Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis

Copyright \ua9 2023 The Author(s). Published by Wolters Kluwer Health, Inc. Background and Aims: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar’s antipruritic effects and IL-31 and bile acid levels in patients with PBC. Approach and Results: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0–10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS (r = 0.54, p < 0.0001), and total (r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (−30%, p = 0.0003) and 10 mg (−52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids (r = 0.63, p < 0.0001) in the seladelpar 10 mg group. Conclusions: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar’s antipruritic effects

Correlation between Progetto Cuore risk score and early cardiovascular damage in never treated subjects

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Between-airport heterogeneity in air toxics emissions associated with individual cancer risk thresholds and population risks

Abstract Background Airports represent a complex source type of increasing importance contributing to air toxics risks. Comprehensive atmospheric dispersion models are beyond the scope of many applications, so it would be valuable to rapidly but accurately characterize the risk-relevant exposure implications of emissions at an airport. Methods In this study, we apply a high resolution atmospheric dispersion model (AERMOD) to 32 airports across the United States, focusing on benzene, 1,3-butadiene, and benzo [a]pyrene. We estimate the emission rates required at these airports to exceed a 10-6 lifetime cancer risk for the maximally exposed individual (emission thresholds) and estimate the total population risk at these emission rates. Results The emission thresholds vary by two orders of magnitude across airports, with variability predicted by proximity of populations to the airport and mixing height (R2 = 0.74–0.75 across pollutants). At these emission thresholds, the population risk within 50 km of the airport varies by two orders of magnitude across airports, driven by substantial heterogeneity in total population exposure per unit emissions that is related to population density and uncorrelated with emission thresholds. Conclusion Our findings indicate that site characteristics can be used to accurately predict maximum individual risk and total population risk at a given level of emissions, but that optimizing on one endpoint will be non-optimal for the other.</p

Variation in surgical demand and time to hip fracture repair: a Canadian database study.

BACKGROUND: Competing demands for operative resources may affect time to hip fracture surgery. We sought to determine the time to hip fracture surgery by variation in demand in Canadian hospitals. METHODS: We obtained discharge abstracts of 151,952 patients aged 65 years or older who underwent surgery for a hip fracture between January, 2004 and December, 2012 in nine Canadian provinces. We compared median time to surgery (in days) when demand could be met within a two-day benchmark and when demand required more days, i.e. clearance time, to provide surgery, overall and stratified by presence of medical reasons for delay. RESULTS: For persons admitted when demand corresponded to a 2-day clearance time, 68% of patients underwent surgery within the 2-day benchmark. When demand corresponded to a clearance time of one week, 51% of patients underwent surgery within 2 days. Compared to demand that could be served within the two-day benchmark, adjusted median time to surgery was 5.1% (95% confidence interval [CI] 4.1-6.1), 12.2% (95% CI 10.3-14.2), and 22.0% (95% CI 17.7-26.2) longer, when demand required 4, 6, and 7 or more days to clear the backlog, respectively. After adjustment, delays in median time to surgery were similar for those with and without medical reasons for delay. CONCLUSION: Increases in demand for operative resources were associated with dose-response increases in the time needed for half of hip fracture patients to undergo surgery. Such delays may be mitigated through better anticipation of day-to-day supply and demand and increased response capability

The association of cold weather and all-cause and cause-specific mortality in the island of Ireland between 1984 and 2007

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.This article has been made available through the Brunel Open Access Publishing Fund.Background This study aimed to assess the relationship between cold temperature and daily mortality in the Republic of Ireland (ROI) and Northern Ireland (NI), and to explore any differences in the population responses between the two jurisdictions. Methods A time-stratified case-crossover approach was used to examine this relationship in two adult national populations, between 1984 and 2007. Daily mortality risk was examined in association with exposure to daily maximum temperatures on the same day and up to 6 weeks preceding death, during the winter (December-February) and cold period (October-March), using distributed lag models. Model stratification by age and gender assessed for modification of the cold weather-mortality relationship. Results In the ROI, the impact of cold weather in winter persisted up to 35 days, with a cumulative mortality increase for all-causes of 6.4% (95%CI=4.8%-7.9%) in relation to every 1oC drop in daily maximum temperature, similar increases for cardiovascular disease (CVD) and stroke, and twice as much for respiratory causes. In NI, these associations were less pronounced for CVD causes, and overall extended up to 28 days. Effects of cold weather on mortality increased with age in both jurisdictions, and some suggestive gender differences were observed. Conclusions The study findings indicated strong cold weather-mortality associations in the island of Ireland; these effects were less persistent, and for CVD mortality, smaller in NI than in the ROI. Together with suggestive differences in associations by age and gender between the two Irish jurisdictions, the findings suggest potential contribution of underlying societal differences, and require further exploration. The evidence provided here will hope to contribute to the current efforts to modify fuel policy and reduce winter mortality in Ireland

Left ventricular geometric patterns and adaptations to hemodynamics are similar in elderly men and women

<p>Abstract</p> <p>Background</p> <p>Common conditions such as obesity and hypertension result in hemodynamic alterations that will induce remodeling of the left ventricle (LV). However, differences between the genders in the relationship of hemodynamics to LV geometry are not well known.</p> <p>The present study aims to investigate differences between the genders in this respect, in a sample of elderly persons.</p> <p>Methods</p> <p>Echocardiography and Doppler was performed in a population-based sample aged 70 - The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 922).</p> <p>Hemodynamic patterns obtained by echocardiography and Doppler were evaluated in relation to four LV geometric groups (normal, concentric remodeling, eccentric hypertrophy and concentric hypertrophy).</p> <p>Results</p> <p>No significant difference between the genders was observed regarding the prevalence of the LV geometric groups.</p> <p>Mean values of most evaluated echocardiography and Doppler variables differed between men and women, such as LA, IVS, LVEDD and IVRT, but the relationship of hemodynamic variables to LV geometric groups did not differ between the genders.</p> <p>Conclusions</p> <p>Although mean values of many echocardiographic variables differed between men and women, the LV geometric adaptations to a given hemodynamic load appear similar in both genders.</p

Association Of Growth And Nutritional Parameters With Pulmonary Function In Cystic Fibrosis: A Literature Review

Objective To review the literature addressing the relationship of growth and nutritional parameters with pulmonary function in pediatric patients with cystic fibrosis. Data source A collection of articles published in the last 15 years in English, Portuguese and Spanish was made by research in electronic databases – PubMed, Cochrane, Medline, Lilacs and Scielo – using the keywords cystic fibrosis, growth, nutrition, pulmonary function in varied combinations. Articles that addressed the long term association of growth and nutritional parameters, with an emphasis on growth, with pulmonary disease in cystic fibrosis, were included, and we excluded those that addressing only the relationship between nutritional parameters and cystic fibrosis and those in which the aim was to describe the disease. Data synthesis Seven studies were included, with a total of 12,455 patients. Six studies reported relationship between growth parameters and lung function, including one study addressing the association of growth parameters, solely, with lung function, and all the seven studies reported relationship between nutritional parameters and lung function. Conclusions The review suggests that the severity of the lung disease, determined by spirometry, is associated with body growth and nutritional status in cystic fibrosis. Thus, the intervention in these parameters can lead to the better prognosis and life expectancy for cystic fibrosis patients. © 2016 Sociedade de Pediatria de São Paulo34450350

Spin-Rotation Symmetry Breaking in the Superconducting State of CuxBi2Se3

Spontaneous symmetry breaking is an important concept for understanding physics ranging from the elementary particles to states of matter. For example, the superconducting state breaks global gauge symmetry, and unconventional superconductors can break additional symmetries. In particular, spin rotational symmetry is expected to be broken in spin-triplet superconductors. However, experimental evidence for such symmetry breaking has not been conclusively obtained so far in any candidate compounds. Here, by 77Se nuclear magnetic resonance measurements, we show that spin rotation symmetry is spontaneously broken in the hexagonal plane of the electron-doped topological insulator Cu0.3Bi2Se3 below the superconducting transition temperature Tc=3.4 K. Our results not only establish spin-triplet superconductivity in this compound, but may also serve to lay a foundation for the research of topological superconductivity

Is there adaptation in the ozone mortality relationship: A multi-city case-crossover analysis

<p>Abstract</p> <p>Background</p> <p>Ozone has been associated with daily mortality, mainly in the summer period. Despite the ample literature on adaptation of inflammatory and pulmonary responses to ozone, and the link, in cohort studies, between lung function and mortality risk there has been little done to date to examine the question of adaptation in the acute mortality risk associated with ambient ozone.</p> <p>Methods</p> <p>We applied a case-crossover design in 48 US cities to examine the ozone effect by season, by month and by age groups, particularly focusing on whether there was an adaptation effect.</p> <p>Results</p> <p>We found that the same day ozone effect was highest in summer with a 0.5% (95% CI: 0.38, 0.62) increase in total mortality for 10 ppb increase in 8-hr ozone, whilst the effect decrease to null in autumn and winter. We found higher effects in the months May- July with a 0.46% (95% CI: 0.24, 0.68) increase in total mortality for 10 ppb increase in ozone in June, and a 0.65% (95% CI: 0.47, 0.82) increase in mortality during July. The effect decreased in August and became null in September. We found similar effects from the age group 51–60 up to age 80 and a lower effect in 80 years and older.</p> <p>Conclusion</p> <p>The mortality effects of ozone appear diminished later in the ozone season, reaching the null effect previously reported in winter by September. More work should address this issue and examine the biological mechanism of adaptation.</p