temperature were calculated for the 12 hours, 24 hours, week, and 2 weeks prior to each visit. We found that a 10°C lower in 1-week and 2-week average & minimum personal apparent temperature exposures, TV, and average ambient temperature exposures were significantly associated with lower total C-ACT scores by up to 2.2, 1.4, 3.3, and 1.4 points, respectively, indicating worsened asthma symptoms. Our results support that personal apparent temperature exposure is potentially a stronger driver than ambient temperature exposures for the variability in asthma symptom scores. Maintaining a proper personal apparent temperature exposure could be an effective strategy for personalized asthma management.
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Contaminantes Atmosféricos , Asma , Humanos , Niño , Contaminantes Atmosféricos/análisis , Temperatura , Asma/complicaciones , Estaciones del Año , Humedad , Exposición a Riesgos AmbientalesRESUMEN
Diesel exhaust has long been of health concern due to established toxicity including carcinogenicity in humans. However, the precise components of diesel engine emissions that drive carcinogenesis are still unclear. Limited work has suggested that nitrated polycyclic aromatic hydrocarbons (NPAHs) such as 1-nitropyrene and 2-nitrofluorene may be more abundant in diesel exhaust. The present study aimed to examine whether urinary amino metabolites of these NPAHs were associated with high levels of diesel engine emissions and urinary mutagenicity in a group of highly exposed workers including both smokers and nonsmokers. Spot urine samples were collected immediately following a standard work shift from each of the 54 diesel engine testers and 55 non-tester controls for the analysis of five amino metabolites of NPAHs, and cotinine (a biomarker of tobacco smoke exposure) using liquid chromatography-mass spectrometry. An overnight urine sample was collected in a subgroup of non-smoking participants for mutagenicity analysis using strain YG1041 in the Salmonella (Ames) mutagenicity assay. Personal exposure to fine particles (PM2.5) and more-diesel-specific constituents (elemental carbon and soot) was assessed for the engine testers by measuring breathing-zone concentrations repeatedly over several full work shifts. Results showed that it was 12.8 times more likely to detect 1-aminopyrene and 2.9 times more likely to detect 2-aminofluorene in the engine testers than in unexposed controls. Urinary concentrations of 1-aminopyrene were significantly higher in engine testers (p < 0.001), and strongly correlated with soot and elemental carbon exposure as well as mutagenicity tested in strain YG1041 with metabolic activation (p < 0.001). Smoking did not affect 1-aminopyrene concentrations and 1-aminopyrene relationships with diesel exposure. In contrast, both engine emissions and smoking affected 2-aminofluorene concentrations. The results confirm that urinary 1-aminopyrene may serve as an exposure biomarker for diesel engine emissions and associated mutagenicity.
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Mutágenos , Hidrocarburos Policíclicos Aromáticos , Humanos , Mutágenos/toxicidad , Emisiones de Vehículos/toxicidad , Emisiones de Vehículos/análisis , Hollín/análisis , Hidrocarburos Policíclicos Aromáticos/orina , Nitratos/análisis , Biomarcadores/orinaRESUMEN
Objectives: Wrist actigraphs (accelerometers) can record motor activity over multiple days and nights. The resulting data can be used to quantify 24-h activity profiles, known as circadian rest-activity rhythms (CRARs). Actigraphic CRARs have been tied to cognitive performance and decline in older adults; however, little is known about links between CRARs and performance or change in specific cognitive domains, or how individual differences may influence these associations. We investigated associations of actigraphic CRARs with cognitive performance and change in middle-aged and older adults, and explored whether age, sex/gender, race, and apolipoprotein E (APOE) e4 carrier status moderated these associations. Materials and methods: Participants (N = 422; 47% male) were cognitively healthy adults (i.e., without mild cognitive impairment or dementia) at baseline aged ≥ 50 years from the Baltimore Longitudinal Study of Aging who completed 5.6 ± 0.89 nights of wrist actigraphy and tests of memory, executive function, attention, language, and visuospatial ability at the same visit the actigraph was issued; 292 participants had repeat cognitive testing 3.12 (1.58) years later. Predictors included indices of rhythm strength [i.e., amplitude; relative amplitude (RA); interdaily stability (IS); mesor], delayed timing of the rhythm peak [i.e., later acrophase; midpoint of an individual's least active 5 h (L5 time); midpoint of an individual's most active 10 h (M10 time)], and fragmentation [i.e., intradaily variability (IV)]. Results: In main effects, later L5 time was cross sectionally associated with poorer memory, and greater IS predicted slower longitudinal memory decline. Associations of CRARs with cognition differed as a function of age, sex/gender, race, and APOE e4 carrier status. Conclusion: Among middle-aged and older adults, delayed circadian phase is associated with poorer memory performance, and greater day-to-day rhythm stability is associated with slower declines in memory. Significant interactions suggest that CRARs are generally more strongly associated with cognitive performance and rate of cognitive decline among women, Black adults, older individuals, and APOE e4 carriers. Replication in independent samples is needed.
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Basket trials pool histologic indications sharing molecular pathophysiology, improving development efficiency. Currently, basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power even with modest effect sizes, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since family wise error rate by indications may sometimes be required, we now simulate a variant of this basket design controlling family wise error rate at 0.025k, the total family wise error rate of k separate randomized trials. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling family wise error rate and minimizing estimation bias were allowable. Optimal performance results when k=3,4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power ("uncorrected") or at the power achieved in the basket trial ("corrected," because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with a higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible. Even under family wise error rate control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical.
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Modelos Estadísticos , Proyectos de Investigación , Sesgo , Tamaño de la MuestraRESUMEN
Dynamic changes of microbiome communities may play important roles in human health and diseases. The recent rise in longitudinal microbiome studies calls for statistical methods that can model the temporal dynamic patterns and simultaneously quantify the microbial interactions and community stability. Here, we propose a novel autoregressive zero-inflated mixed-effects model (ARZIMM) to capture the sparse microbial interactions and estimate the community stability. ARZIMM employs a zero-inflated Poisson autoregressive model to model the excessive zero abundances and the non-zero abundances separately, a random effect to investigate the underlining dynamic pattern shared within the group, and a Lasso-type penalty to capture and estimate the sparse microbial interactions. Based on the estimated microbial interaction matrix, we further derive the estimate of community stability, and identify the core dynamic patterns through network inference. Through extensive simulation studies and real data analyses we evaluate ARZIMM in comparison with the other methods.
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Exposure to fine particulate matter (PM2.5) and ozone (O3) may lead to inflammation and oxidative damage in the oral cavity, which is hypothesized to contribute to the worsening of airway inflammation and asthma symptoms. In this panel study of 43 asthmatic children aged 5-13 years old, each child had 4 clinic visits with a 2-week interval between two consecutive visits. At each visit, saliva samples were collected and subsequently analyzed for interleukin 6 (IL-6) and eosinophil cationic protein (ECP) as biomarkers of inflammation and malondialdehyde (MDA) as a biomarker of oxidative stress in the oral cavity. At each visit, children were measured for fractional exhaled nitric oxide (FeNO) as a marker of pulmonary inflammation. Asthma symptoms of these children were measured using the Childhood Asthma Control Test (C-ACT). We found that an interquartile range (IQR) increase in 24-h average personal exposure to PM2.5 measured 1 and 2 days prior was associated with increased salivary IL-6 concentration by 3.0% (95%CI: 0.2%-6.0%) and 4.2% (0.7%-8.0%), respectively. However, we did not find a clear association between personal O3 exposure and any of the salivary biomarkers, except for a negative association between salivary MDA and O3 exposure measured 1 day prior. An IQR increase in salivary IL-6 concentration was associated with significantly increased FeNO by 28.8% (4.3%-53.4%). In addition, we found that increasing salivary IL-6 concentrations were associated with decreased individual and total C-ACT scores, indicating the worsening of asthma symptoms. We estimated that 13.2%-22.2% of the associations of PM2.5 exposure measured 1 day prior with FeNO and C-ACT scores were mediated by salivary IL-6. These findings suggest that the induction of inflammation in the oral cavity may have played a role in linking air pollution exposure with the worsening of airway inflammation and asthma symptoms.
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Contaminantes Atmosféricos , Contaminación del Aire , Asma , Neumonía , Adolescente , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/análisis , Asma/inducido químicamente , Asma/metabolismo , Niño , Preescolar , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Inflamación/inducido químicamente , Boca/química , Boca/metabolismo , Material Particulado/análisis , Material Particulado/toxicidadRESUMEN
Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) have been widely studied for their mutagenic and carcinogenic effects. This study aims to investigate whether exposure to nitro-PAHs is associated with biomarkers of carbohydrate metabolism, an underlying risk factor for metabolic disorder. Early morning urine and blood samples were longitudinally collected two times with a four-week interval from 43 healthy adults. Five urinary amino-PAHs (1-aminonaphthalene, 2-aminonaphthalene, 9-aminophenanthrene, 2-aminofluorene, and 1-aminopyrene) were measured as biomarkers of nitro-PAH exposures. We measured plasma concentrations of glucose and six amino acids that can regulate insulin secretion, including aspartate (Asp), glutamate (Glu), glutamine (Gln), alanine (Ala), Arginine (Arg), and ornithine (Orn). We found that increasing concentrations of 9-aminophenanthrene were significantly associated with increasing glucose levels and with decreasing Asp, Glu, Ala, and Orn levels. We estimated that 26.4 %-43.8 % of the 9-aminophenanthrene-associated increase in glucose level was mediated by Asp, Glu, and Orn. These results suggest that exposure to certain nitro-PAHs affects glucose homeostasis, partly resulting from the depletion of insulin-stimulating amino acids (Asp, Glu, and Orn).
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Glucemia , Hidrocarburos Policíclicos Aromáticos , Adulto , Aminoácidos , Biomarcadores , Humanos , Nitratos , Óxidos de NitrógenoRESUMEN
Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer (CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.
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Antibacterianos/farmacología , Ciego/inmunología , Ciego/microbiología , Diabetes Mellitus Tipo 1/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Animales , Enfermedades Autoinmunes , Bacterias/clasificación , Bacterias/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Código de Histonas , Intestinos/inmunología , Masculino , Redes y Vías Metabólicas , Metagenoma , Ratones , Ratones Endogámicos NOD , MicroARNsRESUMEN
BACKGROUND/OBJECTIVES: The incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by "Westernization" of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be "trapped" in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences. SUBJECTS/METHODS: We sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects. RESULTS: In SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; [Formula: see text], [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; [Formula: see text], [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; [Formula: see text], [0.338, 1.249]; q = 0.018). CONCLUSIONS: These observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.
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Resistencia a la Insulina/fisiología , Epiplón/fisiopatología , Grasa Subcutánea/fisiopatología , Tejido Adiposo/fisiopatología , Adulto , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/sangre , Femenino , Forminas/análisis , Forminas/sangre , Humanos , Masculino , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/análisis , Proteínas Quinasas Activadas por Mitógenos/sangre , Obesidad/sangre , Obesidad/fisiopatología , Epiplón/anomalías , Receptor para Productos Finales de Glicación Avanzada/análisis , Receptor para Productos Finales de Glicación Avanzada/sangre , Grasa Subcutánea/anomalíasRESUMEN
The molecular mechanisms underlying the associations between air pollution exposure and adverse cardiopulmonary effects remain to be better understood. Altered amino acid metabolism may plays an important role in the development of cardiopulmonary diseases and may be perturbed by air pollution exposure. To test this hypothesized molecular mechanism, we conducted an association analysis from an existing intervention study to examine the relations of air pollution exposures with amino acids in 43 Chinese healthy adults. Plasma levels of amino acids were measured using a UPLC-QqQ-MS system. Time-weighted personal exposure to O3, PM2.5, NO2, and SO2 over four time windows, i.e., 12 h, 24 h, 1 week, and 2 weeks, were calculated using the measured indoor and outdoor concentrations coupled with the time-activity data for each participant. Linear mixed-effects models were used to estimate the associations between air pollutants at each exposure window and amino acids by controlling for potential confounders. We observed significant associations between exposures and plasma concentrations of amino acids, with the direction of associations varying by amino acid and air pollutant. While there is little evidence of associations for NO2 and SO2, the associations with amino acids were fairly pronounced for exposure to PM2.5 and O3. In particular, independent O3 (12- and 24-hour) associations were observed with changes in the amino acids that were related to the urea cycle, including aspartate, asparagine, glutamate, arginine, citrulline, and ornithine. Our findings indicated that air pollution may cause acute perturbation of amino acid metabolism, and that O3 and PM2.5 may affect the metabolism of amino acids in different pathways. Main finding: Acute air pollution exposure might affect the perturbation of amino acid metabolism, and in particular, was associated with amino acids in relation to the urea cycle.
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Contaminantes Atmosféricos , Contaminación del Aire , Adulto , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Aminoácidos , Exposición a Riesgos Ambientales/análisis , Humanos , Material Particulado/análisisRESUMEN
BACKGROUND: Heightening oxidative stress and inflammation is an important pathophysiological mechanism underlying air pollution health effects in people with asthma. Melatonin can suppress oxidative stress and inflammation in pulmonary and circulatory systems. However, the role of melatonin in the oxidative stress and physiological responses to air pollution exposure has not been examined in children with asthma. METHODS: In this panel study of 43 asthmatic children (5-13 years old), each child had 4 clinic visits with a 2-week interval between two consecutive visits. At each visit, urine samples were collected and subsequently analyzed for 6-sulfatoxymelatonin (aMT6s) as a surrogate of circulating melatonin and for malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) as two biomarkers of systemic oxidative stress. At each clinic visit, children were measured for pulmonary function and fractional exhaled nitric oxide (FeNO, a marker of pulmonary inflammation). None of the children reported to have taking melatonin supplementation. Concentrations of indoor and ambient PM2.5 and ozone (O3) were combined with individual time-activity data to calculate personal air pollutant exposures. RESULTS: We found that interquartile range increases in urinary MDA and 8-OHdG concentrations were associated with significantly increased urinary aMT6s concentrations by 73.4% (95% CI: 52.6% to 97.0%) and 41.7% (22.8% to 63.4%), respectively. Increases in daily personal exposure to O3 and to PM2.5 were each associated with increased urinary aMT6s concentrations. Increasing urinary aMT6s concentrations were associated with decreased FeNO and resonant frequency, indicating improved airway inflammation and lung elasticity, respectively. CONCLUSION: The results suggest that systemic oxidative stress heightened by air pollution exposure may stimulate melatonin excretion as a defense mechanism to alleviate the adverse effects.
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Contaminantes Atmosféricos , Asma , Melatonina , Adolescente , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Niño , Preescolar , Humanos , Estrés Oxidativo , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
Fine particulate matter (PM2.5) with a higher oxidative potential has been thought to be more detrimental to pulmonary health. We aim to investigate the associations between personal exposure to PM2.5 oxidative potential and pulmonary outcomes in asthmatic children. We measured each of the 43 asthmatic children 4 times for airway mechanics, lung function, airway inflammation, and asthma symptom scores. Coupling measured indoor and outdoor concentrations of PM2.5 mass, constituents, and oxidative potential with individual time-activity data, we calculated 24 h average personal exposures 0-3 days prior to a health outcome measurement. We found that increases in daily personal exposure to PM2.5 oxidative potential were significantly associated with increased small, large, and total airway resistance, increased airway impedance, decreased lung function, and worsened scores of individual asthma symptoms and the total symptom score. Among the PM2.5 constituents, organic matters largely of indoor origin contributed the greatest to PM2.5 oxidative potential. Given that the variability in PM2.5 oxidative potential was a stronger driver than PM2.5 mass for the variability in the respiratory health outcomes, it is suggested to reduce PM2.5 oxidative potential, particularly by reducing the organic matter constituent of indoor PM2.5, as a targeted source control strategy in asthma management.
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Contaminantes Atmosféricos , Contaminación del Aire Interior , Asma , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Contaminación del Aire Interior/análisis , Niño , Exposición a Riesgos Ambientales , Monitoreo del Ambiente , Humanos , Estrés Oxidativo , Material Particulado/análisisRESUMEN
Concerns on nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) in the environment have mainly arisen from their mutagenic and carcinogenic effects. The objective of this study is to investigate whether nitro-PAH exposures are associated with biomarkers of cardiovascular pathophysiology. In a panel study design, urines and blood samples were collected up to four times with a 2-week interval from 89 healthy adults. We measured 1-naphthylamine, 2-naphthylamine, 9-aminophenanthrene, 2-aminofluorene, and 1-aminopyrene as biomarkers of nitro-PAH exposures. We measured three urinary metabolites of arachidonic acid (AA) including 20-hydroxyeicosatetraenoic acid (20-HETE) from the cytochrome P450 (CYP) pathway, 8-isoprostane from the nonenzymatic pathway, and 11-dehydro-thromboxane B2 (11-dhTXB2) from the cyclooxygenase (COX) pathway. Urinary malondialdehyde, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and 6-sulfatoxymelatonin (aMT6s) were measured to reflect systemic oxidative stress. Plasma concentrations of the soluble P-selectin and von Willebrand factor (vWF) were measured as biomarkers of platelet activation and endothelial dysfunction. We found that increased urinary concentrations of amino-PAHs were significantly associated with increased 20-HETE, 11-dhTXB2, and 8-OHdG and with decreased 8-isoprostane and aMT6s. Increased amino-PAHs were positively associated with P-selectin and vWF, respectively. These results suggest that exposure to nitro-PAHs increases systemic oxidative stress and alters AA metabolism toward CYP and COX pathways, leading to an increased cardiovascular disease risk.
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Hidrocarburos Policíclicos Aromáticos , 8-Hidroxi-2'-Desoxicoguanosina , Adulto , Ácido Araquidónico , Biomarcadores , Desoxiguanosina , Humanos , Nitratos , Hidrocarburos Policíclicos Aromáticos/toxicidadRESUMEN
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.
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Adenocarcinoma/mortalidad , Disbiosis/complicaciones , Neoplasias Pulmonares/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/microbiología , Adenocarcinoma/secundario , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Microbiota , Metástasis de la Neoplasia , Estadificación de Neoplasias , New York , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
Previous work has shown that individual randomized "proof-of-concept" (PoC) studies may be designed to maximize cost-effectiveness, subject to an overall PoC budget constraint. Maximizing cost-effectiveness has also been considered for arrays of simultaneously executed PoC studies. Defining Type III error as the opportunity cost of not performing a PoC study, we evaluate the common pharmaceutical practice of allocating PoC study funds in two stages. Stage 1, or the first wave of PoC studies, screens drugs to identify those to be permitted additional PoC studies in Stage 2. We investigate if this strategy significantly improves efficiency, despite slowing development. We quantify the benefit, cost, benefit-cost ratio, and Type III error given the number of Stage 1 PoC studies. Relative to a single stage PoC strategy, significant cost-effective gains are seen when at least one of the drugs has a low probability of success (10%) and especially when there are either few drugs (2) with a large number of indications allowed per drug (10) or a large portfolio of drugs (4). In these cases, the recommended number of Stage 1 PoC studies ranges from 2 to 4, tracking approximately with an inflection point in the minimization curve of Type III error.