Risk Factors for Long-Term Coronary Artery Calcium Progression in the Multi-Ethnic Study of Atherosclerosis.

BackgroundCoronary artery calcium (CAC) detected by noncontrast cardiac computed tomography scanning is a measure of coronary atherosclerosis burden. Increasing CAC levels have been strongly associated with increased coronary events. Prior studies of cardiovascular disease risk factors and CAC progression have been limited by short follow-up or restricted to patients with advanced disease.Methods and resultsWe examined cardiovascular disease risk factors and CAC progression in a prospective multiethnic cohort study. CAC was measured 1 to 4 times (mean 2.5 scans) over 10 years in 6810 adults without preexisting cardiovascular disease. Mean CAC progression was 23.9 Agatston units/year. An innovative application of mixed-effects models investigated associations between cardiovascular disease risk factors and CAC progression. This approach adjusted for time-varying factors, was flexible with respect to follow-up time and number of observations per participant, and allowed simultaneous control of factors associated with both baseline CAC and CAC progression. Models included age, sex, study site, scanner type, and race/ethnicity. Associations were observed between CAC progression and age (14.2 Agatston units/year per 10 years [95% CI 13.0 to 15.5]), male sex (17.8 Agatston units/year [95% CI 15.3 to 20.3]), hypertension (13.8 Agatston units/year [95% CI 11.2 to 16.5]), diabetes (31.3 Agatston units/year [95% CI 27.4 to 35.3]), and other factors.ConclusionsCAC progression analyzed over 10 years of follow-up, with a novel analytical approach, demonstrated strong relationships with risk factors for incident cardiovascular events. Longitudinal CAC progression analyzed in this framework can be used to evaluate novel cardiovascular risk factors

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism

Prevalence and costs of treating uncomplicated stage 1 hypertension in primary care: a cross-sectional analysis.

BACKGROUND: Treatment for uncomplicated stage 1 hypertension is recommended in most international guidelines but there is little evidence to indicate that therapy is beneficial. AIM: To estimate the prevalence of this condition in an untreated population and the potential costs of initiating therapy in such patients. DESIGN AND SETTING: Cross-sectional study of anonymised patient records in 19 general practices in the West Midlands, UK. METHOD: Data relating to patient demographics, existing cardiovascular disease (CVD), and risk factors (blood pressure and cholesterol) were extracted from patient records. Patients with a blood pressure of 140/90-159/99 mmHg, no CVD, and <20% 10-year cardiovascular risk were classified as having uncomplicated stage 1 hypertension. Missing data were imputed. The prevalence of untreated, uncomplicated stage 1 hypertension was estimated using descriptive statistics and extrapolated using national data. The cost of achieving blood pressure control in this population was examined in a cost-impact analysis using published costs from previous studies. RESULTS: Of the 34 975 patients (aged 40-74 years) in this study, untreated, uncomplicated stage 1 hypertension was present in 2867 individuals (8.2%, 95% confidence interval [CI] = 7.9 to 8.5). This is equivalent to 1 892 519 patients in England and Wales, for whom the additional cost of controlling blood pressure, according to guidelines, was estimated at £106-229 million per annum, depending on the health professional delivering care. CONCLUSION: Untreated, uncomplicated stage 1 hypertension is relatively common, affecting 1 in 12 patients aged 40-74 years in primary care. Current international guidelines and pay-for-performance targets, if followed, will incur significant costs for a patient benefit that is debatable.This work forms part of a larger programme on stroke prevention in primary care supported by the National Institute for Health Research (NIHR) (RP-PG-0606-1153). James P Sheppard holds a Medical Research Council Strategic Skills PostDoctoral Fellowship. Richard J McManus holds an NIHR Professorship. The views and opinions expressed are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health

Impact of Changes to National Hypertension Guidelines on Hypertension Management and Outcomes in the United Kingdom.

In recent years, national and international guidelines have recommended the use of out-of-office blood pressure monitoring for diagnosing hypertension. Despite evidence of cost-effectiveness, critics expressed concerns this would increase cardiovascular morbidity. We assessed the impact of these changes on the incidence of hypertension, out-of-office monitoring and cardiovascular morbidity using routine clinical data from English general practices, linked to inpatient hospital, mortality, and socio-economic status data. We studied 3 937 191 adults with median follow-up of 4.2 years (49% men, mean age=39.7 years) between April 1, 2006 and March 31, 2017. Interrupted time series analysis was used to examine the impact of changes to English hypertension guidelines in 2011 on incidence of hypertension (primary outcome). Secondary outcomes included rate of out-of-office monitoring and cardiovascular events. Across the study period, incidence of hypertension fell from 2.1 to 1.4 per 100 person-years. The change in guidance in 2011 was not associated with an immediate change in incidence (change in rate=0.01 [95% CI, -0.18-0.20]) but did result in a leveling out of the downward trend (change in yearly trend =0.09 [95% CI, 0.04-0.15]). Ambulatory monitoring increased significantly in 2011/2012 (change in rate =0.52 [95% CI, 0.43-0.60]). The rate of cardiovascular events remained unchanged (change in rate =-0.02 [95% CI, -0.05-0.02]). In summary, changes to hypertension guidelines in 2011 were associated with a stabilisation in incidence and no increase in cardiovascular events. Guidelines should continue to recommend out-of-office monitoring for diagnosis of hypertension

Diagnosis and management of resistant hypertension

High blood pressure (hypertension) is one of the most important risk factors for cardiovascular disease,1 2 which is a significant cause of morbidity and mortality worldwide.3 Recent surveys from developed countries suggest that the prevalence of hypertension ranges from 20-30%, with 51-80% receiving treatment but only 27-66% with adequate blood pressure control.4 One subset of uncontrolled hypertensives who do not respond to treatment are known as resistant hypertensives. This article will describe how resistant hypertension is defined, its prevalence and prognosis, methods to diagnose it effectively in routine practice and strategies to effectively manage patients diagnosed with the condition

The Design and Application of Target-Focused Compound Libraries

Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries

Predicting out-of-office blood pressure level using repeated measurements in the clinic: an observational cohort study.

OBJECTIVES: Identification of people with lower (white-coat effect) or higher (masked effect) blood pressure at home compared to the clinic usually requires ambulatory or home monitoring. This study assessed whether changes in SBP with repeated measurement at a single clinic predict subsequent differences between clinic and home measurements. METHODS: This study used an observational cohort design and included 220 individuals aged 35-84 years, receiving treatment for hypertension, but whose SBP was not controlled. The characteristics of change in SBP over six clinic readings were defined as the SBP drop, the slope and the quadratic coefficient using polynomial regression modelling. The predictive abilities of these characteristics for lower or higher home SBP readings were investigated with logistic regression and repeated operating characteristic analysis. RESULTS: The single clinic SBP drop was predictive of the white-coat effect with a sensitivity of 90%, specificity of 50%, positive predictive value of 56% and negative predictive value of 88%. Predictive values for the masked effect and those of the slope and quadratic coefficient were slightly lower, but when the slope and quadratic variables were combined, the sensitivity, specificity, positive and negative predictive values for the masked effect were improved to 91, 48, 24 and 97%, respectively. CONCLUSION: Characteristics obtainable from multiple SBP measurements in a single clinic in patients with treated hypertension appear to reasonably predict those unlikely to have a large white-coat or masked effect, potentially allowing better targeting of out-of-office monitoring in routine clinical practice.This study presents independent research commissioned by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research funding scheme (RP-PG-1209–10051). R.J.Mc.M. holds an NIHR Professorship. J.S. was funded by the NIHR Birmingham and Black Country Collaboration for Leadership in Applied Health Research and Care during part of this work, but now holds a Medical Research Council Strategic Skills Postdoctoral Fellowship. B.W. is a NIHR Senior Investigator and is supported by the NIHR UCL Hospitals Biomedical Research Centre. The TASMINH2 trial was funded by the UK Department of Health Policy Research Programme and the National Coordinating Centre for Research Capacity Development. The views and opinions expressed are those of the authors and do not necessarily reflect those of the NHS, NIHR, or the Department of Health. All equipment used in the study was purchased commercially

Ammonia exposure promotes algal biomass in an ombrotrophic peatland

Nitrogen pollution affects many peatlands with consequences for their biodiversity and ecosystem function. Microorganisms control nutrient cycling and constitute most of the biodiversity of peatlands but their response to nitrogen is poorly characterised and likely to depend on the form of deposition. Using a unique field experiment we show that ammonia exposure at realistic point source levels is associated with a general shift from heterotrophic (bacteria and fungi) to autotrophic (algal) dominance and an increase in total biomass. The biomass of larger testate amoebae increased, suggesting increased food supply for microbial predators. Results show the widespread impacts of N pollution and suggest the potential for microbial community-based bioindicators in these ecosystems