Harnessing Immunomodulatory Polymers for Treatment of Autoimmunity, Allergy, and Transplant Rejection.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.

APLpred: A machine learning-based tool for accurate prediction and characterization of asparagine peptide lyases using sequence-derived optimal features.

Asparagine peptide lyase (APL) is among the seven groups of proteases, also known as proteolytic enzymes, which are classified according to their catalytic residue. APLs are synthesized as precursors or propeptides that undergo self-cleavage through autoproteolytic reaction. At present, APLs are grouped into 10 families belonging to six different clans of proteases. Recognizing their critical roles in many biological processes including virus maturation, and virulence, accurate identification and characterization of APLs is indispensable. Experimental identification and characterization of APLs is laborious and time-consuming. Here, we developed APLpred, a novel support vector machine (SVM) based predictor that can predict APLs from the primary sequences. APLpred was developed using Boruta-based optimal features derived from seven encodings and subsequently trained using five machine learning algorithms. After evaluating each model on an independent dataset, we selected APLpred (an SVM-based model) due to its consistent performance during cross-validation and independent evaluation. We anticipate APLpred will be an effective tool for identifying APLs. This could aid in designing inhibitors against these enzymes and exploring their functions. The APLpred web server is freely available at https://procarb.org/APLpred/.

Computational prediction of phosphorylation sites of SARS-CoV-2 infection using feature fusion and optimization strategies.

SARS-CoV-2's global spread has instigated a critical health and economic emergency, impacting countless individuals. Understanding the virus's phosphorylation sites is vital to unravel the molecular intricacies of the infection and subsequent changes in host cellular processes. Several computational methods have been proposed to identify phosphorylation sites, typically focusing on specific residue (S/T) or Y phosphorylation sites. Unfortunately, current predictive tools perform best on these specific residues and may not extend their efficacy to other residues, emphasizing the urgent need for enhanced methodologies. In this study, we developed a novel predictor that integrated all the residues (STY) phosphorylation sites information. We extracted ten different feature descriptors, primarily derived from composition, evolutionary, and position-specific information, and assessed their discriminative power through five classifiers. Our results indicated that Light Gradient Boosting (LGB) showed superior performance, and five descriptors displayed excellent discriminative capabilities. Subsequently, we identified the top two integrated features have high discriminative capability and trained with LGB to develop the final prediction model, LGB-IPs. The proposed approach shows an excellent performance on 10-fold cross-validation with an ACC, MCC, and AUC values of 0.831, 0.662, 0.907, respectively. Notably, these performances are replicated in the independent evaluation. Consequently, our approach may provide valuable insights into the phosphorylation mechanisms in SARS-CoV-2 infection for biomedical researchers.

Dual role of histone variant H3.3B in spermatogenesis: positive regulation of piRNA transcription and implication in X-chromosome inactivation.

The histone variant H3.3 is encoded by two distinct genes, H3f3a and H3f3b, exhibiting identical amino-acid sequence. H3.3 is required for spermatogenesis, but the molecular mechanism of its spermatogenic function remains obscure. Here, we have studied the role of each one of H3.3A and H3.3B proteins in spermatogenesis. We have generated transgenic conditional knock-out/knock-in (cKO/KI) epitope-tagged FLAG-FLAG-HA-H3.3B (H3.3BHA) and FLAG-FLAG-HA-H3.3A (H3.3AHA) mouse lines. We show that H3.3B, but not H3.3A, is required for spermatogenesis and male fertility. Analysis of the molecular mechanism unveils that the absence of H3.3B led to alterations in the meiotic/post-meiotic transition. Genome-wide RNA-seq reveals that the depletion of H3.3B in meiotic cells is associated with increased expression of the whole sex X and Y chromosomes as well as of both RLTR10B and RLTR10B2 retrotransposons. In contrast, the absence of H3.3B resulted in down-regulation of the expression of piRNA clusters. ChIP-seq experiments uncover that RLTR10B and RLTR10B2 retrotransposons, the whole sex chromosomes and the piRNA clusters are markedly enriched of H3.3. Taken together, our data dissect the molecular mechanism of H3.3B functions during spermatogenesis and demonstrate that H3.3B, depending on its chromatin localization, is involved in either up-regulation or down-regulation of expression of defined large chromatin regions.

Lack of leisure time physical activity and variations in cardiovascular mortality across US communities: a comprehensive county-level analysis (2011-2019).

OBJECTIVES: To investigate the associations between county-level proportions of adults not engaging in leisure-time physical activity (no LTPA) and age-adjusted cardiovascular mortality (AACVM) rates in the overall US population and across demographics. METHODS: Analysing 2900 US counties from 2011 to 2019, we used the Centers for Disease Control and Prevention (CDC) databases to obtain annual AACVM rates. No LTPA data were sourced from the CDC's Behavioural Risk Factor Surveillance System survey and county-specific rates were calculated using a validated multilevel regression and poststratification modelling approach. Multiple regression models assessed associations with county characteristics such as socioeconomic, environmental, clinical and healthcare access factors. Poisson generalised linear mixed models were employed to calculate incidence rate ratios (IRR) and additional yearly deaths (AYD) per 100 000 persons. RESULTS: Of 309.9 million residents in 2900 counties in 2011, 7.38 million (2.4%) cardiovascular deaths occurred by 2019. County attributes such as socioeconomic, environmental and clinical factors accounted for up to 65% (adjusted R2=0.65) of variance in no LTPA rates. No LTPA rates associated with higher AACVM across demographics, notably among middle-aged adults (standardised IRR: 1.06; 95% CI (1.04 to 1.07)), particularly women (1.09; 95% CI (1.07 to 1.12)). The highest AYDs were among elderly non-Hispanic black individuals (AYD=68/100 000). CONCLUSIONS: Our study reveals a robust association between the high prevalence of no LTPA and elevated AACVM rates beyond other social determinants. The most at-risk groups were middle-aged women and elderly non-Hispanic black individuals. Further, county-level characteristics accounted for substantial variance in community LTPA rates. These results emphasise the need for targeted public health measures to boost physical activity, especially in high-risk communities, to reduce AACVM.

Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease.

BACKGROUND: Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated. METHODS: In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the ß estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD. RESULTS: Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th-75th percentile, 33.7-34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71-3.49], Black men: HR, 1.59 [1.20-2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55-1.52], Black men: HR 1.02 [0.70-1.49]). In women, the largest magnitude percent reduction in the ß estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the ß estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors. CONCLUSIONS: In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.

Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.

PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone receptor-positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone receptor-positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. RESULTS: In 8985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR 1.43, 95% CI 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR 1.37, 95% CI 1.05-1.80), dyslipidemia (HR 1.58, 95% CI 1.29-1.92), and hypertension (HR 1.50, 95% CI 1.24-1.82) compared with non-endocrine therapy users. CONCLUSION: Hormone receptor-positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.

Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife: The CARDIA Study.

BACKGROUND: Gestational diabetes (GD) leads to earlier onset and heightened risk of type 2 diabetes, a strong risk factor for cardiovascular disease (CVD). However, it is unclear whether attaining normoglycemia can ameliorate the excess CVD risk associated with GD history. This study sought to evaluate GD history and glucose tolerance after pregnancy associated with coronary artery calcification (CAC) in women, a manifestation of atherosclerotic CVD and a predictor of CVD clinical events. METHODS: Data were obtained from the CARDIA study (Coronary Artery Risk Development in Young Adults), a US multicenter, community-based prospective cohort of young Black (50%) and White adults aged 18 to 30 years at baseline (1985-1986). The sample included 1133 women without diabetes at baseline, who had ≥1 singleton births (n=2066) during follow-up, glucose tolerance testing at baseline and up to 5 times during 25 years (1986-2011), GD status, and CAC measurements obtained from 1 or more follow up examinations at years 15, 20, and 25 (2001-2011). CAC was measured by noncontrast cardiac computed tomography; dichotomized as Any CAC (score>0) or No CAC (score=0). Complementary log-log models for interval-censored data estimated adjusted hazard ratios of CAC and 95% confidence intervals for GD history and subsequent glucose tolerance groups (normoglycemia, prediabetes, or incident diabetes) on average 14.7 years after the last birth adjusted for prepregnancy and follow-up covariates. RESULTS: Of 1133 women, 139 (12.3%) reported GD and were 47.6 years of age (4.8 SD) at follow-up. CAC was present in 25% (34/139) of women with GD and 15% (149/994) of women with no GD. In comparison with no GD/normoglycemia, adjusted hazard ratios (95% CIs) were 1.54 (1.06-2.24) for no GD/prediabetes and 2.17 (1.30-3.62) for no GD/incident diabetes, and 2.34 (1.34-4.09), 2.13 (1.09-4.17), and 2.02 (0.98-4.19) for GD/normoglycemia, GD/prediabetes, and GD/incident diabetes, respectively (overall P=0.003). CONCLUSIONS: Women without previous GD showed a graded increase in the risk of CAC associated with worsening glucose tolerance. Women with a history of GD had a 2-fold higher risk of CAC across all subsequent levels of glucose tolerance. Midlife atherosclerotic CVD risk among women with previous GD is not diminished by attaining normoglycemia.

Risk of heart failure with preserved versus reduced ejection fraction in women with breast cancer.

PURPOSE: While clinical heart failure (HF) is recognized as an adverse effect from breast cancer (BC) treatment, sparse data exist on specific HF phenotypes in affected BC survivors. We examined risk of HF by left ventricular ejection fraction (LVEF) status in women with a history of BC. METHODS: 14,804 women diagnosed with all stages of invasive BC from 2005 to 2013 and with no history of HF were matched 1:5 to 74,034 women without BC on birth year, race, and ethnicity. LVEF values were extracted from echocardiography studies within 30 days before through 90 days after the HF clinical encounter. HF was stratified into HF with preserved ejection fraction (HFpEF, LVEF ≥ 45%) and HF with reduced ejection fraction (HFrEF, LVEF < 45%). Cumulative incidence rates (CIRs) were estimated with competing risk of overall death. Hazard ratios (HR) were calculated by multivariable Cox proportional hazards regression. RESULTS: Mean time to HF diagnosis was 5.31 years (range 0.03-13.03) in cases and 5.25 years (range 0.01-12.94) in controls. 10-year CIRs were 1.2% and 0.9% for overall HF, 0.8% and 0.7% for HFpEF, and 0.4% and 0.2% for HFrEF in cases and controls, respectively. In fully adjusted models, an overall significant increased risk of HF in cases versus controls was observed (HR: 1.31, 95% CI 1.14, 1.51). The increased risk was seen for both HFrEF (HR: 1.59, 95% CI 1.22, 2.08) and HFpEF (HR: 1.22; 95% CI 1.03, 1.45). CONCLUSION: BC survivors experienced higher risk of HF compared with women without BC, and the risk persisted across LVEF phenotypes. Systematic cardio-oncology surveillance should be considered to mitigate this risk in BC patients.

Current Emergency Department Disposition of Patients With Acute Heart Failure: An Opportunity for Improvement.

Emergency department (ED) providers play a critical role in the stabilization and diagnostic evaluation of patients presenting with acute heart failure (AHF), and EDs are key areas for establishing current best practices and future considerations for the disposition of and decision making for patients with AHF. These elements include accurate risk assessment; response to initial treatment and shared decision making concerning optimal venue of care; reframing of physicians' risk perceptions for patients presenting with AHF; exploration of alternative venues of care beyond hospitalization; population-level changes in demographics, management and outcomes of HF patients; development and testing of data-driven pathways to assist with disposition decisions in the ED; and suggested outcomes for measuring success.

Highlights of Cardiovascular Disease Studies Presented at the 2021 American Heart Association Scientific Sessions.

PURPOSE OF REVIEW: This review highlights major studies across a broad array of topics presented at the virtual 2021 American Heart Association (AHA) Scientific Sessions. RECENT FINDINGS: Assessed studies examine a remotely delivered hypertension and lipid program in 10,000 patients across a diverse healthcare network; a cluster-randomized trial of a village doctor-led intervention for hypertension control; empagliflozin in heart failure with preserved ejection fraction (EMPEROR-Preserved); efficacy and safety of empagliflozin in hospitalized heart failure patients (EMPULSE); icosapent ethyl versus placebo in outpatients with coronavirus disease 2019 (PREPARE-IT 2); clinical safety, pharmacokinetics, and low-density lipoprotein cholesterol-lowering efficacy of MK-0161, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor; and effects of aspirin on dementia and cognitive impairment in the ASCEND trial. Research presented at the 2021 AHA Scientific Sessions emphasized the importance of interventions for cardiovascular disease prevention.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2022 American College of Cardiology Scientific Sessions.

PURPOSE OF REVIEW: Focused review highlighting select studies presented at the 2022 American College of Cardiology (ACC) Scientific Sessions. RECENT FINDINGS: Included studies assessed the impact of a low-sodium diet on heart failure outcomes (SODIUM-HF); outcomes of pregnant patients with chronic hypertension treated with antihypertensive therapies (CHAP); cardiovascular outcomes in patients with type 2 diabetes and renal impairment treated with sotagliflozin (SCORED); a safety and efficacy study investigating SLN360, a short interfering RNA targeting lipoprotein(a) (APOLLO); a supermarket and web-based intervention targeting nutrition for cardiovascular risk reduction (SuperWIN); a superiority trial comparing myocardial injury following very mild perioperative hypothermia versus aggressive warming after non-cardiac surgery (PROTECT); and 3-year efficacy outcomes of renal denervation on blood pressure reduction from the SPYRAL HTN-ON MED pilot study. Research presented at the 2022 ACC Scientific Sessions underscores the new potential and meaningful impact of cardiovascular disease prevention and management interventions.

Physical activity from young adulthood to middle age and premature cardiovascular disease events: a 30-year population-based cohort study.

BACKGROUND: Although physical activity is generally protective of cardiovascular disease (CVD), less is known about how young adult physical activity relates to premature CVD events. The objective of this study was to determine the association between level and change in physical activity from young adulthood to middle age and incidence of premature CVD events before age 60. METHODS: We analyzed data collected across four urban sites from nine visits over 30 years of follow-up (1985-2016) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective community-based cohort study of 5115 Black and White women and men aged 18-30 years at baseline (1985-1986). Linear mixed models were used to develop individualized moderate-to-vigorous intensity self-reported physical activity trajectories per participant. Fatal and nonfatal coronary heart disease (CHD), heart failure, and stroke outcomes were analyzed separately and as a combined CVD event outcome. RESULTS: Overall, physical activity declined in young adults as they progressed through middle age. Lower physical activity scores (per 100 exercise units) in 18 year-olds were associated with higher odds of premature CHD (AOR 1.14, 95% CI 1.02-1.28), heart failure (AOR 1.21, 95% CI 1.05-1.38), stroke (AOR 1.20, 95% CI 1.04-1.39), and any CVD (AOR 1.15, 95% CI 1.06-1.24) events. Each additional annual 1-unit reduction in the physical activity score was associated with a higher annual odds of incident heart failure (1.07, 95% CI 1.02-1.13), stroke (1.06, 95% CI 1.00-1.13), and CVD (1.04, 95% CI 1.01-1.07) events. Meeting the minimum (AOR 0.74, 95% CI 0.0.57-0.96) and twice the minimum (AOR 0.55, 95% CI 0.34-0.91) Department of Health and Human Services physical activity guidelines through follow up was protective of premature CVD events. CONCLUSIONS: Given recent trends in declining physical activity with age and associated premature CVD events, the transition from young adult to midlife is an important time period to promote physical activity.

Performance of the pooled cohort equation in South Asians: insights from a large integrated healthcare delivery system.

South Asian ethnicity is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk and has been identified as a "risk enhancer" in the 2018 American College of Cardiology/American Heart Association Guidelines. Risk estimation and statin eligibility in South Asians is not well understood; we studied the accuracy of 10-years ASCVD risk prediction by the pooled cohort equation (PCE), based on statin use, in a South Asian cohort. This is a retrospective cohort study of Kaiser Permanente Northern California South Asian members without existing ASCVD, age range 30-70, and 10-years follow up. ASCVD events were defined as myocardial infarction, ischemic stroke, and cardiovascular death. The cohort was stratified by statin use during the study period: never; at baseline and during follow-up; and only during follow-up. Predicted probability of ASCVD, using the PCE was calculated and compared to observed ASCVD events for low < 5.0%, borderline 5.0 to < 7.5%, intermediate 7.5 to < 20.0%, and high ≥ 20.0% risk groups. A total of 1835 South Asian members were included: 773 never on statin, 374 on statins at baseline and follow-up, and 688 on statins during follow-up only. ASCVD risk was underestimated by the PCE in low-risk groups: entire cohort: 1.8 versus 4.9%, p < 0.0001; on statin at baseline and follow-up: 2.58 versus 8.43%, p < 0.0001; on statin during follow-up only: 2.18 versus 7.77%, p < 0.0001; and never on statin: 1.37 versus 2.09%, p = 0.12. In this South Asian cohort, the PCE underestimated risk in South Asians, regardless of statin use, in the low risk ASCVD risk category.

Prevalence of prediabetes and diabetes vary by ethnicity among U.S. Asian adults at healthy weight, overweight, and obesity ranges: an electronic health record study.

BACKGROUND: Asian adults develop Type 2 diabetes at a lower body mass index (BMI) compared to other racial/ethnic groups. We examined the variation in prevalence of prediabetes and diabetes among Asian ethnic groups within weight strata by comparing middle-aged Chinese, Filipino, South Asian, and White adults receiving care in the same integrated healthcare delivery system. METHODS: Our retrospective cross-sectional U.S. study examined data from 283,110 (non-Hispanic) White, 33,263 Chinese, 38,766 Filipino, and 17,959 South Asian adults aged 45-64 years who were members of a Northern California health plan in 2016 and had measured height and weight. Prediabetes and diabetes were classified based on laboratory data, clinical diagnoses, or diabetes pharmacotherapy. Age-standardized prevalence of prediabetes and diabetes were compared by race/ethnicity within healthy weight, overweight, and obesity categories, using standard BMI thresholds for White adults (18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) and lower BMI thresholds for Asian adults (18.5 to < 23, 23 to < 27.5, ≥ 27.5 kg/m2). Prevalence ratios (PRs) were used to compare the prevalence of diabetes and prediabetes for Asian groups to White adults in each weight category, adjusted for age and BMI. RESULTS: Across all weight categories, diabetes prevalence was higher for Asian than White adults, and among Asian groups it was highest for Filipino and South Asian adults. Compared to White, PRs for South Asian men/women at healthy BMI were 1.8/2.8 for prediabetes and 5.9/8.0 for diabetes, respectively. The PRs for Filipino men/women at healthy BMI were 1.8/2.6 for prediabetes and 5.0/7.5 for diabetes, respectively. For Chinese men/women at healthy BMI, the PRs for prediabetes (2.1/2.9) were similar to Filipino and South Asian, but the PRs for diabetes were lower (2.1/3.4). CONCLUSION: Chinese, Filipino, and South Asian adults have higher prevalence of prediabetes and diabetes than White adults in all weight categories, despite using lower BMI thresholds for weight classification in Asian groups. Within Asian ethnic groups, Filipino and South Asian adults had considerably higher diabetes prevalence than Chinese adults. Our data emphasize the disproportionate metabolic risk among middle-aged Asian adults and underscore the need for diabetes screening among high-risk Asian groups at healthy BMI levels.

Moderate-to-vigorous intensity physical activity from young adulthood to middle age and metabolic disease: a 30-year population-based cohort study.

OBJECTIVES: To determine the association between moderate-to-vigorous intensity physical activity (MVPA) trajectories (course over age and time) through the adult life course and onset of metabolic disease (diabetes and dyslipidaemia). METHODS: We analysed prospective community-based cohort data of 5115 participants in the Coronary Artery Risk Development in Young Adults study, who were black and white men and women aged 18-30 years at baseline (1985-1986) at four urban sites, collected through 30 years of follow-up. Individualised MVPA trajectories were developed for each participant using linear mixed models. RESULTS: Lower estimated MVPA score at age 18 was associated with a 12% (95% CI 6% to 18%) higher odds of incident diabetes, a 4% (95% CI 1% to 7%) higher odds of incident low high-density lipoprotein (HDL) and a 6% (95% CI 2% to 11%) higher odds of incident high triglycerides. Each additional annual 1-unit reduction in the MVPA score was associated with a 6% (95% CI 4% to 9%) higher annual odds of diabetes incidence and a 4% (95% CI 2% to 6%) higher annual odds of high triglyceride incidence. Analysing various MVPA trajectory groups, participants who were in the most active group at age 18 (over 300 min/week), but with sharp declines in midlife, had higher odds of high low-density lipoprotein and low HDL incidence, compared with those in the most active group at age 18 with subsequent gains. CONCLUSION: Given recent trends in declining MVPA across the life course and associated metabolic disease risk, young adulthood is an important time period for interventions to increase and begin the maintenance of MVPA.

Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association.

Cannabis, or marijuana, has potential therapeutic and medicinal properties related to multiple compounds, particularly Δ-9-tetrahydrocannabinol and cannabidiol. Over the past 25 years, attitudes toward cannabis have evolved rapidly, with expanding legalization of medical and recreational use at the state level in the United States and recreational use nationally in Canada and Uruguay. As a result, the consumption of cannabis products is increasing considerably, particularly among youth. Our understanding of the safety and efficacy of cannabis has been limited by decades of worldwide illegality and continues to be limited in the United States by the ongoing classification of cannabis as a Schedule 1 controlled substance. These shifts in cannabis use require clinicians to understand conflicting laws, health implications, and therapeutic possibilities. Cannabis may have therapeutic benefits, but few are cardiovascular in nature. Conversely, many of the concerning health implications of cannabis include cardiovascular diseases, although they may be mediated by mechanisms of delivery. This statement critically reviews the use of medicinal and recreational cannabis from a clinical but also a policy and public health perspective by evaluating its safety and efficacy profile, particularly in relationship to cardiovascular health.

Non-alcoholic fatty liver disease and cognitive function in middle-aged adults: the CARDIA study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) risk factors that have been linked to cognitive decline. Whether NAFLD is associated with cognitive performance in midlife remains uncertain. METHODS: Coronary Artery Risk Development in Young Adults study participants with CT examination and cognitive assessment at Y25 (2010-2011; n = 2809) were included. Cognitive function was reassessed at Y30. NAFLD was defined according to liver attenuation and treated both continuously and categorically (using ≤ 40 and ≤ 51 Hounsfield units to define severity) after exclusion for other causes of liver fat. Cognitive tests including the Digit Symbol Substitution (processing speed), Rey Auditory Verbal Learning (verbal memory), and Stroop (executive function) were analyzed with standardized z-scores. Linear models were constructed to (a) examine the cross-sectional associations of NAFLD with cognitive scores and (b) evaluate its predictive role in 5-year change in cognitive performance. RESULTS: Participants' mean age (Y25) was 50.1 (SD 3.6) years (57% female; 48% black), with 392 (14%) having mild NAFLD and 281 (10%) having severe NAFLD. NAFLD was positively associated with CVD risk factors and inversely associated with cognitive scores. However, after adjustment for CVD risk factors, no associations were shown between NAFLD and cognitive scores (all ßs ≈ 0). Similarly, no associations were observed with 5-year cognitive decline. CVD history, hypertension, smoking, diabetes and hypertriglyceridemia showed stronger associations with baseline cognitive scores and were predictive of subsequent cognitive decline (all P ≤ .05). CONCLUSION: Among middle-aged adults, inverse associations between NAFLD and cognitive scores were attenuated after adjustment for CVD risk factors, with the latter predictive of poorer cognitive performance both at baseline and follow-up.

Use of Machine Learning to Develop a Risk-Stratification Tool for Emergency Department Patients With Acute Heart Failure.

STUDY OBJECTIVE: We use variables from a recently derived acute heart failure risk-stratification rule (STRATIFY) as a basis to develop and optimize risk prediction using additional patient clinical data from electronic health records and machine-learning models. METHODS: Using a retrospective cohort design, we identified all emergency department (ED) visits for acute heart failure between January 1, 2017, and December 31, 2018, among adult health plan members of a large system with 21 EDs. The primary outcome was any 30-day serious adverse event, including death, cardiopulmonary resuscitation, balloon-pump insertion, intubation, new dialysis, myocardial infarction, or coronary revascularization. Starting with the 13 variables from the STRATIFY rule (base model), we tested whether predictive accuracy in a different population could be enhanced with additional electronic health record-based variables or machine-learning approaches (compared with logistic regression). We calculated our derived model area under the curve (AUC), calculated test characteristics, and assessed admission rates across risk categories. RESULTS: Among 26,189 total ED encounters, mean patient age was 74 years, 51.7% were women, and 60.7% were white. The overall 30-day serious adverse event rate was 18.8%. The base model had an AUC of 0.76 (95% confidence interval 0.74 to 0.77). Incorporating additional variables led to improved accuracy with logistic regression (AUC 0.80; 95% confidence interval 0.79 to 0.82) and machine learning (AUC 0.85; 95% confidence interval 0.83 to 0.86). We found that 11.1%, 25.7%, and 48.9% of the study population had predicted serious adverse event risk of less than or equal to 3%, less than or equal to 5%, and less than or equal to 10%, respectively, and 28% of those with less than or equal to 3% risk were admitted. CONCLUSION: Use of a machine-learning model with additional variables improved 30-day risk prediction compared with conventional approaches.

Multigene phylogenetic data place monoraphid diatoms Schizostauron and Astartiella along with other fistula-bearing genera in the Stauroneidaceae1.

Presented here are new insights into the marine monoraphid diatom genera Schizostauron and Astartiella, based on molecular and morphological data, including descriptions of new species. Although no unambiguous morphological synapomorphies between the two genera are currently recognized, they are closely related by DNA sequence data. Heterovalvate frustules of Schizostauron are characterized by a bifid stauros on the raphe-bearing valve and intricate areolate occlusions on the sternum valve. In Astartiella, the raphe-bearing valve is characterized by a process resembling a fistula by morphology, while the sternum valve presents a particular striation pattern. Observations by light and electron microscopy were made, along with a molecular phylogenetic analysis using a three-gene (SSU, rbcL, and psbC) concatenated dataset. Three new Schizostauron species are described (S. kajotkei, S. rawaii, S. papilliareae), and two new combinations proposed (S. citronella and S. trachyderma) for species that were previously included either in Achnanthes and Cocconeis, respectively. Likewise, six new species of Astartiella (A. almalikii, A. bornmanii, A. chunlianlii, A. marksii, A. persica, and A. wangii) are described. Molecular results exclude Schizostauron and Astartiella from three clades of exclusively monoraphid diatoms, the Achnanthaceae, Cocconeidaceae, and Achnanthidiaceae, instead placing them in the Stauroneidaceae. Morphological features of Schizostauron and Astartiella, such as the stauros, fistula, and coaxial internal proximal raphe endings, are found in other genera in this clade, whereas the only common feature with monoraphid diatoms as whole group is the heterovalvy of frustules.