Adverse Health Impacts of Outdoor Air Pollution, Including from Wildland Fires, in the United States: "Health of the Air," 2018-2020.

Rationale: Adverse health impacts from outdoor air pollution occur across the United States, but the magnitude of these impacts varies widely by geographic region. Ambient pollutant concentrations, emission sources, baseline health conditions, and population sizes and distributions are all important factors that need to be taken into account to quantify local health burdens. Objectives: To determine health impacts from ambient air pollution concentrations in the United States that exceed the levels recommended by the American Thoracic Society. Methods: Using a methodology that has been well established in previous "Health of the Air" reports, this study provides policy-relevant estimates for every monitored county and city in the United States for the adverse health impacts of outdoor pollution concentrations using U.S. Environmental Protection Agency design values for years 2018-2020. Additionally, for the first time, the report includes adverse birth outcomes as well as estimates of health impacts specifically attributable to wildland fires using an exposure dataset generated through Community Multiscale Air Quality simulations. Results: The adverse health burdens attributable to air pollution occur across the entire age spectrum, including adverse birth outcomes (10,660 preterm and/or low-weight births; 95% confidence interval [CI], 3,180-18,330), in addition to mortality impacts (21,300 avoidable deaths; 95% CI, 16,180-26,200), lung cancer incidence (3,000 new cases; 95% CI, 1,550-4,390), multiple types of cardiovascular and respiratory morbidity (748,660 events; 95% CI, 326,050-1,057,080), and adversely impacted days (52.4 million days; 95% CI, 7.9-92.4 million days). Two different estimates of mortality impacts from wildland fires were created based on assumptions regarding the underlying toxicity of particles from wildland fires (low estimate of 4,080 deaths, 95% CI, 240-7,890; middle estimate of 28,000 deaths, 95% CI, 27,300-28,700). Conclusions: This year's report identified sizable health benefits that would be expected to occur across the United States with compliance with more health-protective air quality standards such as those recommended by the American Thoracic Society. This study also indicates that a large number of excess deaths are attributable to emissions from wildland fires; air quality management strategies outside what is required by the Clean Air Act will be needed to best address this important source of air pollution and its associated health risks.

The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

Pulmonary and Critical Care Considerations for e-Cigarette, or Vaping, Product Use-Associated Lung Injury.

BACKGROUND: In 2019, the United States experienced a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). More than one-half of these patients required admission to an ICU. RESEARCH QUESTION: What are the recent literature and expert opinions which inform the diagnosis and management of patients with critical illness with EVALI? STUDY DESIGN AND METHODS: To synthesize information critical to pulmonary/critical care specialists in the care of patients with EVALI, this study examined data available from patients hospitalized with EVALI between August 2019 and January 2020; reviewed the clinical course and critical care experience with those patients admitted to the ICU; and compiled opinion of national experts. RESULTS: Of the 2,708 patients with confirmed or probable EVALI requiring hospitalization as of January 21, 2020, a total of 1,604 (59.2%) had data available on ICU admission; of these, 705 (44.0%) were admitted to the ICU and are included in this analysis. The majority of ICU patients required respiratory support (88.5%) and in severe cases required intubation (36.1%) or extracorporeal membrane oxygenation (6.7%). The majority (93.0%) of these ICU patients survived to discharge. Review of the clinical course and expert opinion provided insight into: imaging; considerations for bronchoscopy; medical treatment, including use of empiric antibiotics, antiviral agents, and corticosteroids; respiratory support, including considerations for intubation, positioning maneuvers, and extracorporeal membrane oxygenation; and patient outcomes. INTERPRETATION: Review of the clinical course of patients with EVALI requiring ICU admission and compilation of expert opinion provided critical insight into pulmonary/critical care-specific considerations for this patient population. Because a large proportion of patients hospitalized with EVALI required ICU admission, it is important to remain prepared to care for patients with EVALI.

Excess Morbidity and Mortality Associated with Air Pollution above American Thoracic Society Recommended Standards, 2017-2019.

Rationale: Over the past year, the American Thoracic Society (ATS), led by its Environmental Health Policy Committee, has reviewed the most current air quality scientific evidence and has revised their recommendations to 8 µg/m3 and 25 µg/m3 for long- and short-term fine particulate matter (PM2.5) and reaffirmed the recommendation of 60 ppb for ozone to protect the American public from the known adverse health effects of air pollution. The current U.S. Environmental Protection Agency (EPA) standards, in contrast, expose the American public to pollution levels that are known to result in significant morbidity and mortality. Objectives: To provide county-level estimates of annual air pollution-related health outcomes across the United States using the most recent federal air quality data, and to support the ATS's recent update to the long-term PM2.5 recommended standard. This study is presented as part of the annual ATS/Marron Institute "Health of the Air" report. Methods: Daily air pollution values were obtained from the EPA's air quality system for monitored counties in the United States from 2017-2019. Concentration-response functions used in the EPA's regulatory review process were applied to pollution increments corresponding to differences between the rolling 3-year design values and ATS-recommended levels for long-term PM2.5 (8 µg/m3), short-term PM2.5 (25 µg/m3), and ground-level ozone (O3; 60 ppb). Health impacts were estimated at the county level in locations with valid monitoring data. Results: Meeting ATS recommendations throughout the country prevents an estimated 14,650 (95% confidence interval [CI], 8,660-22,610) deaths; 2,950 (95% CI, 1,530-4,330) lung cancer incidence events; 33,100 (95% CI, 7,300-71,000) morbidities, and 39.8 million (95% CI, 14.6-63.3 million) impacted days annually. This prevents 11,850 more deaths; 2,580 more lung cancer incidence events; 25,400 more morbidities; and 27.2 million more impacted days than meeting EPA standards alone. Conclusions: Significant health benefits to be gained by U.S. communities that work to meet ATS-recommended air quality standards have now been identified under scenarios meeting the new ATS recommendation for long-term PM2.5 (8 µg/m3). The "Health of the Air" report presents an opportunity for air quality managers to quantify local health burdens and EPA officials to update their standards to reflect the latest science.

Effects of an In-Frame Deletion of the 6k Gene Locus from the Genome of Ross River Virus.

UNLABELLED: The alphaviral6kgene region encodes the two structural proteins 6K protein and, due to a ribosomal frameshift event, the transframe protein (TF). Here, we characterized the role of the6kproteins in the arthritogenic alphavirus Ross River virus (RRV) in infected cells and in mice, using a novel6kin-frame deletion mutant. Comprehensive microscopic analysis revealed that the6kproteins were predominantly localized at the endoplasmic reticulum of RRV-infected cells. RRV virions that lack the6kproteins 6K and TF [RRV-(Δ6K)] were more vulnerable to changes in pH, and the corresponding virus had increased sensitivity to a higher temperature. While the6kdeletion did not reduce RRV particle production in BHK-21 cells, it affected virion release from the host cell. Subsequentin vivostudies demonstrated that RRV-(Δ6K) caused a milder disease than wild-type virus, with viral titers being reduced in infected mice. Immunization of mice with RRV-(Δ6K) resulted in a reduced viral load and accelerated viral elimination upon secondary infection with wild-type RRV or another alphavirus, chikungunya virus (CHIKV). Our results show that the6kproteins may contribute to alphaviral disease manifestations and suggest that manipulation of the6kgene may be a potential strategy to facilitate viral vaccine development. IMPORTANCE: Arthritogenic alphaviruses, such as chikungunya virus (CHIKV) and Ross River virus (RRV), cause epidemics of debilitating rheumatic disease in areas where they are endemic and can emerge in new regions worldwide. RRV is of considerable medical significance in Australia, where it is the leading cause of arboviral disease. The mechanisms by which alphaviruses persist and cause disease in the host are ill defined. This paper describes the phenotypic properties of an RRV6kdeletion mutant. The absence of the6kgene reduced virion release from infected cells and also reduced the severity of disease and viral titers in infected mice. Immunization with the mutant virus protected mice against viremia not only upon exposure to RRV but also upon challenge with CHIKV. These findings could lead to the development of safer and more immunogenic alphavirus vectors for vaccine delivery.

Antiviral efficacy of the novel compound BIT225 against HIV-1 release from human macrophages.

Building on previous findings that amiloride analogues inhibit HIV-1 replication in monocyte-derived macrophages (MDM), Biotron Limited has generated a library of over 300 small-molecule compounds with significant improvements in anti-HIV-1 activity. Our lead compound, BIT225, blocks Vpu ion channel activity and also shows anti-HIV-1 activity, with a 50% effective concentration of 2.25+/-0.23 microM (mean+/-the standard error) and minimal in vitro toxicity (50% toxic concentration, 284 microM) in infected MDM, resulting in a selectivity index of 126. In this study, we define the antiretroviral efficacy of BIT225 activity in macrophages, which are important drug targets because cells of the monocyte lineage are key reservoirs of HIV-1, disseminating virus to the peripheral tissues as they differentiate into macrophages. In assays with acutely and chronically HIV-1Ba-L-infected MDM, BIT225 resulted in significant reductions in viral integration and virus release as measured by real-time PCR and a reverse transcriptase (RT) activity assay at various stages of monocyte-to-macrophage differentiation. Further, the TZM-bl assay showed that the de novo virus produced at low levels in the presence of BIT225 was less infectious than virus produced in the absence of the compound. No antiviral activity was observed in MDM chronically infected with HIV-2, which lacks Vpu, confirming our initial targeting of and screening against this viral protein. The activity of BIT225 is post-virus integration, with no direct effects on the HIV-1 enzymes RT and protease. The findings of this study suggest that BIT225 is a late-phase inhibitor of the viral life cycle, targeting Vpu, and is a drug capable of significantly inhibiting HIV-1 release from both acute and chronically infected macrophages.

Hexamethylene amiloride blocks E protein ion channels and inhibits coronavirus replication.

All coronaviruses encode a small hydrophobic envelope (E) protein, which mediates viral assembly and morphogenesis by an unknown mechanism. We have previously shown that the E protein from Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) forms cation-selective ion channels in planar lipid bilayers (Wilson, L., McKinlay, C., Gage, P., Ewart, G., 2004. SARS coronavirus E protein forms cation-selective ion channels. Virology 330(1), 322-331). We now report that three other E proteins also form cation-selective ion channels. These E proteins were from coronaviruses representative of taxonomic groups 1-3: human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and infectious bronchitis virus (IBV), respectively. It appears, therefore, that coronavirus E proteins in general, belong to the virus ion channels family. Hexamethylene amiloride (HMA)--an inhibitor of the HIV-1 Vpu virus ion channel--inhibited the HCoV-229E and MHV E protein ion channel conductance in bilayers and also inhibited replication of the parent coronaviruses in cultured cells, as determined by plaque assay. Conversely, HMA had no antiviral effect on a recombinant MHV with the entire coding region of E protein deleted (MHVDeltaE). Taken together, the data provide evidence of a link between inhibition of E protein ion channel activity and the antiviral activity of HMA.

SARS coronavirus E protein forms cation-selective ion channels.

Severe Acute Respiratory Syndrome (SARS) is caused by a novel coronavirus (SARS-CoV). Coronaviruses including SARS-CoV encode an envelope (E) protein, a small, hydrophobic membrane protein. We report that, in planar lipid bilayers, synthetic peptides corresponding to the SARS-CoV E protein forms ion channels that are more permeable to monovalent cations than to monovalent anions. Affinity-purified polyclonal antibodies recognizing the N-terminal 19 residues of SARS-CoV E protein were used to establish the specificity of channel formation by inhibiting the ion currents generated in the presence of the E protein peptides.

Potential new anti-human immunodeficiency virus type 1 compounds depress virus replication in cultured human macrophages.

We report that the amiloride analogues 5-(N,N-hexamethylene)amiloride and 5-(N,N-dimethyl)amiloride inhibit, at micromolar concentrations, the replication of human immunodeficiency virus type 1 (HIV-1) in cultured human blood monocyte-derived macrophages. These compounds also inhibit the in vitro activities of the HIV-1 Vpu protein and might represent lead compounds for a new class of anti-HIV-1 drugs.

Alphavirus 6K proteins form ion channels.

Ross River virus and Barmah Forest virus are Australian arboviruses of the Alphavirus genus. Features of alphavirus infection include an increased permeability of cells to monovalent cations followed by virion budding. Virally encoded ion channels are thought to have a role in these processes. In this paper, the 6K proteins of Ross River virus and Barmah Forest virus are shown to form cation-selective ion channels in planar lipid bilayers. Using a novel purification method, bacterially expressed 6K proteins were inserted into bilayers with a defined orientation (i.e. N-terminal cis, C-terminal trans). Channel activity was reversibly inhibited by antibodies to the N and C termini of 6K protein added to the cis and trans baths, respectively. Channel conductances varied from 40-800 picosiemens, suggesting that the protein is able to form channels with a range of possible oligomerization states.