Precision medicine and adverse drug reactions related to cardiovascular drugs

Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient’s genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The identification of specific variants associated with adverse drug effects aims to predict those at greatest risk of harm, allowing alternative therapies to be given. This review will explore current guidance available for pharmacogenomic-based prescribing as well as exploring the potential implementation of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records will be discussed to help facilitate the integration of pharmacogenomics into primary care, the heartland of prescribing

Retinal Vascular Measures from Diabetes Retinal Screening Photographs and Risk of Incident Dementia in Type 2 Diabetes:A GoDARTS Study

OBJECTIVE: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. RESEARCH DESIGN AND METHODS: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox’s proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. RESULTS: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08–1.26) and AD (HR 1.33; 1.16–1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74–0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07–1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83–0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78–0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. CONCLUSIONS: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be amore limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria

Response of ocean ecosystems to climate warming

Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 18 (2004): GB3003, doi:10.1029/2003GB002134.We examine six different coupled climate model simulations to determine the ocean biological response to climate warming between the beginning of the industrial revolution and 2050. We use vertical velocity, maximum winter mixed layer depth, and sea ice cover to define six biomes. Climate warming leads to a contraction of the highly productive marginal sea ice biome by 42% in the Northern Hemisphere and 17% in the Southern Hemisphere, and leads to an expansion of the low productivity permanently stratified subtropical gyre biome by 4.0% in the Northern Hemisphere and 9.4% in the Southern Hemisphere. In between these, the subpolar gyre biome expands by 16% in the Northern Hemisphere and 7% in the Southern Hemisphere, and the seasonally stratified subtropical gyre contracts by 11% in both hemispheres. The low-latitude (mostly coastal) upwelling biome area changes only modestly. Vertical stratification increases, which would be expected to decrease nutrient supply everywhere, but increase the growing season length in high latitudes. We use satellite ocean color and climatological observations to develop an empirical model for predicting chlorophyll from the physical properties of the global warming simulations. Four features stand out in the response to global warming: (1) a drop in chlorophyll in the North Pacific due primarily to retreat of the marginal sea ice biome, (2) a tendency toward an increase in chlorophyll in the North Atlantic due to a complex combination of factors, (3) an increase in chlorophyll in the Southern Ocean due primarily to the retreat of and changes at the northern boundary of the marginal sea ice zone, and (4) a tendency toward a decrease in chlorophyll adjacent to the Antarctic continent due primarily to freshening within the marginal sea ice zone. We use three different primary production algorithms to estimate the response of primary production to climate warming based on our estimated chlorophyll concentrations. The three algorithms give a global increase in primary production of 0.7% at the low end to 8.1% at the high end, with very large regional differences. The main cause of both the response to warming and the variation between algorithms is the temperature sensitivity of the primary production algorithms. We also show results for the period between the industrial revolution and 2050 and 2090.J. L. Sarmiento and R. Slater were supported by the NOAA Office of Global Programs grant NA56GP0439 to the Carbon Modeling Consortium for model development and by NSF grant OCE00973166 for model and observational interpretations as part of the JGOFS Synthesis and Modeling Project. R. Barber was supported by NSF grant OCE 0136270 as part of the JGOFS Synthesis and Modeling Project. S. Doney and J. Kleypas wish to thank the Community Climate System Model science team and the Climate Simulation Laboratory at NCAR and acknowledge support from NOAA-OGP grant NOAA-NA96GP0360S. Spall is funded through the UK Department for Environment, Food and Rural Affairs contract PECD 7/12/37