A dedicated flavin-dependent monooxygenase catalyzes the hydroxylation of demethoxyubiquinone into ubiquinone (coenzyme Q) in Arabidopsis.

Ubiquinone (Coenzyme Q) is a vital respiratory cofactor and liposoluble antioxidant. In plants, it is not known how the C-6 hydroxylation of demethoxyubiquinone, the penultimate step in ubiquinone biosynthesis, is catalyzed. The combination of cross-species gene network modeling along with mining of embryo-defective mutant databases of Arabidopsis thaliana identified the embryo lethal locus EMB2421 (At1g24340) as a top candidate for the missing plant demethoxyubiquinone hydroxylase. In marked contrast with prototypical eukaryotic demethoxyubiquinone hydroxylases, the catalytic mechanism of which depends on a carboxylate-bridged di-iron domain, At1g24340 is homologous to FAD-dependent oxidoreductases that instead use NAD(P)H as an electron donor. Complementation assays in Saccharomyces cerevisiae and Escherichia coli demonstrated that At1g24340 encodes a functional demethoxyubiquinone hydroxylase and that the enzyme displays strict specificity for the C-6 position of the benzoquinone ring. Laser-scanning confocal microscopy also showed that GFP-tagged At1g24340 is targeted to mitochondria. Silencing of At1g24340 resulted in 40 to 74% decrease in ubiquinone content and de novo ubiquinone biosynthesis. Consistent with the role of At1g24340 as a benzenoid ring modification enzyme, this metabolic blockage could not be bypassed by supplementation with 4-hydroxybenzoate, the immediate precursor of ubiquinone's ring. Unlike in yeast, in Arabidopsis overexpression of demethoxyubiquinone hydroxylase did not boost ubiquinone content. Phylogenetic reconstructions indicated that plant demethoxyubiquinone hydroxylase is most closely related to prokaryotic monooxygenases that act on halogenated aromatics and likely descends from an event of horizontal gene transfer between a green alga and a bacterium.

Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40 and Beyond.

More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the "Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40" symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.

Cardio-Oncology Rehabilitation to Manage Cardiovascular Outcomes in Cancer Patients and Survivors: A Scientific Statement From the American Heart Association.

Cardiovascular disease is a competing cause of death in patients with cancer with early-stage disease. This elevated cardiovascular disease risk is thought to derive from both the direct effects of cancer therapies and the accumulation of risk factors such as hypertension, weight gain, cigarette smoking, and loss of cardiorespiratory fitness. Effective and viable strategies are needed to mitigate cardiovascular disease risk in this population; a multimodal model such as cardiac rehabilitation may be a potential solution. This statement from the American Heart Association provides an overview of the existing knowledge and rationale for the use of cardiac rehabilitation to provide structured exercise and ancillary services to cancer patients and survivors. This document introduces the concept of cardio-oncology rehabilitation, which includes identification of patients with cancer at high risk for cardiac dysfunction and a description of the cardiac rehabilitation infrastructure needed to address the unique exposures and complications related to cancer care. In this statement, we also discuss the need for future research to fully implement a multimodal model of cardiac rehabilitation for patients with cancer and to determine whether reimbursement of these services is clinically warranted.

Terminating rice innate immunity induction requires a network of antagonistic and redox-responsive E3 ubiquitin ligases targeting a fungal sirtuin.

Fungal phytopathogens can suppress plant immune mechanisms in order to colonize living host cells. Identifying all the molecular components involved is critical for elaborating a detailed systems-level model of plant infection probing pathogen weaknesses; yet, the hierarchy of molecular events controlling fungal responses to the plant cell is not clear. Here we show how, in the blast fungus Magnaporthe oryzae, terminating rice innate immunity requires a dynamic network of redox-responsive E3 ubiquitin ligases targeting fungal sirtuin 2 (Sir2), an antioxidation regulator required for suppressing the host oxidative burst. Immunoblotting, immunopurification, mass spectrometry and gene functional analyses showed that Sir2 levels responded to oxidative stress via a mechanism involving ubiquitination and three antagonistic E3 ubiquitin ligases: Grr1 and Ptr1 maintained basal Sir2 levels in the absence of oxidative stress; Upl3 facilitated Sir2 accumulation in response to oxidative stress. Grr1 and Upl3 interacted directly with Sir2 in a manner that decreased and scaled with oxidative stress, respectively. Deleting UPL3 depleted Sir2 during growth in rice cells, triggering host immunity and preventing infection. Overexpressing SIR2 in the Δupl3 mutant remediated pathogenicity. Our work reveals how redox-responsive E3 ubiquitin ligases in M. oryzae mediate Sir2 accumulation-dependent antioxidation to modulate plant innate immunity and host susceptibility.

Genetic evidence for Magnaporthe oryzae vitamin B3 acquisition from rice cells.

Following penetration, the devastating rice blast fungus Magnaporthe oryzae, like some other important eukaryotic phytopathogens, grows in intimate contact with living plant cells before causing disease. Cell-to-cell growth during this biotrophic growth stage must involve nutrient acquisition, but experimental evidence for the internalization and metabolism of host-derived compounds is exceedingly sparse. This striking gap in our knowledge of the infection process undermines accurate conceptualization of the plant-fungal interaction. Here, through our general interest in Magnaporthe metabolism and with a specific focus on the signalling and redox cofactor nicotinamide adenine dinucleotide (NAD), we deleted the M. oryzae QPT1 gene encoding quinolinate phosphoribosyltransferase, catalyst of the last step in de novo NAD biosynthesis from tryptophan. We show how QPT1 is essential for axenic growth on minimal media lacking nicotinic acid (NA, an importable NAD precursor). However, Δqpt1 mutant strains were fully pathogenic, indicating de novo NAD biosynthesis is dispensable for lesion expansion following invasive hyphal growth in leaf tissue. Because overcoming the loss of de novo NAD biosynthesis in planta can only occur if importable NAD precursors (which solely comprise the NA, nicotinamide and nicotinamide riboside forms of vitamin B3) are accessible, we unexpectedly but unequivocally demonstrate that vitamin B3 can be acquired from the host and assimilated into Magnaporthe metabolism during growth in rice cells. Our results furnish a rare, experimentally determined example of host nutrient acquisition by a fungal plant pathogen and are significant in expanding our knowledge of events at the plant-fungus metabolic interface.

Estimating Longitudinal Risks and Benefits From Cardiovascular Preventive Therapies Among Medicare Patients: The Million Hearts Longitudinal ASCVD Risk Assessment Tool: A Special Report From the American Heart Association and American College of Cardiology.

The Million Hearts Initiative has a goal of preventing 1 million heart attacks and strokes-the leading causes of mortality-through several public health and healthcare strategies by 2017. The American Heart Association and American College of Cardiology support the program. The Cardiovascular Risk Reduction Model was developed by Million Hearts and the Center for Medicare & Medicaid Services as a strategy to assess a value-based payment approach toward reduction in 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD) by implementing cardiovascular preventive strategies to manage the "ABCS" (aspirin therapy in appropriate patients, blood pressure control, cholesterol management, and smoking cessation). The purpose of this special report is to describe the development and intended use of the Million Hearts Longitudinal ASCVD Risk Assessment Tool. The Million Hearts Tool reinforces and builds on the "2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk" by allowing clinicians to estimate baseline and updated 10-year ASCVD risk estimates for primary prevention patients adhering to the appropriate ABCS over time, alone or in combination. The tool provides updated risk estimates based on evidence from high-quality systematic reviews and meta-analyses of the ABCS therapies. This novel approach to personalized estimation of benefits from risk-reducing therapies in primary prevention may help target therapies to those in whom they will provide the greatest benefit, and serves as the basis for a Center for Medicare & Medicaid Services program designed to evaluate the Million Hearts Cardiovascular Risk Reduction Model.

Vital Signs: State-Level Variation in Nonfatal and Fatal Cardiovascular Events Targeted for Prevention by Million Hearts 2022.

INTRODUCTION: Despite its preventability, cardiovascular disease remains a leading cause of morbidity, mortality, and health care costs in the United States. This study describes the burden, in 2016, of nonfatal and fatal cardiovascular events targeted for prevention by Million Hearts 2022, a national initiative working to prevent one million cardiovascular events during 2017-2021. METHODS: Emergency department (ED) visits and hospitalizations were identified using Healthcare Cost and Utilization Project databases, and deaths were identified using National Vital Statistics System data. Age-standardized Million Hearts-preventable event rates and hospitalization costs among adults aged ≥18 years in 2016 are described nationally and across states, as data permit. Expected 2017-2021 event totals and hospitalization costs were estimated assuming 2016 values remain unchanged. RESULTS: Nationally, in 2016, 2.2 million hospitalizations (850.9 per 100,000 population) resulting in $32.7 billion in costs, and 415,480 deaths (157.4 per 100,000) occurred. Hospitalization and mortality rates were highest among men (989.6 and 172.3 per 100,000, respectively) and non-Hispanic blacks (211.6 per 100,000, mortality only) and increased with age. However, 805,000 hospitalizations and 75,245 deaths occurred among adults aged 18-64 years. State-level variation occurred in rates of ED visits (from 56.4 [Connecticut] to 274.8 per 100,000 [Kentucky]), hospitalizations (484.0 [Wyoming] to 1670.3 per 100,000 [DC]), and mortality (111.2 [Vermont] to 267.3 per 100,000 [Mississippi]). Approximately 16.3 million events and $173.7 billion in hospitalization costs could occur during 2017-2021 without preventive intervention. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Million Hearts-preventable events place a considerable health and economic burden on the United States. With coordinated efforts, many of these events could be prevented in every state to achieve the initiative's goal.

Characteristics of Health Care Practices and Systems That Excel in Hypertension Control.

Approximately 1 in 3 US adults has hypertension, but only half have their blood pressure controlled. We identified characteristics of health care practices and systems (hereinafter practices) effective in achieving control rates at or above 70% by using data collected via applications submitted from April through June 2017 for consideration in the Million Hearts Hypertension Control Challenge. We included 96 practices serving 635,000 patients with hypertension across 34 US states in the analysis. Mean hypertension control rate was 77.1%; 27.1% of practices had a control rate of 80% or greater. Although many practices served large populations with multiple risk factors for uncontrolled hypertension, high control rates were achieved with implementation of evidenced-based strategies.

CDC Grand Rounds: A Public Health Approach to Detect and Control Hypertension.

Hypertension is generally defined as systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg. A person who currently uses blood pressure-lowering medication is also defined as having hypertension. Hypertension is a leading risk factor for cardiovascular disease and stroke (1,2). Hypertension affects nearly one third of U.S. residents aged ≥18 years (approximately 75 million persons), and in approximately one half of adults with hypertension (nearly 35 million persons), it is uncontrolled (2). Among these 35 million U.S. residents with uncontrolled hypertension, 33% (11.5 million persons) are not aware of their hypertension, 20% (7 million persons) are aware of their hypertension, but are not being treated for it, and approximately 47% (16.1 million persons) are aware of their hypertension and being treated for it, but treatment (by medication and/or lifestyle modification) is not adequately controlling their blood pressure (Figure) (2).

Using electronic clinical quality measure reporting for public health surveillance.

By June 2013, three fourths of office-based practicing physicians in the United States had adopted some form of electronic health record (EHR) system. With greater EHR use, more health data are linked with available patient demographic information in a format that is easily retrievable and collected at the point of care. This highlights the potential of electronic clinical quality measure (CQM) reporting data for use in monitoring population health for those receiving health care services. To assess this possibility, electronic CQM data that were submitted to the Medicare EHR Incentive Program were analyzed to assess provider progress toward achieving blood pressure control among their patients with hypertension. Approximately 63,000 health care providers reported at least 1 time over 3 years, representing approximately 17 million patients with hypertension. On average, 62% of patients with hypertension had controlled blood pressure. Use of EHR data for public health surveillance could streamline reporting, facilitating more timely and possibly more complete data collection in key areas of public health concern.

Principles of carbon catabolite repression in the rice blast fungus: Tps1, Nmr1-3, and a MATE-family pump regulate glucose metabolism during infection.

Understanding the genetic pathways that regulate how pathogenic fungi respond to their environment is paramount to developing effective mitigation strategies against disease. Carbon catabolite repression (CCR) is a global regulatory mechanism found in a wide range of microbial organisms that ensures the preferential utilization of glucose over less favourable carbon sources, but little is known about the components of CCR in filamentous fungi. Here we report three new mediators of CCR in the devastating rice blast fungus Magnaporthe oryzae: the sugar sensor Tps1, the Nmr1-3 inhibitor proteins, and the multidrug and toxin extrusion (MATE)-family pump, Mdt1. Using simple plate tests coupled with transcriptional analysis, we show that Tps1, in response to glucose-6-phosphate sensing, triggers CCR via the inactivation of Nmr1-3. In addition, by dissecting the CCR pathway using Agrobacterium tumefaciens-mediated mutagenesis, we also show that Mdt1 is an additional and previously unknown regulator of glucose metabolism. Mdt1 regulates glucose assimilation downstream of Tps1 and is necessary for nutrient utilization, sporulation, and pathogenicity. This is the first functional characterization of a MATE-family protein in filamentous fungi and the first description of a MATE protein in genetic regulation or plant pathogenicity. Perturbing CCR in Δtps1 and MDT1 disruption strains thus results in physiological defects that impact pathogenesis, possibly through the early expression of cell wall-degrading enzymes. Taken together, the importance of discovering three new regulators of carbon metabolism lies in understanding how M. oryzae and other pathogenic fungi respond to nutrient availability and control development during infection.

Hypertension in Pregnancy: Current Challenges and Future Opportunities for Surveillance and Research.

Hypertension in pregnancy (HP) includes eclampsia/preeclampsia, chronic hypertension, superimposed preeclampsia, and gestational hypertension. In the United States, HP prevalence doubled over the last three decades, based on birth certificate data. In 2019, the estimated percent of births with a history of HP varied from 10.1% to 15.9% for birth certificate data and hospital discharge records, respectively. The use of electronic medical records may result in identifying an additional third to half of undiagnosed cases of HP. Individuals with gestational hypertension or preeclampsia are at 3.5 times higher risk of progressing to chronic hypertension and from 1.7 to 2.8 times higher risk of developing cardiovascular disease (CVD) after childbirth compared with individuals without these conditions. Interventions to identify and address CVD risk factors among individuals with HP are most effective if started during the first 6 weeks postpartum and implemented during the first year after childbirth. Providing access to affordable health care during the first 12 months after delivery may ensure healthy longevity for individuals with HP. Average attendance rates for postpartum visits in the United States are 72.1%, but the rates vary significantly (from 24.9% to 96.5%). Moreover, even among individuals with CVD risk factors who attend postpartum visits, approximately 40% do not receive counseling on a healthy lifestyle. In the United States, as of the end of September 2023, 38 states and the District of Columbia have extended Medicaid coverage eligibility, eight states plan to implement it, and two states proposed a limited coverage extension from 2 to 12 months after childbirth. Currently, data gaps exist in national health surveillance and health systems to identify and monitor HP. Using multiple data sources, incorporating electronic medical record data algorithms, and standardizing data definitions can improve surveillance, provide opportunities to better track progress, and may help in developing targeted policy recommendations.

An Opportunity to Better Address Hypertension in Women: Self-Measured Blood Pressure Monitoring.

More than 56 million women in the United States have hypertension, including almost one in five women of reproductive age. The prevalence of hypertensive disorders of pregnancy is on the rise, putting more women at risk for adverse pregnancy-related outcomes and atherosclerotic cardiovascular disease later in life. Hypertension can be better detected and controlled in women throughout their life course by supporting self-measured blood pressure monitoring. In this study, we present some potential strategies for strengthening our nation's ability to address hypertension in women focusing on pregnancy-related considerations for self-measured blood pressure monitoring.

County-Level Trends in Hypertension-Related Cardiovascular Disease Mortality-United States, 2000 to 2019.

Background Amid stagnating declines in national cardiovascular disease (CVD) mortality, documenting trends in county-level hypertension-related CVD death rates can help activate local efforts prioritizing hypertension prevention, detection, and control. Methods and Results Using death certificate data from the National Vital Statistics System, Bayesian spatiotemporal models were used to estimate county-level hypertension-related CVD death rates and corresponding trends during 2000 to 2010 and 2010 to 2019 for adults aged ≥35 years overall and by age group, race or ethnicity, and sex. Among adults aged 35 to 64 years, county-level hypertension-related CVD death rates increased from a median of 23.2 per 100 000 in 2000 to 43.4 per 100 000 in 2019. Among adults aged ≥65 years, county-level hypertension-related CVD death rates increased from a median of 362.1 per 100 000 in 2000 to 430.1 per 100 000 in 2019. Increases were larger and more prevalent among adults aged 35 to 64 years than those aged ≥65 years. More than 75% of counties experienced increasing hypertension-related CVD death rates among patients aged 35 to 64 years during 2000 to 2010 and 2010 to 2019 (76.2% [95% credible interval, 74.7-78.4] and 86.2% [95% credible interval, 84.6-87.6], respectively), compared with 48.2% (95% credible interval, 47.0-49.7) during 2000 to 2010 and 66.1% (95% credible interval, 64.9-67.1) for patients aged ≥65 years. The highest rates for both age groups were among men and Black populations. All racial and ethnic categories in both age groups experienced widespread county-level increases. Conclusions Large, widespread county-level increases in hypertension-related CVD mortality sound an alarm for intensified clinical and public health actions to improve hypertension prevention, detection, and control and prevent subsequent CVD deaths in counties across the nation.

How Do We Jump-Start Self-measured Blood Pressure Monitoring in the United States? Addressing Barriers Beyond the Published Literature.

Hypertension is highly prevalent in the United States, and many persons with hypertension do not have controlled blood pressure. Self-measured blood pressure monitoring (SMBP), when combined with clinical support, is an evidence-based strategy for lowering blood pressure and improving control in persons with hypertension. For years, there has been support for widespread implementation of SMBP by national organizations and the federal government, and SMBP was highlighted as a primary intervention in the 2020 Surgeon General's Call to Action to Control Hypertension, yet optimal SMBP use remains low. There are well-known patient and clinician barriers to optimal SMBP documented in the literature. We explore additional high-level barriers that have been encountered, as broad policy and systems-level changes have been attempted, and offer potential solutions. Collective efforts could modernize data transfer and processing, improve broadband access, expand device coverage and increase affordability, integrate SMBP into routine care and reimbursement practices, and strengthen patient engagement, trust, and access.

Proceedings From a National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention Workshop to Control Hypertension.

Hypertension treatment and control prevent more cardiovascular events than management of other modifiable risk factors. Although the age-adjusted proportion of US adults with controlled blood pressure (BP) defined as <140/90 mm Hg, improved from 31.8% in 1999-2000 to 48.5% in 2007-2008, it remained stable through 2013-2014 and declined to 43.7% in 2017-2018. To address the rapid decline in hypertension control, the National Heart, Lung, and Blood Institute and the Division for Heart Disease and Stroke Prevention of the Centers for Disease Control and Prevention convened a virtual workshop with multidisciplinary national experts. Also, the group sought to identify opportunities to reverse the adverse trend and further improve hypertension control. The workshop immediately preceded the Surgeon General's Call to Action to Control Hypertension, which recognized a stagnation in progress with hypertension control. The presentations and discussions included potential reasons for the decline and challenges in hypertension control, possible "big ideas," and multisector approaches that could reverse the current trend while addressing knowledge gaps and research priorities. The broad set of "big ideas" was comprised of various activities that may improve hypertension control, including: interventions to engage patients, promotion of self-measured BP monitoring with clinical support, supporting team-based care, implementing telehealth, enhancing community-clinical linkages, advancing precision population health, developing tailored public health messaging, simplifying hypertension treatment, using process and outcomes quality metrics to foster accountability and efficiency, improving access to high-quality health care, addressing social determinants of health, supporting cardiovascular public health and research, and lowering financial barriers to hypertension control.