Desenvolvimento de metodologia analítica para determinação de atrazina e seus principais produtos de transformação nas águas superficiais da Bacia Hidrográfica do Paraná 3

A Bacia Hidrográfica do Paraná 3 (BP3) situada no oeste do estado do Paraná, apresenta um consumo de agrotóxicos acima da média do estado. A atrazina (ATZ) é um dos principais agrotóxicos utilizados na BP3. Foram avaliadas três técnicas de extração e de préconcentração: extração em fase sólida (SPE), microextração em fase sólida (SPME) e microextração dispersiva líquido-líquido (DLLME), com o objetivo de avaliar a capacidade de extração de ATZ e seus produtos de transformação (TPs), deisopropilatrazina (DIA) e deetilatrazina (DEA). A DLLME foi realizada a otimização através do planejamento Doehlert. A SPE e SPME foram realizadas a partir de adaptações da literatura. A escolha da técnica de extração foi realizada através da análise de custos e demanda temporal. A DLLME apresentou o menor valor de custo de extração e demanda temporal quando comparada com as outras. Esta técnica foi utilizada como rotina na análise das amostras da BP3. Foram analisadas 407 amostras, sendo que dessas, 23.83 % apresentaram a presença de ATZ, e uma amostra apresentou concentração acima do limite estabelecido na resolução CONAMA 357/2005. Sobre os TPs, 1,22 % das amostras apresentaram o DEA. Já para o DIA, somente em uma amostra esse analito foi quantificado.The Paraná 3 Hydrographic Basin (BP3), located in the western part of the state of Paraná, shows a consumption of pesticides above the state average. Atrazine (ATZ) is one of the main pesticides used in BP3. Three extraction and preconcentration techniques were used: solid phase extraction (SPE), solid phase microextraction (SPME) and dispersive liquid-liquid microextraction (DLLME), with the objective of evaluating the extraction capacity of ATZ and its transformation products (TPs), deisopropylatrazine (DIA) and deethylatrazine (DEA). The DLLME was optimized through Doehlert planning. SPE and SPME were carried out based on adaptations of the literature. The extraction technique was chosen through the analysis of costs and time demand. DLLME presented the lowest value of extraction cost and temporal demand when compared to the others. This technique was used routinely in the analysis of BP3 samples. A total of 407 samples were analyzed, of which, 23.83% presented the presence of ATZ, and one sample presented concentration above the limit established in CONAMA Resolution 357/2005. On the TPs, 1.22% of the samples presented the DEA. For the DIA, only in one sample this analyte was quantified

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Avaliação do acoplamento de processos fotocatalíticos solares e processo de adsorção para amitigação de fármacos em efluente hospitalar

A presença de contaminantes de interesse emergente no meio ambiente vem aumentando nos últimos anos devido ao amplo uso de fármacos, produtos de higiene pessoal, agrotóxicos, retardantes de chamas, organoclorados e organobromados, entre outros. Nesse sentido, especial atenção tem sido dada aos fármacos, uma vez que tais compostos, quando presentes nos diferentes compartimentos ambientais, podem causar efeitos adversos variados e, até mesmo, gerar ou ampliar a resistência bacteriana em organismos aquáticos e nos seres humanos. Além disso, as estações de tratamentos de efluentes geralmente empregam tratamentos biológicos. Tais sistemas não foram projetados para o tratamento de fármacos. Isso porque estes contaminantes não são biodegradáveis e, em muitos casos, podem ser tóxicos ou inibir o consórcio de microrganismos que constitui os diferentes processos biológicos convencionalmente empregados nos sistemas de tratamento convencionais. Assim, surge a necessidade de realizar novos estudos que avaliem o emprego de diferentes tecnologias de tratamentos para a degradação e remoção desses contaminantes de interesse emergente. Dentre os tratamentos mais promissores para o tratamento de efluentes e águas residuais complexas pode-se destacar os Processos Avançados de Oxidação (AOPs), em especial o processo Fenton e foto-Fenton em pH próximo da neutralidade. Por sua vez, técnicas cromatográficas acopladas à espectrometria de massas de alta resolução são uma alternativa instrumental válida para o monitoramento dos contaminantes de interesse emergente e, também, para poder realizar a identificação de produtos de transformação (TPs). Quando combinadas a modelagem in silico, por métodos de relações quantitativas entre a estrutura e atividade ((Q)SAR), ajudam na tomada de decisão sobre quais os contaminantes e TPs de maior risco ambiental e até que ponto os tratamentos avaliados devem perdurar. Por sua vez, quando os AOPs têm sua aplicação limitada por diferentes fatores, os processos de adsorção, em especial, os tratamentos que empregam carvão ativo produzido através de biomassas, se apresentam como uma alternativa interessante para, mediante um sistema de tratamentos alternativos acoplados, viabilizara remoção de diferentes contaminantes ou TPs recalcitrantes/tóxicos gerados nos processos de AOPs. Considerando essas questões, a presente tese está dividida em três capítulos, detalhados a seguir. O Capítulo 1 apresenta o estudo individualizado da Flutamida via degradação por processo foto-Fenton solar (SPF). O fármaco selecionado para estudo é utilizado no tratamento do câncer da próstata. As identificações dos TPs foram realizadas por cromatografia líquida de alta eficiência acoplada ao analisador de massas híbrido quadrupolo-tempo de voo. Ainda, associadas às ferramentas de predições in silico, foram preditos parâmetros de ecotoxicidade desses TPs. Na condição otimizada do processo foto-Fenton solar, um total de 13 TPs nunca antes relatados na literatura científica atual, foram preditos e os resultados da avaliação in sílico indicam que tais TPs são persistentes, mutagênicos e carcinogênicos, além de não serem biodegradáveis. O Capítulo 2 apresenta o tratamento de um efluente hospitalar contaminado com a Flutamida. Nesse estudo, priorizou-se a identificação dos TPs no efluente, utilizando análise não-alvo (non-target screening) por meio de uma base de dados construída especificamente para identificação dos TPs da Flutamida, e a remoção da Flutamida e seus TPs por combinação de processos solar foto-Fenton e de adsorção utilizando carvão ativo. Ainda, foi otimizado o processo de adsorção para remoção dos analitos em estudo. O acople dos processos permitiu remover com segurança a grande maioria dos TPs, com altas taxas de remoção. Contudo, para os TPs que apresentam abertura do anel aromático, taxas inferiores foram obtidas em decorrência de serem TPs com uma polaridade maior. O Capítulo 3 é o estudo do tratamento de um efluente hospitalar real fortificado com uma mistura de 9 compostos farmacêuticos (cloranfenicol, fluconazol, flutamida, furosemida, gemfibrozil, ibuprofeno, losartana, nimesulida e paracetamol) de diferentes classes. Inicialmente foram comparadas quatro abordagens de degradação por foto-Fenton solar. Ao mesmo tempo, os TPs gerados por essas diferentes abordagens foram identificados mediante o uso de uma base de dados especialmente construída que continha informações de 127 TPs provenientes dos 9 fármacos selecionados. As diferentes abordagens geraram um total de 38 TPs, sendo que duas novas estruturas foram pospostas para os TPs de nimesulida. Ainda, ao realizar a combinação de processos, altas taxas de remoção foram alcançadas para os fármacos e TPs, exceto no caso de TPs que apresentam uma polaridade maior. Ao longo dos diferentes estudos realizados, estratégias para a degradação dos compostos farmacêuticos aliadas à remoção dos TPs foram propostas. Adicionalmente, novas estruturas de TPs, que nunca haviam sido identificados e publicados, foram divulgadas por meio dos estudos que compõe essa Tese, evidenciando que o presente trabalho apresenta relevância na temática de remoção de fármacos e TPs presentes em efluentes hospitalares.The presence of emerging contaminants into the environment has increased in recent years due to the widespread use of pharmaceuticals, personal care products, pesticides, flame retardants, organochlorines and organobromines, among others. In this sense, special attention has been given to pharmaceuticals, since such compounds, when present in different environmental compartments, can cause adverse effects, and even generate or increase bacterial resistance in aquatic organisms and humans. In addition, wastewater treatment plants employ biological treatments. Such systems are not designed for pharmaceutical treatment as these contaminants are non-biodegradable. Moreover, in many cases, they can be toxic or inhibit the consortium of microorganisms that constitute the different biological processes conventionally used. Thus, novel studies must be proposed to evaluate the use of different treatments for the degradation and removal of pharmaceuticals. Advanced Oxidation Processes (AOPs) are among the most promising treatments for effluents and complex wastewaters, especially Fenton and photo-Fenton processes at circumneutral pH. In turn, chromatographic techniques coupled with high resolution mass spectrometry are a valid instrumental alternative to monitor contaminants of emerging interest and also to identify transformation products (TPs). When combined with in silico modeling by methods of quantitative structure-activity relationship ((Q)SAR), these analyses help to decide which contaminants and TPs pose the greatest environmental risk and how long the evaluated treatments should last. On the other hand, when AOPs have their application limited by different factors, the adsorption processes, in particular, treatments that use active carbon produced from biomass, present themselves as an interesting alternative. This is because an alternative system of coupling treatments enables the removal of different contaminants or recalcitrant/toxic TPs generated in AOPs processes. Taking this into consideration, the present thesis is divided into three chapters, detailed below. Chapter 1 presents the individualized study of Flutamide via solar photo-Fenton degradation. The drug selected for this study is used in the treatment of prostate cancer. The identifications of the PTs were performed by high performance liquid chromatography coupled with hybrid mass analyzer (quadrupole-time-of-flight). Additionally, associated with in silico prediction tools, ecotoxicity parameters of these new PTs were predicted. In the optimized condition of the solar photo-Fenton process, a total of 13 TPs never before reported in the current scientific literature were identified. Furthermore, the results of the in silico evaluation indicate that these TPs are persistent, mutagenic and carcinogenic, in addition to being non-biodegradable. Chapter 2 presents the treatment of a hospital effluent contaminated with Flutamide. In this study, priority was given to the identification of TPs in the effluent, applying non-target screening and using a purpose built database to identify the TPs of Flutamide, and the removal of Flutamide and its TPs by combining photo-Fenton solar processes and adsorption using active carbon. Furthermore, the adsorption process was optimized to remove the analytes under study. The coupling of the processes allowed to safely remove the vast majority of TPs, with high removal rates. However, for TPs that present aromatic ring opening, lower rates were obtained as a result of TPs having a higher polarity. Chapter 3 focuses on the study of the treatment of a real hospital effluent fortified with a mixture of nine pharmaceuticals (chloramphenicol, fluconazole, flutamide, furosemide, gemfibrozil, ibuprofen, losartan, nimesulide and paracetamol) from different classes. Initially, four degradation approaches by solar photo-Fenton were compared. At the same time, the TPs generated by these different approaches were identified using a specially constructed database that contained information on 127 TPs from the nine selected drugs. The different approaches generated a total of 38 TPs, with two new chemical structures being proposed for the nimesulide TPs. In addition, when performing the combination of processes, high removal rates were achieved for initial pharmaceuticals and TPs, except in the case of TPs that have a higher polarity. Throughout the different studies carried out, strategies for the degradation of pharmaceutical compounds allied to the removal of TPs were proposed. Additionally, new structures of TPs, which had never been identified and published, were disclosed through the studies that make up this Thesis, showing that the present work is relevant in the theme of removal of drugs and TPs present in hospital effluents

Comprehensive investigation of pesticides in Brazilian surface water by high resolution mass spectrometry screening and gas chromatography–mass spectrometry quantitative analysis

In this work, a comprehensive investigation on the occurrence of pesticides in the Paraná 3 hydrographic basin of Paraná State, Brazil, was made by application of wide-scope screening based on ultra-high performance liquid chromatography (LC) and gas chromatography (GC) both coupled to quadrupole time-of-flight mass spectrometry (QTOF MS). The use of two complementary techniques, such as GC-QTOF MS and LC-QTOF MS, allowed screening a large number of compounds with different polarity and volatility. This screening approach was applied to 17 samples, enabling the detection of fifty-two pesticides and six metabolites. In a second step, an specific research was made on the herbicide atrazine, one of the most frequent compounds in samples, and its major transformation products (TPs), which were quantitatively analyzed by dispersive liquid-liquid microextraction (DLLME) followed by GC–MS measurement. Twenty-one agricultural streams from the Paraná 3 hydrographic basin were sampled twice in 2017, each time along six successive weeks. Additional samples were also collected after rain events exceeding 10 mm. In total, 407 samples were quantitatively analyzed by DLLME/GC–MS. Atrazine concentrations did not exceed the maximum permitted concentration of 2 μg L−1 according to Brazilian legislation, and only one surface water sample, collected after precipitation events, was slightly above this value (2.89 μg L−1). The maximum concentrations for the TPs desethylatrazine and deisopropylatrazine were 0.80 and 1.22 μg L−1, respectively. Based on the quantification results, a map was produced showing the occurrence of atrazine and its TPs in the area under study. This is the first time that the presence of agrochemicals is evaluated in the Paraná 3 hydrographic basin

Presentation, management, and outcomes of older compared to younger adults with hospital-acquired bloodstream infections in the intensive care unit: a multicenter cohort study

Purpose: Older adults admitted to the intensive care unit (ICU) usually have fair baseline functional capacity, yet their age and frailty may compromise their management. We compared the characteristics and management of older (≥ 75 years) versus younger adults hospitalized in ICU with hospital-acquired bloodstream infection (HA-BSI). Methods: Nested cohort study within the EUROBACT-2 database, a multinational prospective cohort study including adults (≥ 18 years) hospitalized in the ICU during 2019-2021. We compared older versus younger adults in terms of infection characteristics (clinical signs and symptoms, source, and microbiological data), management (imaging, source control, antimicrobial therapy), and outcomes (28-day mortality and hospital discharge). Results: Among 2111 individuals hospitalized in 219 ICUs with HA-BSI, 563 (27%) were ≥ 75 years old. Compared to younger patients, these individuals had higher comorbidity score and lower functional capacity; presented more often with a pulmonary, urinary, or unknown HA-BSI source; and had lower heart rate, blood pressure and temperature at presentation. Pathogens and resistance rates were similar in both groups. Differences in management included mainly lower rates of effective source control achievement among aged individuals. Older adults also had significantly higher day-28 mortality (50% versus 34%, p < 0.001), and lower rates of discharge from hospital (12% versus 20%, p < 0.001) by this time. Conclusions: Older adults with HA-BSI hospitalized in ICU have different baseline characteristics and source of infection compared to younger patients. Management of older adults differs mainly by lower probability to achieve source control. This should be targeted to improve outcomes among older ICU patients

The role of centre and country factors on process and outcome indicators in critically ill patients with hospital-acquired bloodstream infections

Purpose: The primary objective of this study was to evaluate the associations between centre/country-based factors and two important process and outcome indicators in patients with hospital-acquired bloodstream infections (HABSI). Methods: We used data on HABSI from the prospective EUROBACT-2 study to evaluate the associations between centre/country factors on a process or an outcome indicator: adequacy of antimicrobial therapy within the first 24 h or 28-day mortality, respectively. Mixed logistical models with clustering by centre identified factors associated with both indicators. Results: Two thousand two hundred nine patients from two hundred one intensive care units (ICUs) were included in forty-seven countries. Overall, 51% (n = 1128) of patients received an adequate antimicrobial therapy and the 28-day mortality was 38% (n = 839). The availability of therapeutic drug monitoring (TDM) for aminoglycosides everyday [odds ratio (OR) 1.48, 95% confidence interval (CI) 1.03-2.14] or within a few hours (OR 1.79, 95% CI 1.34-2.38), surveillance cultures for multidrug-resistant organism carriage performed weekly (OR 1.45, 95% CI 1.09-1.93), and increasing Human Development Index (HDI) values were associated with adequate antimicrobial therapy. The presence of intermediate care beds (OR 0.63, 95% CI 0.47-0.84), TDM for aminoglycoside available everyday (OR 0.66, 95% CI 0.44-1.00) or within a few hours (OR 0.51, 95% CI 0.37-0.70), 24/7 consultation of clinical pharmacists (OR 0.67, 95% CI 0.47-0.95), percentage of vancomycin-resistant enterococci (VRE) between 10% and 25% in the ICU (OR 1.67, 95% CI 1.00-2.80), and decreasing HDI values were associated with 28-day mortality. Conclusion: Centre/country factors should be targeted for future interventions to improve management strategies and outcome of HABSI in ICU patients