Does life satisfaction reduce risk of incident hypertension and stroke? Evidence from the Whitehall II cohort

Background: Previous studies showed life satisfaction is related to reduced risk of coronary heart disease and diabetes, but its association with other cardiometabolic endpoints including hypertension and stroke remains unexplored. This study examined life satisfaction's prospective association with incident hypertension and stroke in middle-aged adults. Methods: At baseline (1985–1988), 6225 healthy British civil servants aged 35–55 from the Whitehall II cohort completed the validated Satisfaction with Life Scale and provided information regarding sociodemographics, a range of health-related factors, and psychological distress. Incident hypertension was ascertained according to clinic-derived measures of systolic or diastolic blood pressure of ≥140/90 mmHg, respectively, or self-reports of either physician-diagnosed hypertension or hypertensive medication use. Incident stroke and transient ischemic attack (TIA) were ascertained by self-reported physician diagnosis. Follow-up assessments occurred every 2–5 years through 2017. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) of hypertension and stroke/TIA risk separately. Results: Over a 31-year follow-up, 2703 cases of hypertension and 370 cases of stroke/TIA occurred. Life satisfaction was not related to risk of developing hypertension but was associated with 12% decreased risk of stroke/TIA after controlling for sociodemographics, health status, and health behaviors (HRper 1-SD = 0.88; 95%CI = 0.79–0.98). However, the association was attenuated after adjustment for psychological distress. Conclusions: No robust associations were found between life satisfaction and incident hypertension and stroke/TIA, respectively, after accounting for well-established risk factors and psychological distress. More research is needed to understand why associations of life satisfaction with cardiometabolic health seem to vary across endpoints

Urologist burnout: Frequency, causes, and potential solutions to an unspoken entity

Physician burnout has been linked to decreased job performance, increased medical errors, interpersonal conflicts, and depression. Recent multispecialty studies suggest that urologists have higher rates (up to 63.6%) of burnout compared to physicians in other specialties; however, these reports were limited by low sample sizes.1 We aimed to evaluate the prevalence of urologist burnout, verify risk factors, and recommend preventative measures and solutions for colleagues at risk or suffering from burnout. Urologist burnout is a true entity that transcends level of training and nationality. Its roots appear to be deep-seated in our tireless efforts to strive for excellence in care for our patients, our growing academic and research pursuits, and surmounting administrative responsibilities; these virtues, which are regarded as the foundations of our career successes, are often obtained at the expense of personal health and wellbeing, as well as family sacrifice. Various other medical societies have become increasingly vocal about the issue of physician burnout and have actively initiated successful strategies to minimize its impact on their members. As an organization with a strong national presence, the Canadian Urological Association (CUA) should promote tools to prevent and interventions to assist those at risk for and suffering from burnout. Increased awareness in the general medical community has led to strategies and tools that can help prevent, identify, or assist physicians in their recovery from burnout. The CUA should develop and facilitate access to information and offer comprehensive support for urologists struggling with burnout

The Coplane Analysis Technique for Three-Dimensional Wind Retrieval Using the HIWRAP Airborne Doppler Radar

The coplane analysis technique for mapping the three-dimensional wind field of precipitating systems is applied to the NASA High Altitude Wind and Rain Airborne Profiler (HIWRAP). HIWRAP is a dual-frequency Doppler radar system with two downward pointing and conically scanning beams. The coplane technique interpolates radar measurements to a natural coordinate frame, directly solves for two wind components, and integrates the mass continuity equation to retrieve the unobserved third wind component. This technique is tested using a model simulation of a hurricane and compared to a global optimization retrieval. The coplane method produced lower errors for the cross-track and vertical wind components, while the global optimization method produced lower errors for the along-track wind component. Cross-track and vertical wind errors were dependent upon the accuracy of the estimated boundary condition winds near the surface and at nadir, which were derived by making certain assumptions about the vertical velocity field. The coplane technique was then applied successfully to HIWRAP observations of Hurricane Ingrid (2013). Unlike the global optimization method, the coplane analysis allows for a transparent connection between the radar observations and specific analysis results. With this ability, small-scale features can be analyzed more adequately and erroneous radar measurements can be identified more easily

Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells. © 2010 MacTavish et al

Variations in the Peritrophic Matrix Composition of Heparan Sulphate from the Tsetse Fly, Glossina morsitans morsitans

Tsetse flies are the principal insect vectors of African trypanosomes—sleeping sickness in humans and Nagana in cattle. One of the tsetse fly species, Glossina morsitans morsitans, is host to the parasite, Trypanosoma brucei, a major cause of African trypanosomiasis. Precise details of the life cycle have yet to be established, but the parasite life cycle involves crossing the insect peritrophic matrix (PM). The PM consists of the polysaccharide chitin, several hundred proteins, and both glycosamino- and galactosaminoglycan (GAG) polysaccharides. Owing to the technical challenges of detecting small amounts of GAG polysaccharides, their conclusive identification and composition have not been possible until now. Following removal of PMs from the insects and the application of heparinases (bacterial lyase enzymes that are specific for heparan sulphate (HS) GAG polysaccharides), dot blots with a HS-specific antibody showed heparan sulphate proteoglycans (HSPGs) to be present, consistent with Glossina morsitans morsitans genome analysis, as well as the likely expression of the HSPGs syndecan and perlecan. Exhaustive HS digestion with heparinases, fluorescent labeling of the resulting disaccharides with BODIPY fluorophore, and separation by strong anion exchange chromatography then demonstrated the presence of HS for the first time and provided the disaccharide composition. There were no significant differences in the type of disaccharide species present between genders or between ages (24 vs. 48 h post emergence), although the HS from female flies was more heavily sulphated overall. Significant differences, which may relate to differences in infection between genders or ages, were evident, however, in overall levels of 2-O-sulphation between sexes and, for females, between 24 and 48 h post-emergence, implying a change in expression or activity for the 2-O-sulphotransferase enzyme. The presence of significant quantities of disaccharides containing the monosaccharide GlcNAc6S contrasts with previous findings in Drosophila melanogaster and suggests subtle differences in HS fine structure between species of the Diptera

Mantle redox state drives outgassing chemistry and atmospheric composition of rocky planets

Volcanic degassing of planetary interiors has important implications for their corresponding atmospheres. The oxidation state of rocky interiors affects the volatile partitioning during mantle melting and subsequent volatile speciation near the surface. Here we show that the mantle redox state is central to the chemical composition of atmospheres while factors such as planetary mass, thermal state, and age mainly affect the degassing rate. We further demonstrate that mantle oxygen fugacity has an effect on atmospheric thickness and that volcanic degassing is most efficient for planets between 2 and 4 Earth masses. We show that outgassing of reduced systems is dominated by strongly reduced gases such as H2, with only smaller fractions of moderately reduced/oxidised gases (CO, H2O). Overall, a reducing scenario leads to a lower atmospheric pressure at the surface and to a larger atmospheric thickness compared to an oxidised system. Atmosphere predictions based on interior redox scenarios can be compared to observations of atmospheres of rocky exoplanets, potentially broadening our knowledge on the diversity of exoplanetary redox states

Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (<i>K</i>_i = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range

Empirical Bayesian Mixture Models for Medical Image Translation

Automatically generating one medical imaging modality from another is known as medical image translation, and has numerous interesting applications. This paper presents an interpretable generative modelling approach to medical image translation. By allowing a common model for group-wise normalisation and segmentation of brain scans to handle missing data, the model allows for predicting entirely missing modalities from one, or a few, MR contrasts. Furthermore, the model can be trained on a fairly small number of subjects. The proposed model is validated on three clinically relevant scenarios. Results appear promising and show that a principled, probabilistic model of the relationship between multi-channel signal intensities can be used to infer missing modalities -- both MR contrasts and CT images.Comment: Accepted to the Simulation and Synthesis in Medical Imaging (SASHIMI) workshop at MICCAI 201

Heparan sulfate and heparin interactions with proteins.

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissuespecific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure–activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure–activity relationships and regulation will be discussed

Characterization of 3D PET systems for accurate quantification of myocardial blood flow

Three-dimensional (3D) mode imaging is the current standard for positron emission tomography-computed tomography (PET-CT) systems. Dynamic imaging for quantification of myocardial blood flow (MBF) with short-lived tracers, such as Rb-82- chloride (Rb-82), requires accuracy to be maintained over a wide range of isotope activities and scanner count-rates. We propose new performance standard measurements to characterize the dynamic range of PET systems for accurate quantitative imaging. Methods: 1100-3000 MBq of Rb-82 or N-13-ammonia was injected into the heart wall insert of an anthropomorphic torso phantom. A decaying isotope scan was performed over 5 half-lives on 9 different 3D PET-CT systems and 1 3D/twodimensional (2D) PET-only system. Dynamic images (28x15s) were reconstructed using iterative algorithms with all corrections enabled. Dynamic range was defined as the maximum activity in the myocardial wall with <10% bias, from which corresponding dead-time, count-rates and/or injected activity limits were established for each scanner. Scatter correction residual bias was estimated as the maximum cavity blood-tomyocardium activity ratio. Image quality was assessed via the coefficient of variation measuring non-uniformity of the left ventricle (LV) myocardium activity distribution. Results: Maximum recommended injected activity/body-weight, peak dead-time correction factor, count-rates and residual scatter bias for accurate cardiac MBF imaging were: 3-14 MBq/kg, 1.5-4.0, 22-64 Mcps singles and 4-14 Mcps prompt coincidence count-rates, and 2-10% on the investigated scanners. Non-uniformity of the myocardial activity distribution varied from 3-16%. Conclusion: Accurate dynamic imaging is possible on the 10 3D-PET systems if the maximum injected MBq/kg values are respected to limit peak dead-time losses during the bolus first-pass transit