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.

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.

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.

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.

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 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.

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.

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.

A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC-treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 µm) and nitric oxide (100 µm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 µm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

Safety and toxicology assessment of sodium nitrite administered by intramuscular injection.

Intramuscular (IM) injection of nitrite (1-10 mg/kg) confers survival benefit and protects against lung injury after exposure to chlorine gas in preclinical models. Herein, we evaluated safety/toxicity parameters after single, and repeated (once daily for 7 days) IM injection of nitrite in male and female Sprague Dawley rats and Beagle dogs. The repeat dose studies were performed in compliance with the Federal Drug Administration's (FDA) Good Laboratory Practices Code of Federal Regulations (21 CFR Part 58). Parameters evaluated consisted of survival, clinical observations, body weights, clinical pathology, plasma drug levels, methemoglobin and macroscopic and microscopic pathology. In rats and dogs, single doses of ≥100 mg/kg and 60 mg/kg resulted in death and moribundity, while repeated administration of ≤30 or ≤ 10 mg/kg/day, respectively, was well tolerated. Therefore, the maximum tolerated dose following repeated administration in rats and dogs were determined to be 30 mg/kg/day and 10 mg/kg/day, respectively. Effects at doses below the maximum tolerated dose (MTD) were limited to emesis (in dogs only) and methemoglobinemia (in both species) with clinical signs (e.g. blue discoloration of lips) being dose-dependent, transient and reversible. These signs were not considered adverse, therefore the No Observed Adverse Effect Level (NOAEL) for both rats and dogs was 10 mg/kg/day in males (highest dose tested for dogs), and 3 mg/kg/day in females. Toxicokinetic assessment of plasma nitrite showed no difference between male and females, with Cmax occurring between 5 mins and 0.5 h (rats) or 0.25 h (dogs). In summary, IM nitrite was well tolerated in rats and dogs at doses previously shown to confer protection against chlorine gas toxicity.

Adherence to Social Distancing Guidelines Throughout the COVID-19 Pandemic: The Roles of Pseudoscientific Beliefs, Trust, Political Party Affiliation, and Risk Perceptions.

BACKGROUND: Adherence to COVID-19 social distancing guidelines varies across individuals. PURPOSE: This study examined the relations of pseudoscientific and just world beliefs, generalized and institutional trust, and political party affiliation to adherence to COVID-19 social distancing guidelines over three months, as well as the explanatory role of COVID-19 risk perceptions in these relations. METHODS: A U.S. nationwide sample of 430 adults (49.8% women; mean age = 40.72) completed a prospective online study, including an initial assessment (between March 27 and April 5, 2020), a 1 month follow-up (between April 27 and May 21, 2020), and a 3 month follow-up (between June 26 and July 15, 2020). We hypothesized that greater pseudoscientific and just world beliefs, lower governmental, institutional, and dispositional trust, and Republican Party affiliation would be associated with lower initial adherence to social distancing and greater reductions in social distancing over time and that COVID-19 risk perceptions would account for significant variance in these relations. RESULTS: Results revealed unique associations of lower governmental trust, greater COVID-19 pseudoscientific beliefs, and greater trust in the Centers for Disease Control and Prevention (CDC) to lower initial adherence to social distancing. Whereas greater COVID-19 risk perceptions and CDC trust were associated with less steep declines in social distancing over time, both Republican (vs. Democratic) Party affiliation and greater COVID-19 pseudoscientific beliefs were associated with steeper declines in social distancing over time (relations accounted for by lower COVID-19 risk perceptions). CONCLUSIONS: Results highlight the utility of public health interventions aimed at improving scientific literacy and emphasizing bipartisan support for social distancing guidelines.

Cross-sectional evaluation of perceived health care provider engagement, self-efficacy, and ART adherence in people living with HIV/AIDS.

Despite advancements in the treatment and prevention of HIV/AIDS, adherence to antiretroviral therapy (ART) remains suboptimal. Research indicates that health care provider (HCP) engagement is related to adherence, yet little is known about the specific pathways that underlie this relation. This cross-sectional study examined the relation between perceived HCP engagement and ART adherence in people living with HIV/AIDS (PLWHA), as well as the role of adherence self-efficacy in this relation. Participants (N = 207) completed self-report measures assessing monthly ART adherence, perceived ability to take ART as prescribed, and perceptions of HCP engagement. Results of a path analysis revealed a direct positive relation between perceived HCP engagement and ART adherence, and a significant indirect relation of perceived HCP engagement to ART adherence through adherence self-efficacy. Higher perceived HCP engagement was related to greater adherence self-efficacy, which, in turn was related to higher ART adherence. Findings are consistent with research demonstrating that HCP support leads to increased motivation to engage in treatment and extends past work on the importance of positive patient-provider relationships. Notably, results suggest that increasing patient perceptions of HCP engagement may be one way to boost adherence self-efficacy and improve ART adherence in PLWHA.

No evidence of hemoglobin damage by SARS-CoV-2 infection.

SARS-CoV-2 disease (COVID-19) has affected over 22 million patients worldwide as of August 2020. As the medical community seeks better understanding of the underlying pathophysiology of COVID-19, several theories have been proposed. One widely shared theory suggests that SARS-CoV-2 proteins directly interact with human hemoglobin (Hb) and facilitate removal of iron from the heme prosthetic group, leading to the loss of functional hemoglobin and accumulation of iron. Herein, we refute this theory. We compared clinical data from 21 critically ill COVID-19 patients to 21 non-COVID-19 ARDS patient controls, generating hemoglobin-oxygen dissociation curves from venous blood gases. This curve generated from the COVID-19 cohort matched the idealized oxygen-hemoglobin dissociation curve well (Pearson correlation, R2 = 0.97, P.

Examining Relationships between Gender, Opioid Dependence, and Distress Tolerance among Patients in Substance Use Disorder Treatment.

Background: Opioid abuse/dependence is associated with multiple negative outcomes relative to other forms of substance abuse/dependence, including relapse. Research identifying modifiable characteristics associated with opioid dependence and associated negative outcomes may inform the development of targeted interventions for this high-risk population. One factor warranting investigation is low distress tolerance (DT). Purpose/Objectives: In a sample of patients in substance use disorder (SUD) treatment, the present study examined DT levels among patients with current opioid dependence versus no history of opioid dependence, as well as the moderating role of gender. We predicted that patients with opioid dependence would exhibit lower DT than those without a history of opioid dependence, and that women with opioid dependence would exhibit lower levels of DT than men with opioid dependence. Methods: A sample of 203 patients in residential SUD treatment were administered a series of diagnostic interviews and a behavioral measure of DT. Results: DT did not differ significantly as a function of opioid dependence. However, there was a significant opioid dependence by gender interaction, such that men with current opioid dependence exhibited significantly lower levels of DT than women with opioid dependence and men without a history of opioid dependence. Conclusions/Importance: Findings highlight a modifiable characteristic associated with opioid dependence among men that may be targeted in interventions.

The Zebrafish Cytochrome b5/Cytochrome b5 Reductase/NADH System Efficiently Reduces Cytoglobins 1 and 2: Conserved Activity of Cytochrome b5/Cytochrome b5 Reductases during Vertebrate Evolution.

Cytoglobin is a heme protein evolutionarily related to hemoglobin and myoglobin. Cytoglobin is expressed ubiquitously in mammalian tissues; however, its physiological functions are yet unclear. Phylogenetic analyses indicate that the cytoglobin gene is highly conserved in vertebrate clades, from fish to reptiles, amphibians, birds, and mammals. Most proposed roles for cytoglobin require the maintenance of a pool of reduced cytoglobin (FeII). We have shown previously that the human cytochrome b5/cytochrome b5 reductase system, considered a quintessential hemoglobin/myoglobin reductant, can reduce human and zebrafish cytoglobins ≤250-fold faster than human hemoglobin or myoglobin. It was unclear whether this reduction of zebrafish cytoglobins by mammalian proteins indicates a conserved pathway through vertebrate evolution. Here, we report the reduction of zebrafish cytoglobins 1 and 2 by the zebrafish cytochrome b5 reductase and the two zebrafish cytochrome b5 isoforms. In addition, the reducing system also supports reduction of Globin X, a conserved globin in fish and amphibians. Indeed, the zebrafish reducing system can maintain a fully reduced pool for both cytoglobins, and both cytochrome b5 isoforms can support this process. We determined the P50 for oxygen to be 0.5 Torr for cytoglobin 1 and 4.4 Torr for cytoglobin 2 at 25 °C. Thus, even at low oxygen tensions, the reduced cytoglobins may exist in a predominant oxygen-bound form. Under these conditions, the cytochrome b5/cytochrome b5 reductase system can support a conserved role for cytoglobins through evolution, providing electrons for redox signaling reactions such as nitric oxide dioxygenation, nitrite reduction, and phospholipid oxidation.

Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning.

OBJECTIVES: Carbon monoxide poisoning affects 50,000 per year in the United States alone. Mortality is approximately 3%, and up to 40% of survivors suffer from permanent neurocognitive and affective deficits. Hyperbaric oxygen therapy has shown benefit on reducing the long-term neurologic sequelae of carbon monoxide poisoning but has not demonstrated improved survival. The objective of this study is to assess the efficacy of hyperbaric oxygen for acute and long-term mortality in carbon monoxide poisoning using a large clinical databank. DESIGN: Retrospective analysis. SETTING: University of Pittsburgh Medical Center healthcare system (Pittsburgh, PA). PATIENTS: One-thousand ninety-nine unique encounters of adult patients with carbon monoxide poisoning. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical information from charting were obtained from the electronic medical record. In propensity-adjusted analysis, hyperbaric oxygen therapy was associated with a reduction in inpatient mortality (absolute risk reduction, 2.1% [3.7-0.9%]; p = 0.001) and a reduction in 1-year mortality (absolute risk reduction, 2.1% [3.8-0.4%]; p = 0.013). CONCLUSIONS: These data demonstrate that hyperbaric oxygen is associated with reduced acute and reduced 1-year mortality. Further studies are needed on the mortality effects of hyperbaric oxygen therapy in carbon monoxide poisoning.

Suppression of Metastasis by Primary Tumor and Acceleration of Metastasis Following Primary Tumor Resection: A Natural Law?

We study metastatic cancer progression through an extremely general individual-patient mathematical model that is rooted in the contemporary understanding of the underlying biomedical processes yet is essentially free of specific biological assumptions of mechanistic nature. The model accounts for primary tumor growth and resection, shedding of metastases off the primary tumor and their selection, dormancy and growth in a given secondary site. However, functional parameters descriptive of these processes are assumed to be essentially arbitrary. In spite of such generality, the model allows for computing the distribution of site-specific sizes of detectable metastases in closed form. Under the assumption of exponential growth of metastases before and after primary tumor resection, we showed that, regardless of other model parameters and for every set of site-specific volumes of detected metastases, the model-based likelihood-maximizing scenario is always the same: complete suppression of metastatic growth before primary tumor resection followed by an abrupt growth acceleration after surgery. This scenario is commonly observed in clinical practice and is supported by a wealth of experimental and clinical studies conducted over the last 110 years. Furthermore, several biological mechanisms have been identified that could bring about suppression of metastasis by the primary tumor and accelerated vascularization and growth of metastases after primary tumor resection. To the best of our knowledge, the methodology for uncovering general biomedical principles developed in this work is new.

Carbon Monoxide Poisoning: Pathogenesis, Management, and Future Directions of Therapy.

Carbon monoxide (CO) poisoning affects 50,000 people a year in the United States. The clinical presentation runs a spectrum, ranging from headache and dizziness to coma and death, with a mortality rate ranging from 1 to 3%. A significant number of patients who survive CO poisoning suffer from long-term neurological and affective sequelae. The neurologic deficits do not necessarily correlate with blood CO levels but likely result from the pleiotropic effects of CO on cellular mitochondrial respiration, cellular energy utilization, inflammation, and free radical generation, especially in the brain and heart. Long-term neurocognitive deficits occur in 15-40% of patients, whereas approximately one-third of moderate to severely poisoned patients exhibit cardiac dysfunction, including arrhythmia, left ventricular systolic dysfunction, and myocardial infarction. Imaging studies reveal cerebral white matter hyperintensities, with delayed posthypoxic leukoencephalopathy or diffuse brain atrophy. Management of these patients requires the identification of accompanying drug ingestions, especially in the setting of intentional poisoning, fire-related toxic gas exposures, and inhalational injuries. Conventional therapy is limited to normobaric and hyperbaric oxygen, with no available antidotal therapy. Although hyperbaric oxygen significantly reduces the permanent neurological and affective effects of CO poisoning, a portion of survivors still have substantial morbidity. There has been some early success in therapies targeting the downstream inflammatory and oxidative effects of CO poisoning. New methods to directly target the toxic effect of CO, such as CO scavenging agents, are currently under development.

Experiencing is believing: prior experience moderates the impact of self-based and socially-based cues in the context of blood donation.

Two studies explored how self-based cues (i.e., self-efficacy), socially-based cues (i.e., perceived social norms), and prior blood donation experience differentially influence behavioral intentions. In Study 1, undergraduate students (N = 766) completed an online study that evaluated prior experiences, self-efficacy, perceived norms, and behavioral intentions in the context of blood donation. In Study 2, a community sample (N = 199) from a clinic waiting room completed similar measures. Across both studies, having high self-efficacy was a necessary and sufficient antecedent to high intentions, regardless of norm perception for donors. For non-donors, however, high self-efficacy was necessary but not sufficient; non-donors' intentions were higher when giving blood was perceived to be normative, but far lower when it was not. When self-efficacy was low, the effects of experience and norms did not exert meaningful effects and donation intentions were quite low. These results demonstrate that the impact of self-based and socially-based cues on behavioral intentions may differ as a function of experience. The findings can inform public health initiatives and enhance the accuracy of theoretical models by directly examining experience as a moderator.