Ventilation and Public Health: A Fraught History.

Since the beginning of the COVID-19 pandemic, a vigorous public health discussion has arisen over indoor air quality and ventilation. In popular press articles, bestselling books, and the US Environmental Protection Agency's recently announced Clean Air in Buildings Challenge, scholars and policy experts have claimed that improved ventilation systems can lead to better productivity and performance. By reevaluating those claims in light of the history of public health in Great Britain and the United States, we found that better ventilation has frequently been proposed as a cost-effective and nonintrusive means of improving health in institutions experiencing structural and environmental public health problems. Furthermore, our examination of efforts to provide ventilation for enslaved people, incarcerated people, and the urban poor revealed a consistent lack of government regulation and a disassociation of air quality concerns from broader environmental, social, and economic realities. By continuing to ignore these broader contexts, current ventilation efforts risk repeating this pattern. (Am J Public Health. 2024;114(8):798-804. https://doi.org/10.2105/AJPH.2024.307670).

Practical considerations for using low-cost sensors to assess wildfire smoke exposure in school and childcare settings.

BACKGROUND: More frequent and intense wildfires will increase concentrations of smoke in schools and childcare settings. Low-cost sensors can assess fine particulate matter (PM2.5) concentrations with high spatial and temporal resolution. OBJECTIVE: We sought to optimize the use of sensors for decision-making in schools and childcare settings during wildfire smoke to reduce children's exposure to PM2.5. METHODS: We measured PM2.5 concentrations indoors and outdoors at four schools in Washington State during wildfire smoke in 2020-2021 using low-cost sensors and gravimetric samplers. We randomly sampled 5-min segments of low-cost sensor data to create simulations of brief portable handheld measurements. RESULTS: During wildfire smoke episodes (lasting 4-19 days), median hourly PM2.5 concentrations at different locations inside a single facility varied by up to 49.6 µg/m3 (maximum difference) during school hours. Median hourly indoor/outdoor ratios across schools ranged from 0.22 to 0.91. Within-school differences in concentrations indicated that it is important to collect measurements throughout a facility. Simulation results suggested that making handheld measurements more often and over multiple days better approximates indoor/outdoor ratios for wildfire smoke. During a period of unstable air quality, PM2.5 over the next hour indoors was more highly correlated with the last 10-min of data (mean R2 = 0.94) compared with the last 3-h (mean R2 = 0.60), indicating that higher temporal resolution data is most informative for decisions about near-term activities indoors. IMPACT STATEMENT: As wildfires continue to increase in frequency and severity, staff at schools and childcare facilities are increasingly faced with decisions around youth activities, building use, and air filtration needs during wildfire smoke episodes. Staff are increasingly using low-cost sensors for localized outdoor and indoor PM2.5 measurements, but guidance in using and interpreting low-cost sensor data is lacking. This paper provides relevant information applicable for guidance in using low-cost sensors for wildfire smoke response.

The Effect of Participatory Heat Education on Agricultural Worker Knowledge.

OBJECTIVES: Farmworkers disproportionately experience preventable adverse health effects from heat exposure. We sought to evaluate the effect of participatory heat education on farmworker knowledge. METHODS: We conducted a parallel, comparison group intervention study to investigate the effectiveness of a Spanish/English participatory, culturally-tailored, heat education-based intervention on farmworker heat knowledge in the Summer 2019. We used convenience sampling to recruit adult outdoor farmworkers from Central/Eastern Washington State, USA. Crews were randomized to receive the intervention (n = 40 participants) versus not receive the intervention (n = 43 participants). We assessed changes in heat knowledge, scored on a scale from 0 to 11, between baseline, immediate post-intervention, and post-season, which was approximately three months after baseline, using the Wilcoxon signed-rank test. We compared differences in knowledge scores from baseline to post-season between groups using analysis of variance. RESULTS: Average knowledge scores improved from 4.6 (standard deviation [sd] 1.5) to 6.3 (sd 2.0) pre to post season in the intervention group (p < 0.001). There was a greater improvement in pre-post knowledge scores in the intervention (average difference 1.6, sd 2.0) versus the comparison group (average difference 0.41, sd 1.7) (p = 0.04). CONCLUSIONS: Participatory heat training was effective in improving farmworker heat knowledge over the course of a summer season. Results of this study will be used to guide heat prevention efforts for farmworkers. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT04234802.

"The lungs of a ship": Ventilation, acclimatization, and labor in the maritime environment, 1740-1800.

This article examines the connection between projects for shipboard ventilation and the shifting medical discourse about acclimatization in the British Empire during the eighteenth century. I argue that the design, use, and disuse of a class of shipboard "ventilators" proposed by natural philosopher Stephen Hales helps us to trace changing ideas about the ability of European bodies to acclimate, or "season," to tropical environments. These ventilating machines appealed to British administrators because they represented an embodiment of providential and enlightened ideas that validated the expansion of overseas empire. In addition, they promised to increase labor efficiency by reducing the mortality and misery experienced by the sailors and enslaved people during long sea voyages. As skepticism about acclimatization grew in response to stubbornly high mortality rates in the West Indies, Hales' ventilators fell out of favor - a development underscored by their dismissal as a potential solution for the appalling conditions found in the transatlantic slave trade. By examining ventilators' nearly fifty-year career in naval and slave ships, this article will show the role of technology and the shipboard environment in the transition from enlightened optimism about acclimatization toward later attitudes of racial and environmental essentialism.

The effect of the participatory heat education and awareness tools (HEAT) intervention on agricultural worker physiological heat strain: results from a parallel, comparison, group randomized study.

BACKGROUND: Farmworkers are at risk of heat-related illness (HRI). We sought to: 1) evaluate the effectiveness of farmworker Spanish/English participatory heat education and a supervisor decision-support mobile application (HEAT intervention) on physiological heat strain; and 2) describe factors associated with HRI symptoms reporting. METHODS: We conducted a parallel, comparison group intervention study from May-September of 2019 in Central/Eastern Washington State, USA. We used convenience sampling to recruit adult outdoor farmworkers and allocated participating crews to intervention (n = 37 participants) and alternative-training comparison (n = 38 participants) groups. We measured heat strain monthly using heart rate and estimated core body temperature to compute the maximum work-shift physiological strain index (PSImax) and assessed self-reported HRI symptoms using a weekly survey. Multivariable linear mixed effects models were used to assess associations of the HEAT intervention with PSImax, and bivariate mixed models were used to describe factors associated with HRI symptoms reported (0, 1, 2+ symptoms), with random effects for workers. RESULTS: We observed larger decreases in PSImax in the intervention versus comparison group for higher work exertion levels (categorized as low, low/medium-low, and high effort), after adjustment for maximum work-shift ambient Heat Index (HImax), but this was not statistically significant (interaction - 0.91 for high versus low/medium-low effort, t = - 1.60, p = 0.11). We observed a higher PSImax with high versus low/medium-low effort (main effect 1.96, t = 3.81, p < 0.001) and a lower PSImax with older age (- 0.03, t = - 2.95, p = 0.004), after covariate adjustment. There was no clear relationship between PSImax and the number of HRI symptoms reported. Reporting more symptoms was associated with older age, higher HImax, 10+ years agricultural work, not being an H-2A guest worker, and walking > 3 min to get to the toilet at work. CONCLUSIONS: Effort level should be addressed in heat management plans, for example through work/rest cycles, rotation, and pacing, in addition to education and other factors that influence heat stress. Both symptoms and indicators of physiological heat strain should be monitored, if possible, during periods of high heat stress to increase the sensitivity of early HRI detection and prevention. Structural barriers to HRI prevention must also be addressed. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT04234802 , date first posted 21/01/2020.

Within-City Variation in Ambient Carbon Monoxide Concentrations: Leveraging Low-Cost Monitors in a Spatiotemporal Modeling Framework.

BACKGROUND: Based on human and animal experimental studies, exposure to ambient carbon monoxide (CO) may be associated with cardiovascular disease outcomes, but epidemiological evidence of this link is limited. The number and distribution of ground-level regulatory agency monitors are insufficient to characterize fine-scale variations in CO concentrations. OBJECTIVES: To develop a daily, high-resolution ambient CO exposure prediction model at the city scale. METHODS: We developed a CO prediction model in Baltimore, Maryland, based on a spatiotemporal statistical algorithm with regulatory agency monitoring data and measurements from calibrated low-cost gas monitors. We also evaluated the contribution of three novel parameters to model performance: high-resolution meteorological data, satellite remote sensing data, and copollutant (PM2.5, NO2, and NOx) concentrations. RESULTS: The CO model had spatial cross-validation (CV) R2 and root-mean-square error (RMSE) of 0.70 and 0.02 parts per million (ppm), respectively; the model had temporal CV R2 and RMSE of 0.61 and 0.04 ppm, respectively. The predictions revealed spatially resolved CO hot spots associated with population, traffic, and other nonroad emission sources (e.g., railroads and airport), as well as sharp concentration decreases within short distances from primary roads. DISCUSSION: The three novel parameters did not substantially improve model performance, suggesting that, on its own, our spatiotemporal modeling framework based on geographic features was reliable and robust. As low-cost air monitors become increasingly available, this approach to CO concentration modeling can be generalized to resource-restricted environments to facilitate comprehensive epidemiological research. https://doi.org/10.1289/EHP10889.

Associations between repeated measures of urinary phthalate metabolites and biomarkers of oxidative stress in a rural agricultural cohort of children with asthma.

Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %-14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %-28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %-12.2 %) and 6.5 % (95 % CI: 1.4 %-11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.

Longitudinal measures of phthalate exposure and asthma exacerbation in a rural agricultural cohort of Latino children in Yakima Valley, Washington.

Phthalates are a class of widely used synthetic chemicals found in commonly used materials and products. Epidemiological studies suggest phthalate exposure is associated with asthma outcomes, though most studies have not investigated phthalates as triggers of exacerbations in children diagnosed with asthma. This study used data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine relationships between phthalate exposure and outcomes related to childhood asthma exacerbation. We used measures of phthalate metabolites and respiratory health measures including fractional exhaled nitric oxide (FENO), the Asthma Control Test (ACT), caregiver report of symptoms, and urinary leukotriene E4 (uLTE4) to estimate longitudinal associations using mixed effects models, adjusted for covariates. For 100% (i.e., doubling) increases in mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and mono-ethyl phthalate (MEP), concentrations of FENO increased by 8.7% (95% CI: 0.7-17.3), 7.2% (95% CI: 0.0-14.9), and 6.4% (95% CI: 0.0-13.3), respectively. All phthalate metabolites demonstrated associations with uLTE4, effect sizes ranging from an 8.7% increase in uLTE4 (95% CI: 4.3-12.5) for a 100% increase in MEHP to an 18.1% increase in uLTE4 (95% CI: 13.3-23.1) for a 100% increase in MNBP. In models of caregiver report of symptoms, no phthalate metabolites were significantly associated in primary models. No phthalate metabolites were associated with standardized ACT score. Our results suggest urinary phthalate metabolites are significant predictors of inflammatory biomarkers related to asthma exacerbation in children but not child and caregiver report of airway symptomatology.

Accuracy of an estimated core temperature algorithm for agricultural workers.

There is a substantial burden of occupational health effects from heat exposure. We sought to assess the accuracy of estimated core body temperature (CBTest) derived from an algorithm that uses sequential heart rate and initializing CBT,1 compared with gastrointestinal temperature measured using more invasive ingestible sensors (CBTgi), among outdoor agricultural workers. We analyzed CBTest and CBTgi data from Washington State, USA, pear and apple harvesters collected across one work shift in 2015 (13,413 observations, 35 participants) using Bland Altman methods. The mean (standard deviation, range) CBTgi was 37.7 (0.4, 36.5-39.4)°C. Overall CBT bias (limits of agreement) was -0.14 (±0.76)°C. Biases ranged from -0.006 to -0.75 °C. The algorithm, which does not require the use of ingestible sensors, may be a practical tool in research among groups of workers for evaluating the effectiveness of interventions to prevent adverse occupational heat health effects.

Randomized trial of a portable HEPA air cleaner intervention to reduce asthma morbidity among Latino children in an agricultural community.

BACKGROUND: Data on pediatric asthma morbidity and effective environmental interventions in U.S. agricultural settings are few. We evaluated the effectiveness of HEPA air cleaners on asthma morbidity among a cohort of rural Latino children. METHODS: Seventy-five children with poorly controlled asthma and living in non-smoking homes were randomly assigned to asthma education alone or along with HEPA air cleaners placed in their sleeping area and home living room. The Asthma Control Test (ACT) score, asthma symptoms in prior 2 weeks, unplanned clinical utilization, creatinine-adjusted urinary leukotriene E4 (uLTE4 [ng/mg]), and additional secondary outcomes were evaluated at baseline, six, and 12 months. Group differences were assessed using multivariable-adjusted generalized estimating equations. Incident rate ratios of ever experiencing the metrics of poorer asthma health during follow-up (suboptimal asthma management) were estimated using Poisson regression models in secondary analysis. RESULTS: Mean child age was 9.2 and 8.6 years in intervention and control groups, respectively, and two-thirds of participants were male. Primary analysis of repeated measures of ACT score did not differ between groups (HEPA group mean change compared to controls 10% [95% CI: - 12-39%]). A suggestion of greater decrease in uLTE4 (ng/mg creatinine) was observed (- 10% [95% CI: - 20 -1%]). Secondary analysis showed children with HEPAs were less likely to have an ACT score meeting a clinically defined cutoff for poorly controlled asthma using repeated measures (IRR: 0.45 [95% CI: 0.21-0.97]). In Poisson models, intervention participants had reduced risk of ever meeting this cutoff (IRR: 0.43 [95% CI: 0.21-0.89]), ever having symptoms in the past 2 weeks (IRR: 0.71 [95% CI: 0.52-0.98]), and lower risk of any unplanned clinical utilization (IRR: 0.35 [95% CI: 0.13-0.94]) compared to control participants. DISCUSSION: The HAPI study showed generally improved outcomes among children in the HEPA air cleaner group. However, primary analyses did not meet statistical significance and many outcomes were subjective (self-report) in this unblinded study, so findings must be interpreted cautiously. HEPA air cleaners may provide additional benefit for child asthma health where traditional asthmagens (traffic, tobacco smoke) are not prominent factors, but larger studies with more statistical power and blinded designs are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04919915 . Date of retrospective registration: May 19, 2021.

Publicly available low-cost sensor measurements for PM2.5 exposure modeling: Guidance for monitor deployment and data selection.

High-resolution, high-quality exposure modeling is critical for assessing the health effects of ambient PM2.5 in epidemiological studies. Using sparse regulatory PM2.5 measurements as principal model inputs may result in two issues in exposure prediction: (1) they may affect the models' accuracy in predicting PM2.5 spatial distribution; (2) the internal validation based on these measurements may not reliably reflect the model performance at locations of interest (e.g., a cohort's residential locations). In this study, we used the PM2.5 measurements from a publicly available commercial low-cost PM2.5 network, PurpleAir, with an external validation dataset at the residential locations of a representative sample of participants from the Adult Changes in Thought - Air Pollution (ACT-AP) study, to improve the accuracy of exposure prediction at the cohort participant locations. We also proposed a metric based on principal component analysis (PCA) - the PCA distance - to assess the similarity between monitor and cohort locations to guide monitor deployment and data selection. The analysis was based on a spatiotemporal modeling framework with 51 "gold-standard" monitors and 58 PurpleAir monitors for model development, as well as 105 home monitors at the cohort locations for model validation, in the Puget Sound region of Washington State from June 2017 to March 2019. After including calibrated PurpleAir measurements as part of the dependent variable, the external spatiotemporal validation R2 and root-mean-square error, RMSE, for two-week concentration averages improved from 0.84 and 2.22 µg/m3 to 0.92 and 1.63 µg/m3, respectively. The external spatial validation R2 and RMSE for long-term averages over the modeling period improved from 0.72 and 1.01 µg/m3 to 0.79 and 0.88 µg/m3, respectively. The exposure predictions incorporating PurpleAir measurements demonstrated sharper urban-suburban concentration gradients. The PurpleAir monitors with shorter PCA distances improved the model's prediction accuracy more substantially than the monitors with longer PCA distances, supporting the use of this similarity metric.

Exploring the Potential of 2-(2-Nitrophenyl)ethyl-Caged N-Hydroxysulfonamides for the Photoactivated Release of Nitroxyl (HNO).

The emergence of nitroxyl (HNO) as a biological signaling molecule is attracting increasing attention. HNO-based prodrugs show considerable potential in treating congestive heart failure, with HNO reacting rapidly with metal centers and protein-bound and free thiols. A new class of 2-(2-nitrophenyl)ethyl (2-NPE)-photocaged N-hydroxysulfonamides has been developed, and the mechanisms of photodecomposition have been investigated. Three photodecomposition pathways are observed: the desired concomitant C-O/N-S bond cleavage to generate HNO, sulfinate, and 2-nitrostyrene, C-O bond cleavage to give the parent sulfohydroxamic acid and 2-nitrostyrene, and O-N bond cleavage to release a sulfonamide and 2-nitrophenylacetaldehyde. Laser flash photolysis experiments provide support for a Norrish type II mechanism involving 1,5-hydrogen atom abstraction to generate an aci-nitro species. A mechanism is proposed in which the (Z)-aci-nitro intermediate undergoes either C-O bond cleavage to release RSO2NHO(H), concerted C-O/N-S bond cleavage to generate sulfinate and HNO, or isomerization to the (E)-isomer prior to O-N bond cleavage. The pKa of the N(H) of the N-hydroxysulfonamide plays a key role in determining whether C-O or concerted C-O/N-S bond cleavage occurs. Deprotonating this site favors the desired C-O/N-S bond cleavage at the expense of an increased level of undesired O-N bond cleavage. Triplet state quenchers have no effect on the observed photoproducts.

Effectiveness of portable HEPA air cleaners on reducing indoor endotoxin, PM10, and coarse particulate matter in an agricultural cohort of children with asthma: A randomized intervention trial.

We conducted a randomized trial of portable HEPA air cleaners in the homes of children age 6-12 years with asthma in the Yakima Valley, Washington. All families received asthma education while intervention families also received two HEPA cleaners (child's bedroom, living room). We collected 14-day integrated samples of endotoxin in settled dust and PM10 and PM10-2.5 in the air of the children's bedrooms at baseline and one-year follow-up, and used linear regression to compare follow-up levels, adjusting for baseline. Seventy-one families (36 HEPA, 35 control) completed the study. Baseline geometric mean (GSD) endotoxin loadings were 1565 (6.3) EU/m2 and 2110 (4.9) EU/m2 , respectively, in HEPA vs. control homes while PM10 and PM10-2.5 were 22.5 (1.9) µg/m3 and 9.5 (2.9) µg/m3 , respectively, in HEPA homes, and 19.8 (1.8) µg/m3 and 7.7 (2.0) µg/m3 , respectively, in control homes. At follow-up, HEPA families had 46% lower (95% CI, 31%-57%) PM10 on average than control families, consistent with prior studies. In the best-fit heterogeneous slopes model, HEPA families had 49% (95% CI, 6%-110%) and 89% lower (95% CI, 28%-177%) PM10-2.5 at follow-up, respectively, at 50th and 75th percentile baseline concentrations. Endotoxin loadings did not differ significantly at follow-up (4% lower, HEPA homes; 95% CI, -87% to 50%).

Fine-Scale Air Pollution Models for Epidemiologic Research: Insights From Approaches Developed in the Multi-ethnic Study of Atherosclerosis and Air Pollution (MESA Air).

PURPOSE OF REVIEW: Epidemiological studies of short- and long-term health impacts of ambient air pollutants require accurate exposure estimates. We describe the evolution in exposure assessment and assignment in air pollution epidemiology, with a focus on spatiotemporal techniques first developed to meet the needs of the Multi-ethnic Study of Atherosclerosis and Air Pollution (MESA Air). Initially designed to capture the substantial variation in pollutant levels and potential health impacts that can occur over small spatial and temporal scales in metropolitan areas, these methods have now matured to permit fine-scale exposure characterization across the contiguous USA and can be used for understanding long- and short-term health effects of exposure across the lifespan. For context, we highlight how the MESA Air models compare to other available exposure models. RECENT FINDINGS: Newer model-based exposure assessment techniques provide predictions of pollutant concentrations with fine spatial and temporal resolution. These validated models can predict concentrations of several pollutants, including particulate matter less than 2.5 µm in diameter (PM2.5), oxides of nitrogen, and ozone, at specific locations (such as at residential addresses) over short time intervals (such as 2 weeks) across the contiguous USA between 1980 and the present. Advances in statistical methods, incorporation of supplemental pollutant monitoring campaigns, improved geographic information systems, and integration of more complete satellite and chemical transport model outputs have contributed to the increasing validity and refined spatiotemporal spans of available models. Modern models for predicting levels of outdoor concentrations of air pollutants can explain a substantial amount of the spatiotemporal variation in observations and are being used to provide critical insights into effects of air pollutants on the prevalence, incidence, progression, and prognosis of diseases across the lifespan. Additional enhancements in model inputs and model design, such as incorporation of better traffic data, novel monitoring platforms, and deployment of machine learning techniques, will allow even further improvements in the performance of pollutant prediction models.

The multi-level heat education and awareness tools [HEAT] intervention study for farmworkers: Rationale and methods.

BACKGROUND: The burden of adverse health effects from heat exposure is substantial, and outdoor workers who perform heavy physical work are at high risk. Though heat prevention interventions have been developed, studies have not yet systematically evaluated the effectiveness of approaches that address risk factors at multiple levels. OBJECTIVE: We sought to test the effectiveness of a multi-level heat prevention approach (heat education and awareness tools [HEAT]), which includes participatory training for outdoor agricultural workers that addresses individual and community factors and a heat awareness mobile application for agricultural supervisors that supports decisions about workplace heat prevention, in the Northwest United States. DESIGN: We designed the HEAT study as a parallel, comparison, randomized group intervention study that recruited workers and supervisors from agricultural workplaces. In intervention arm crews, workers received HEAT training, and supervisors received the HEAT awareness application. In comparison arm crews, workers were offered non-HEAT training. Primary outcomes were worker physiological heat strain and heat-related illness (HRI) symptoms. In both worker groups, we assessed HRI symptoms approximately weekly, and heat strain physiological monitoring was conducted at worksites approximately monthly, from June through August. DISCUSSION: To our knowledge, this is the first study to evaluate the effectiveness of a multi-level heat prevention intervention on physiological heat strain and HRI symptoms for outdoor agricultural workers. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT04234802.

Mechanistic Insights into Rapid Generation of Nitroxyl from a Photocaged N-Hydroxysulfonamide Incorporating the (6-Hydroxynaphthalen-2-yl)methyl Chromophore.

HNO is a highly reactive molecule that shows promise in treating heart failure. Molecules that rapidly release HNO with precise spatial and temporal control are needed to investigate the biology of this signaling molecule. (Hydroxynaphthalen-2-yl)methyl-photocaged N-hydroxysulfonamides are a new class of photoactive HNO generators. Recently, it was shown that a (6-hydroxynaphthalen-2-yl)methyl (6,2-HNM)-photocaged derivative of N-hydroxysulfonamide incorporating the trifluoromethanesulfonamidoxy group (1) quantitatively generates HNO. Mechanistic studies have now been carried out on this system and reveal that the ground state protonation state plays a key role in whether concerted heterolytic C-O/N-S bond cleavage to release HNO occurs versus undesired O-N bond cleavage. N-Deprotonation of 1 can be achieved by adding an aqueous buffer or a carboxylate salt to an aprotic solvent. Evidence is presented for C-O/N-S bond heterolysis occurring directly from the singlet excited state of the N-deprotonated parent molecule on the picosecond time scale, using femtosecond time-resolved transient absorption spectroscopy, to give a carbocation and 1NO-. This is consistent with the observation of significant fluorescence quenching when HNO is generated. The carbocation intermediate reacts rapidly with nucleophiles including water, MeOH, or even (H)NO in the absence of a molecule that reacts rapidly with (H)NO to give an oxime.

Effectiveness of portable HEPA air cleaners on reducing indoor PM2.5 and NH3 in an agricultural cohort of children with asthma: A randomized intervention trial.

We conducted a randomized trial of portable HEPA air cleaners with pre-filters designed to also reduce NH3 in non-smoking homes of children age 6-12 with asthma in Yakima Valley (Washington, USA). Participants were recruited through the Yakima Valley Farm Workers Clinic asthma education program. All participants received education on home triggers while intervention families additionally received two HEPA cleaners (child's sleeping area, main living area). Fourteen-day integrated samples of PM2.5 and NH3 were measured at baseline and one-year follow-up. We fit ANCOVA models to compare follow-up concentrations in HEPA vs control homes, adjusting for baseline concentrations. Seventy-one households (36 HEPA, 35 control) completed the study. Most were single-family homes, with electric heat and stove, A/C, dogs/cats, and mean (SD) 5.3 (1.8) occupants. In the sleeping area, baseline geometric mean (GSD) PM2.5 was 10.7 (2.3) µg/m3 (HEPA) vs 11.2 (1.9) µg/m3 (control); in the living area, it was 12.5 (2.3) µg/m3 (HEPA) vs 13.6 (1.9) µg/m3 (control). Baseline sleeping area NH3 was 62.4 (1.6) µg/m3 (HEPA) vs 65.2 (1.8) µg/m3 (control). At follow-up, HEPA families had 60% (95% CI, 41%-72%; p < .0001) and 42% (19%-58%; p = .002) lower sleeping and living area PM2.5 , respectively, consistent with prior studies. NH3 reductions were not observed.

The home air in agriculture pediatric intervention (HAPI) trial: Rationale and methods.

BACKGROUND: Data addressing air quality effects on children with asthma in rural U.S. communities are rare. Our community engaged research partnership previously demonstrated associations between neighborhood NH3 and ambient PM2.5 and asthma in the agricultural lower Yakima Valley of Washington. As a next step, the partnership desired an intervention approach to address concerns about pediatric asthma in this largely Latino immigrant, farm worker community. OBJECTIVE: The Home Air in Agriculture Pediatric Intervention (HAPI) sought to examine the effectiveness of enrichment of an existing asthma education program with portable high-efficiency particulate air (HEPA) cleaners designed to reduce PM2.5 and NH3. We investigated the effect of this enriched approach on these exposures and asthma health measures. DESIGN: We randomized children with poorly controlled asthma to a control arm (current asthma education program) or an intervention arm (current asthma education program + placement of two indoor air cleaners in the family's home). Outcomes included (1) 14-day integrated samples of indoor air contaminants (PM2.5 and NH3) at baseline and one-year follow-up and (2) child asthma health metrics at baseline, midpoint (4-6 months) and one-year follow-up. These included the Asthma Control Test, symptoms days, clinical utilization, oral corticosteroid use, pulmonary function, fractional exhaled nitric oxide, and urinary leukotriene E4 concentration. DISCUSSION: To our knowledge, this is the first randomized HEPA cleaner intervention designed to assess NH3 as well as PM2.5 and to evaluate health outcomes of children with asthma in an agricultural region.

Maternal Instruction About Jaundice and the Incidence of Acute Bilirubin Encephalopathy in Nigeria.

OBJECTIVE: To evaluate whether teaching mothers about neonatal jaundice will decrease the incidence of acute bilirubin encephalopathy among infants admitted for jaundice. STUDY DESIGN: This was a multicenter, before-after and cross-sectional study. Baseline incidences of encephalopathy were obtained at 4 collaborating medical centers between January 2014 and May 2015 (Phase 1). Structured jaundice instruction was then offered (May to November 2015; Phase 2) in antenatal clinics and postpartum. Descriptive statistics and logistic regression models compared 3 groups: 843 Phase 1 controls, 338 Phase 2 infants whose mothers received both antenatal and postnatal instruction (group A), and 215 Phase 2 infants whose mothers received no instruction (group B) either because the program was not offered to them or by choice. RESULTS: Acute bilirubin encephalopathy occurred in 147 of 843 (17%) Phase 1 and 85 of 659 (13%) Phase 2 admissions, which included 63 of 215 (29%) group B and 5 of 338 (1.5%) group A infants. OR for having acute bilirubin encephalopathy, comparing group A and group B infants adjusted for confounding risk factors, was 0.12 (95% CI 0.03-0.60). Delayed care-seeking (defined as an admission total bilirubin ≥18 mg/dL at age ≥48 hours) was the strongest single predictor of acute bilirubin encephalopathy (OR 11.4; 6.6-19.5). Instruction decreased delay from 49% to 17%. Other major risk factors were home births (OR 2.67; 1.69-4.22) and hemolytic disease (hematocrit ≤35% plus bilirubin ≥20 mg/dL) (OR 3.03; 1.77-5.18). The greater rate of acute bilirubin encephalopathy with home vs hospital birth disappeared if mothers received jaundice instruction. CONCLUSIONS: Providing information about jaundice to mothers was associated with a reduction in the incidence of bilirubin encephalopathy per hospital admission.

Estimated time-varying exposures to air emissions from animal feeding operations and childhood asthma.

BACKGROUND/AIM: Industrial-scale animal feeding operations (AFOs) have adverse impacts on regional air quality. Air emissions include endotoxins and other pro-inflammatory components, and exposure may cause airway inflammation and respiratory effects in susceptible individuals residing nearby. We aimed to develop and validate metrics for estimating time-varying exposure to AFO air pollution in surrounding communities and, secondly, to determine whether exposure is associated with health effects in children with asthma. METHODS: We conducted a longitudinal panel study of N = 58 children with asthma in an agricultural region of Washington State with a high density of dairy AFOs. Children were followed for up to 26 months with repeated measures of respiratory health (N = 2023 interviews; N = 3853 lung function measurements); urine was collected in a subcohort (N = 16) at six-day intervals over three months and analyzed for leukotriene E4 (LTE4), a biomarker of systemic inflammation (N = 138 measurements). We developed an approach to estimate daily exposure to AFO airborne emissions based on distance to AFOs, AFO size, and daily wind speed and direction, and validated the estimates against direct measurements of ammonia, a chemical marker of AFO emissions, measured biweekly at 18 sites across the region for 14 months. Short-term relationships between AFO pollutant exposure and outcomes were assessed using regression models accounting for within-participant correlation and several potential confounders. RESULTS: Estimates of daily AFO air pollution correlated moderately well with outdoor ammonia measurements (N = 842; r = 0.62). Forced expiratory volume in 1 s (FEV1) as percent of predicted was 2.0% (95% CI: 0.5, 3.5) lower with each interquartile increase in previous day exposure, but no associations with asthma symptoms were observed. There was suggestive evidence that LTE4 concentrations were higher following days of elevated exposure to AFO emissions (p = 0.06). CONCLUSIONS: A simple metric of time-varying exposure to AFO emissions was correlated with daily outdoor ammonia levels. Children with asthma may be adversely affected by exposure to AFO emissions.