Carbon Monoxide Poisoning: From Microbes to Therapeutics.

Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.

Dimensional and social comparisons in a health fitness context.

Whereas prior research has found that people are influenced by both internal (e.g., dimensional) and external (e.g., social) comparative information in academic contexts, we experimentally examined the influence of such comparisons in a health fitness context. Participants engaged in "physical and mental fitness" tasks (e.g., performing sit-ups, memorizing words) and were randomly assigned to receive (1) social comparative feedback indicating their physical or mental fitness was better or worse than their peers or (2) dimensional comparative feedback indicating their performance in a target domain (e.g., mental fitness) was better or worse than a referent domain (e.g., physical fitness). Results showed that participants who made upward comparisons had lower fitness self-evaluations and more negative (less positive) emotional reactions to the feedback for the target domain, with the effect being nominally stronger for social than dimensional comparisons and for mental than physical fitness. Findings are discussed in the context of comparison-based models and health behavior theories.

Tendencies for Comparing Up and Down: An Examination of the Directional Subscales of the Iowa-Netherlands Comparison Orientation Measure.

People vary in their individual tendencies to compare to others-referred to as social comparison orientation (SCO). Researchers have heretofore developed and validated a scale to assess SCO-the Iowa-Netherlands Comparison Orientation Measure (INCOM). The standard INCOM assesses non-directional comparisons, but not directional comparisons to better- and worse-off others. The goal of the present research was to examine the factor structure and validity of directional (and non-directional) comparison tendencies using the expanded INCOM. Across four archival studies and one pre-registered study using student and non-student samples, we provide evidence for 1) a 3-factor structure for the INCOM with non-directional, directional-upward, and directional-downward SCO dimensions, 2) inter-correlations among the SCO dimensions suggesting convergent validity of the directional scales, 3) greater endorsement of non-directional, then directional-upward, and directional-downward SCO, 4) lower SCO among older individuals and members of racial/ethnic minority groups, and 5) strong and consistent associations of directional-upward SCO with well-being and affect, appearance beliefs (e.g., body satisfaction), social emotions (e.g., envy), and agency-related motivations and consequences in interpersonal contexts, but smaller and less consistent associations of non-directional and directional-downward SCO with outcomes (with notable exceptions). Taken together, this research indicates that SCO is a multi-faceted individual difference variable.

Challenges and Opportunities for Commercializing Technologies in the Pulmonary Arena: An Official American Thoracic Society Report.

"Translational medicine" has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new "bench-to-bedside" approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

Thiol-catalyzed formation of NO-ferroheme regulates intravascular NO signaling.

Nitric oxide (NO) is an endogenously produced signaling molecule that regulates blood flow and platelet activation. However, intracellular and intravascular diffusion of NO are limited by scavenging reactions with several hemoproteins, raising questions as to how free NO can signal in hemoprotein-rich environments. We explore the hypothesis that NO can be stabilized as a labile ferrous heme-nitrosyl complex (Fe2+-NO, NO-ferroheme). We observe a reaction between NO, labile ferric heme (Fe3+) and reduced thiols to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation occurs when heme is solubilized in lipophilic environments such as red blood cell membranes or bound to serum albumin. The resulting NO-ferroheme resists oxidative inactivation, is soluble in cell membranes and is transported intravascularly by albumin to promote potent vasodilation. We therefore provide an alternative route for NO delivery from erythrocytes and blood via transfer of NO-ferroheme and activation of apo-soluble guanylyl cyclase.

Which measures of perceived vulnerability predict protective intentions-and when?

Assessing perceived vulnerability to a health threat is essential to understanding how people conceptualize their risk, and to predicting how likely they are to engage in protective behaviors. However, there is limited consensus about which of many measures of perceived vulnerability predict behavior best. We tested whether the ability of different measures to predict protective intentions varies as a function of the type of information people learn about their risk. Online participants (N = 909) read information about a novel respiratory disease before answering measures of perceived vulnerability and vaccination intentions. Type-of-risk information was varied across three between-participant groups. Participants learned either: (1) only information about their comparative standing on the primary risk factors (comparative-only), (2) their comparative standing as well as the base-rate of the disease in the population (+ base-rate), or (3) their comparative standing as well as more specific estimates of their absolute risk (+ absolute-chart). Experiential and affective measures of perceived vulnerability predicted protective intentions well regardless of how participants learned about their risk, while the predictive ability of deliberative numeric and comparative measures varied based on the type of risk information provided. These results broaden the generalizability of key prior findings (i.e., some prior findings about which measures predict best may apply no matter how people learn about their risk), but the results also reveal boundary conditions and critical points of distinction for determining how to best assess perceived vulnerability.

Heart-Brain 346-7 Score: the development and validation of a simple mortality prediction score for carbon monoxide poisoning utilizing deep learning.

INTRODUCTION: Acute mortality from carbon monoxide poisoning is 1-3%. The long-term mortality risk of survivors of carbon monoxide poisoning is doubled compared to age-matched controls. Cardiac involvement also increases mortality risk. We built a clinical risk score to identify carbon monoxide-poisoned patients at risk for acute and long-term mortality. METHODS: We performed a retrospective analysis. We identified 811 adult carbon monoxide-poisoned patients in the derivation cohort, and 462 adult patients in the validation cohort. We utilized baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical charting information in the electronic medical record in Stepwise Akaike's Information Criteria with Firth logistic regression to determine optimal parameters to create a prediction model. RESULTS: In the derivation cohort, 5% had inpatient or 1-year mortality. Three variables following the final Firth logistic regression minimized Stepwise Akaike's Information Criteria: altered mental status, age, and cardiac complications. The following predict inpatient or 1-year mortality: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. The sensitivity of the score was 82% (95% confidence interval: 65-92%), the specificity was 80% (95% confidence interval: 77-83%), negative predictive value was 99% (95% confidence interval: 98-100%), positive predictive value 17% (95% confidence interval: 12-23%), and the area under the receiver operating characteristic curve was 0.81 (95% confidence interval: 0.74-0.87). A score above the cut-off point of -2.9 was associated with an odds ratio of 18 (95% confidence interval: 8-40). In the validation cohort (462 patients), 4% had inpatient death or 1-year mortality. The score performed similarly in the validation cohort: sensitivity was 72% (95% confidence interval: 47-90%), specificity was 69% (95% confidence interval: 63-73%), negative predictive value was 98% (95% confidence interval: 96-99%), positive predictive value was 9% (95% confidence interval: 5-15%) and the area under the receiver operating characteristic curve was 0.70 (95% confidence interval: 60%-81%). CONCLUSIONS: We developed and validated a simple, clinical-based scoring system, the Heart-Brain 346-7 Score to predict inpatient and long-term mortality based on the following: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. With further validation, this score will hopefully aid decision-making to identify carbon monoxide-poisoned patients with higher mortality risk.

Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products: A Scientific Statement From the American Heart Association.

Vaping and electronic cigarette (e-cigarette) use have grown exponentially in the past decade, particularly among youth and young adults. Cigarette smoking is a risk factor for both cardiovascular and pulmonary disease. Because of their more limited ingredients and the absence of combustion, e-cigarettes and vaping products are often touted as safer alternative and potential tobacco-cessation products. The outbreak of e-cigarette or vaping product use-associated lung injury in the United States in 2019, which led to >2800 hospitalizations, highlighted the risks of e-cigarettes and vaping products. Currently, all e-cigarettes are regulated as tobacco products and thus do not undergo the premarket animal and human safety studies required of a drug product or medical device. Because youth prevalence of e-cigarette and vaping product use was as high as 27.5% in high school students in 2019 in the United States, it is critical to assess the short-term and long-term health effects of these products, as well as the development of interventional and public health efforts to reduce youth use. The objectives of this scientific statement are (1) to describe and discuss e-cigarettes and vaping products use patterns among youth and adults; (2) to identify harmful and potentially harmful constituents in vaping aerosols; (3) to critically assess the molecular, animal, and clinical evidence on the acute and chronic cardiovascular and pulmonary risks of e-cigarette and vaping products use; (4) to describe the current evidence of e-cigarettes and vaping products as potential tobacco-cessation products; and (5) to summarize current public health and regulatory efforts of e-cigarettes and vaping products. It is timely, therefore, to review the short-term and especially the long-term implications of e-cigarettes and vaping products on cardiopulmonary health. Early molecular and clinical evidence suggests various acute physiological effects from electronic nicotine delivery systems, particularly those containing nicotine. Additional clinical and animal-exposure model research is critically needed as the use of these products continues to grow.

Contaminant Back Diffusion from Low-Conductivity Matrices: Case Studies of Remedial Strategies.

Recalcitrant groundwater contamination is a common problem at hazardous waste sites worldwide. Groundwater contamination persists despite decades of remediation efforts at many sites because contaminants sorbed or dissolved within low-conductivity zones can back diffuse into high-conductivity zones, and therefore act as a continuing source of contamination to flowing groundwater. A review of the available literature on remediation of plume persistence due to back diffusion was conducted, and four sites were selected as case studies. Remediation at the sites included pump and treat, enhanced bioremediation, and thermal treatment. Our review highlights that a relatively small number of sites have been studied in sufficient detail to fully evaluate remediation of back diffusion; however, three general conclusions can be made based on the review. First, it is difficult to assess the significance of back diffusion without sufficient data to distinguish between multiple factors contributing to contaminant rebound and plume persistence. Second, high-resolution vertical samples are decidedly valuable for back diffusion assessment but are generally lacking in post-treatment assessments. Third, complete contaminant mass removal from back diffusion sources may not always be possible. Partial contaminant mass removal may nonetheless have potential benefits, similar to partial mass removal from primary DNAPL source zones.

Increased levels of autistic traits are associated with atypical moral judgments.

Despite evidence often showing differences between groups with Autism Spectrum Disorder (ASD) and neurotypical controls in moral judgment, the precise nature of these differences has been difficult to establish. At least two reasons for this are (1) that ASD (and its associated characteristics) is difficult to define and (2) that morality, and the inclinations that undergird it, are hard to measure empirically. These challenges have made conclusive associations between ASD and particular patterns of moral judgment hard to come by. Thus, in the current study, participants levels of a traits associated with ASD were assessed by their responses to a questionnaire (i.e., the Iowa Screener) before they made moral judgments across a set of 20 moral dilemmas that independently assess utilitarian and deontological processing. Interestingly, results indicated that increased levels of autistic traits were associated with fewer moral judgments corresponding to either moral theory; that is, higher levels of autistic traits were associated with atypical patterns of moral judgment. In addition, and consistent with some prior methods (e.g., Gaeth et al., 2016), participant scores on the Iowa Screener, as well as their self-identification, were used to categorize participants between two groups (i.e., ASD and Typical) for exploratory purposes. Taken together, this research better informs the relationship between ASD and its associated traits with moral judgment and can inform certain discrepant findings in the field. Implications and ideas for future research are discussed, such as whether traits associated with ASD might relate to alternative moral inclinations, beyond deontology and utilitarianism.

Thiol catalyzed formation of NO-ferroheme regulates canonical intravascular NO signaling.

Nitric oxide (NO) is an endogenously produced physiological signaling molecule that regulates blood flow and platelet activation. However, both the intracellular and intravascular diffusion of NO is severely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoproteins, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments, like blood and cardiomyocytes. We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe 2+ -NO, NO-ferroheme) either in solution within membranes or bound to albumin. Unexpectedly, we observed a rapid reaction of NO with free ferric heme (Fe 3+ ) and a reduced thiol under physiological conditions to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when the hemin is solubilized in lipophilic environments, such as red blood cell membranes, or bound to serum albumin. NO-ferroheme albumin is stable, even in the presence of excess oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme-albumin administered intravenously to mice dose-dependently vasodilates at low- to mid-nanomolar concentrations. In conclusion, we report the fastest rate of reductive nitrosylation observed to date to generate a NO-ferroheme molecule that resists oxidative inactivation, is soluble in cell membranes, and is transported intravascularly by albumin to promote potent vasodilation.

The effects of social-media based social comparison information and similarity mindsets on COVID-19 vaccination uptake cognitions.

Vaccine hesitancy-delays in vaccine uptake when one is readily available-is an important public health issue. During the COVID-19 pandemic, the role of psychosocial factors in influencing cognitions and behaviors related to vaccine uptake have been examined. Using an online sample of unvaccinated U.S. adults (N = 300), we examined the influence of COVID-19-related social media-based comparison information (e.g., others' attitudes about taking the vaccine)-as well as the moderating impact of (dis)similarity mindsets and indirect influence of affective associations, norm perceptions, and self-evaluations of efficacy-on vaccination uptake intentions. Participants reported higher intentions for vaccine uptake following exposure to cautious comparison models (e.g., those that engaged in health prevention behaviors, intended to get vaccinated) versus risky comparison models (e.g., those who did not engage in health prevention behaviors, did not intend to get vaccinated) and neutral comparison models and this effect was indirect through positive affective associations about taking the vaccine. There were no main or interactive effects of (dis)similarity mindsets. Understanding the psychosocial factors that influence health cognitions and behaviors in the context of an infectious disease pandemic will advance theoretical development and aid in creating interventions targeting vaccine uptake.

The impact of stay-at-home orders on vulnerability assessments and precautionary intentions during a pandemic.

In 2020, a novel emerging infectious disease - COVID-19 - became a global pandemic and prompted unprecedented social distancing measures. We examined the associations of voluntary stay-at-home (SAH) orders during the COVID-19 pandemic with vulnerability assessments and precautionary intentions (e.g. social distancing, hand washing). A quasi-experimental study using an online adult sample was conducted in U.S. states with and without voluntary SAH orders during the COVID-19 pandemic. Self-report surveys assessed vulnerability assessments and precautionary intentions. Participants living in states with SAH orders showed inflated vulnerability assessments for contracting COVID-19, and this association was stronger for affect-laden than cognitively-based assessments. Moreover, only affect-laden vulnerability assessments were uniquely associated with precautionary intentions and accounted for the relationship between SAH orders and precautionary intentions. Our study was among the first to explore the impact of voluntary SAH orders on vulnerability assessments and precautionary intentions. Results are discussed in terms of their implications for health behavioral models and applications for promoting self-protective actions during a pandemic.

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.

Multisite Qualification of an Automated Incubator and Colony Counter for Environmental and Bioburden Applications in Pharmaceutical Microbiology.

Traditional microbiological techniques have been used for well over a century as the basis for contamination testing of pharmaceutical products and processes. With more recent focus on faster product release and concerns around the integrity of the test data, new technologies have been implemented to detect and enumerate organisms faster and provide paperless processes to minimize data integrity issues. Manual colony counting technologies, where incubation is performed in a standard incubator, and the plate is manually transferred to the colony counter for a single read at the end of incubation, have been used for many years to reduce the potential for human error; however, they pose validation challenges due to poor counting accuracy. Colony counters that automatically perform both the incubation and enumeration functions (multiple enumeration calculations through the incubation phase) have recently been implemented for quality control (QC) laboratory analytical processes, supporting a cGMP environment. This article summarizes the findings of eight companies demonstrating the qualification of an automated colony counter technology to perform the majority of microbial tests required for QC, environmental monitoring, and bioburden for in-process, bulk drug substance, and water system testing. Comparable analytical performance and time to result data generated during individual studies at all companies allows the system to be qualified and implemented for cGMP processes while reducing data integrity risks.

The prospective relations of substance use frequency to social distancing behaviors and intentions during the COVID-19 pandemic: the role of social distancing self-efficacy.

To identify factors that increase risk for nonadherence to recommended health protective behaviors during pandemics, this study examined the prospective relations of substance use frequency to both adherence to social distancing recommendations and social distancing intentions during the COVID-19 pandemic, as well as the role of social distancing self-efficacy in these relations. A U.S. community sample of 377 adults completed a prospective online study, including an initial assessment between March 27 and April 5, 2020, and a follow-up assessment one-month later. Results revealed a significant direct relation of baseline substance use frequency to lower adherence to social distancing recommendations one-month later. Results also revealed significant indirect relations of greater substance use frequency to lower levels of both social distancing behaviors and intentions one-month later through lower social distancing self-efficacy. Results highlight the relevance of substance use and social distancing self-efficacy to lower adherence to social distancing during the COVID-19 pandemic.

Cell-free and alkylated hemoproteins improve survival in mouse models of carbon monoxide poisoning.

I.v. administration of a high-affinity carbon monoxide-binding (CO-binding) molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to discover how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating 3 readily available hemoproteins, 2,3-diphosphoglycerate stripped human hemoglobin (StHb); N-ethylmaleimide modified hemoglobin (NEMHb); and equine myoglobin (Mb). These molecules efficiently sequester CO from hemoglobin in erythrocytes in vitro. A kinetic model was developed to predict the CO binding efficacy for hemoproteins, based on their measured in vitro oxygen and CO binding affinities, suggesting that the therapeutic efficacy of hemoproteins for CO poisoning relates to a high M value, which is the binding affinity for CO relative to oxygen (KA,CO/KA,O2). In a lethal CO poisoning mouse model, StHb, NEMHb, and Mb improved survival by 100%, 100%, and 60%, respectively, compared with saline controls and were well tolerated in 48-hour toxicology assessments. In conclusion, both StHb and NEMHb have high CO binding affinities and M values, and they scavenge CO efficiently in vitro and in vivo, highlighting their therapeutic potential for point-of-care antidotal therapy of CO poisoning.

Discussions and Misinformation About Electronic Nicotine Delivery Systems and COVID-19: Qualitative Analysis of Twitter Content.

BACKGROUND: Misinformation and conspiracy theories related to COVID-19 and electronic nicotine delivery systems (ENDS) are increasing. Some of this may stem from early reports suggesting a lower risk of severe COVID-19 in nicotine users. Additionally, a common conspiracy is that the e-cigarette or vaping product use-associated lung injury (EVALI) outbreak of 2019 was actually an early presentation of COVID-19. This may have important public health ramifications for both COVID-19 control and ENDS use. OBJECTIVE: Twitter is an ideal tool for analyzing real-time public discussions related to both ENDS and COVID-19. This study seeks to collect and classify Twitter messages ("tweets") related to ENDS and COVID-19 to inform public health messaging. METHODS: Approximately 2.1 million tweets matching ENDS-related keywords were collected from March 1, 2020, through June 30, 2020, and were then filtered for COVID-19-related keywords, resulting in 67,321 original tweets. A 5% (n=3366) subsample was obtained for human coding using a systematically developed codebook. Tweets were coded for relevance to the topic and four overarching categories. RESULTS: A total of 1930 (57.3%) tweets were coded as relevant to the research topic. Half (n=1008, 52.2%) of these discussed a perceived association between ENDS use and COVID-19 susceptibility or severity, with 42.4% (n=818) suggesting that ENDS use is associated with worse COVID-19 symptoms. One-quarter (n=479, 24.8%) of tweets discussed the perceived similarity/dissimilarity of COVID-19 and EVALI, and 13.8% (n=266) discussed ENDS use behavior. Misinformation and conspiracy theories were present throughout all coding categories. CONCLUSIONS: Discussions about ENDS use and COVID-19 on Twitter frequently highlight concerns about the susceptibility and severity of COVID-19 for ENDS users; however, many contain misinformation and conspiracy theories. Public health messaging should capitalize on these concerns and amplify accurate Twitter messaging.