Developing and validating a cardiovascular risk score for patients in the community with prior cardiovascular disease

OBJECTIVE: Patients with atherosclerotic cardiovascular disease (CVD) vary significantly in their risk of future CVD events; yet few clinical scores are available to aid assessment of risk. We sought to develop a score for use in primary care that estimates short-term CVD risk in these patients. METHODS: Adults aged <80 years with prior CVD were identified from a New Zealand primary care cohort study (PREDICT), and linked to national mortality, hospitalisation and dispensing databases. A Cox model with an outcome of myocardial infarction, stroke or CVD death within 2 years was developed. External validation was performed in a cohort from the UK. RESULTS: 24 927 patients, 63% men, 63% European, median age 65 years (IQR 58-72 years), experienced 1480 CVD events within 2 years after a CVD risk assessment. A risk score including ethnicity, comorbidities, body mass index, creatine creatinine and treatment, in addition to established risk factors used in primary prevention, predicted a median 2-year CVD risk of 5.0% (IQR 3.5%-8.3%). A plot of actual against predicted event rates showed very good calibration throughout the risk range. The score performed well in the UK cohort but overestimated risk for those at highest risk, who were predominantly patients defined as having heart failure. CONCLUSIONS: The PREDICT-CVD secondary prevention score uses routine measurements from clinical practice that enable it to be implemented in a primary care setting. The score will facilitate risk communication between primary care practitioners and patients with prior CVD, particularly as a resource to show the benefit of risk factor modification

Type I-E CRISPR-cas systems discriminate target from non-target DNA through base pairing-independent PAM recognition

This is the final version of the article. Available from the publisher via the DOI in this record.Discriminating self and non-self is a universal requirement of immune systems. Adaptive immune systems in prokaryotes are centered around repetitive loci called CRISPRs (clustered regularly interspaced short palindromic repeat), into which invader DNA fragments are incorporated. CRISPR transcripts are processed into small RNAs that guide CRISPR-associated (Cas) proteins to invading nucleic acids by complementary base pairing. However, to avoid autoimmunity it is essential that these RNA-guides exclusively target invading DNA and not complementary DNA sequences (i.e., self-sequences) located in the host's own CRISPR locus. Previous work on the Type III-A CRISPR system from Staphylococcus epidermidis has demonstrated that a portion of the CRISPR RNA-guide sequence is involved in self versus non-self discrimination. This self-avoidance mechanism relies on sensing base pairing between the RNA-guide and sequences flanking the target DNA. To determine if the RNA-guide participates in self versus non-self discrimination in the Type I-E system from Escherichia coli we altered base pairing potential between the RNA-guide and the flanks of DNA targets. Here we demonstrate that Type I-E systems discriminate self from non-self through a base pairing-independent mechanism that strictly relies on the recognition of four unchangeable PAM sequences. In addition, this work reveals that the first base pair between the guide RNA and the PAM nucleotide immediately flanking the target sequence can be disrupted without affecting the interference phenotype. Remarkably, this indicates that base pairing at this position is not involved in foreign DNA recognition. Results in this paper reveal that the Type I-E mechanism of avoiding self sequences and preventing autoimmunity is fundamentally different from that employed by Type III-A systems. We propose the exclusive targeting of PAM-flanked sequences to be termed a target versus non-target discrimination mechanism.This work was financially supported by an NWO Vidi grant to SJJB (864.11.005). RNJ and BW are supported by the National Institutes of Health (GM 103500) and the Montana State University Agricultural Experimental Station. ES, KAD and KS are supported by an NIH grant RO1 GM10407, a program grant in Molecular and Cell Biology from Presidium of Russian Academy of Sciences and a Russian Foundation for Basic Research grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Understanding the impact of legislation on 'reduction of disease risk' claims on food and drinks: The REDICLAIM project

The Nutrition and Health Claims Regulation (EC No. 1924/2006) has established a common framework for the regulation of nutrition and health claims used on foods across the European Union. This regulation aims to provide the European food industry opportunities for product innovation whilst protecting consumer interests with respect to controlling misleading advertising and promoting public health. However, in order to satisfy the approval of new health claims procedure particularly for new 'reduction of disease risk' claims [Article 14(1)(a) claims], significant research activity is required by industry to scientifically substantiate the claims they wish to make. There is a need to establish whether the implementation of this legislation is in fact driving product innovation and the development of healthy foods or whether it forms a barrier to such developments. The EU-funded REDICLAIM project is currently considering these issues. This article describes the project's preliminary results and outlines the further programme of work

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children

Thermal and electrical conductivity of iron at Earth's core conditions

The Earth acts as a gigantic heat engine driven by decay of radiogenic isotopes and slow cooling, which gives rise to plate tectonics, volcanoes, and mountain building. Another key product is the geomagnetic field, generated in the liquid iron core by a dynamo running on heat released by cooling and freezing to grow the solid inner core, and on chemical convection due to light elements expelled from the liquid on freezing. The power supplied to the geodynamo, measured by the heat-flux across the core-mantle boundary (CMB), places constraints on Earth's evolution. Estimates of CMB heat-flux depend on properties of iron mixtures under the extreme pressure and temperature conditions in the core, most critically on the thermal and electrical conductivities. These quantities remain poorly known because of inherent difficulties in experimentation and theory. Here we use density functional theory to compute these conductivities in liquid iron mixtures at core conditions from first principles- the first directly computed values that do not rely on estimates based on extrapolations. The mixtures of Fe, O, S, and Si are taken from earlier work and fit the seismologically-determined core density and inner-core boundary density jump. We find both conductivities to be 2-3 times higher than estimates in current use. The changes are so large that core thermal histories and power requirements must be reassessed. New estimates of adiabatic heat-flux give 15-16 TW at the CMB, higher than present estimates of CMB heat-flux based on mantle convection; the top of the core must be thermally stratified and any convection in the upper core driven by chemical convection against the adverse thermal buoyancy or lateral variations in CMB heat flow. Power for the geodynamo is greatly restricted and future models of mantle evolution must incorporate a high CMB heat-flux and explain recent formation of the inner core.Comment: 11 pages including supplementary information, two figures. Scheduled to appear in Nature, April 201

Assessing cognitive dysfunction in Parkinson’s: An online tool to detect visuo-perceptual deficits

BACKGROUND: People with Parkinson’s disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuoperceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD. Objective: We developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias. METHODS: We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks. RESULTS: People with PD were worse than controls at object recognition, showing no deficits in other visuoperceptual tests. Specifically, they were worse at identifying skewed images (P <.0001); at detecting hidden objects (P 5.0039); at identifying objects in peripheral vision (P <.0001); and at detecting biological motion (P 5.0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias. CONCLUSIONS: Online tests can detect visuo-perceptual defi- cits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia

TAVR Closure Devices and Their Effect on Bedrest Time

In transfemoral transcatheter aortic valve replacement patients, how do different bed rest times as well as different closure devices affect the patient outcomes postoperatively?https://knowledgeconnection.mainehealth.org/nurseresidency/1090/thumbnail.jp

Remarks on Andrew Lang's World Trade Law After Neo-Liberalism

No abstract available