a survey of healthcare providers across the WHO European region

FundingThis work was supported by European AIDS Clinical Society.Women living with HIV are reaching older age and experiencing menopause and age-related comorbidities. Data suggest that women living with HIV experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. However, there are no guidelines on the screening for and management of age-related comorbidities and events in women living with HIV. Moreover, little is known about provision of care to this population across Europe. We surveyed 121 HIV healthcare providers in 25 World Health Organization European countries to ascertain screening practices for, and management of, menopause, psychosocial and sexual well-being and age-related comorbidities in women with HIV. Most respondents screened for diabetes, cardiovascular disease (CVD) risk factors and poor mental health at least annually. Low bone mineral density (BMD) was regularly checked but less than once a year. Fewer regularly screened for sexual well-being and intimate partner violence. Menstrual pattern and menopausal symptoms in women aged 45–54 were assessed by 67% and 59% of respondents. 44% stated that they were not confident assessing menopausal status and/or symptoms. CVD, diabetes, low BMD and poor mental health were managed mainly within HIV clinics, whereas menopause care was mainly provided by gynaecology or primary care. Most respondents stated a need for HIV and menopause guidelines. In conclusion, we found that whilst metabolic risk factors and poor mental health are regularly screened for, psychosocial and sexual well-being and menopausal symptoms could be improved. This highlights the need for international recommendations and clinician training to ensure the health of this population.publishersversionepub_ahead_of_prin

A simple method to measure sulfonation in man using paracetamol as probe drug

Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index-PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual's sulfonator status. To the best of our knowledge, our method provides the first standardised in vivo empirical measure of an individual's phenol sulfonation capability and of its intraindividual variability. EUDRA-CT 2016-001395-29, NCT03182595 June 9, 2017.publishersversionpublishe

Current perspectives

The increasing knowledge of the mechanisms involved in metabolism is shifting the paradigms by which the pathophysiology of many pulmonary diseases is understood. Metabolic dysfunction is recognized in obesity-associated asthma, but other metabolic conditions have been shown to be independently related to asthma. Novel insights have also recently been brought by metabolomics in this filed. The purpose of this review is to discuss current perspectives regarding metabolic dysfunction in asthma, from obesity-related asthma to other metabolic conditions and the role of current pharmacological therapeutic strategies and lifestyle interventions. Obesity is a well-recognized risk factor for asthma across the lifespan, which is generally associated with poorer response to current available treatments, rendering a more severe, refractory disease status. Besides the epidemiological and clinical link, untargeted metabolomics studies have recently supported the obesity-associated asthma phenotype at the molecular level. Not only obesity-related, but also other aspects of metabolic dysregulation can be independently linked to asthma. These include hyperinsulinemia, dyslipidemia and hypertension, which need to be taken into account, even in the non-obese patient. Untargeted metabolomics studies have further highlighted several other metabolic pathways that can be altered in asthma, namely regarding oxidative stress and systemic inflammation, and also suggesting the importance of microbiota in asthma pathogenesis. Considering the reduced response to corticosteroids, other pharmacologic treatments have been shown to be effective regardless of body mass index. Non-pharmacologic treatments (namely weight reduction and dietary changes) may bring substantial benefit to the asthmatic patient. Taken together, this evidence points towards the need to improve our knowledge in this filed and, in particular, to address the influence of environmental factors in metabolic dysfunction and asthma development. Personalized medicine is definitely needed to optimize treatment, including a holistic view of the asthmatic patient in order to set accurate pharmacologic therapy together with dietary, physical exercise and lifestyle interventions.publishersversionpublishe

A Metabolomics-Inspired Strategy for the Identification of Protein Covalent Modifications

This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal, through projects UID/QUI/00100/2019, IF/01091/2013/CP1163/CT0001 and PTDC/QUIQAN/32242/2017 as well as doctoral fellowships SFRH/BD/102846/2014 (to CC) and SFRH/BD/140157/2018 (to JN);joint funding from FCT and the COMPETE Program is also acknowledge through RNEM-LISBOA-01-0145-FEDER-022125-funded postdoctoral fellowship (to JM).Identification of protein covalent modifications (adducts) is a challenging task mainly due to the lack of data processing approaches for adductomics studies. Despite the huge technological advances in mass spectrometry (MS) instrumentation and bioinformatics tools for proteomics studies, these methodologies have very limited success on the identification of low abundant protein adducts. Herein we report a novel strategy inspired on the metabolomics workflows for the identification of covalently-modified peptides that consists on LC-MS data preprocessing followed by statistical analysis. The usefulness of this strategy was evaluated using experimental LC-MS data of histones isolated from HepG2 and THLE2 cells exposed to the chemical carcinogen glycidamide. LC-MS data was preprocessed using the open-source software MZmine and potential adducts were selected based on the m/z increments corresponding to glycidamide incorporation. Then, statistical analysis was applied to reveal the potential adducts as those ions are differently present in cells exposed and not exposed to glycidamide. The results were compared with the ones obtained upon the standard proteomics methodology, which relies on producing comprehensive MS/MS data by data dependent acquisition and analysis with proteomics data search engines. Our novel strategy was able to differentiate HepG2 and THLE2 and to identify adducts that were not detected by the standard methodology of adductomics. Thus, this metabolomics driven approach in adductomics will not only open new opportunities for the identification of protein epigenetic modifications, but also adducts formed by endogenous and exogenous exposure to chemical agents.publishersversionpublishe

Comorbidities and menopause assessment in women living with HIV: a survey of healthcare providers across the WHO European region

Women living with HIV are reaching older age and experiencing menopause and age-related comorbidities. Data suggest that women living with HIV experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. However, there are no guidelines on the screening for and management of age-related comorbidities and events in women living with HIV. Moreover, little is known about provision of care to this population across Europe. We surveyed 121 HIV healthcare providers in 25 World Health Organization European countries to ascertain screening practices for, and management of, menopause, psychosocial and sexual well-being and age-related comorbidities in women with HIV. Most respondents screened for diabetes, cardiovascular disease (CVD) risk factors and poor mental health at least annually. Low bone mineral density (BMD) was regularly checked but less than once a year. Fewer regularly screened for sexual well-being and intimate partner violence. Menstrual pattern and menopausal symptoms in women aged 45-54 were assessed by 67% and 59% of respondents. 44% stated that they were not confident assessing menopausal status and/or symptoms. CVD, diabetes, low BMD and poor mental health were managed mainly within HIV clinics, whereas menopause care was mainly provided by gynaecology or primary care. Most respondents stated a need for HIV and menopause guidelines. In conclusion, we found that whilst metabolic risk factors and poor mental health are regularly screened for, psychosocial and sexual well-being and menopausal symptoms could be improved. This highlights the need for international recommendations and clinician training to ensure the health of this population

Aryl hydrocarbon receptor and cysteine redox dynamics underlie (Mal)adaptive mechanisms to chronic intermittent hypoxia in kidney cortex

Funding Information: Funding: This work was supported by Fundação para Ciência e Tecnologia [PTDC/MED-TOX/30418/2017] and iNOVA4Health [UID/Multi/04462/2013]. M.J.C., F.L.-C., N.R.C., C.G.-D. and J.M. are supported by FCT grants [SFRH/BD/131331/2017, PD/BD/128337/2017, PD/BD/114257/2016, and PD/BD/105892/2014, PTDC/MED-TOX/30418/2017 respectively]. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.publishersversionpublishe

Cysteine as a Multifaceted Player in Kidney, the Cysteine-Related Thiolome and Its Implications for Precision Medicine

Funding Information: This research was supported by Fundação para a Ciência e Tecnologia (PTDC/MED-TOX/30418/2017) and iNOVA4Health (UID/Multi/04462/2013). M.J.C., D.G.F.F. and J.M. were supported by FCT (PhD grant SFRH/BD/131331/2017, PhD grant PD/BD/135484/2018 and postdoctoral contract PTDC/MED-TOX/30418/2017, respectively).In this review encouraged by original data, we first provided in vivo evidence that the kidney, comparative to the liver or brain, is an organ particularly rich in cysteine. In the kidney, the total availability of cysteine was higher in cortex tissue than in the medulla and distributed in free reduced, free oxidized and protein-bound fractions (in descending order). Next, we provided a comprehensive integrated review on the evidence that supports the reliance on cysteine of the kidney beyond cysteine antioxidant properties, highlighting the relevance of cysteine and its renal metabolism in the control of cysteine excess in the body as a pivotal source of metabolites to kidney biomass and bioenergetics and a promoter of adaptive responses to stressors. This view might translate into novel perspectives on the mechanisms of kidney function and blood pressure regulation and on clinical implications of the cysteine-related thiolome as a tool in precision medicine.publishersversionpublishe

Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis

Funding: Sociedade Portuguesa de Nefrologia (SPN) SPN funded a project and Ana Rita Martins, MD, Nephrology fellow, for a residence at Jiménez Díaz Foundation University Hospital, Madrid under the scope of novel serum biomarkers of CKD. iNOVA4Health research program (UIDP/04462/2020) is also acknowledged to support J.M.Peritoneal membrane status, clinical data and aging-related molecules were investigated as predictors of long-term peritoneal dialysis (PD) outcomes. A 5-year prospective study was conducted with the following endpoints: (a) PD failure and time until PD failure, (b) major cardiovascular event (MACE) and time until MACE. A total of 58 incident patients with peritoneal biopsy at study baseline were included. Peritoneal membrane histomorphology and aging-related indicators were assessed before the start of PD and investigated as predictors of study endpoints. Fibrosis of the peritoneal membrane was associated with MACE occurrence and earlier MACE, but not with the patient or membrane survival. Serum α-Klotho bellow 742 pg/mL was related to the submesothelial thickness of the peritoneal membrane. This cutoff stratified the patients according to the risk of MACE and time until MACE. Uremic levels of galectin-3 were associated with PD failure and time until PD failure. This work unveils peritoneal membrane fibrosis as a window to the vulnerability of the cardiovascular system, whose mechanisms and links to biological aging need to be better investigated. Galectin-3 and α-Klotho are putative tools to tailor patient management in this home-based renal replacement therapy.publishersversionpublishe

Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury

Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution