Shared genetic contribution of type 2 diabetes and cardiovascular disease: Implications for prognosis and treatment

Purpose of Review: The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes. Recent Findings: Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap. Summary: Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses

Effects of Classical Exposure Measurement Error on the Shape of Exposure-Disease Associations

In epidemiology many exposures of interest are measured with error. Random, or 'classical', error in exposure measurements attenuates linear exposure-disease associations. However, its precise effects on different nonlinear associations are not well known. We use simulation studies to assess how classical measurement error affects observed association shapes and power to detect nonlinearity. We focus on a proportional hazards model for the exposure-disease association and consider six true association shapes of relevance in epidemiology: linear, threshold, U-shaped, J- shaped, increasing quadratic, asymptotic. The association shapes are modeled using three popular methods: grouped exposure analyses, fractional polynomials, P-splines. Under each true association shape and each method we illustrate the effects of classical exposure measurement error, considering varying degrees of random error. We also assess what we refer to as MacMahon's method for correcting for classical exposure measurement error under grouped exposure analyses, which uses replicate measurements to estimate usual exposure within observed exposure groups. The validity of this method for nonlinear associations has not previously been investigated. Under nonlinear exposure-disease associations, classical measurement error results in increasingly linear shapes and not always an attenuated association at a given exposure level. Fractional polynomials and P-splines give similar results and offer advantages over grouped exposure analyses by providing realistic models. P-splines offer greatest power to detect nonlinearity, however random exposure measurement error results in a potential considerable loss of power to detect nonlinearity under all methods. MacMahon's method performs well for quadratic associations, but does not in general recover nonlinear shapes

Ground-based remote sensing of an elevated forest fire aerosol layer at Whistler, BC: implications for interpretation of mountaintop chemistry

On 30 August 2009, intense forest fires in interior British Columbia (BC) coupled with winds from the east and northeast resulted in transport of a broad forest fire plume across southwestern BC. The physico-chemical and optical characteristics of the plume as observed from Saturna Island (AERONET), CORALNet-UBC and the Whistler Mountain air chemistry facility were consistent with forest fire plumes that have been observed elsewhere in continental North America. However, the importance of three-dimensional transport in relation to the interpretation of mountaintop chemistry observations is highlighted on the basis of deployment of both a <i>CL31</i> ceilometer and a single particle mass spectrometer (SPMS) in a mountainous setting. The SPMS is used to identify the biomass plume based on levoglucosan and potassium markers. Data from the SPMS are also used to show that the biomass plume was correlated with nitrate, but not correlated with sulphate or sodium. This study not only provides baseline measurements of biomass burning plume physico-chemical characteristics in western Canada, but also highlights the importance of lidar remote sensing methods in the interpretation of mountaintop chemistry measurements

Characterizing Short-Wave Infrared Fluorescence of Conventional Near-Infrared Fluorophores

The observed behavior of short-wave infrared (SWIR) light in tissue, characterized by relatively low scatter and subdiffuse photon transport, has generated considerable interest for the potential of SWIR imaging to produce high-resolution, subsurface images of fluorescence activity in vivo. These properties have important implications for fluorescence-guided surgery and preclinical biomedical research. Until recently, translational efforts have been impeded by the conventional understanding that fluorescence molecular imaging in the SWIR regime requires custom molecular probes that do not yet have proven safety profiles in humans. However, recent studies have shown that two readily available near-infrared (NIR-I) fluorophores produce measurable SWIR fluorescence, implying that other conventional fluorophores produce detectable fluorescence in the SWIR window. Using SWIR spectroscopy and wide-field SWIR imaging with tissue-simulating phantoms, we characterize and compare the SWIR emission properties of eight commercially available red/NIR-I fluorophores commonly used in preclinical and clinical research, in addition to a SWIR-specific fluorophore. All fluorophores produce measurable fluorescence emission in the SWIR, including shorter wavelength dyes such as Alexa Fluor 633 and methylene blue. This study is the first to report SWIR fluorescence from six of the eight conventional fluorophores and establishes an important comparative reference for developing and evaluating SWIR imaging strategies for biomedical applications

An electronic family health history tool to identify and manage patients at increased risk for colorectal cancer: protocol for a randomized controlled trial.

BackgroundColorectal cancer is the fourth most commonly diagnosed cancer in the United States. Approximately 3-10% of the population has an increased risk for colorectal cancer due to family history and warrants more frequent or intensive screening. Yet, &lt; 50% of that high-risk population receives guideline-concordant care. Systematic collection of family health history and decision support may improve guideline-concordant screening for patients at increased risk of colorectal cancer. We seek to test the effectiveness of a web-based, systematic family health history collection tool and decision support platform (MeTree) to improve risk assessment and appropriate management of colorectal cancer risk among patients in the Department of Veterans Affairs primary care practices.MethodsIn this ongoing randomized controlled trial, primary care providers at the Durham Veterans Affairs Health Care System and the Madison VA Medical Center are randomized to immediate intervention or wait-list control. Veterans are eligible if assigned to enrolled providers, have an upcoming primary care appointment, and have no conditions that would place them at increased risk for colorectal cancer (such as personal history, adenomatous polyps, or inflammatory bowel disease). Those with a recent lower endoscopy (e.g. colonoscopy, sigmoidoscopy) are excluded. Immediate intervention patients put their family health history information into a web-based platform, MeTree, which provides both patient- and provider-facing decision support reports. Wait-list control patients access MeTree 12 months post-consent. The primary outcome is the risk-concordant colorectal cancer screening referral rate obtained via chart review. Secondary outcomes include patient completion of risk management recommendations (e.g. colonoscopy) and referral for genetic consultation. We will also conduct an economic analysis and an assessment of providers' experience with MeTree clinical decision support recommendations to inform future implementation efforts if the intervention is found to be effective.DiscussionThis trial will assess the feasibility and effectiveness of patient-collected family health history linked to decision support to promote risk-appropriate screening in a large healthcare system such as the Department of Veterans Affairs.Trial registrationClinicalTrials.gov, NCT02247336 . Registered on 25 September 2014

The High Arctic in Extreme Winters: Vortex, Temperature, and MLS and ACE-FTS Trace Gas Evolution

The first three Canadian Arctic Atmospheric Chemistry Experiment (ACE) Validation Campaigns at Eureka (80° N, 86° W) were during two extremes of Arctic winter variability: Stratospheric sudden warmings (SSWs) in 2004 and 2006 were among the strongest, most prolonged on record; 2005 was a record cold winter. New satellite measurements from ACE-Fourier Transform Spectrometer (ACE-FTS), Sounding of the Atmosphere using Broadband Emission Radiometry, and Aura Microwave Limb Sounder (MLS), with meteorological analyses and Eureka lidar and radiosonde temperatures, are used to detail the meteorology in these winters, to demonstrate its influence on transport and chemistry, and to provide a context for interpretation of campaign observations. During the 2004 and 2006 SSWs, the vortex broke down throughout the stratosphere, reformed quickly in the upper stratosphere, and remained weak in the middle and lower stratosphere. The stratopause reformed at very high altitude, above where it could be accurately represented in the meteorological analyses. The 2004 and 2006 Eureka campaigns were during the recovery from the SSWs, with the redeveloping vortex over Eureka. 2005 was the coldest winter on record in the lower stratosphere, but with an early final warming in mid-March. The vortex was over Eureka at the start of the 2005 campaign, but moved away as it broke up. Disparate temperature profile structure and vortex evolution resulted in much lower (higher) temperatures in the upper (lower) stratosphere in 2004 and 2006 than in 2005. Satellite temperatures agree well with Eureka radiosondes, and with lidar data up to 50–60 km. Consistent with a strong, cold upper stratospheric vortex and enhanced radiative cooling after the SSWs, MLS and ACE-FTS trace gas measurements show strongly enhanced descent in the upper stratospheric vortex during the 2004 and 2006 Eureka campaigns compared to that in 2005

Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease

IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA = 0.11, P = 6.73E−5 and chromosome 14, rs4902762, BETA = 0.12, P = 5.76E−6) and one for eosinophil count (rs72797327, BETA = −0.10, P = 1.41E−6). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA = 0.04, P = 0.2763, I2 = 24, I2 − P = 0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2 = 0.93 with rs56183820) BETA = −0.10, P = 8.64E−6 and rs11739623 (r2 = 0.96 with rs72797327) BETA = −0.23, P = 1.74E−29, respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels

Real-time in vivo Cherenkoscopy Imaging During External Beam Radiation Therapy

Cherenkov radiation is induced when charged particles travel through dielectric media (such as biological tissue) faster than the speed of light through that medium. Detection of this radiation or excited luminescence during megavoltage external beam radiotherapy (EBRT) can allow emergence of a new approach to superficial dose estimation, functional imaging, and quality assurance for radiation therapy dosimetry. In this letter, the first in vivo Cherenkov images of a real-time Cherenkoscopy during EBRT are presented. The imaging system consisted of a time-gated intensified charge coupled device (ICCD) coupled with a commercial lens. The ICCD was synchronized to the linear accelerator to detect Cherenkov photons only during the 3.25-μs radiation bursts. Images of a tissue phantom under irradiation show that the intensity of Cherenkov emission is directly proportional to radiation dose, and images can be acquired at 4.7  frames/s with SNR\u3c30 . Cherenkoscopy was obtained from the superficial regions of a canine oral tumor during planned, Institutional Animal Care and Use Committee approved, conventional (therapeutically appropriate) EBRT irradiation. Coregistration between photography and Cherenkoscopy validated that Cherenkov photons were detected from the planned treatment region. Real-time images correctly monitored the beam field changes corresponding to the planned dynamic wedge movement, with accurate extent of overall beam field, and expected cold and hot regions

Static Scaling Behavior of High-Molecular-Weight Polymers in Dilute Solution: A Reexamination

Previous theories of dilute polymer solutions have failed to distinguish clearly between two very different ways of taking the long-chain limit: (I) $N \to\infty$ at fixed temperature $T$, and (II) $N \to\infty$, $T \to T_\theta$ with $x \equiv N^\phi (T-T_\theta)$ fixed. I argue that the modern two-parameter theory (continuum Edwards model) applies to case II --- not case I --- and in fact gives exactly the crossover scaling functions for $x \ge 0$ modulo two nonuniversal scale factors. A Wilson-type renormalization group clarifies the connection between crossover scaling functions and continuum field theories. [Also contains a general discussion of the connection between the Wilson and field-theoretic renormalization groups. Comments solicited.]Comment: 10 pages including 1 figure, 181159 bytes Postscript (NYU-TH-93/05/01

The importance of both setting and intensity of physical activity in relation to non-clinical anxiety and depression

Physical activity is associated with good physical and mental health. Current recommendations suggest that people should achieve 30 minutes of moderate-intensity activity most days of the week to gain health benefits. This activity may be accumulated in leisure time, in active commuting, at work or in the home. Here we look at the cross-sectional relationship between physical activity and mental health as measured by the HADS anxiety and depression scores in a sample of 1,742 participants from a Scottish general population survey. The participants were men and women in three age cohorts aged around 24, 44 and 64 years who, in 1995, were interviewed face to face and also self-completed the HADS depression and anxiety scale. Respondents reported their levels of physical activity at work, in the home and in leisure time; the intensities of activity were also determined. Physical activity was related to depression scores but not to anxiety scores. There was no relationship between work physical activity and depression score. Among women, depression score increased with each additional episode of vigorous home activity. In both sexes, depression score decreased with each additional episode of vigorous leisure activity, but among men the decrease in depression score with moderate leisure activity was reversed if a lot of moderate activity was undertaken. We have found a variable relationship between depression scores and various settings for physical activity. Researchers, policymakers and practitioners who are interested in the relationship between physical activity and mental health should take into account the setting for activity as well as frequency, duration and intensity of activity