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Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A 3 receptor (A 3 R) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5'-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive Z agonist form and a photoinduced, pharmacologically active E configuration. As a result, our photoswitchable agonist allowed the precise modulation of A 3 R function both in vitro and in vivo , which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for in vivo photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action.

Introduction: Asthma is a prevalent chronic respiratory condition that significantly impacts public health, with severe asthma subtypes, such as severe eosinophilic asthma, imposing substantial socioeconomic burdens., Methods: Real-world data from the Italian Health Information System were analyzed to evaluate the economic consequences of asthma in Italy. An in-depth comparative analysis was conducted to investigate the economic implications of various asthma subtypes, focusing on severe eosinophilic asthma. Additionally, the study projected the potential cost-effectiveness of novel treatments aimed at reducing hospitalization rates, specialist visits, and oral corticosteroid use for patients with severe eosinophilic asthma in Italy., Results: The analysis revealed that severe asthma, and notably severe eosinophilic asthma, places a substantial economic burden on the Italian National Health System. Estimates demonstrated that implementing innovative treatments to mitigate the risks of hospitalization and specialist visits, as well as reducing oral corticosteroid usage in severe eosinophilic asthma patients, could lead to significant cost savings. The cost-consequence analysis indicated potential yearly reductions of €50.0 million (27%) for the treatment of severe asthma and €31.7 million (26%) for severe eosinophilic asthma., Conclusions: This study presents a comprehensive evaluation of the economic repercussions of severe asthma in Italy. The findings emphasize the necessity of identifying and developing effective therapeutic strategies to improve the management of severe asthma while simultaneously reducing the economic burden on the healthcare system. These results offer valuable insights for healthcare policymakers and practitioners, facilitating evidence-based decisions in asthma management and healthcare policy in Italy., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Breast cancer (BC) constitutes a significant public health challenge in Italy, with a considerable impact on healthcare resources and societal costs. Despite advancements in diagnostics and therapies, the economic burden of BC remains substantial, necessitating a comprehensive evaluation to inform healthcare policy and resource allocation. The aim of this study is to estimate both direct health costs and social security costs related to BC., Methods: This study utilized real-world data from the Italian Health Information System (HIS) and Local Health Unit (LHU) Umbria 2 HIS databases spanning 2010-2019. Direct health costs, encompassing hospitalizations, outpatient visits, and drug prescriptions, were assessed alongside social security costs associated with BC-related work inability. Statistical analyses and probabilistic models were employed to estimate costs and evaluate trends over time., Results: The analysis revealed an annual cost of €273 million for hospital admissions related to BC in Italy, with metastatic BC (MBC) incurring the highest average annual cost per patient (€5018). When outpatient visits and drug consumption were incorporated, the mean annual cost per patient in LHU Umbria 2 rose to €11,380 for MBC. Social security costs, predominantly comprising disability benefits (DBs), totaled €579 million annually. Overall, the study estimated the total annual economic impact of BC in Italy to exceed €1 billion, with social costs representing 50.4% of the total burden., Conclusions: This comprehensive assessment underscores the substantial economic strain imposed by BC in Italy and highlights the need for early detection and intervention strategies to mitigate costs and enhance patient outcomes. These findings offer valuable insights into the economic landscape of BC, guiding policy decisions and resource allocation efforts aimed at optimizing BC management and alleviating its societal burden., Competing Interests: Declarations. Funding: The study was funded by Daiichi sankyo. Role of the funder/sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflicts of interest: The authors have no relevant financial or non-financial interests to disclose. Availability of data and material: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Code availability: The code is available from the corresponding author upon reasonable request. Author contributions: All authors contributed to the study conception. A.M., P.S., and F.S.M. developed the study design; P.S. and M.S. conducted the statistical analysis, derived the analytical results, and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript., (© 2024. The Author(s).)

Background: Atherosclerotic cardiovascular diseases remain the primary cause of mortality in Italy. Individuals with a history of acute coronary syndrome, peripheral arterial disease, and ischemic stroke/transient ischemic attack face an elevated risk of recurrent major adverse cardiovascular events, including mortality. The population aging, coupled with increasing risk factors such as diabetes mellitus and obesity, exacerbates the disease's economic impact., Objectives: This study aims to comprehensively assess the economic burden of atherosclerotic cardiovascular diseases in Italy, specifically focusing on direct healthcare costs., Methods: We analyzed real-world data from administrative databases in the Marche region and Local Health Unit Umbria 2. The economic burden of patients discharged with acute coronary syndrome, peripheral arterial disease, and ischemic stroke/transient ischemic attack was evaluated, with a focus on direct costs associated with hospitalizations, drugs, and outpatient visits. Results were stratified by age, sex, comorbidities at baseline, and adherence to lipid-lowering therapy and antihypertensive agents., Results: Annually, nearly 350,000 patients were hospitalized for peripheral arterial disease, acute coronary syndrome, or ischemic stroke/transient ischemic attack. Direct health costs averaged €7190 per patient over a 2-year follow-up, with hospitalizations accounting for nearly 70% of the total. Male patients incurred significantly higher costs (€7467) than female patients (€6625). Costs correlated positively with age and with the number of baseline comorbidities, with a range from €5259 (0-1 comorbidities) to €17,095 (4+ comorbidities). Costs were significantly lower in adherent subjects (€6813) compared with non-adherent subjects (€7757)., Conclusions: This study provides valuable insights into the economic implications of atherosclerotic cardiovascular diseases in Italy, emphasizing the necessity of a comprehensive approach to preventive measures, optimal medication adherence, and lifestyle modifications to mitigate its impact., (© 2024. The Author(s).)

The fungi Botryosphaeriaceae are involved in olive declines in both the world hemispheres and in all continents where this species is cultivated. In Salento (Apulia, Italy), the Botryosphaeriaceae Neofusicoccum mediterraneum and N. stellenboschiana have been reported as the agents of a branch and twig dieback that overlaps with olive quick decline syndrome caused by Xylella fastidiosa subsp. pauca . In this study, we report the finding of Diplodia seriata , another Botryosphaeriaceae species, in Salento in Xylella fastidiosa -infected olive trees affected by symptoms of branch and twig dieback. Given that its presence was also reported in olive in the Americas and in Europe (Croatia) with different degrees of virulence, we were prompted to assess its role in the Apulian decline. We identified representative isolates based on morphological features and a multilocus phylogeny. In vitro tests showed that the optimum growth temperature of the isolates is around 25-30 °C, and that they are highly thermo-tolerant. In pathogenicity trials conducted over eleven months, D. seriata expressed a very low virulence. Nonetheless, when we imposed severe water stress before the inoculation, D. seriata significatively necrotized bark and wood in a time frame of 35 days. Moreover, the symptoms which resulted were much more severe in the trial performed in summer compared with that in autumn. In osmolyte-supplemented media with a water potential from -1 to -3 Mpa, the isolates increased or maintained their growth rate compared with non-supplemented media, and they also grew, albeit to a lesser extent, on media with a water potential as low as -7 Mpa. This suggests that olives with a low water potential, namely those subjected to drought, may offer a suitable environment for the fungus' development. The analysis of the meteorological parameters, temperatures and rainfall, in Salento in the timeframe 1989-2023, showed that this area is subjected to a progressive increase of temperature and drought during the summer. Thus, overall, D. seriata has to be considered a contributor to the manifestation of branch and twig dieback of olive in Salento. Coherently with the spiral decline concept of trees, our results suggest that heat and drought act as predisposing/inciting factors facilitating D. seriata as a contributor. The fact that several adverse factors, biotic and abiotic, are simultaneously burdening olive trees in Salento offers a cue to discuss the possible complex nature of the olive decline in Salento.

Xylella fastidiosa subsp. pauca ST53 (XFP), the causal agent of olive quick decline syndrome (OQDS), was thoroughly investigated after a 2013 outbreak in the Salento region of Southern Italy. Some trees from Ogliarola Salentina and Cellina di Nardò, susceptible cultivars in the Gallipoli area, the first XFP infection hotspot in Italy, have resprouted crowns and are starting to flower and yield fruits. Satellite imagery and Normalized Difference Vegetation Index analyses revealed a significant improvement in vegetation health and productivity from 2018 to 2022 of these trees. Lipid molecules have long been recognized as plant defense modulators, and recently, we investigated their role in XFP-positive hosts and in XFP-resistant as well as in XFP-susceptible cultivars of olive trees. Here, we present a case study regarding 36 olive trees (12 XFP-positive resprouting, 12 XFP-positive OQDS-symptomatic, and 12 XFP-negative trees) harvested in 2022 within the area where XFP struck first, killing millions of trees in a decade. These trees were analyzed for some free fatty acid, oxylipin, and plant hormones, in particular jasmonic and salicylic acid, by targeted LC-MS/MS. Multivariate analysis revealed that lipid markers of resistance (e.g., 13-HpOTrE), along with jasmonic and salicylic acid, were accumulated differently in the XFP-positive resprouting trees from both cultivars with respect to XFP-positive OQDS symptomatic and XFP-negative trees, suggesting a correlation of lipid metabolism with the resprouting, which can be an indication of the resiliency of these trees to OQDS. This is the first report concerning the resprouting of OQDS-infected olive trees in the Salento area.

In 2013, an outbreak of Xylella fastidiosa (Xf) was identified for the first time in Europe, in the extreme south of Italy (Apulia, Salento territory). The locally identified subspecies pauca turned out to be lethal for olive trees, starting an unprecedented phytosanitary emergency for one of the most iconic cultivations of the Mediterranean area. Xf pauca (Xfp) is responsible for a severe disease, the olive quick decline syndrome (OQDS), spreading epidemically and with dramatic impact on the agriculture, the landscape, the tourism and the cultural heritage of this region. The bacterium, transmitted by insects that feed on xylem sap, causes rapid wilting in olive trees due to biofilm formation, which obstructs the plant xylematic vessels. The aim of this review is to perform a thorough analysis that offers a general overview of the published work, from 2013 to December 2023, related to the Xfp outbreak in Apulia. This latter hereto has killed millions of olive trees and left a ghostly landscape with more than 8000 square kilometers of infected territory, that is 40% of the region. The majority of the research efforts made to date to combat Xfp in olive plants are listed in the present review, starting with the early attempts to identify the bacterium, the investigations to pinpoint and possibly control the vector, the assessment of specific diagnostic techniques and the pioneered therapeutic approaches. Interestingly, according to the general set criteria for the preliminary examination of the accessible scientific literature related to the Xfp outbreak on Apulian olive trees, fewer than 300 papers can be found over the last decade. Most of them essentially emphasize the importance of developing diagnostic tools that can identify the disease early, even when infected plants are still asymptomatic, in order to reduce the risk of infection for the surrounding plants. On the other hand, in the published work, the diagnostic focus (57%) overwhelmingly encompasses all other possible investigation goals such as vectors, impacts and possible treatments. Notably, between 2013 and 2023, only 6.3% of the literature reports addressing the topic of Xfp in Apulia were concerned with the application of specific treatments against the bacterium. Among them, those reporting field trials on infected plants, including simple pruning indications, were further limited (6%).

Short-term exposure to ground-level ozone in cities is associated with increased mortality and is expected to worsen with climate and emission changes. However, no study has yet comprehensively assessed future ozone-related acute mortality across diverse geographic areas, various climate scenarios, and using CMIP6 multi-model ensembles, limiting our knowledge on future changes in global ozone-related acute mortality and our ability to design targeted health policies. Here, we combine CMIP6 simulations and epidemiological data from 406 cities in 20 countries or regions. We find that ozone-related deaths in 406 cities will increase by 45 to 6,200 deaths/year between 2010 and 2014 and between 2050 and 2054, with attributable fractions increasing in all climate scenarios (from 0.17% to 0.22% total deaths), except the single scenario consistent with the Paris Climate Agreement (declines from 0.17% to 0.15% total deaths). These findings stress the need for more stringent air quality regulations, as current standards in many countries are inadequate., Competing Interests: Declaration of Interests The authors declare no competing interests.

Interest has been focused in recent years on the analgesic effects exerted by adenosine and its receptors, A 1 , A 2A , A 2B , and A 3 adenosine receptor (AR) subtypes, in different in vivo models of chronic pain. In particular, it was demonstrated that selective A 3 AR agonists reduced pro-nociceptive N-type Ca 2+ channels in dorsal root ganglion (DRG) neurons isolated from rats and, by this mechanism, inhibit post inflammatory visceral hypersensitivity. In the present study, we investigate the effect of a previously reported irreversibly binding A 3 AR agonist, ICBM, on Ca 2+ currents (I Ca ) in rat DRG neurons. Present data demonstrate that ICBM, an isothiocyanate derivative designed for covalent binding to the receptor, concentration-dependently inhibits I Ca . This effect is irreversible, since it persists after drug removal, differently from the prototypical A 3 AR agonist, Cl-IB-MECA. ICBM pre-exposure inhibits the effect of a subsequent Cl-IB-MECA application. Thus, covalent A 3 AR agonists such as ICBM may represent an innovative, beneficial, and longer-lasting strategy to achieve efficacious chronic pain control versus commonly used, reversible, A 3 AR agonists. However, the possible limitations of this drug and other covalent drugs may be, for example, a characteristic adverse effect profile, suggesting that more pre-clinical studies are needed., (© 2023. The Author(s).)

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.)

Xylella fastidiosa subsp. pauca (XFP), Neofusicoccum mediterraneum , N. stellenboschiana and other fungi have been found in olive groves of Salento (Apulia, Italy) that show symptoms of severe decline. XFP is well known to be the cause of olive quick decline syndrome (OQDS). It has also been assessed that Neofusicoccum spp. causes a distinct disease syndrome, namely, branch and twig dieback (BTD). All these phytopathogens incite severe symptoms that can compromise the viability of large canopy sectors or the whole tree. However, their specific symptoms are not easily distinguished, especially during the final stages of the disease when branches are definitively desiccated. By contrast, they can be differentiated during the initial phases of the infection when some facets of the diseases are typical, especially wood discoloration, incited solely by fungi. Here, we describe the typical symptomatological features of OQDS and BTD that can be observed in the field and that have been confirmed by Koch postulate experiments. Similar symptoms, caused by some abiotic adverse conditions and even by additional biotic factors, are also described. Thus, this review aims at: (i) raising the awareness that declining olive trees in Salento do not have to be linked a priori to XFP; (ii) defining the guidelines for a correct symptomatic diagnosis to orient proper laboratory analyses, which is crucial for the application of effective control measures. The possibility that bacterium and fungi could act as a polyspecies and in conjunction with predisposing abiotic stresses is also widely discussed.

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.)

The aim of this study was to establish a link between genetic diversity and the geographic origin of Pectobacterium strains belonging to three species- P. carotovorum , P. versatile , and P. odoriferum -isolated from cabbage in Serbia by comparing their sequences with those of strains sourced from different hosts and countries in Europe, Asia, and North America. Phylogeographic relatedness was reconstructed using the Templeton, Crandall, and Sing's (TCS) haplotype network based on concatenated sequences of the housekeeping genes dnaX , icdA , mdh , and proA , while pairwise genetic distances were computed by applying the p-distance model. The obtained TCS haplotype networks indicated the existence of high intra-species genetic diversity among strains of all three species, as reflected in the 0.2-2.3%, 0.2-2.5%, and 0.1-1.7% genetic distance ranges obtained for P. carotovorum , P. versatile , and P. odoriferum , respectively. Five new haplotypes (denoted as HPc1-HPc5) were detected among cabbage strains of P. carotovorum , while one new haplotype was identified for both P. versatile (HPv1) and P. odoriferum (HPo1). None of the TCS haplotype networks provided evidence of significant correlation between geographic origin and the determined haplotypes, i.e., the infection origin. However, as haplotype network results are affected by the availability of sequencing data in public databases for the used genes and the number of analyzed strains, these findings may also be influenced by small sample size.

Here we report the medium-term effects of foliar spray and endo-therapy treatments with different doses of a Cu/Zn citric acid biocomplex (Dentamet ® ) in Xylella fastidiosa infected olive trees of Salento, Apulia region (South-east Italy). Leaf extract samples from field-treated 150 years old olive trees cvs Ogliarola salentina and Cellina di Nardò were studied by 1 H NMR-based metabolomics. The result of different applications of Dentamet ® endo-therapy after 60, 120 and 180 days in comparison with traditional foliar spray treatment and water injection as a control have been investigated. The metabolic profile analyses, performed by 1 H NMR-based metabolomic approach, indicated plant metabolites variations connected to the disease progression such as mannitol, quinic acid, and oleuropein related compounds. The best results, in terms of discrimination of the metabolic profiles with respect to water injection, were found for monthly endo-therapy treatments. Dentamet ® foliar application demonstrated more specific time related progressive effectiveness with respect to intravascular treatments. Therefore, besides a possible more effective performance of endo-therapy with respect to foliar treatments, the need of further doses/frequencies trimming to obtain long-term results was also assessed. The present field studies confirmed the indication of Dentamet ® effectiveness in metabolic variation induction, potentially linked with reducing the X. fastidiosa subspecies pauca related Olive Quick Decline Syndrome (OQDS) symptoms development.

Xylella fastidiosa subsp. pauca (Xfp), has attacked the olive trees in Southern Italy with severe impacts on the olive agro-ecosystem. To reduce both the Xfp cell concentration and the disease symptom, a bio-fertilizer restoration technique has been used. Our study applied multi-resolution satellite data to evaluate the effectiveness of such technique at both field and tree scale. For field scale, a time series of High Resolution (HR) Sentinel-2 images, acquired in the months of July and August from 2015 to 2020, was employed. First, four spectral indices from treated and untreated fields were compared. Then, their trends were correlated to meteo-events. For tree-scale, Very High Resolution (VHR) Pléiades images were selected at the closest dates of the Sentinel-2 data to investigate the response to treatments of each different cultivar. All indices from HR and VHR images were higher in treated fields than in those untreated. The analysis of VHR indices revealed that Oliarola Salentina can respond better to treatments than Leccino and Cellina cultivars. All findings were in agreement with in-field PCR results. Hence, HR data could be used to evaluate plant conditions at field level after treatments, while VHR imagery could be used to optimize treatment doses per cultivar., (© 2023. The Author(s).)

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.)

For about a decade, olive groves in Apulia (Southern Italy) have been progressively destroyed by Olive Quick Decline Syndrome (OQDS), a disease caused by the bacterium Xylella fastidiosa subsp. pauca (Xfp). Recently, we described an additional wilting syndrome affecting olive trees in that area. The botryosphaeriaceous fungus Neofusicoccum mediterraneum was found associated with the diseased trees, and its high virulence toward olive trees was demonstrated. Given the common features with Branch and Twig Dieback (BTD) of olive tree, occurring in Spain and California, we suggested that the observed syndrome was BTD. During our first survey, we also found a botryosphaeriaceous species other than N. mediterraneum . In the present article, we report the morphological and molecular characterization of this fungal species which we identified as Neofusicoccum stellenboschiana . In the study, we also included for comparison additional N. stellenboschiana isolates obtained from olive trees in Latium and Tuscany region (Central Italy). The occurrence of N. stellenboschiana in olive trees is reported here for the first time in the northern hemisphere. The pathogenicity and virulence were tested in nine inoculation trials, where the Apulian N. stellenboschiana isolate was compared with the isolate from Latium and with the Apulian isolate of N. mediterraneum . Both isolates of N. stellenboschiana proved pathogenic to olive trees. They caused evident bark canker and wood discolouration when inoculated at the base of the stem of two/three-year-old trees and on one-year-old twigs. However, virulence of N. stellenboschiana was significantly lower, though still remarkable, compared with N. mediterraneum in term of necrosis progression in the bark and the wood and capacity of wilting the twigs. Virulence of N. stellenboschiana and N. mediterraneum did not substantially change when inoculations were performed in spring/summer and in autumn, suggesting that these fungal species have the potential to infect and damage olive trees in all seasons. The high thermotolerance of N. stellenboschiana was also revealed with in vitro growth and survival tests. The high virulence of these Botryosphaeriaceae species highlights their contribution in BTD aetiology and the necessity to investigate right away their diffusion and, possibly, the role of additional factors other than Xfp in the general decline of olive groves in Apulia. Hence the importance of assessing the degree of overlap of BTD/Botryosphariaceae with OQDS/Xfp is discussed.

This study focuses on interacting with insects and their ectosymbiont ( lato sensu ) microorganisms for environmentally safe plant production and protection. Some cases help compare ectosymbiont microorganisms that are insect-borne, -driven, or -spread relevant to endosymbionts' behaviour. Ectosymbiotic bacteria can interact with insects by allowing them to improve the value of their pabula. In addition, some bacteria are essential for creating ecological niches that can host the development of pests. Insect-borne plant pathogens include bacteria, viruses, and fungi. These pathogens interact with their vectors to enhance reciprocal fitness. Knowing vector-phoront interaction could considerably increase chances for outbreak management, notably when sustained by quarantine vector ectosymbiont pathogens, such as the actual Xylella fastidiosa Mediterranean invasion episode. Insect pathogenic viruses have a close evolutionary relationship with their hosts, also being highly specific and obligate parasites. Sixteen virus families have been reported to infect insects and may be involved in the biological control of specific pests, including some economic weevils. Insects and fungi are among the most widespread organisms in nature and interact with each other, establishing symbiotic relationships ranging from mutualism to antagonism. The associations can influence the extent to which interacting organisms can exert their effects on plants and the proper management practices. Sustainable pest management also relies on entomopathogenic fungi; research on these species starts from their isolation from insect carcasses, followed by identification using conventional light or electron microscopy techniques. Thanks to the development of omics sciences, it is possible to identify entomopathogenic fungi with evolutionary histories that are less-shared with the target insect and can be proposed as pest antagonists. Many interesting omics can help detect the presence of entomopathogens in different natural matrices, such as soil or plants. The same techniques will help localize ectosymbionts, localization of recesses, or specialized morphological adaptation, greatly supporting the robust interpretation of the symbiont role. The manipulation and modulation of ectosymbionts could be a more promising way to counteract pests and borne pathogens, mitigating the impact of formulates and reducing food insecurity due to the lesser impact of direct damage and diseases. The promise has a preventive intent for more manageable and broader implications for pests, comparing what we can obtain using simpler, less-specific techniques and a less comprehensive approach to Integrated Pest Management (IPM).

Lipids are central at various stages of host-pathogen interactions in determining virulence and modulating plant defense. Free fatty acids may act as substrates for oxidizing enzymes [e.g., lipoxygenases (LOXs) and dioxygenases (DOXs)] that synthesize oxylipins. Fatty acids and oxylipins function as modulators of several pathways in cell-to-cell communication; their structural similarity among plant, fungal, and bacterial taxa suggests potential in cross-kingdom communication. We provide a prospect of the known role of fatty acids and oxylipins in fungi and bacteria during plant-pathogen interactions. In the pathogens, oxylipin-mediated signaling pathways are crucial both in development and host infection. Here, we report on case studies suggesting that oxylipins derived from oleic, linoleic, and linolenic acids are crucial in modulating the pathogenic lifestyle in the host plant. Intriguingly, overlapping (fungi-plant/bacteria-plant) results suggest that different inter-kingdom pathosystems use similar lipid signals to reshape the lifestyle of the contenders and occasionally determine the outcome of the challenge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beccaccioli, Pucci, Salustri, Scortichini, Zaccaria, Momeni, Loreti, Reverberi and Scala.)

Background: Epidemiological literature on the health risks associated with non-optimal temperature has mostly reported average estimates across large areas or specific population groups. However, the heterogeneous distribution of drivers of vulnerability can result in local differences in health risks associated with heat and cold. We aimed to analyse the association between ambient air temperature and all-cause mortality across England and Wales and characterise small scale patterns in temperature-related mortality risks and impacts., Methods: We performed a country-wide small-area analysis using data on all-cause mortality and air temperature for 34 753 lower super output areas (LSOAs) within 348 local authority districts (LADs) across England and Wales between Jan 1, 2000, and Dec 31, 2019. We first performed a case time series analysis of LSOA-specific and age-specific mortality series matched with 1 × 1 km gridded temperature data using distributed lag non-linear models, and then a repeated-measure multivariate meta-regression to pool LAD-specific estimates using area-level climatological, socioeconomic, and topographical predictors., Findings: The final analysis included 10 716 879 deaths from all causes. The small-area assessment estimated that each year in England and Wales, there was on average 791 excess deaths (empirical 95% CI 611-957) attributable to heat and 60 573 (55 796-65 145) attributable to cold, corresponding to standardised excess mortality rates of 1·57 deaths (empirical 95% CI 1·21-1·90) per 100 000 person-years for heat and 122·34 deaths (112·90-131·52) per 100 000 person-years for cold. The risks increased with age and were highly heterogeneous geographically, with the minimum mortality temperature ranging from 14·9°C to 22·6°C. Heat-related mortality was higher in urban areas, whereas cold-related mortality showed a more nuanced geographical pattern and increased risk in areas with greater socioeconomic deprivation., Interpretation: This study provides a comprehensive assessment of excess mortality related to non-optimal outdoor temperature, with several risk indicators reported by age and multiple geographical levels. The analysis provides detailed risk maps that are useful for designing effective public health and climate policies at both local and national levels., Funding: Medical Research Council, Natural Environment Research Council, EU Horizon 2020 Programme, National Institute of Health Research., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The World Health Assembly recognizes the growing economic and societal burden of neurological disorders, a leading cause of disability and the second cause of mortality in the world. In this context we analysed the socio-economic impact of epilepsy in Italy with a specific focus on hospitalizations and costs related to disability pensions (DPs) and ordinary disability allowances. In the case of epilepsy, between 2009 and 2015 we observed an alarming increasing trend for DPs (+26%), indicating that substantial expenses must be supported throughout the patients' lifetimes by both the social security system and the National Health Service (NHS) on top of the impact on caregivers. We also analysed the hospital expenditure on epilepsy through the information available in the Hospital Discharge Cards between 2015 and 2018. Almost all admissions (76% ordinary hospitalizations, 24% day hospitals) were acute (95%), followed by rehabilitation (4%) and long-term care (1%). The cost of acute and ordinary hospitalizations was by far the highest in 2018, the last year of analysis. This large expense due to hospitalizations could be reduced through the implementation of different organizational and management approaches. Our recommendation is that the policy maker should consider the best approach to ensure an early diagnosis for patients and provide early access to drugs and/or surgery. Finally, the adoption of new innovative treatments should improve effectiveness and, at the same time, reduce the expense of the NHS, of the social system as a whole, with a tangible improvement in patients' quality of life., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (Copyright © 2022, The Authors.)

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.)

Aims: We aimed at investigating the relationship between particulate matter (PM) and daily admissions for cardiovascular diseases (CVDs) at national level in Italy., Methods and Results: Daily numbers of cardiovascular hospitalizations were collected for all 8084 municipalities of Italy, in the period 2013-2015. A satellite-based spatiotemporal model was used to estimate daily PM10 (inhalable particles) and PM2.5 (fine particles) concentrations at 1-km2 resolution. Multivariate Poisson regression models were fit to estimate the association between daily PM and cardiovascular admissions. Flexible functions were estimated to explore the shape of the associations at low PM concentrations, also in non-urban areas. We analysed 2 154 810 acute hospitalizations for CVDs (25% stroke, 24% ischaemic heart diseases, 22% heart failure, and 5% atrial fibrillation). Relative increases of total cardiovascular admissions, per 10 µg/m3 variation in PM10 and PM2.5 at lag 0-5 (average of last 6 days since admission), were 0.55% (95% confidence intervals: 0.32%, 0.77%) and 0.97% (0.67%, 1.27%), respectively. The corresponding estimates for heart failure were 1.70% (1.28%, 2.13%) and 2.66% (2.09%, 3.23%). We estimated significant effects of PM10 and PM2.5 also on ischaemic heart diseases, myocardial infarction, atrial fibrillation, and ischaemic stroke. Associations were similar between less and more urbanized areas, and persisted even at low concentrations, e.g. below WHO guidelines., Conclusion: PM was robustly associated with peaks in daily cardiovascular admissions, especially for heart failure, both in large cities and in less urbanized areas of Italy. Current WHO Air Quality Guidelines for PM10 and PM2.5 are not sufficient to protect public health., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In 2013, Xylella fastidiosa (Xf) was detected for the first time in Apulia and, subsequently, recognized as the causal agent of the olive quick decline syndrome (OQDS). To contain the disease, the olive germplasm was evaluated for resistance to Xf , identifying cultivars with different susceptibility to the pathogen. Regarding this, the resistant cultivar Leccino has generally a lower bacterial titer compared with the susceptible cultivar Ogliarola salentina. Among biomolecules, lipids could have a pivotal role in the interaction of Xf with its host. In the grapevine Pierce's disease, fatty acid molecules, the diffusible signaling factors (DSFs), act as regulators of Xf lifestyle and are crucial for its virulence. Other lipid compounds derived from fatty acid oxidation, namely, oxylipins, can affect, in vitro , biofilm formation in Xf subsp. pauca (Xfp) strain De Donno, that is, the strain causing OQDS. In this study, we combined high-performance liquid chromatography-mass spectrometry-MS-based targeted lipidomics with supervised learning algorithms (random forest, support vector machine, and neural networks) to classify olive tree samples from Salento. The dataset included samples from either OQDS-positive or OQDS-negative olive trees belonging either to cultivar Ogliarola salentina or Leccino treated or not with the zinc-copper-citric acid biocomplex Dentamet ® . We built classifiers using the relative differences in lipid species able to discriminate olive tree samples, namely, (1) infected and non-infected, (2) belonging to different cultivars, and (3) treated or untreated with Dentamet ® . Lipid entities emerging as predictors of the thesis are free fatty acids (C16:1, C18:1, C18:2, C18:3); the LOX-derived oxylipins 9- and 13-HPOD/TrE; the DOX-derived oxylipin 10-HPOME; and diacylglyceride DAG36:4(18:1/18:3)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scala, Salustri, Loreti, Pucci, Cacciotti, Tatulli, Scortichini and Reverberi.)

Xylella fastidiosa is a xylem-limited bacterium causing a range of economically important plant diseases in hundreds of crops. Over the last decade, a severe threat due to Olive Quick Decline Syndrome (OQDS), caused by Xylella fastidiosa subspecies pauca, affected the Salento olive groves (Apulia, South-East Italy). Very few phyto-therapeutics, including a Zn/Cu citric acid biocomplex foliar treatment, were evaluated to mitigate this disease. However, the traditional foliar applications result in the agro-actives reaching only partially their target. Therefore the development of novel endo-therapeutic systems was suggested. Metabolite fingerprinting is a powerful method for monitoring both, disease progression and treatment effects on the plant metabolism, allowing biomarkers detection. We performed, for the first time, short-term monitoring of metabolic pathways reprogramming for infected Ogliarola salentina and Cima di Melfi olive trees after precision intravascular biocomplex delivery using a novel injection system. Upon endo therapy, we observed specific variations in the leaf content of some metabolites. In particular, the 1 H NMR-based metabolomics approach showed, after the injection, a significant decrease of both the disease biomarker quinic acid and mannitol with simultaneous increase of polyphenols and oleuropein related compounds in the leaf's extracts. This combined metabolomics/endo-therapeutic methodology provided useful information in the comprehension of plant physiology for future applications in OQDS control., (© 2022. The Author(s).)

Background/aim: The relationship between air pollution and respiratory morbidity has been widely addressed in urban and metropolitan areas but little is known about the effects in non-urban settings. Our aim was to assess the short-term effects of PM10 and PM2.5 on respiratory admissions in the whole country of Italy during 2006-2015., Methods: We estimated daily PM concentrations at the municipality level using satellite data and spatiotemporal predictors. We collected daily counts of respiratory hospital admissions for each Italian municipality. We considered five different outcomes: all respiratory diseases, asthma, chronic obstructive pulmonary disease (COPD), lower and upper respiratory tract infections (LRTI and URTI). Meta-analysis of province-specific estimates obtained by time-series models, adjusting for temperature, humidity and other confounders, was applied to extrapolate national estimates for each outcome. At last, we tested for effect modification by sex, age, period, and urbanization score. Analyses for PM 2.5 were restricted to 2013-2015 cause the goodness of fit of exposure estimation., Results: A total of 4,154,887 respiratory admission were registered during 2006-2015, of which 29% for LRTI, 12% for COPD, 6% for URTI, and 3% for asthma. Daily mean PM 10 and PM 2.5 concentrations over the study period were 23.3 and 17 μg/m 3 , respectively. For each 10 μg/m 3 increases in PM 10 and PM 2.5 at lag 0-5 days, we found excess risks of total respiratory diseases equal to 1.20% (95% confidence intervals, 0.92, 1.49) and 1.22% (0.76, 1.68), respectively. The effects for the specific diseases were similar, with the strongest ones for asthma and COPD. Higher effects were found in the elderly and in less urbanized areas., Conclusions: Short-term exposure to PM is harmful for the respiratory system throughout an entire country, especially in elderly patients. Strong effects can be found also in less urbanized areas., 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 © 2021 Elsevier B.V. All rights reserved.)

We recently reported N 4 -substituted 3-methylcytidine-5'-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16 ; K i = 0.673 nM) and 4-iodo (MRS4620 18 ; K i = 0.436 nM) substitution of the N 4 -benzyloxy group decreased K i by ∼20-fold. Primary alkylamine derivatives coupled through a p -amido group with a varying methylene chain length ( 24 and 25 ) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformational adaptation, and the benzyloxyimino group ( E configuration) binds to the same region (between the C-terminal and N-terminal domains) as N 4 -benzyl groups in adenine inhibitors. Molecular dynamics identified stabilizing interactions and predicted conformational diversity. Thus, by N 4 -benzyloxy substitution, we have greatly enhanced the inhibitory potency and added functionality enabling molecular probes. Their potential as anticancer drugs was confirmed by blocking CD73 activity in tumor tissues in situ.

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.)

Olive trees are infected and damaged by Botryosphaeriaceae fungi in various countries. The botryosphaeriaceous fungus Neofusicoccum mediterraneum is highly aggressive and is a major concern for olive groves in Spain and California (USA), where it causes 'branch and twig dieback' characterized by wood discoloration, bark canker, and canopy blight. During surveys of olive groves in Apulia (southern Italy), we noticed that-in some areas-trees were heavily affected by severe branch and twig dieback. In addition, chlorosis and the appearance of red-bronze patches on the leaf preceded the wilting of the foliage, with necrotic leaves persisting on the twigs. Given the severity of the manifestation in zones also subject to olive quick decline syndrome (OQDS) caused by Xylella fastidiosa subsp. pauca , we investigated the etiology and provide indications for differentiating the symptoms from OQDS. Isolation from diseased wood samples revealed a mycete, which was morphologically and molecularly identified as N. mediterraneum. The pathogenicity tests clearly showed that this fungus is able to cause the natural symptoms. Therefore, also considering the low number of tested samples, N. mediterraneum is a potential causal agent of the observed disease. Specifically, inoculation of the twigs caused complete wilting in two to three weeks, while inoculation at the base of the stem caused severe girdling wedge-shaped cankers. The growth rate of the fungus in in vitro tests was progressively higher from 10 to 30 °C, failing to grow at higher temperatures, but keeping its viability even after prolonged exposure at 50 °C. The capacity of the isolate to produce catenulate chlamydospores, which is novel for the species, highlights the possibility of a new morphological strain within N. mediterraneum . Further investigations are ongoing to verify whether additional fungal species are involved in this symptomatology.

Background: Short-term exposure to particulate matter (PM) has been related to mortality worldwide. Most evidence comes from studies conducted in major cities, while little is known on the effects of low concentrations of PM and in less urbanized areas. We aim to investigate the relationship between PM and all-cause mortality at national level in Italy., Methods: Daily numbers of all-cause mortality were collected for all 8092 municipalities of Italy, from 2006 to 2015. A satellite-based spatiotemporal model was developed to estimate daily PM 10 (inhalable particles) and PM 2.5 (fine particles) concentrations at 1-km resolution. Multivariate Poisson regression models were fit to estimate the association between daily PM and mortality at province level, and then, results were pooled with a random-effects meta-analysis. Associations were estimated by combination of age and sex and degree of urbanization of the municipalities. Flexible functions were estimated to explore the shape of the associations at low PM concentrations., Results: We analyzed 5,884,900 deaths (40% among subjects older than 85 years, 60% occurring outside the main urban areas). National daily mean (interquartile range) PM 10 and PM 2.5 concentrations were 23 (14) μg/m 3 and 15 (11) μg/m 3 , respectively. Relative increases of mortality per 10 μg/m 3 variation in lag 0-5 (average of last six days since death) PM 10 and PM 2.5 were 1.47% (95% Confidence Intervals (CI): 1.15%, 1.79%) and 1.96% (1.33%, 2.59%), respectively. Associations were highest among elderly and women for PM 10 only, similar between rural and urbanized areas, and were present even at low concentrations, e.g., below WHO guidelines., Conclusions: Air pollution was robustly associated with peaks in daily all-cause mortality in Italy, both in large cities and in less urbanized areas of Italy. Current WHO Air Quality Guidelines (2021) for PM 10 and PM 2.5 are not sufficient to protect public health.

Background: Many regions of the world are now facing more frequent and unprecedentedly large wildfires. However, the association between wildfire-related PM 2·5 and mortality has not been well characterised. We aimed to comprehensively assess the association between short-term exposure to wildfire-related PM 2·5 and mortality across various regions of the world., Methods: For this time series study, data on daily counts of deaths for all causes, cardiovascular causes, and respiratory causes were collected from 749 cities in 43 countries and regions during 2000-16. Daily concentrations of wildfire-related PM 2·5 were estimated using the three-dimensional chemical transport model GEOS-Chem at a 0·25° × 0·25° resolution. The association between wildfire-related PM 2·5 exposure and mortality was examined using a quasi-Poisson time series model in each city considering both the current-day and lag effects, and the effect estimates were then pooled using a random-effects meta-analysis. Based on these pooled effect estimates, the population attributable fraction and relative risk (RR) of annual mortality due to acute wildfire-related PM 2·5 exposure was calculated., Findings: 65·6 million all-cause deaths, 15·1 million cardiovascular deaths, and 6·8 million respiratory deaths were included in our analyses. The pooled RRs of mortality associated with each 10 μg/m 3 increase in the 3-day moving average (lag 0-2 days) of wildfire-related PM 2·5 exposure were 1·019 (95% CI 1·016-1·022) for all-cause mortality, 1·017 (1·012-1·021) for cardiovascular mortality, and 1·019 (1·013-1·025) for respiratory mortality. Overall, 0·62% (95% CI 0·48-0·75) of all-cause deaths, 0·55% (0·43-0·67) of cardiovascular deaths, and 0·64% (0·50-0·78) of respiratory deaths were annually attributable to the acute impacts of wildfire-related PM 2·5 exposure during the study period., Interpretation: Short-term exposure to wildfire-related PM 2·5 was associated with increased risk of mortality. Urgent action is needed to reduce health risks from the increasing wildfires., Funding: Australian Research Council, Australian National Health & Medical Research Council., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The G q -coupled P2Y 6 receptor (P2Y 6 R) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2Y 6 R agonist and P2Y 14 R partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2Y 6 R agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2Y 6 R potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2Y 14 R, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2Y 6 R activation. Thus, we have identified new α,β-methylene bridged N 4 -extended CDP analogues as P2Y 6 R agonists that are highly selective over the P2Y 14 R., (Copyright © 2021 Elsevier Ltd. All rights reserved.)