Do Pharmaceuticals in the Environment Pose a Risk to Wildlife?

The vast majority of knowledge related to the question “To what extent do pharmaceuticals in the environment pose a risk to wildlife?” stems from the Asian vulture crisis (\u3e99% decline of some species of Old World vultures on the Indian subcontinent related to the veterinary use of the nonsteroidal anti‐inflammatory drug [NSAID] diclofenac). The hazard of diclofenac and other NSAIDs (carprofen, flunixin, ketoprofen, nimesulide, phenylbutazone) to vultures and other avian species has since been demonstrated; indeed, only meloxicam and tolfenamic acid have been found to be vulture‐safe. Since diclofenac was approved for veterinary use in Spain and Italy in 2013 (home to ~95% of vultures in Europe), the risk of NSAIDs to vultures in these countries has become one of the principal concerns related to pharmaceuticals and wildlife. Many of the other bodies of work on pharmaceutical exposure, hazard and risk to wildlife also relate to adverse effects in birds (e.g., poisoning of scavenging birds in North America and Europe from animal carcasses containing pentobarbital, secondary and even tertiary poisoning of birds exposed to pesticides used in veterinary medicine as cattle dips, migratory birds as a vector for the transfer of antimicrobial and antifungal resistance). Although there is some research related to endocrine disruption in reptiles and potential exposure of aerial insectivores, there remain numerous knowledge gaps for risk posed by pharmaceuticals to amphibians, reptiles, and mammals. Developing noninvasive sampling techniques and new approach methodologies (e.g., genomic, in vitro, in silico, in ovo) is important if we are to bridge the current knowledge gaps without extensive vertebrate testing

Do pharmaceuticals in the environment pose a risk to wildlife?

The vast majority of knowledge related to the question of, “To what extent do pharmaceuticals in the environment pose a risk to wildlife?”, stems from the Asian vulture crisis (>99% decline of some species of old-world vultures on the Indian subcontinent related to the veterinary use of the non-steroidal anti-inflammatory drug (NSAID) diclofenac). The hazard of diclofenac and other NSAIDs (carprofen, flunixin, ketoprofen, nimesulide, phenylbutazone) to vultures and other avian species has since been demonstrated; indeed only meloxicam and tolfenamic acid have been found to be vulture-safe. Since diclofenac was approved for veterinary use in Spain and Italy in 2013 (home to ~95% of vultures in Europe), the risk of NSAIDs to vultures in these countries has become one of the principal concerns related to pharmaceuticals and wildlife. Many of the other bodies of work on pharmaceutical exposure, hazard and risk to wildlife also relate to adverse effects in birds, (e.g., poisoning of scavenging birds in North America and Europe from animal carcasses containing pentobarbital; secondary and even tertiary poisoning of birds exposed to pesticides used in veterinary medicine as cattle dips; migratory birds as a vector for the transfer of antimicrobial and antifungal resistance). While there is some research related to endocrine disruption in reptiles and potential exposure of aerial insectivores, there remain numerous knowledge gaps for risk posed by pharmaceuticals to amphibians, reptiles and mammals. Developing non-invasive sampling techniques and new approach methodologies (e.g., genomic, in vitro, in silico, in ovo) are important if we are to bridge the current knowledge gaps without extensive vertebrate testing

Do pharmaceuticals in the environment pose a risk to wildlife?

DATA AVAILABILITY : The present study is a review, we have extensively referenced our sources. Data, associated metadata, and calculation tools are available from the corresponding author ([email protected]).The vast majority of knowledge related to the question “To what extent do pharmaceuticals in the environment pose a risk to wildlife?” stems from the Asian vulture crisis (>99% decline of some species of Old World vultures on the Indian subcontinent related to the veterinary use of the nonsteroidal anti-inflammatory drug [NSAID] diclofenac). The hazard of diclofenac and other NSAIDs (carprofen, flunixin, ketoprofen, nimesulide, phenylbutazone) to vultures and other avian species has since been demonstrated; indeed, only meloxicam and tolfenamic acid have been found to be vulture-safe. Since diclofenac was approved for veterinary use in Spain and Italy in 2013 (home to ~95% of vultures in Europe), the risk of NSAIDs to vultures in these countries has become one of the principal concerns related to pharmaceuticals and wildlife. Many of the other bodies of work on pharmaceutical exposure, hazard and risk to wildlife also relate to adverse effects in birds (e.g., poisoning of scavenging birds in North America and Europe from animal carcasses containing pentobarbital, secondary and even tertiary poisoning of birds exposed to pesticides used in veterinary medicine as cattle dips, migratory birds as a vector for the transfer of antimicrobial and antifungal resistance). Although there is some research related to endocrine disruption in reptiles and potential exposure of aerial insectivores, there remain numerous knowledge gaps for risk posed by pharmaceuticals to amphibians, reptiles, and mammals. Developing noninvasive sampling techniques and new approach methodologies (e.g., genomic, in vitro, in silico, in ovo) is important if we are to bridge the current knowledge gaps without extensive vertebrate testing. Environ Toxicol Chem 2023;00:1–16. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.The Contaminant Biology Program of the US Geological Survey Ecosystems Mission Area.https://setac.onlinelibrary.wiley.com/journal/15528618Paraclinical Science

Weasel exposure to the anticoagulant rodenticide bromadiolone in agrarian landscapes of southwestern Europe

Bromadiolone is an anticoagulant rodenticide (AR) commonly used as a plant protection product (PPP) against rodent pests in agricultural lands. ARs can be transferred trophically to predators/scavengers when they consume intoxicated live or dead rodents. ARs exposure in weasels Mustela nivalis, small mustelids specialized on rodent predation, is poorly known in southern Europe. Moreover, in this species there is no information on bioaccumulation of AR diastereomers e.g., cis- and trans-bromadiolone. Trans-bromadiolone is more persistent in the rodent liver and thus, is expected to have a greater probability of trophic transfer to predators. Here, we report on bromadiolone occurrence, total concentrations and diastereomers proportions (trans- and cis-bromadiolone) in weasels from Castilla y León (north-western Spain) collected in 2010–2017, where bromadiolone was irregularly applied to control outbreaks of common voles Microtus arvalis mainly with cereal grain bait distributed by the regional government. We also tested variables possibly associated with bromadiolone occurrence and concentration, such as individual features (e.g., sex), spatio-temporal variables (e.g., year), and exposure risk (e.g., vole outbreaks). Overall bromadiolone occurrence in weasels was 22% (n = 32, arithmetic mean of concentration of bromadiolone positives = 0.072 mg/kg). An individual showed signs of bromadiolone intoxication (i.e., evidence of macroscopic hemorrhages or hyperaemia and hepatic bromadiolone concentration > 0.1 mg/kg). All the exposed weasels (n = 7) showed only trans-bromadiolone diastereomer in liver, whilst a single analyzed bait from those applied in Castilla y León contained trans- and cis-bromadiolone at 65/35%. Bromadiolone occurrence and concentration in weasels varied yearly. Occurrence was higher in 2012 (100% of weasels), when bromadiolone was widely distributed, compared to 2016–2017 (2016: 20%; 2017: 8.33%) when bromadiolone was exceptionally permitted. The highest concentrations happened in 2014 and 2017, both years with vole outbreaks. Our findings indicate that specialist rodent predators could be exposed to bromadiolone in areas and periods with bromadiolone treatments against vole outbreaks.Francisco Díaz-Ruiz enjoyed a postdoctoral research contract “Juan de la Cierva” (ref: FJCI-2015-24949) from the Spanish Ministry of Economy, Industry, and Competitiveness and a postdoctoral contract funded by the University of Málaga through the grants programme ‘Ayudas para la Incorporación de Doctores del I Plan Propio de Investigación de la Universidad de Málaga’ (Call 2020). Julio Domínguez was supported by a predoctoral grant: “Programa Talento Formación” funded by Fondo Social Europeo (FSE) and Castilla La Mancha regional government (JCCM) (ref: SBPLY/16/180501/000205).Peer reviewe

Algunos resultados de la aplicación del nuevo Plan de Estudios

Este dossier coordinado por Alfredo Alvar Ezquerra contiene los siguientes artículos: La inclusa de Madrid; El protocolo 258 y Madrid hacia 1562; Evolución de dos casas panadería en el Madrid de la época moderna; Canencia: un ejercicio de demografía histórica.Este artículo está sujeto a una licencia CC BY 4.0Peer reviewe

Tractament de manteniment amb metadona: manual de pràctica clínica

Tractament de manteniment amb metadona; Pràctica clínica; DrogodependènciesTratamiento de mantenimiento con metadona; Práctica clínica; DrogodependenciasMethadone maintenance treatment; Clinical practice; Drug addictionsEl Manual pretén ser una eina útil per disminuir la variabilitat de la pràctica clínica i garantir un nivell òptim de qualitat i millora de l'atenció sanitària en el tractament de manteniment amb metadona (TMM). Aplica les normes bàsiques utilitzades per a la preparació de guies de pràctica clínica; en primer lloc, incloent-hi la millor evidència possible sobre la base de revisions sistemàtiques de la literatura, en segon lloc, amb recomanacions clares i curtes, i en tercer lloc, en absència d’una evidència fiable en la literatura, incorporant-hi la opinió d’experts per mitjà de tècniques de consens com el mètode Delphi

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Determinants of exposure to veterinary pharmaceuticals in avian scavengers to improve environmental risk assessment

Memoria para optar al grado de Doctora con Mención Internacional.[EN] Pharmaceuticals are considered emerging contaminants. These compounds are increasing worldwide and their presence in the environment is now ubiquitous. Their negative impacts on biota are an increasing concern globally. The clearest example of this has been the dramatic decline in Asian vulture populations in recent decades, driven primarily by the non-steroidal anti-inflammatory drug (NSAID) diclofenac. This caused acute intoxication in Gyps vultures when they consumed carcasses of previously treated livestock. This well-known NSAID was then subsequently authorized for veterinary use in Spain in 2013, which was highly controversial given Spain is an important stronghold for European vulture conservation. In this context, this thesis focused on the description and analyses of parallel scenarios in Spain regarding veterinary pharmaceuticals and their potential negative effects in wildlife with scavenging habits (mainly vultures). This thesis describes the prevalence of highly toxic compounds (like NSAIDs and barbiturates) to avian scavengers in Spain, but also considers other commonly used veterinary pharmaceuticals like antibiotics or antiparasitic drugs. Data are reported here for avian scavenger samples and for their main source of exposure, livestock carcasses supplied at feeding stations. Using these data, we determined risk factors for exposure to pharmaceuticals that are associated with livestock carcasses supplied for avian scavengers in Spain. To accomplish these objectives, various analytical methods were developed to detect veterinary pharmaceuticals in samples using liquid and gas chromatography coupled to mass spectrometry. This included a ‘final’ multiresidue method to analyse up to 49 pharmaceuticals commercialized for veterinary use in Spain. The prevalence of different NSAIDs detected here ranged between 0.3-14.3% in avian scavengers (in plasma and tissues) and between 0.6-4.4% in domestic animal carcasses. Barbiturates were found in 3.4% of wildlife tissues analysed, with avian scavengers showing barbiturate residues in 2.7% of samples collected. For antibiotics, prevalence among the different compounds detected ranged between 0.3-13.1% in avian scavengers and between 0.6-17.6% in livestock carcasses, while antiparasitic drugs (like avermectins) were not detected. Considering the levels found here, we estimated that in most cases the carcasses supplied for avian scavengers contained low concentrations that would probably not cause mortality in vultures feeding on them. However, we must highlight that some carcasses had potentially toxic levels of flunixin and two pig carcasses contained diclofenac, one at toxic levels. This thesis also contains a description of the first case of a cinereous vulture dying due to diclofenac poisoning in Europe, which highlights the risk of this for avian scavengers. We also report on intoxications with other highly toxic pharmaceuticals like NSAIDs (i.e., flunixin) and pentobarbital. In the case of the latter, we note a worrying increase in the incidence of poisoning events (mainly in the north of Spain). Together with the pharmaceuticals described here, caffeine was observed in plasma from a big proportion of avian scavengers (64.1%) for the first time. We noted caffeine may be a good biomarker for landfill use by vultures. This thesis contributes to knowledge regarding the ecotoxicology of pharmaceuticals in avian scavengers in Spain. This is a fundamental starting point to establish research needs and to perform adequate risk assessments for these compounds in wildlife. This thesis also includes general recommendations for decision makers to improve the management of domestic animal carcasses in terms of preventing exposure to pharmaceuticals in wildlife.[ES] Actualmente los fármacos están considerados como contaminantes emergentes. El uso de estos compuestos está aumentando a nivel global y su presencia en el medio ambiente ya es ubicua. Los impactos negativos de estos compuestos en la biota se han visto incrementados en los últimos años y suponen una preocupación global. El ejemplo más claro de ello fue la dramática disminución de las poblaciones de buitres asiáticos en las últimas décadas, provocada por el antinflamatorio no esteroideo (AINE) diclofenaco. Este AINE causa una intoxicación aguda en buitres del género Gyps al consumir las carroñas de ganado previamente tratado. Este AINE fue autorizado para su uso en medicina veterinaria en España en 2013, lo cual fue una decisión controvertida debido a que España alberga la mayor población de buitres europeos. En este contexto, esta tesis se centra en describir y analizar diferentes escenarios en España en relación con los fármacos de uso veterinario y sus potenciales efectos adversos en fauna con hábitos carroñeros (especialmente en buitres). Esta tesis describe la prevalencia de compuestos altamente tóxicos (como AINEs y barbitúricos) para aves carroñeras en España, pero también considera otros fármacos veterinarios de uso común como los antibióticos o los antiparasitarios. Los datos que se exponen aquí incluyen muestras de aves carroñeras y de su principal fuente de exposición a fármacos; lascarroñas de ganado suministradas en muladares. Con estos datos, hemos determinado los factores de riesgo de exposición a los fármacos de uso veterinario asociados con las características de las carroñas de animales domésticos suplementados a las aves carroñeras en España. Para cumplir estos objetivos, se desarrollaron varios métodos analíticos para detectar fármacos de uso veterinario en las muestrasanalizadas aquí utilizando cromatografía de líquidos y gases acoplada a espectrometría de masas. Este proceso derivó en el desarrollo de un método multirresiduo para analizar en plasma y tejidos hasta 49 fármacos comercializados para uso veterinario en España. La prevalencia de los diferentes AINEs detectados aquí osciló entre el 0.3 y el 14.3% en aves carroñeras (en plasma y tejidos) y entre el 0.6 y el 4.4% en carroñas de animales domésticos. Se detectaron barbitúricos en el 3.4% de la fauna silvestre encontrada muerta con sospecha de intoxicación, y específicamente el 2.7% de las aves carroñeras analizadas mostraron residuos de barbitúricos. En el caso de los antibióticos, la prevalencia entre los diferentes compuestos detectados osciló entre el 0.3 y el 13.1% en aves carroñeras y entre el 0.6 y el 17.6% en carroñas de animales domésticos, mientras que no se detectaron fármacos antiparasitarios (como las avermectinas). Teniendo en cuenta los niveles detectados aquí, estimamos que, en la mayoría de los casos, los cadáveres suministrados para las aves carroñeras contenían concentraciones bajas que probablemente no causarían mortalidad en los buitres que se alimentan de ellos. Sin embargo, debemos destacar que algunas carroñas presentaban niveles potencialmente tóxicos de flunixino y dos carroñas de cerdo contenían diclofenaco, una de ellas a niveles tóxicos. Esta tesis también contiene una descripción del primer caso de mortalidad en un buitre negro por intoxicación con diclofenaco en Europa, lo que pone de manifiesto el riesgo que supone este AINE para las aves carroñeras. También se detallan intoxicaciones con otros productos farmacéuticos altamente tóxicos como los AINEs (concretamente flunixino) y pentobarbital. En el caso de estos últimos, se constata un preocupante aumento de la incidencia de intoxicaciones (principalmente en el norte de España). Junto con los fármacos descritos aquí, se observó cafeína en el plasma de aves carroñeras por primera vez en un elevado porcentaje de las aves (64.1%). Además, observamos que la cafeína puede ser un buen biomarcador del uso de vertederos por parte de los buitres. Esta tesis contribuye al conocimiento de la ecotoxicología de fármacos en aves carroñeras en España. Este es un punto de partida fundamental para establecer las necesidades de investigación y realizar evaluaciones de riesgo adecuadas para estos compuestos en la fauna silvestre. Esta tesis también incluye recomendaciones generales para los responsables que han de tomar las decisiones para mejorar el manejo de las carroñas de animales domésticos en términos de prevención de la exposición a fármacos de uso veterinario en fauna silvestre.Peer reviewe

Medicated livestock carcasses and landfill sites: Sources of highly toxic veterinary pharmaceuticals and caffeine for avian scavengers

Veterinary drugs are of concern in terms of potential environmental pollution and their negative impacts on avian scavengers. These pharmaceuticals reach vultures through the consumption of carcasses of previously treated livestock. Here, we analysed samples from livestock carcasses (n = 159), avian scavenger tissues (n = 116) and plasma (n = 312) for 49 compounds commonly used in veterinary medicine in Aragon (NE Spain) and nearby regions. Samples were analysed using liquid chromatography with electrospray ionization mass spectrometry (LC-ESI-MS/MS). We detected pharmaceuticals in 54.1% of livestock carcasses analysed (50.3% with antibiotics, 10.8% with NSAIDs). For veterinary pharmaceuticals in tissues and plasma from avian scavengers, we detected pharmaceuticals in 51.7% and 28.5% of samples, respectively. Antibiotics were detected in 50.9% and 25.3% while NSAIDs were determined in 6.0% and 5.5% of tissues and plasma from avian scavengers, respectively. Moreover, caffeine was detected in plasma in 73.7% of vultures sampled at landfill sites, indicating its usefulness as a biomarker of urban garbage ingestion. We found an association between livestock carcasses, especially pigs and chickens, and the presence of veterinary pharmaceuticals in avian scavengers. We highlight that carcass disposal for feeding avian scavengers must address the potential risks posed by veterinary pharmaceutical residues.Peer reviewe