A prospective cohort study of neighborhood stress and ischemic heart disease in Japan: a multilevel analysis using the JACC study data

<p>Abstract</p> <p>Background</p> <p>A body of research has shown that neighborhood environment may have an effect on a variety of health outcomes, including cardiovascular disease. One explanation for the mechanism of the effect of neighborhood on cardiovascular disease is psychosocial pathways. Direct evidence for an effect of neighborhood on cardiovascular disease with adjustment for perceived stress at the individual level has not been obtained, however. The Japan Collaborative Cohort Study for the Evaluation of Cancer Risk provides a unique dataset which has aggregated area-based cohorts from 45 areas throughout Japan. The purpose of the present study was to examine the contextual effect of area-level stress on ischemic heart disease using data from a large prospective cohort in Japan.</p> <p>Methods</p> <p>A baseline survey of 110,792 residents of 45 areas aged 40-79 years was conducted between 1988 and 1990. Analysis was restricted to subjects from the 33 of 45 areas providing information about self-rated stress (32183 men and 45896 women). Multilevel Poisson regression models were employed in a two-level structure of individuals nested within the 33 areas. Area-level stress was calculated by sex as the number of persons who rated their stress level as high divided by the total number of subjects in that area. Mortality rate ratios (MRRs) per 1 percentage point increase in area-level stress were estimated with adjustment for compositional individual factors.</p> <p>Results</p> <p>During 15 years of follow-up (1,116,895 person-years), 936 deaths due to ischemic heart disease were recorded. Area-level stress varied from 6% to 22%. In the multivariable models, MRRs of area-level stress were 1.06 (95% confidence interval: 1.00-1.12, p = 0.043) in men and 1.07 (95% confidence interval: 1.00-1.14, p = 0.057) in women.</p> <p>Conclusions</p> <p>Area-level stress affects the likelihood of death due to ischemic heart disease of individuals in men. The present findings may suggest that stress should be considered not only within the individual but also within the neighborhood context.</p

Quantitative Modeling of GRK-Mediated β2AR Regulation

We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved

Neighborhood disparities in stroke and myocardial infarction mortality: a GIS and spatial scan statistics approach

<p>Abstract</p> <p>Background</p> <p>Stroke and myocardial infarction (MI) are serious public health burdens in the US. These burdens vary by geographic location with the highest mortality risks reported in the southeastern US. While these disparities have been investigated at state and county levels, little is known regarding disparities in risk at lower levels of geography, such as neighborhoods. Therefore, the objective of this study was to investigate spatial patterns of stroke and MI mortality risks in the East Tennessee Appalachian Region so as to identify neighborhoods with the highest risks.</p> <p>Methods</p> <p>Stroke and MI mortality data for the period 1999-2007, obtained free of charge upon request from the Tennessee Department of Health, were aggregated to the census tract (neighborhood) level. Mortality risks were age-standardized by the direct method. To adjust for spatial autocorrelation, population heterogeneity, and variance instability, standardized risks were smoothed using Spatial Empirical Bayesian technique. Spatial clusters of high risks were identified using spatial scan statistics, with a discrete Poisson model adjusted for age and using a 5% scanning window. Significance testing was performed using 999 Monte Carlo permutations. Logistic models were used to investigate neighborhood level socioeconomic and demographic predictors of the identified spatial clusters.</p> <p>Results</p> <p>There were 3,824 stroke deaths and 5,018 MI deaths. Neighborhoods with significantly high mortality risks were identified. Annual stroke mortality risks ranged from 0 to 182 per 100,000 population (median: 55.6), while annual MI mortality risks ranged from 0 to 243 per 100,000 population (median: 65.5). Stroke and MI mortality risks exceeded the state risks of 67.5 and 85.5 in 28% and 32% of the neighborhoods, respectively. Six and ten significant (p < 0.001) spatial clusters of high risk of stroke and MI mortality were identified, respectively. Neighborhoods belonging to high risk clusters of stroke and MI mortality tended to have high proportions of the population with low education attainment.</p> <p>Conclusions</p> <p>These methods for identifying disparities in mortality risks across neighborhoods are useful for identifying high risk communities and for guiding population health programs aimed at addressing health disparities and improving population health.</p

P2 receptor-mediated modulation of neurotransmitter release—an update

Presynaptic nerve terminals are equipped with a number of presynaptic auto- and heteroreceptors, including ionotropic P2X and metabotropic P2Y receptors. P2 receptors serve as modulation sites of transmitter release by ATP and other nucleotides released by neuronal activity and pathological signals. A wide variety of P2X and P2Y receptors expressed at pre- and postsynaptic sites as well as in glial cells are involved directly or indirectly in the modulation of neurotransmitter release. Nucleotides are released from synaptic and nonsynaptic sites throughout the nervous system and might reach concentrations high enough to activate these receptors. By providing a fine-tuning mechanism these receptors also offer attractive sites for pharmacotherapy in nervous system diseases. Here we review the rapidly emerging data on the modulation of transmitter release by facilitatory and inhibitory P2 receptors and the receptor subtypes involved in these interactions

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included.Peer reviewe

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS