RAF inhibitor re-challenge therapy in BRAF-aberrant pan-cancers: the RE-RAFFLE study.

Previous studies have shown the clinical benefit of rechallenging the RAF pathway in melanoma patients previously treated with BRAF inhibitors. 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor, either as monotherapy or in combination with other therapies, after prior therapy with a first RAF inhibitor. This retrospective observational study results showed that rechallenging with RAFi(s) led to an overall response rate of 18.1% [PR in thyroid (1 anaplastic; 3 papillary), 1 ovarian, 2 melanoma, 1 cholangiocarcinoma, and 1 anaplastic astrocytoma]. The clinical benefit rate was 54.5%; more than 30% of patients had durable responses with PR and SD lasting > 6 months. The median progression-free survival on therapy with second RAF inhibitor in the rechallenge setting either as monotherapy or combination was shorter at 2.7 months (0.9-30.1 m) compared to 8.6 months (6.5-11.5 m) with RAF-1i. However, the median PFS with RAF-2i responders (PFS-2) improved at 12.8 months compared to 11.4 months with RAF-1i responders. The median OS from retreatment with RAF-2i was 15.5 months (11.1-30.8 m). Further prospective studies are needed to validate these results and expand targeted therapy options for RAF-aberrant cancers.

Disparities in Guideline-Recommended Statin Use for Prevention of Atherosclerotic Cardiovascular Disease by Race, Ethnicity, and Gender : A Nationally Representative Cross-Sectional Analysis of Adults in the United States.

BACKGROUND: Although statins are a class I recommendation for prevention of atherosclerotic cardiovascular disease and its complications, their use is suboptimal. Differential underuse may mediate disparities in cardiovascular health for systematically marginalized persons. OBJECTIVE: To estimate disparities in statin use by race-ethnicity-gender and to determine whether these potential disparities are explained by medical appropriateness of therapy and structural factors. DESIGN: Cross-sectional analysis. SETTING: National Health and Nutrition Examination Survey from 2015 to 2020. PARTICIPANTS: Persons eligible for statin therapy based on 2013 and 2018 American College of Cardiology/American Heart Association blood cholesterol guidelines. MEASUREMENTS: The independent variable was race-ethnicity-gender. The outcome of interest was use of a statin. Using the Institute of Medicine framework for examining unequal treatment, we calculated adjusted prevalence ratios (aPRs) to estimate disparities in statin use adjusted for age, disease severity, access to health care, and socioeconomic status relative to non-Hispanic White men. RESULTS: For primary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors among non-Hispanic Black men (aPR, 0.73 [95% CI, 0.59 to 0.88]) and non-Mexican Hispanic women (aPR, 0.74 [CI, 0.53 to 0.95]). For secondary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors for non-Hispanic Black men (aPR, 0.81 [CI, 0.64 to 0.97]), other/multiracial men (aPR, 0.58 [CI, 0.20 to 0.97]), Mexican American women (aPR, 0.36 [CI, 0.10 to 0.61]), non-Mexican Hispanic women (aPR, 0.57 [CI, 0.33 to 0.82), non-Hispanic White women (aPR, 0.69 [CI, 0.56 to 0.83]), and non-Hispanic Black women (aPR, 0.75 [CI, 0.57 to 0.92]). LIMITATION: Cross-sectional data; lack of geographic, language, or statin-dose data. CONCLUSION: Statin use disparities for several race-ethnicity-gender groups are not explained by measurable differences in medical appropriateness of therapy, access to health care, and socioeconomic status. These residual disparities may be partially mediated by unobserved processes that contribute to health inequity, including bias, stereotyping, and mistrust. PRIMARY FUNDING SOURCE: National Institutes of Health.

American Indian Alaska Native (AIAN) adolescents and obesity: the influence of social determinants of health, mental health, and substance use.

OBJECTIVE: To explore the prevalence of obesity among American Indian and Alaska Native (AIAN) adolescents aged 12-19 years in association with social determinants of health (SDOH), and mental health and substance use disorders. METHODS: Guided by the World Health Organization's Social Determinants of Health Framework, we examined data from the Indian Health Service (IHS) Improving Health Care Delivery Data Project from Fiscal Year 2013, supplemented by county-level data from the U.S. Census and USDA. Our sample included 26,226 AIAN adolescents ages 12-19 years. We described obesity prevalence in relationship to SDOH and adolescents' mental health and substance use disorder status. We then fit a multivariable logit generalized linear mixed model to estimate the relationships after adjusting for other individual and county level characteristics. RESULTS: We observed a prevalence of 32.5% for obesity, 13.8% for mental health disorders, and 5.5% for substance use disorders. Females had lower odds of obesity than males (OR = 0.76, p < 0.001), which decreased with age. Having Medicaid coverage (OR = 1.09, p < 0.01), residing in a county with lower education attainment (OR = 1.17, p < 0.05), and residing in a county with higher rates of poverty (OR = 1.51, p < 0.001) were each associated with higher odds of obesity. Residing in a county with high access to a grocery store (OR = 0.73, p < 0.001) and residing in a county with a higher proportion of AIANs (OR = 0.83, p < 0.01) were each associated with lower odds of obesity. Those with mental health disorders had higher odds of obesity (OR = 1.26, p < 0.001); substance use disorders were associated with decreased odds of obesity (OR = 0.73, p < 0.001). CONCLUSIONS: Our findings inform future obesity prevention and treatment programs among AIAN youth; in particular, the need to consider mental health, substance use, and SDOH.

Health Literacy is Essential to ASCVD Prevention in Youth.

PURPOSE OF REVIEW: Health literacy is fundamental to primary and primordial prevention of atherosclerotic vascular disease (ASCVD) in children and adolescents. Here we summarize essential components of interventions which address health literacy challenges to reduce ASCVD risk in youth. RECENT FINDINGS: There is a global pandemic of suboptimal health behaviors among youth that may contribute to the increasing rates of ASCVD worldwide. Deficiencies in youth cardiovascular health have promoted increased attention to health education that incorporates health literacy. Studies conducted in both the child (0 to 9 years) and adolescent (10 to 17 years) population have shown improvement in health knowledge, health behaviors such as physical activity and eating habits, and objective measures such as body mass index (BMI), blood pressure, and serum lipid levels. The available literature affirms that the involvement of family and community members in young people's surroundings-including parents, teachers, and peers-can influence educational interventions' protective effects. Educational interventions which incorporate health literacy have demonstrated potential to address ASCVD risk factors in youth and may be augmented by caregiver and community involvement.

Coronary perfusion pressure is associated with adverse outcomes in advanced heart failure.

BACKGROUND: Myocardial perfusion is an important determinant of cardiac function. We hypothesized that low coronary perfusion pressure (CPP) would be associated with adverse outcomes in heart failure. Myocardial perfusion impacts the contractile efficiency thus a low CPP would signal low myocardial perfusion in the face of increased cardiac demand as a result of volume overload. METHODS: We analyzed patients with complete hemodynamic data in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial using Cox Proportional Hazards regression for the primary outcome of the composite risk of death, heart transplantation, or left ventricular assist device [(LVAD). DT × LVAD] and the secondary outcome of the composite risk of DT × LVAD and heart failure hospitalization (DT × LVADHF). CPP was calculated as the difference between diastolic blood pressure and pulmonary artery wedge pressure. Heart failure categories (ischemic vs non-ischemic) were also stratified based on CPP strata. RESULTS: The 158 patients (56.7 ± 13.6 years, 28.5% female) studied had a median CPP of 40 mmHg (IQR 35-52 mmHg). During 6 months of follow-up, 35 (22.2%) had the composite primary outcome and 109 (69.0%) had the composite secondary outcome. When these outcomes were then stratified based on the median, CPP was associated with these outcomes. Increasing CPP was associated with lower risk of both the primary outcome of DT × LVAD (HR 0.96, 95% CI 0.94-0.99 p = .002) and as well as the secondary outcome of DT × LVADHF (p = .0008) There was significant interaction between CPP and ischemic etiology (p = .04). CONCLUSION: A low coronary artery perfusion pressure below (median) 40mmHg in patients with advanced heart failure undergoing invasive hemodynamic monitoring with a pulmonary artery catheter was associated with adverse outcomes. CPP could useful in guiding risk stratification of advanced heart failure patients and timely evaluation of advanced heart failure therapies.

I Want to Die Well.

Public health scholars, practitioners, organizations, and governmental agencies broadly declared that racism is a public health crisis in 2020. Their declarations highlight the need to address how racism destroys Black life and communities. This poem looks at the various ways Black people have died in the United States due to racism, and offers a comparison to wealthy white men whom often die peacefully, of old age, surrounded by money and generations of family. This poem is but a glimpse into the many ways Black life ends painfully at the hands of racist systems, policies, and people-an unfiltered reminder of the imperative of committing to antiracist praxis within health promotion research and practice. To view the original version of this poem, see the supplemental material section of this article online.

Racial Diversity Among American Cardiologists: Implications for the Past, Present, and Future.

In the United States, race-based disparities in cardiovascular disease care have proven to be pervasive, deadly, and expensive. African American/Black, Hispanic/Latinx, and Native/Indigenous American individuals are at an increased risk of cardiovascular disease and are less likely to receive high-quality, evidence-based medical care as compared with their White American counterparts. Although the United States population is diverse, the cardiovascular workforce that provides its much-needed care lacks diversity. The available data show that care provided by physicians from racially diverse backgrounds is associated with better quality, both for minoritized patients and for majority patients. Not only is cardiovascular workforce diversity associated with improvements in health care quality, but racial diversity among academic teams and research scientists is linked with research quality. We outline documented barriers to achieving workforce diversity and suggest evidence-based strategies to overcome these barriers. Key strategies to enhance racial diversity in cardiology include improving recruitment and retention of racially diverse members of the cardiology workforce and focusing on cardiovascular health equity for patients. This review draws attention to academic institutions, but the implications should be considered relevant for nonacademic and community settings as well.

Evaluating the Effect of Dye-Dye Interactions of Xanthene-Based Fluorophores in the Fluorosequencing of Peptides.

A peptide sequencing scheme utilizing fluorescence microscopy and Edman degradation to determine the amino acid position in fluorophore-labeled peptides was recently reported, referred to as fluorosequencing. It was observed that multiple fluorophores covalently linked to a peptide scaffold resulted in a decrease in the anticipated fluorescence output and worsened the single-molecule fluorescence analysis. In this study, we report an improvement in the photophysical properties of fluorophore-labeled peptides by incorporating long and flexible (PEG)10 linkers at the peptide attachment points. Long linkers to the fluorophores were installed using copper-catalyzed azide-alkyne cycloaddition conditions. The photophysical properties of these peptides were analyzed in solution and immobilized on a microscope slide at the single-molecule level under peptide fluorosequencing conditions. Solution-phase fluorescence analysis showed improvements in both quantum yield and fluorescence lifetime with the long linkers. While on the solid support, photometry measurements showed significant increases in fluorescence brightness and 20 to 60% improvements in the ability to determine the amino acid position with fluorosequencing. This spatial distancing strategy demonstrates improvements in the peptide sequencing platform and provides a general approach for improving the photophysical properties in fluorophore-labeled macromolecules.

Association between neighborhood deprivation and presenting with a ruptured abdominal aortic aneurysm before screening age.

OBJECTIVE: Recent data indicate social determinants of health (SDOH) have a great impact on prevention and treatment outcomes across a broad variety of disease states, especially cardiovascular diseases. The area deprivation index (ADI) is a validated measure of neighborhood level disadvantage capturing key social determinate factors. Abdominal aortic aneurysm rupture (rAAA) is highly morbid, but also preventable through evidence-based screening. However, the association between rAAA and SDOH is poorly characterized. Our objective is to study the association of SDOH with rAAA and screening age. METHODS: This retrospective study included patients who underwent operative repair of a rAAA at a multihospital healthcare system (2003-2019). Deprivation was measured by the ADI (scale 1-100), grouped into quintiles for simplicity, with higher quintiles indicating greater deprivation. Patients with the highest quintile ADI (89-100) were categorized as the most deprived. We investigated the association between neighborhood deprivation with the odds of (i) undergoing repair for rAAA before screening age 65 and (ii) undergoing endovascular aortic repair (EVAR) using logistic regression, sequentially modeling nonmodifiable then both nonmodifiable and modifiable confounding variables. RESULTS: There were 632 patients who met the inclusion criteria (aged 74.2 ± 9.4 years; 174 women [27.6%]; 564 White [89.2%]; ADI 66.8 ± 22.3). Those from the most deprived neighborhoods (n = 118) were younger (71.7 ± 10.0 years vs 74.8 ± 9.2 years; P = .002), more likely to be female (36% vs 26%; P = .031), more likely to be Black (5.9% vs 0.4%; P = .007), and fewer underwent EVAR (28% vs 39.5%; P = .020) compared with those from other neighborhoods. On sequential modeling, residing in the most deprived neighborhoods was associated with undergoing rAAA repair before age 65 after adjusting for nonmodifiable factors (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.39-2.95; P < .001), and nonmodifiable as well as modifiable factors (OR, 2.22; 95% CI, 1.56-3.16; P < .001). Those in the most deprived neighborhoods had a lower odds of undergoing EVAR compared with open repair after adjusting for nonmodifiable factors (OR, 0.64; 95% CI, 0.41-0.98; P = .042), and nonmodifiable as well as modifiable factors (OR, 0.61; 95% CI, 0.37-0.99; P = .047). CONCLUSIONS: Among patients who underwent rAAA, residing in the most deprived neighborhoods was associated with greater adjusted odds of presenting under age 65 and undergoing an open repair. These neighborhoods represent tangible geographic targets that may benefit from a younger screening age, enhanced education, and access to care. These findings stress the importance of developing strategies for early prevention and diagnosis of cardiovascular diseases among patients with disadvantageous SDOH.

Cancer Cell-Intrinsic Expression of MHC Class II Regulates the Immune Microenvironment and Response to Anti-PD-1 Therapy in Lung Adenocarcinoma.

MHC class II (MHCII) expression is usually restricted to APC but can be expressed by cancer cells. We examined the effect of cancer cell-specific MHCII (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis lung carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, whereas LLC tumors are resistant. RNA sequencing analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, whereas resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII and converted tumors from anti-PD-1 sensitive to anti-PD-1 resistant. This was associated with lower levels of Th1 cytokines, decreased T cell infiltration, increased B cell numbers, and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, which provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.

Choice of home blood pressure monitoring device: the role of device characteristics among Alaska Native and American Indian peoples.

BACKGROUND: Home blood pressure monitoring (HBPM) is an effective tool in treatment and long-term management of hypertension. HBPM incorporates more data points to help patients and providers with diagnosis and management. The characteristics of HBPM devices matter to patients, but the relative importance of the characteristics in choosing a device remains unclear. METHODS: We used data from a randomized cross-over pilot study with 100 Alaska Native and American Indian (ANAI) people with hypertension to assess the choice of a wrist or arm HBPM device. We use a random utility framework to evaluate the relationship between stated likely use, perceived accuracy, ease of use, comfort, and participant characteristics with choice of device. Additional analyses examined willingness to change to a more accurate device. RESULTS: Participants ranked the wrist device higher compared to the arm on a 5-point Likert scale for likely use, ease of use, and comfort (0.3, 0.5, 0.8 percentage points, respectively). Most participants (66%) choose the wrist device. Likely use (wrist and arm devices) was related to the probability of choosing the wrist (0.7 and - 1.4 percentage points, respectively). Independent of characteristics, 75% of participants would be willing to use the more accurate device. Ease of use (wrist device) and comfort (arm device) were associated with the probability of changing to a more accurate device (- 1.1 and 0.5 percentage points, respectively). CONCLUSION: Usability, including comfort, ease, and likely use, appeared to discount the relative importance of perceived accuracy in the device choice. Our results contribute evidence that ANAI populations value accurate HBPM, but that the devices should also be easy to use and comfortable to facilitate long-term management.

Social determinants of obesity in American Indian and Alaska Native peoples aged ≥ 50 years.

OBJECTIVE: American Indian and Alaska Native peoples (AI/ANs) have a disproportionately high rate of obesity, but little is known about the social determinants of obesity among older AI/ANs. Thus, our study assessed social determinants of obesity in AI/ANs aged ≥ 50 years. DESIGN: We conducted a cross-sectional analysis using multivariate generalized linear mixed models to identify social determinants associated with the risk of being classified as obese (BMI ≥ 30.0 kg/m2). Analyses were conducted for the total study population and stratified by median county poverty level. SETTING: Indian Health Service (IHS) data for AI/ANs who used IHS services in FY2013. PARTICIPANTS: 27,696 AI/ANs aged ≥ 50 years without diabetes. RESULTS: Mean BMI was 29.8 ± 6.6 with 43% classified as obese. Women were more likely to be obese than men, and younger ages were associated with higher obesity risk. While having Medicaid coverage was associated with lower odds of obesity, private health insurance was associated with higher odds. Living in areas with lower rates of educational attainment and longer drive times to primary care services were associated with higher odds of obesity. Those who lived in a county where a larger percentage of people had low access to a grocery store were significantly less likely to be obese. CONCLUSIONS: Our findings contribute to the understanding of social determinants of obesity among older AI/ANs and highlight the need to investigate AI/AN obesity, including longitudinal studies with a life course perspective to further examine social determinants of obesity in older AI/ANs.

Associations Between Rurality, pre-pregnancy Health Status, and Macrosomia in American Indian/Alaska Native Populations.

OBJECTIVES: To examine the relationships between pre-pregnancy diabetes mellitus (DM), gestational diabetes mellitus (GDM), pre-pregnancy body mass index (BMI) and county-level social determinants of health, with infant macrosomia within a sample of American Indian/Alaska Native (AI/AN) women receiving Indian Health Service (IHS) care. METHODS: The sample included women-infant dyads representing 1,136 singleton births from fiscal year 2011 (10/1/2019-9/30/2011). Data stemmed from the IHS Improving Health Care Delivery Data Project. Multivariate generalized linear mixed models were fitted to assess the association of macrosomia with pre-pregnancy health status and social determinants of health. RESULTS: Nearly half of the women in the sample were under age 25 years (48.6%), and most had Medicaid health insurance coverage (76.7%). Of those with a pre-pregnancy BMI measure, 66.2% were overweight or obese. Although few women had pre-pregnancy DM (4.0%), GDM was present in 12.8% of women. Most women had a normal term delivery (85.4%). Overweight, obesity, pre-pregnancy DM, and county-level rurality were all significantly associated with higher odds of infant macrosomia.

Utilizing Artificial Intelligence to Enhance Health Equity Among Patients with Heart Failure.

Patients with heart failure (HF) are heterogeneous with various intrapersonal and interpersonal characteristics contributing to clinical outcomes. Bias, structural racism, and social determinants of health have been implicated in unequal treatment of patients with HF. Through several methodologies, artificial intelligence (AI) can provide models in HF prediction, prognostication, and provision of care, which may help prevent unequal outcomes. This review highlights AI as a strategy to address racial inequalities in HF; discusses key AI definitions within a health equity context; describes the current uses of AI in HF, strengths and harms in using AI; and offers recommendations for future directions.

Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention: A Scientific Statement From the American Heart Association.

Cardiovascular disease (CVD) is the leading cause of death in women, who have a notable increase in the risk for this disease after menopause and typically develop coronary heart disease several years later than men. This observation led to the hypothesis that the menopause transition (MT) contributes to the increase in coronary heart disease risk. Over the past 20 years, longitudinal studies of women traversing menopause have contributed significantly to our understanding of the relationship between the MT and CVD risk. By following women over this period, researchers have been able to disentangle chronological and ovarian aging with respect to CVD risk. These studies have documented distinct patterns of sex hormone changes, as well as adverse alterations in body composition, lipids and lipoproteins, and measures of vascular health over the MT, which can increase a woman's risk of developing CVD postmenopausally. The reported findings underline the significance of the MT as a time of accelerating CVD risk, thereby emphasizing the importance of monitoring women's health during midlife, a critical window for implementing early intervention strategies to reduce CVD risk. Notably, the 2011 American Heart Association guidelines for CVD prevention in women (the latest sex-specific guidelines to date) did not include information now available about the contribution of the MT to increased CVD in women. Therefore, there is a crucial need to discuss the contemporary literature on menopause and CVD risk with the intent of increasing awareness of the significant adverse cardiometabolic health-related changes accompanying midlife and the MT. This scientific statement provides an up-to-date synthesis of the existing data on the MT and how it relates to CVD.

Changes to the genetic counseling workforce as a result of the COVID-19 pandemic.

The COVID-19 pandemic has affected all aspects of our lives. The full impact of the pandemic is still unfolding and will take years to fully understand. This longitudinal study followed a sample of 189 genetic counselors from June to November of 2020, starting with an online retrospective baseline survey of pre-COVID-19 functioning and continuing with a monthly online survey (average retention = 89.2%) to assess changes in self-reported stress, employment status, billing practices, self-efficacy, and their use of telehealth. Participants were recruited from specific states representing geographic diversity with publicly available databases of contact information as well as social media. The sample was largely reflective of the professional demographics reported in the 2020 Professional Status Survey (PSS). Comparisons were made between the PSS, baseline assessment of pre-COVID-19 status, June, and November data. Genetic counselor workload did not significantly change in terms of hours worked from baseline to November, though patients served per week dropped initially before returning to pre-COVID-19 levels. Genetic counselors were increasingly working remotely and supervising students less frequently in November compared to pre-COVID-19 baseline. Approximately 50% of the sample were unable to bill for services throughout the study period, with billing practices not changing during this time. Approximately 40% experienced a negative employment change in June, which dropped to ~10% in November. Personal and family stress levels were elevated during the study period, while financial stress increased from baseline to June it returned to pre-COVID-19 levels by November. Self-efficacy for common genetic counseling skills decreased from baseline to June but returned to baseline levels by November. The results suggest the workforce faced transitions but has rebounded in most areas studied. The pandemic highlighted pre-existing billing issues, and the current billing structures were not able to shift in the face of practice transitions. The long-term implications of the pandemic remain to be seen, but the results indicate returns toward baseline data in most areas with the exceptions of supervision, personal and family stress, and billing.

MyD88 regulates a prolonged adaptation response to environmental dust exposure-induced lung disease.

BACKGROUND: Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies. METHODS: Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE. RESULTS: Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge. CONCLUSIONS: MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.

Communication With American Indians and Alaska Natives About Cardiovascular Disease.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death among American Indians and Alaska Natives. Reducing CVD risk requires effective communication about risk factors and preventive behaviors. Messages should be designed with an understanding of where people seek health information, their perceptions of a hazard, and their perception of information sufficiency. We examined these components of message design to inform strategies to effectively communicate information about CVD to American Indians and Alaska Natives. METHODS: We surveyed 220 adults who self-identified as American Indians or Alaska Natives at 2 Native-focused events in urban areas. Our survey included items on demographic characteristics, place of residence, sources of information used to learn about CVD, perceived information sufficiency, and perceptions about the importance of CVD as a health problem. RESULTS: Respondents used the internet (67%), their doctors (66%), friends and relatives (63%), brochures (62%), and television (61%) to learn about CVD. Participants aged 60 or older and those living on a reservation were more likely to use their doctor to learn about CVD than their younger (≤30 y) or urban peers. CVD was viewed as a major problem for American Indians and Alaska Natives (84%) and for Americans in general (86%). Most respondents felt moderately (54%) or well informed (37%) about CVD. CONCLUSION: Various information sources should be used to increase awareness about CVD. Special attention may be needed to optimize communication to American Indians and Alaska Natives aged 60 or older and people living on reservations. Further study is needed to determine how our findings can best inform effective interventions to reduce CVD morbidity and mortality among these populations.

Adrenergic Polymorphisms and Survival in African Americans With Heart Failure: Results From A-HeFT.

BACKGROUND: Polymorphisms in adrenergic signaling affect the molecular function of adrenergic receptors and related proteins. The ß1 adrenergic receptor (ADRB1) Arg389Gly, G-protein receptor kinase type 5 (GRK5) Gln41Leu, G-protein ß-3 subunit (GNB3) 825 C/T, and α2c deletion affect adrenergic tone, impact heart failure outcomes and differ in prevalence by ethnicity. Their combined effect within black cohorts remains unknown. METHODS AND RESULTS: We analyzed subjects from the African American Heart Failure Trial (A-HeFT) by assessing event-free survival, quality of life, and gene coinheritance. Significant coinheritance effects on survival included GRK5 Leu41 among subjects co-inheriting GNB3 825 C alleles (n = 166, 90.4% vs 69.0%, P < 0.001). By contrast, the impact of ADRB1 Arg389Arg genotype was magnified among subjects with GNB3 825 TT genotype (n = 181, 66.3% vs 85.7%, P = .002). The lack of the α2c deletion (ie, insertion) led to a greater impact of the ARG389Arg genotype (n = 289, 76.4% vs 86.1%, P = .007). CONCLUSIONS: Polymorphisms in adrenergic signaling affects outcomes in black subjects with heart failure. Coinheritance patterns in genetic variation may help determine heart failure survival.