Search

Abstract Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.

Background Coronary artery calcium testing using noncontrast cardiac computed tomography is a guideline‐indicated test to help refine eligibility for aspirin in primary prevention. However, access to cardiac computed tomography remains limited, with carotid ultrasound used much more often internationally. We sought to update the role of aspirin allocation in primary prevention as a function of subclinical carotid atherosclerosis. Methods and Results The study included 11 379 participants from the MESA (Multi‐Ethnic Study of Atherosclerosis) and ARIC (Atherosclerosis Risk in Communities) studies. A harmonized carotid plaque score (range, 0–6) was derived using the number of anatomic sites with plaque from the left and right common, bifurcation, and internal carotid artery on ultrasound. The 5‐year number needed to treat and number needed to harm as a function of the carotid plaque score were calculated by applying a 12% relative risk reduction in atherosclerotic cardiovascular disease (ASCVD) events and 42% relative increase in major bleeding events related to aspirin use, respectively. The mean age was 57 years, 57% were women, 23% were Black, and the median 10‐year ASCVD risk was 12.8%. The 5‐year incidence rates (per 1000 person‐years) were 5.5 (4.9–6.2) for ASCVD and 1.8 (1.5–2.2) for major bleeding events. The overall 5‐year number needed to treat with aspirin was 306 but was 2‐fold lower for individuals with carotid plaque versus those without carotid plaque (212 versus 448). The 5‐year number needed to treat was less than the 5‐year number needed to harm when the carotid plaque score was ≥2 for individuals with ASCVD risk 5% to 20%, whereas the presence of any carotid plaque demarcated a favorable risk–benefit for individuals with ASCVD risk >20%. Conclusions Quantification of subclinical carotid atherosclerosis can help improve the allocation of aspirin therapy.

Objective: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. Methods: Eligible participants were aged 40–70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus

Abstract Background This study explores the association between psychosocial stressors and current e-cigarette use among adolescents in the United States. Methods We used data from 12,767 participants in the 2019 National Youth Risk Behavioral Survey to examine the association between psychosocial stressors (bullying, sexual assault, safety-related absence from school, depressive symptoms, suicidal ideation, physical altercation, and weapon threats) and past-30-day e-cigarette use using multivariable-adjusted logistic regression models. We examined the association for each stressor and then as a burden score (0–7). To compare the strength of the association between stressors and current e-cigarette use to current combustible cigarette use, we additionally examined the association between each stressor and current combustible cigarette use. Results Approximately 32.7% reported current e-cigarette use. The weighted prevalence of current e-cigarette use was higher among individuals who experienced stressors than those who did not. For example, bullying (43.9% vs. 29.0%). Similar prevalence patterns were seen among other stressors. Individuals who experienced stressors had significantly higher adjusted odds of current e-cigarette use than those who did not (OR [Odds Ratio] range: 1.47–1.75). Similarly, individuals with higher burden scores had a higher prevalence (zero [20.5%], one [32.8%], two [41.4%], three [49.6%], four to seven [60.9%]) and higher odds of current e-cigarette use (OR range: 1.43–2.73) than those with a score of zero. The strength of the association between the stressors and e-cigarette use was similar to that between the stressors and combustible cigarette use. Conclusion The study demonstrates a significant association between psychosocial stressors and adolescent e-cigarette use, highlighting the potential importance of interventions, such as targeted school-based programs that address stressors and promote stress management, as possible means of reducing adolescent e-cigarette use. Future research directions include exploring underlying mechanisms linking stressors to e-cigarette use and evaluating the effectiveness of interventions addressing stressors in reducing adolescent e-cigarette use.

Background & aimsThe treatment options for systemically progressed hepatocellular carcinoma (HCC) have significantly expanded in recent years. In this study, we aimed to evaluate the potential of Google searches as a reflection of prescription rates for HCC drugs in the United States (US).MethodsWe conducted an in-depth analysis of US prescription data obtained from the IQVIA National Prescription Audit (NPA) and corresponding Google Trends data from January 2017 to December 2022. We focused on drugs used in the first line and second or later treatment lines for HCC, collecting data on their prescriptions and search rates. Search volumes were collected as aggregated search queries for both generic drugs and their respective brand names.ResultsDuring the study period from Q1 2017 to Q4 2022, monthly prescriptions for drugs used in HCC treatment showed an 173% increase (from 1253 to 3422). Conversely online searches increased by 3.5% (from 173 to 179 per 10 million searches). Notably, strong correlations were observed between search interest and prescriptions for newer drugs, which indicates increasing usage, while older drugs with declining usage displayed limited correlation. Our findings suggest a growing role of non-physician professions in managing systemically progressed HCC within the US healthcare system, although oncologists remained primarily responsible for drug prescriptions.ConclusionsIn conclusion, online search monitoring can offer the potential to reflect prescription trends specifically related to the treatment of HCC. This approach provides a swift and accessible means of evaluating the evolving landscape of HCC treatment.

Introduction E-cigarette use among youth and young adults remains of public health concern. Pod-based e-cigarettes, including JUUL, significantly changed the e-cigarette landscape in the US. Using an online survey, we explored the socio-behavioral correlates, predisposing factors, and addictive behaviors, among young adult pod-mod users within a University in Maryland, USA. Methods In total, 112 eligible college students aged 18–24 years, recruited from a University in Maryland, who reported using pod-mods were included in this study. Participants were categorized into current/non-current users based on past- 30-day use. Descriptive statistics were used to analyze participants’ responses. Results The mean age of the survey participants was 20.5 ± 1.2 years, 56.3% were female, 48.2% White, and 40.2% reported past-30-day (current) use of pod-mods. The mean age of first experimentation with pod-mods was 17.8 ± 1.4 years, while the mean age of regular use was 18.5 ± 1.4 years, with the majority (67.9%) citing social influence as the reason for initiation. Of the current users, 62.2% owned their own devices, and 82.2% predominantly used JUUL and menthol flavor (37.8%). A significant proportion of current users (73.3%) reported buying pods in person, 45.5% of whom were aged

Abstract Background The impact of the U.S. Food and Drug Administration's (FDA) initial enforcement policy on flavored cartridge-based e-cigarettes and subsequent notice for the removal of flavored disposable electronic cigarettes (e-cigarettes) such as Puff Bar from the market has not been well evaluated. We, therefore, sought to examine the impact of the e-cigarette flavor-related policy changes on the online popularity of Puff Bar, a prototypic disposable e-cigarette. Methods We tabulated the total weekly Google search queries originating from the U.S. for "Puff Bar" and "Puff Bars" from January 1, 2019, to December 31, 2021. We divided the three years into four (4) distinct periods using the dates of the initial announcement to ban non-tobacco flavored e-cigarettes (September 11, 2019), the finalization of the FDA enforcement policy on cartridge-based flavors (January 2, 2020), and the notice for the market withdrawal of flavored disposable e-cigarettes (July 20, 2020) as reference time points. Then, we used piecewise linear regression and autoregressive integrated moving average (ARIMA) to compare the trends in searches for Puff Bar for the four (4) periods. Results Before the initial announcement to ban non-tobacco flavored e-cigarettes, online search queries (per 10 million Google searches) for Puff Bar were slowly rising at a rate of 0.58 queries per week (95%CI: -0.80 – 1.97). Following the announcement, searches for Puff Bar increased significantly at a rate of 16.61 queries per week (95%CI: 12.13 – 21.10). The rate of searches for Puff Bar then increased exponentially at 40.08 queries per week (95%CI: 27.32 – 52.84) following the FDA flavor ban, which excluded disposable e-cigarettes. Then, the rate of increase declined but remained relatively stable at 3.67 queries per week (95%CI: 0.69–6.65) until the FDA's notice to remove flavored Puff Bar products from the market. Following this notice, the rate of searches for Puff Bar significantly declined (rate: -4.97 queries per week; 95%CI: -5.40—-4.54). Conclusions The tracking of online search data demonstrates rapid public recognition of the FDA's announcements of tobacco regulatory actions.

Among adolescents, sole use is the most common pattern of e-cigarette use. However, concurrent use of e-cigarettes with other tobacco products is not uncommon and may be associated with high-risk behaviors. We used data from 12,767 participants in the 2019 Youth Risk Behavior Survey to examine the patterns of tobacco product use among youth in the US. First, we examined the prevalence of e-cigarette-specific patterns of tobacco use (nonuse[no tobacco product use], sole use[sole e-cigarette use], dual-use[e-cigarette and one other tobacco product], and poly use[e-cigarette and two or more other tobacco products]). Then, using multivariable Poisson regression, we assessed how the tobacco use patterns were associated with the misuse of nine substances of abuse (alcohol, marijuana, cocaine, ecstasy, hallucinogens, heroin, inhalants, injectables, and methamphetamines).62.9% of youth reported nonuse of any tobacco product. The weighted prevalence of sole e-cigarette use, dual use, and poly use was 23.2%, 4.2%, and 3.3%, respectively. Across all the substances explored, the prevalence was highest among poly users, followed by dual users, sole users, and non-users. Compared to non-users, sole, dual, and poly users had 7.8(95 %CI:6.1–10.0), 14.3(95 %CI:10.8–18.8), and 19.7(95 %CI:15.0–25.9) times higher adjusted prevalence of reporting past-30-day binge drinking, after adjusting for age, sex, race/ethnicity, sexual orientation, and depressive symptoms. This pattern was seen across all the different substances explored. These findings highlight the high prevalence of substance misuse among youth who use tobacco products and the need to educate and counsel on substances of abuse among this population, particularly among poly-tobacco users.

MR perfusion imaging is important in the clinical evaluation of primary brain tumors, particularly in differentiating between true progression and treatment-induced change. The utility of velocity-selective ASL (VSASL) compared to the more commonly utilized DSC perfusion technique was assessed in routine clinical surveillance MR exams of 28 patients with high-grade gliomas at 1.5T. Using RANO criteria, patients were assigned to two groups, one with detectable residual/recurrent tumor (“RT”, n = 9), and the other with no detectable residual/recurrent tumor (“NRT”, n = 19). An ROI was drawn to encompass the largest dimension of the lesion with measures normalized against normal gray matter to yield rCBF and tSNR from VSASL, as well as rCBF and leakage-corrected relative CBV (lc-rCBV) from DSC. VSASL (rCBF and tSNR) and DSC (rCBF and lc-rCBV) metrics were significantly higher in the RT group than the NRT group allowing adequate discrimination (p < 0.05, Mann–Whitney test). Lin’s concordance analyses showed moderate to excellent concordance between the two methods, with a stronger, moderate correlation between VSASL rCBF and DSC lc-rCBV (r = 0.57, p = 0.002; Pearson’s correlation). These results suggest that VSASL is clinically feasible at 1.5T and has the potential to offer a noninvasive alternative to DSC perfusion in monitoring high-grade gliomas following therapy.

Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP)-glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In co-cultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro, mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment.

Abstract Background MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene expression at the post-transcriptional level can act extracellularly as signaling molecules. The identity of miRNA species serving as membrane receptor ligands involved in neuronal apoptosis in the central nervous system (CNS), as well as the miRNAs’ sequence and structure required for this mode of action remained largely unresolved. Methods Using a microarray-based screening approach we analyzed apoptotic cortical neurons of C56BL/6 mice and their supernatant with respect to alterations in miRNA expression/presence. HEK-Blue Toll-like receptor (TLR) 7/8 reporter cells, primary microglia and macrophages derived from human and mouse were employed to test the potential of the identified miRNAs released from apoptotic neurons to serve as signaling molecules for the RNA-sensing receptors. Biophysical and bioinformatical approaches, as well as immunoassays and sequential microscopy were used to analyze the interaction between candidate miRNA and TLR. Immunocytochemical and -histochemical analyses of murine CNS cultures and adult mice intrathecally injected with miRNAs, respectively, were performed to evaluate the impact of miRNA-induced TLR activation on neuronal survival and microglial activation. Results We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling. Conclusion Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration.

Detailed description of the prevalence and sources of e-cigarettes among youth is needed to inform effective regulatory policies. We used the Youth Risk Behavior Surveillance System data (2015–2019) to assess trends in current (past-30-day-use) and frequent (≥10 days in past-30-days) e-cigarette use among United States high schoolers before the COVID-19 pandemic. First, we assessed trends overall and then stratified by participants’ sociodemographic characteristics, use of other tobacco products, and experiences of psychosocial stress. We also evaluated past year quit attempts and the changing sources of e-cigarettes.Our sample size was 41,021 (15,356–2015; 12,873–2017; 12,792–2019). The prevalence of current e-cigarette use increased from 24.0% (95%CI:21.9%–26.3%) in 2015 to 32.7% (30.4%–35.1%) in 2019. The proportion of current users who reported frequent use also increased significantly from 22.6% (20.4%–24.8%) to 45.4% (42.7%–48.2%). Thus, an increasing proportion of US high school students who use e-cigarettes reported frequent use, indicating greater nicotine dependence. The increase in current and frequent e-cigarette use was more pronounced in youth who reported other substance use and psychosocial stressors such as bullying. Between 2017 and 2019, there was a decline in the proportion of youth who bought e-cigarettes online (6.9% to 3.2%) or from convenience stores (22.0% to 16.6%). Conversely, there was an increase in the proportion who borrowed (34.5% to 40.1%) or purchased e-cigarettes through other people (10.7% to 18.0%), indicating that most youth are evading age-related restrictions by obtaining e-cigarettes from other people. Finally, a considerable proportion of youth tobacco users are making quit attempts; 47.6% (45.1%–50.1%) in 2019.

Several clinical trials have demonstrated that many SGLT-2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) can reduce the risk of cardiovascular events in patients with Type 2 diabetes and atherosclerotic cardiovascular disease. Recent reports indicate an underutilization of new cardiometabolic drugs, including SGLT2i and GLP-1 RA. We aimed to evaluate the use of online search volumes to reflect United States prescription rates. A repeated cross-sectional analysis of Google search volumes and corresponding data from the IQVIA National Prescription Audit (NPA) of pharmacy dispensing of newly prescribed drugs was performed. Monthly data for online searches and prescription between January 1, 2016 and December 31, 2021 were collected for selected SGLT2i and GLP-1 RA. Prescription data for drugs classes (SGLT2i and GLP-1 RA) and individual drugs were calculated as the total of queried data for branded drug names. Trends were analyzed for visual and quantitative correlation as well as predictive patterns. Overall, online searches increased by 157.6% (95% CI: 142.2–173.1%) and 295.2% (95% CI: 257.7–332.6%) for SGLT2i and GLP-1RA between 2016 and 2021. Prescription rates raised by 114.6% (95% CI: 110.8–118.4%) and 221.0% (95% CI: 212.1–229.9%) for SGLT2i and GLP-1RA for this period. Correlation coefficients (range 0.86–0.99) were strongest for drugs with growing number of prescriptions, for example dapagliflozin, empagliflozin, ertugliflozin, dulaglutide, and semaglutide. Online searches might represent an additional tool to monitor the utilization trends of cardiometabolic drugs. Associations were strongest for drugs with reported cardioprotective effect. Thus, trends in online searches complement conventionally acquired data to reflect and forecast prescription trends of cardiometabolic drugs.

Background Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age. Methods and Results Lp(a) was measured at ARIC visit 4 (1996–1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018–2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34–2.47), CAC (aOR, 1.40; 95% CI, 1.08–1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07–1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06–1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05–1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex. Conclusions Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.

Objective: To evaluate interest in coronary artery calcium (CAC) among the general public during the past 17 years and to compare trends with real-world data on number of CAC procedures performed. Methods: We used Google Trends, a publicly available database, to access search query data in a systematic and quantitative fashion to search for CAC-related key terms. Search terms included calcium test, heart score, calcium score, coronary calcium, and calcium test score. We accessed Google Trends in January 2021 and analyzed data from 2004 to 2020. Results: From 2004 to December 31, 2020, CAC-related search interest (in relative search volume) increased continually worldwide (+201.9%) and in the United States (+354.8%). Three main events strongly influenced search interest in CAC: reports of a CAC scan of the president of the United States led to a transient 10-fold increase in early January 2018. American College of Cardiology/American Heart Association guideline release led to a sustained increase, and lockdown after the global pandemic due to COVID-19 led to a transient decrease. Real-world data on performed CAC scans showed an increase between 2006 and 2017 (+200.0%); during the same time period, relative search volume for CAC-related search terms increased in a similar pattern (+70.6%-1511.1%). For the search term coronary calcium scan near me, a potential representative of active online search for CAC scanning, we found a +28.8% increase in 2020 compared with 2017. Conclusion: Google Trends, a valuable tool for assessing public interest in health-related topics, suggests increased overall interest in CAC during the last 17 years that mirrors real-world usage data. Increased interest is seemingly linked to reports of CAC testing in world leaders and endorsement in major guidelines.

Stagnating COVID-19 vaccination rates and vaccine hesitancy remain a threat to public health. Improved strategies for real-time tracking and estimation of population-level behavior regarding vaccinations are needed. The aim of this study was to evaluate whether online search trends for COIVD-19 and influenza mirror vaccination rates. State-level weekly fraction of online searches for top vaccination-related search terms and CDC vaccination data were obtained from June 1, 2020, to May 31, 2021. Next, trends in online search and vaccination data for COVID-19 and influenza were analyzed for visual and quantitative correlation patterns using Spearman’s rank correlation analysis. Online searches in the US for COVID-19 vaccinations increased 2.71-fold (95% CI: 1.98-3.45) in the 4 weeks after the FDA emergency authorization compared to the precedent 4 weeks. In March-April 2021, US online searches reached a plateau that was followed by a decline of 83.3% (95% CI: 31.2%-135.3%) until May 31, 2021. The timing of peaks in online searches varied across US states. Online searches were strongly correlated with vaccination rates (r=0.71, 95% CI: 0.45 - 0.87), preceding actual reported vaccination rates in 44 of 51 states. Online search trends preceded vaccination trends by a median of 3.0 weeks (95% CI: 2.0-4.0 weeks) across all states. For influenza vaccination searches, seasonal peaks in September-October between 2016-2020 were noted. Influenza search trends highly correlated with the timing of actual vaccinations for the 2019-2020 (r=0.82, 95% CI: 0.64 – 0.93) and 2020-2021 season (r=0.91, 95% CI: 0.78 – 0.97). Search trends and real-world vaccination rates are highly correlated. Temporal alignment and correlation levels were higher for influenza vaccinations; however, only online searches for COVID-19 vaccination preceded vaccination trends. These findings indicate that US online search data can potentially guide public health efforts, including policy changes and identifying geographical areas to expand vaccination campaigns.

The e-cigarette or vaping product-use-associated lung injury (EVALI) epidemic was primarily associated with the use of e-cigarettes containing tetrahydrocannabinol (THC)- the principal psychoactive substance in cannabis, and vitamin-E-acetate- an additive sometimes used in informally sourced THC-containing e-liquids. EVALI case burden varied across states, but it is unclear whether this was associated with state-level cannabis vaping prevalence. We, therefore, used linear regression models to assess the cross-sectional association between state-level cannabis vaping prevalence (obtained from the 2019 behavioral Risk Factor Surveillance System) and EVALI case burden (obtained from the Centers for Disease Control and Prevention) adjusted for state cannabis policies. Cannabis vaping prevalence ranged from 1.14%(95%CI, 0.61%-2.12%) in Wyoming to 3.11%(95%CI, 2.16%-4.44%) in New Hampshire. EVALI cases per million population ranged from 1.90(0.38-3.42) in Oklahoma to 59.10(19.70-96.53) in North Dakota. There was no significant positive association but an inverse association between state cannabis vaping prevalence and EVALI case burden (Coefficient, -18.6; 95%CI, -37.5-0.4; p-value, 0.05). Thus, state-level cannabis vaping prevalence was not positively associated with EVALI prevalence, suggesting that there may not be a simple direct link between state cannabis vaping prevalence and EVALI cases, but rather the relationship is likely more nuanced and possibly reflective of access to informal sources of THC-containing e-cigarettes.

Objective: Aspirin has been widely utilized over several decades for atherosclerotic cardiovascular disease (ASCVD) prevention among adults in the United States. We examined trends in aspirin use among adults aged ≥40 years from 1998 to 2019 and assessed factors associated with its use for primary and secondary ASCVD prevention. Methods: Using 1998–2019 Behavioral Risk Factor Surveillance System data, we obtained weighted prevalence of aspirin use among adults aged ≥40 years for each year and examined trends in use over this period. Using multivariable logistic regression and utilizing data from 54,388 respondents aged ≥40 years in the 2019 data, we assessed factors associated with aspirin use for secondary prevention and for primary prevention stratified by the number of traditional ASCVD risk factors reported (hypertension, diabetes mellitus, high cholesterol, overweight/obesity, and cigarette smoking). Results: Aspirin use prevalence increased from 29.0%(95%CI, 27.9%-30.2%) in 1998 to 37.5%(36.9%-38.0%) in 2009. However, use has slightly declined over the last decade: 35.6%(34.6%-36.6%) in 2011 to 33.5%(32.5%-34.6%) in 2019. In 2019, among respondents without cardiovascular disease (CVD), 27.5%(26.4%-28.6%) reported primary prevention aspirin use while 69.7%(67.0%-72.2%) of respondents with CVD reported secondary prevention aspirin use. Of concern, 45.6%(43.5%-47.7%) of adults aged ≥70 years without CVD reported primary prevention aspirin use. Additionally, among individuals without any self-reported traditional ASCVD risk factor, males (adjusted odds ratio(aOR):1.60, 95%CI:1.12–2.27), persons aged ≥70 years (aOR:3.22, 95%CI:2.27–4.55), and individuals with healthcare coverage (aOR:2.28, 95%CI:1.17–4.44) had higher odds of primary prevention aspirin use compared to females, persons aged 40–69 years, and individuals without healthcare coverage, respectively. Females were less likely than males to report secondary prevention aspirin use (aOR:0.64, 95%CI:0.50–0.82). Conclusion: Aspirin use has slightly declined over the last decade. A significant proportion of adults aged ≥70 years reported primary prevention aspirin use in 2019. Since current guidelines do not recommend primary prevention aspirin use among adults aged ≥70 years, such use should be discouraged.

Background: many of the modifiable variables in the Pooled Cohort Equations (PCE) are shared risk factors for cardiovascular disease (CVD) and cancer, which are the two leading causes of death in the United States. We sought to determine the utility of the PCE risk for the synergistic risk prediction of CVD and cancer. Methods: we identified 5,773 participants (61.5 years and 53% women) without baseline CVD or cancer from the Multi-Ethnic study of atherosclerosis. The primary outcome was time to first event of either incident CVD or incident cancer. We calculated competing risk and cause-specific hazard models to examine the association of the PCE groups (

The chaperone protein Unc-93 homolog B1 (UNC93B1) regulates internalization, trafficking, and stabilization of nucleic acid-sensing Toll-like receptors (TLR) in peripheral immune cells. We sought to determine UNC93B1 expression and its functional relevance in inflammatory and injurious processes in the central nervous system (CNS). We found that UNC93B1 is expressed in various CNS cells including microglia, astrocytes, oligodendrocytes, and neurons, as assessed by PCR, immunocyto-/histochemistry, and flow cytometry. UNC93B1 expression in the murine brain increased during development. Exposure to the microRNA let-7b, a recently discovered endogenous TLR7 activator, but also to TLR3 and TLR4 agonists, led to increased UNC93B1 expression in microglia and neurons. Microglial activation by extracellular let-7b required functional UNC93B1, as assessed by TNF ELISA. Neuronal injury induced by extracellular let-7b was dependent on UNC93B1, as UNC93B1-deficient neurons were unaffected by the microRNA’s neurotoxicity in vitro. Intrathecal application of let-7b triggered neurodegeneration in wild-type mice, whereas mice deficient for UNC93B1 were protected against injurious effects on neurons and axons. In summary, our data demonstrate broad UNC93B1 expression in the murine brain and establish this chaperone as a modulator of neuroinflammation and neuronal injury triggered by extracellular microRNA and subsequent induction of TLR signaling.

Abstract Background E-cigarette use prevalence has grown rapidly in the US. Despite the popularity of these products, few acute exposure toxicity studies exist, and studies on long-term pulmonary health effects are limited. E-cigarette users who are never combustible cigarette smokers (sole users) constitute a unique group of young adults that may be at increased risk of bronchial hyperreactivity and development of asthma. Given the public health concern about the potential pulmonary health effects of sole e-cigarette use, we aimed to examine the association between e-cigarette use and asthma among never combustible cigarette smokers. Methods We pooled 2016 and 2017 data of the Behavioral Risk Factor Surveillance System (BRFSS), a large, cross-sectional telephone survey of adults aged 18 years and older in the U.S. We included 402,822 participants without any history of combustible cigarette smoking (defined as lifetime smoking

Background: Reports have suggested decreasing attention to CVD comorbidities during the COVID-19 pandemic, despite their association with worse virus-related outcomes. Using nowcasting tools, we sought to explore temporal trends in public interest by studying use of online search terms related to CVD comorbidities during the pandemic time period. Methods: We queried Google Trends for recent (October 2019–October 2020) and seasonal (October 2016–October 2020) trends of search terms pertaining to cardiovascular-related behaviors or clinical care including clinical diagnostic and therapeutic-related terms. Additionally, we acquired data from Google Shopping Insights to explore consumer behavior. Data for search results in the US were compared using mean relative search volumes (RSV), tabulated by month. Results: Online search interest in the terms “Exercise” and “Cigarettes” changed by +18.0% and −52.5%, respectively, comparing March–April with January–February 2020. Key terms related to CVD-related care, including diagnostic and therapeutic-related terms such as “Statin”, “Lipid profile”, “Low-density lipoprotein”, and “Hemoglobin A1C” declined to a four-year low in late March 2020 but regained pre-pandemic search query frequency by July 2020. Results were supported by Google Shopping analysis; for example, online consumer shopping-related searches for tobacco products reached at an all-year low after May 2020. Conclusion: We report an increase in search interest for an overall healthier CVD-related lifestyle starting in March 2020, supported by online consumer shopping behavior. However, a months-long trough in public interest for CVD care-related search terms from March–May 2020 suggests a transient but substantial decrease in public focus on cardiovascular-related healthcare engagement. Future research is needed to understand if these mixed signals will persist into 2021 and how they potentially translate into real-world CVD-related event rates.

Background The optimal method for communicating coronary heart disease (CHD) risk to individual patients is not yet clear. Recent research supports the concept of "coronary age" for more effective risk communication. We defined an individual's coronary age as the age at which an average healthy individual would have an equivalent estimated CHD risk as that calculated for the index individual, building on our previously validated MESA (Multi‐Ethnic Study of Atherosclerosis) 10‐year CHD Risk Score equations with and without coronary artery calcium (CAC). Methods and Results We derived a coronary age by (1) calculating the MESA 10‐year CHD risk; (2) mathematically setting this equal to an equation describing risk of an average healthy MESA participant, as a function of age; and (3) solving for age. The risk discrimination of the resultant coronary age was compared with that of chronological age, the MESA CHD Risk Score, and CAC alone. Approximately 95% of coronary age values ranged from 30 years less to 30 years higher than chronological age. Although the mean chronological age of individuals experiencing CHD events compared with those free of events was 67.4 versus 61.8 years, the difference in coronary age including CAC was larger (80.6 versus 62.8 years). Coronary age with CAC had identical predictive ability to that of MESA CHD Risk Score and outperformed chronological age and CAC alone. Conclusions The newly derived coronary age is a convenient transformation of MESA CHD Risk, retaining very good risk discrimination. This easy‐to‐communicate tool will be available for patients and clinicians, potentially facilitating risk communication in routine care.

Background: Identifying cancer patients at high risk of CVD is important for targeting CVD prevention strategies and evaluating chemotherapy options in the context of cardiotoxicity. Coronary artery calcium (CAC), a strong marker of coronary atherosclerosis, is used clinically to enhance risk assessment, yet the value of CAC for assessing risk of CVD complications in cancer is poorly understood. Objective: In cases of cancer mortality, to determine the value of CAC for predicting risk of CVD as a supporting cause of death. Methods: The CAC Consortium is a multi-center cohort of 66,636 asymptomatic adults without CVD who underwent CAC scanning. During a follow-up of 12.5 years, 1129 patients died of cancer and were included in this analysis. The primary outcome was presence of CVD listed as a supporting cause of cancer mortality on official death certificates obtained from the National Death Index. Logistic regression models were used to assess the odds of CVD being listed as a supporting cause of death by CAC. Results: CVD was listed as a supporting cause of death in 306 (27%) cancer mortality cases. Baseline CAC was significantly higher in individuals with CVD-supported mortality. Odds ratios of having CVD-supported death increased by ASCVD risk score category [1.15 (0.81, 1.65) for 5–20% 10-year risk and 1.97 (1.36, 2.89) for ≥20% risk, in reference to

Background Coronary artery calcium (CAC) is a predictor for the development of cardiovascular disease (CVD) and to a lesser extent cancer. The age‐ and sex‐specific relationship of CAC with CVD and cancer mortality is unknown. Methods and Results Asymptomatic patients aged 40 to 75 years old without known CVD were included from the CAC Consortium. We calculated sex‐specific mortality rates per 1000 person‐years’ follow‐up. Using parametric survival regression modeling, we determined the age‐ and sex‐specific CAC score at which the risk of death from CVD and cancer were equal. Among the 59 502 patients included in this analysis, the mean age was 54.9 (±8.5) years, 34% were women, and 89% were white. There were 671 deaths attributable to CVD and 954 deaths attributable to cancer over a mean follow‐up of 12±3 years. Among patients with CAC=0, cancer was the leading cause of death, the total mortality rate was low (women, 1.8; men, 1.5), and the CVD mortality rate was exceedingly low for women (0.3) and men (0.3). The age‐specific CAC score at which the risk of CVD and cancer mortality were equal had a U‐shaped relationship for women, while the relationship was exponential for men. Conclusions The age‐ and sex‐specific relationship of CAC with CVD and cancer mortality differed significantly for women and men. Our age‐ and sex‐specific CAC score provides a more precise estimate and further facilitates the use of CAC as a synergistic tool in strategies for the prediction and prevention of CVD and cancer mortality.

Summary: Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma. : Buonfiglioli et al. elucidate the role of let-7 miRNAs acting as Toll-like receptor (TLR) ligands in the brain. Select let-7 miRNAs function as signaling molecules to modulate diverse microglial functions and glioma growth through TLR7. These data establish let-7 miRNAs as TLR7 signaling activators of microglia in health and glioma. Keywords: glioblastoma, lethal-7, microglia, microRNA, Toll-like receptor 7

BACKGROUND:The popularity of electronic cigarettes (E-cigarettes) has risen considerably. Several studies have suggested that nicotine may affect insulin resistance, however, the impact of E-cigarette exposure on insulin resistance, an early measure of cardiometabolic risk, is not known. METHODS AND RESULTS:Using experimental animals and human data obtained from 3,989 participants of the United States National Health and Nutrition Examination Survey (NHANES), respectively, we assessed the association between E-cigarette and conventional cigarette exposures and insulin resistance, as modelled using the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose tolerance tests (GTT). C57BL6/J mice (on standard chow diet) exposed to E-cigarette aerosol or mainstream cigarette smoke (MCS) for 12 weeks showed HOMA-IR and GTT levels comparable with filtered air-exposed controls. In the NHANES cohort, there was no significant association between defined tobacco product use categories (non-users; sole E-cigarette users; cigarette smokers and dual users) and insulin resistance. Compared with non-users of e-cigarettes/conventional cigarettes, sole E-cigarette users showed no significant difference in HOMA-IR or GTT levels following adjustment for age, sex, race, physical activity, alcohol use and BMI. CONCLUSION:E-cigarettes do not appear to be linked with insulin resistance. Our findings may inform future studies assessing potential cardiometabolic harms associated with E-cigarette use.

The 2018 American Heart Association and American College of Cardiology (AHA/ACC) cholesterol management guideline considers current evidence on coronary artery calcium (CAC) testing while incorporating learnings from previous guidelines. More than any previous guideline update, this set encourages CAC testing to facilitate shared decision-making and to individualize treatment plans. An important novelty is further separation of risk groups. Specifically, the current prevention guideline recommends CAC testing for primary atherosclerotic cardiovascular disease (ASCVD) prevention among asymptomatic patients in borderline and intermediate risk groups (5–7.5% and 7.5–20% 10-year ASCVD risk). This additional subclassification reflects the uncertainty of treatment strategies for patients broadly considered to be “intermediate risk,” as treatment recommendations for high- and low-risk groups are well established. The 2018 guidelines, for the first time, clearly recognize the significance of a CAC score of zero, where intensive statin therapy is likely not beneficial and not routinely recommended in selected patients. Lifestyle modification should be the focus in patients with CAC = 0. In this article, we review the recent AHA/ACC cholesterol management guideline and contextualize the transition of CAC testing to a guideline-endorsed decision aid for borderline- to intermediate-risk patients who seek more definitive risk assessment as part of a clinician-patient discussion. CAC testing can reduce low-value treatment and focus primary prevention therapy on those most likely to benefit.