Search

Background: The epidemiological evidence on the interaction between heat and ambient air pollution on mortality is still inconsistent., Objectives: To investigate the interaction between heat and ambient air pollution on daily mortality in a large dataset of 620 cities from 36 countries., Methods: We used daily data on all-cause mortality, air temperature, particulate matter ≤ 10 μm (PM 10 ), PM ≤ 2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) from 620 cities in 36 countries in the period 1995-2020. We restricted the analysis to the six consecutive warmest months in each city. City-specific data were analysed with over-dispersed Poisson regression models, followed by a multilevel random-effects meta-analysis. The joint association between air temperature and air pollutants was modelled with product terms between non-linear functions for air temperature and linear functions for air pollutants., Results: We analyzed 22,630,598 deaths. An increase in mean temperature from the 75 th to the 99 th percentile of city-specific distributions was associated with an average 8.9 % (95 % confidence interval: 7.1 %, 10.7 %) mortality increment, ranging between 5.3 % (3.8 %, 6.9 %) and 12.8 % (8.7 %, 17.0 %), when daily PM 10 was equal to 10 or 90 μg/m 3 , respectively. Corresponding estimates when daily O 3 concentrations were 40 or 160 μg/m 3 were 2.9 % (1.1 %, 4.7 %) and 12.5 % (6.9 %, 18.5 %), respectively. Similarly, a 10 μg/m 3 increment in PM 10 was associated with a 0.54 % (0.10 %, 0.98 %) and 1.21 % (0.69 %, 1.72 %) increase in mortality when daily air temperature was set to the 1 st and 99 th city-specific percentiles, respectively. Corresponding mortality estimate for O 3 across these temperature percentiles were 0.00 % (-0.44 %, 0.44 %) and 0.53 % (0.38 %, 0.68 %). Similar effect modification results, although slightly weaker, were found for PM 2.5 and NO 2 ., Conclusions: Suggestive evidence of effect modification between air temperature and air pollutants on mortality during the warm period was found in a global dataset of 620 cities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Three novel cytosine-derived α,β-methylene diphosphonates designated MRS4598, MRS4552, and MRS4602 were tested in the range of 1 × 10 -9 to 1 × 10 -3  M for their efficacy and potency in inhibiting membrane-bound ecto-5'-nucleotidase/CD73 activity in primary astrocytes in vitro. The compounds were also tested for their ability to attenuate the reactive astrocyte phenotype induced by proinflammatory cytokines. The main findings are as follows: A) The tested compounds induced concentration-dependent inhibition of CD73 activity, with maximal inhibition achieved at ∼1 × 10 -3 M; B) All compounds showed high inhibitory potency, as reflected by IC 50 values in the submicromolar range; C) All compounds showed high binding capacity, as reflected by Ki values in the low nanomolar range; D) Among the tested compounds, MRS4598 showed the highest inhibitory efficacy and potency, as reflected by IC 50 and Ki values of 0.11 μM and 18.2 nM; E) Neither compound affected astrocyte proliferation and cell metabolic activity at concentrations near to IC 50 ; E) MRS4598 was able to inhibit CD73 activity in reactive astrocytes stimulated with TNF-α and to induce concentration-dependent inhibition of CD73 in reactive astrocytes stimulated with IL-1β, with an order of magnitude higher IC 50 value; F) MRS4598 was the only compound tested that was able to induce shedding of the CD73 from astrocyte membranes and to enhance astrocyte migration in the scratch wound migration assay, albeit at concentration well above its IC 50 value. Given the role of CD73 in neurodegenerative diseases, MRS4598, MRS4552, and MRS4602 are promising pharmacological tools for the treatment of neurodegeneration and neuroinflammation., Competing Interests: Declaration of competing interest The authors' individual contributions are listed in a separate section of the manuscript. The authors declare no professional, financial, personal, or other conflicts of interest. All authors have approved the manuscript and submission to European Journal of Pharmacology and agree with the order of authors in the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Evidence on the potential interactive effects of heat and ambient air pollution on cause-specific mortality is inconclusive and limited to selected locations., Objectives: We investigated the effects of heat on cardiovascular and respiratory mortality and its modification by air pollution during summer months (six consecutive hottest months) in 482 locations across 24 countries., Methods: Location-specific daily death counts and exposure data (e.g., particulate matter with diameters ≤ 2.5 µm [PM 2.5 ]) were obtained from 2000 to 2018. We used location-specific confounder-adjusted Quasi-Poisson regression with a tensor product between air temperature and the air pollutant. We extracted heat effects at low, medium, and high levels of pollutants, defined as the 5th, 50th, and 95th percentile of the location-specific pollutant concentrations. Country-specific and overall estimates were derived using a random-effects multilevel meta-analytical model., Results: Heat was associated with increased cardiorespiratory mortality. Moreover, the heat effects were modified by elevated levels of all air pollutants in most locations, with stronger effects for respiratory than cardiovascular mortality. For example, the percent increase in respiratory mortality per increase in the 2-day average summer temperature from the 75th to the 99th percentile was 7.7% (95% Confidence Interval [CI] 7.6-7.7), 11.3% (95%CI 11.2-11.3), and 14.3% (95% CI 14.1-14.5) at low, medium, and high levels of PM 2.5 , respectively. Similarly, cardiovascular mortality increased by 1.6 (95%CI 1.5-1.6), 5.1 (95%CI 5.1-5.2), and 8.7 (95%CI 8.7-8.8) at low, medium, and high levels of O 3 , respectively., Discussion: We observed considerable modification of the heat effects on cardiovascular and respiratory mortality by elevated levels of air pollutants. Therefore, mitigation measures following the new WHO Air Quality Guidelines are crucial to enhance better health and promote sustainable development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

A 2B adenosine receptor (A 2B AR) antagonists have therapeutic potential in inflammation-related diseases such as asthma, chronic obstructive pulmonary disease and cancer. However, no drug is currently clinically approved, creating a demand for research on novel antagonists. Over the last decade, the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as A 2B AR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All 28 final compounds were assessed in radioligand binding experiments, to evaluate their affinity and for those qualifying, kinetic binding parameters. Both structure-affinity and structure-kinetic relationships were derived, providing a clear relationship between affinity and dissociation rate constants. Two structurally similar compounds, 17 and 18, were further evaluated in a label-free assay due to their divergent kinetic profiles. An extended cellular response was associated with long A 2B AR residence times. This link between a ligand's A 2B AR residence time and its functional effect highlights the importance of binding kinetics as a selection parameter in the early stages of drug discovery., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Previous studies reported a link between short-term exposure to environmental stressors (air pollution and air temperature) and atherothrombotic cardiovascular diseases. However, only few of them reported consistent associations with venous thromboembolism (VTE). Our aim was to estimate the association between daily air temperature and particulate matter (PM) air pollution with hospital admissions for pulmonary embolism (PE) and venous thrombosis (VT) at national level in Italy., Methods: We collected daily hospital PE and VT admissions from the Italian Ministry of Health during 2006-2015 in all the 8,084 municipalities of Italy, and we merged them with air temperature and daily PM10 concentrations estimated by satellite-based spatiotemporal models. First, we applied multivariate Poisson regression models at province level. Then, we obtained national overall effects by random-effects meta-analysis., Results: This analysis was conducted on 219,952 PE and 275,506 VT hospitalizations. Meta-analytical results showed weak associations between the two exposures and the study outcomes in the full year analysis. During autumn and winter, PE hospital admissions increased by 1.07% (95% confidence intervals [CI]: 0.21%; 1.92%) and 0.96% (95% CI: 0.07%; 1.83%) respectively, per 1 °C decrement of air temperature in the previous 10 days (lag 0-10). In summer we observed adverse effects at high temperatures, with a 1% (95% CI: 0.10%; 1.91%) increasing risk per 1 °C increment. We found no association between VT and cold temperatures., Conclusion: Results show a significant effect of air temperature on PE hospitalizations in the cold seasons and summer. No effect of particulate matter was detected., (Copyright © 2021. Published by Elsevier B.V.)

Background: Despite the relevance for occupational safety policies, the health effects of temperature on occupational injuries have been scarcely investigated. A nationwide epidemiological study was carried out to estimate the risk of injuries for workers exposed to extreme temperature and identify economic sectors and jobs most at risk., Materials and Methods: The daily time series of work-related injuries in the industrial and services sector from the Italian national workers' compensation authority (INAIL) were collected for each of the 8090 Italian municipalities in the period 2006-2010. Daily air temperatures with a 1 × 1 km resolution derived from satellite land surface temperature data using mixed regression models were included. Distributed lag non-linear models (DLNM) were used to estimate the association between daily mean air temperature and injuries at municipal level. A meta-analysis was then carried out to retrieve national estimates. The relative risk (RR) and attributable cases of work-related injuries for an increase in mean temperature above the 75th percentile (heat) and for a decrease below the 25th percentile (cold) were estimated. Effect modification by gender, age, firm size, economic sector and job type were also assessed., Results: The study considered 2,277,432 occupational injuries occurred in Italy in the period 2006-2010. There were significant effects for both heat and cold temperatures. The overall relative risks (RR) of occupational injury for heat and cold were 1.17 (95% CI: 1.14-1.21) and 1.23 (95% CI: 1.17-1.30), respectively. The number of occupational injuries attributable to temperatures above and below the thresholds was estimated to be 5211 per year. A higher risk of injury on hot days was found among males and young (age 15-34) workers occupied in small-medium size firms, while the opposite was observed on cold days. Construction workers showed the highest risk of injuries on hot days while fishing, transport, electricity, gas and water distribution workers did it on cold days., Conclusions: Prevention of the occupational exposure to extreme temperatures is a concern for occupational health and safety policies, and will become a critical issue in future years considering climate change. Epidemiological studies may help identify vulnerable jobs, activities and workers in order to define prevention plans and training to reduce occupational exposure to extreme temperature and the risk of work-related injuries., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

An increase in the global health burden of temperature was projected for 459 locations in 28 countries worldwide under four representative concentration pathway scenarios until 2099. We determined that the amount of temperature increase for each 100 ppm increase in global CO 2 concentrations is nearly constant, regardless of climate scenarios. The overall average temperature increase during 2010-2099 is largest in Canada (1.16 °C/100 ppm) and Finland (1.14 °C/100 ppm), while it is smallest in Ireland (0.62 °C/100 ppm) and Argentina (0.63 °C/100 ppm). In addition, for each 1 °C temperature increase, the amount of excess mortality is increased largely in tropical countries such as Vietnam (10.34%p/°C) and the Philippines (8.18%p/°C), while it is decreased in Ireland (-0.92%p/°C) and Australia (-0.32%p/°C). To understand the regional variability in temperature increase and mortality, we performed a regression-based modeling. We observed that the projected temperature increase is highly correlated with daily temperature range at the location and vulnerability to temperature increase is affected by health expenditure, and proportions of obese and elderly population., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Particulate matter (PM) air pollution is one of the major causes of death worldwide, with demonstrated adverse effects from both short-term and long-term exposure. Most of the epidemiological studies have been conducted in cities because of the lack of reliable spatiotemporal estimates of particles exposure in nonurban settings. The objective of this study is to estimate daily PM 10 (PM < 10 μm), fine (PM < 2.5 μm, PM 2.5 ) and coarse particles (PM between 2.5 and 10 μm, PM 2.5-10 ) at 1-km 2 grid for 2013-2015 using a machine learning approach, the Random Forest (RF). Separate RF models were defined to: predict PM 2.5 and PM 2.5-10 concentrations in monitors where only PM 10 data were available (stage 1); impute missing satellite Aerosol Optical Depth (AOD) data using estimates from atmospheric ensemble models (stage 2); establish a relationship between measured PM and satellite, land use and meteorological parameters (stage 3); predict stage 3 model over each 1-km 2 grid cell of Italy (stage 4); and improve stage 3 predictions by using small-scale predictors computed at the monitor locations or within a small buffer (stage 5). Our models were able to capture most of PM variability, with mean cross-validation (CV) R 2 of 0.75 and 0.80 (stage 3) and 0.84 and 0.86 (stage 5) for PM 10 and PM 2.5 , respectively. Model fitting was less optimal for PM 2.5-10 , in summer months and in southern Italy. Finally, predictions were equally good in capturing annual and daily PM variability, therefore they can be used as reliable exposure estimates for investigating long-term and short-term health effects., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)