Protocol of a Hybrid Type 1 Cluster-Randomised Trial

Funding Information: This project was awarded with the Academic Excellence Scholarship 2016-2017 (Bolsa de Excelência Académica 2016-2017) from Fundação Eugénio de Almeida. Publisher Copyright: © 2022 The Author(s). Published by S. Karger AG, Basel on behalf of NOVA National School of Public Health.Introduction: Excessive benzodiazepine (BZD) prescription has long been considered a serious mental health concern in many countries. Many interventions using different methodologies have been implemented to change BZD prescription patterns in primary health care settings, with limited positive results. Objectives: The primary objective of our study was to analyse the effectiveness and implementation process of an intervention aimed at changing BZD prescription patterns in a primary health care setting in Portugal. Methodology: We chose as methodology an effectiveness-implementation hybrid type 1 intervention. Our intervention was based on the development of an online platform, named ePrimaPrescribe, which was delivered using a Digital Behaviour Change Intervention (DBCI), using a two-arm cluster-randomised clinical trial. Results: We primarily aimed to evaluate the effectiveness of our DBCI in changing BZD prescription patterns using the frequency of BZD prescriptions issued per month as an outcome measure. Secondarily, we aimed to analyse the effect of ePrimaPrescribe on antidepressant prescriptions, to study the effect of the platform on diagnosis registration associated with BZDs and antidepressant prescription, and to perform a cost analysis considering the monthly National Health Service spending on BZD co-payments. Finally, we aimed to analyse the implementation process using quantitative and qualitative methods. Conclusion: With this study, we expect to contribute with a cost-effective intervention to change the complex matter of excessive BZD prescriptions, and also to improve insight into the challenges to intervention implementation processes in primary health care settings. We believe that our findings are relevant not only to the specific setting where the study was implemented, but also to all countries where primary health care plays a central role in care provision.publishersversionepub_ahead_of_prin

Monitorização das concentrações plasmáticas de Efavirenz: critérios de aplicabilidade à prática clínica e efeitos do fármaco a longo termo

Resumo O objectivo geral deste trabalho foi contribuir para optimizar a terapêutica anti-retroviral e o seu impacto na qualidade de vida do indivíduo infectado pelo vírus da imunodeficiência humana. Pretendia-se definir se o análogo não-nucleósido inibidor da transcriptase reversa do vírus da imunodeficiência humana, efavirenz, cumpria os requisitos para ser monitorizado na prática clínica, estabelecer as condições para a sua eventual monitorização e, simultaneamente, investigar outras acções farmacodinâmicas do efavirenz em terapêuticas prolongadas. Os critérios que fundamentam a indicação da monitorização das concentrações plasmáticas de fármacos, em geral, incluem: correlação entre a concentração do fármaco e a eficácia/toxicidade; variabilidade inter-individual elevada; variabilidade intra-individual e janela terapêutica reduzidas e ainda a elevada probabilidade de interacções medicamentosas. A correlação entre concentração plasmática de efavirenz e eficácia/toxicidade era conhecida e o facto de o efavirenz ser substrato, indutor e inibidor do sistema enzimático citocromo P450 e ser utilizado em terapêuticas crónicas e nunca em monoterapia, constituíam fortes argumentos para a aplicação da monitorização terapêutica ao efavirenz. O presente trabalho contribuiu para o conhecimento de outros critérios, nomeadamente, a variabilidade nas concentrações plasmáticas deste fármaco, entre indivíduos e no mesmo indivíduo, e permitiu definir diferentes aspectos para a prática da monitorização terapêutica deste fármaco, entre eles, o volume de plasma necessário, o parâmetro farmacocinético a avaliar e a periodicidade das quantificações. Para se atingirem os objectivos definidos foi necessário, em primeiro lugar, proceder à instalação e validação de um método de quantificação de concentrações de efavirenz, em plasma de indivíduos infectados pelo vírus da imunodeficiência humana: ficou disponível no Laboratório de Farmacologia da Faculdade de Ciências Médicas, um método que permite a monitorização das concentrações plasmáticas de nove fármacos anti-retrovirais (nevirapina, indinavir, amprenavir, atazanavir, ritonavir, efavirenz, lopinavir, saquinavir e nelfinavir). O método desenvolvido está presentemente a ser utilizado na monitorização terapêutica destes fármacos e em estudos Farmacológicos. Esta quantificação é realizada numa única corrida analítica de cromatografia líquida de elevada eficiência, a partir de 0,4 mL de plasma de cada indivíduo e a sua qualidade é avaliada, bianualmente, por uma entidade externa. Posteriormente, com o objectivo de as comparar, procurou-se conhecer a variabilidade entre indivíduos e intra-individual das concentrações lasmáticas do fármaco e concluiu-se que a variabilidade entre indivíduos é superior à intra-individual, o que suporta a monitorização das suas concentrações. Uma vez encontrada uma variabilidade inter-individual elevada, surgiu um outro objectivo específico, que consistiu na identificação de possíveis factores a justificassem. Na presente dissertação foi mostrado que o sexo, idade, peso e etnia não justificam por si só esta variação, não sendo possível o ajuste de dose com base nestas variáveis. Esta conclusão constitui um factor adicional que reforça que a toma da dose recomendada de efavirenz poderá não ser apropriada para todos os indivíduos. A co-infecção pelos vírus da hepatite B e/ou C é comum nesta população e poderia ser um dos factores implicados nesta variabilidade farmacocinética. A realização do presente trabalho permitiu sugerir que a presença desta co-infecção per se não contribui para o aumento das concentrações plasmáticas do fármaco; que, em indivíduos co-infectados com função hepática normal, não há um risco acrescido de toxicidade dependente da concentração e que as indicações para a monitorização terapêutica de efavirenz em indivíduos co-infectados, com função hepática normal, são semelhantes aquelas descritas para indivíduos mono-infectados pelo vírus da imunodeficiência humana. Um outro objectivo específico deste trabalho surgiu quando foi descrito que os efeitos dos análogos não-nucleósidos inibidores da transcriptase reversa no perfil de lípidos e lipoproteínas dos indivíduos pareciam diferir dos efeitos descritos para os inibidores de protease, que eram frequentemente associados a deslipidémia. Os análogos não-nucleósidos inibidores da transcriptase reversa tinham sido associados a aumentos nos níveis de colesterol associado às lipoproteínas de elevada densidade. Esta observação, além de não ser consensual, podia ser imputada ao decréscimo na carga viral dos indivíduos em terapêutica e correspondia a estudos observacionais de curta-duração. Estes factos estimularam a realização de uma análise prospectiva dos valores da concentração de lípidos e lipoproteínas em doentes medicados com efavirenz e à avaliação da sua eventual relação com a concentração deste nti-retroviral, a curto e a longo-termo. Pela primeira vez, foi demonstrado que o efeito do efavirenz no colesterol associado às lipoproteínas de elevada densidade permaneceu durante 36 meses, que o aumento é dependente do valor basal destas lipoproteínas e da concentração plasmática do fármaco. Mostrou-se também que, em associação a este aumento quantitativo, o efavirenz estava associado a um aumento qualitativo, com uma melhoria da função antioxidante destas lipoproteínas, avaliada pela actividade do enzima paraoxonase-1. Em resumo, os diferentes estudos incluídos na presente dissertação têm como conclusão geral que é possível optimizar a resposta à terapêutica com efavirenz através da monitorização das suas concentrações plasmáticas. A realização deste trabalho contribuiu para o conhecimento científico através: 1. Da instalação e validação de um método de quantificação de concentrações de análogos não-nucleósidos inibidores da transcriptase reversa e inibidores da protease em plasma de indivíduos infectados pelo vírus da imunodeficiência humana. 2. Do estudo da variabilidade inter e intra-individual nas concentrações plasmáticas de efavirenz. A superioridade da variabilidade inter-individual relativamente à associada ao mesmo indivíduo comprova a importância de monitorizar as concentrações plasmáticas deste fármaco. 3. Da definição de procedimentos operativos para a monitorização terapêutica do efavirenz em geral e numa população particular: os indivíduos co-infectados pelos vírus da hepatite B e/ou C com função hepática normal. 4. Da descoberta de acções farmacodinâmicas do efavirenz, a longo prazo, nomeadamente o efeito benéfico (quantitativo e qualitativo) no colesterol associado às lipoproteínas de elevada densidade. Este efeito é mantido durante três anos e é dependente da concentração plasmática do fármaco, o que salienta a importância de monitorizar as suas concentrações

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

Alternative proteins for fish diets: implications beyond growth

Aquaculture has been challenged to find alternative ingredients to develop innovative feed formulations that foster a sustainable future growth. Given the most recent trends in fish feed formulation on the use of alternative protein sources to decrease the dependency of fishmeal, it is fundamental to evaluate the implications of this new paradigm for fish health and welfare. This work intends to comprehensively review the impacts of alternative and novel dietary protein sources on fish gut microbiota and health, stress and immune responses, disease resistance, and antioxidant capacity. The research results indicate that alternative protein sources, such as terrestrial plant proteins, rendered animal by-products, insect meals, micro- and macroalgae, and single cell proteins (e.g., yeasts), may negatively impact gut microbiota and health, thus affecting immune and stress responses. Nevertheless, some of the novel protein sources, such as insects and algae meals, have functional properties and may exert an immunostimulatory activity. Further research on the effects of novel protein sources, beyond growth, is clearly needed. The information gathered here is of utmost importance, in order to develop innovative diets that guarantee the production of healthy fish with high quality standards and optimised welfare conditions, thus contributing to a sustainable growth of the aquaculture industry.info:eu-repo/semantics/publishedVersio

Endolysin binding domain is highly conserved in staphylococcal phage genomes

Bacteriophages are the most predominant and diverse entities in any ecosystem, mostly driven by constant predatorprey evolution dynamics and horizontal gene transfer. Phage population remains an untapped and uncharacterized source of genetic diversity with highly mosaic genomes and no universal genes. To better understand the genetic diversity and the evolutionary relationships of staphylococci infecting phages, we performed an in silico comparative study of all phage genomes infecting Staphylococcus genus. A total of 205 genomes, encoding 20579 proteins which could be sorted into 2137 phamilies (phams) of related sequences, 742 of which possessing only a single (orphams) unrelated sequence, where analysed. Based on shared gene content, phages could be grouped into 4 clusters (A, B, C and D), 14 subclusters (A1-A2, B1-B5, C1-C6 and D) and few singletons. Strikingly, we found that the endolysin molecular organization is shared by most members, showing an intriguing selective pressure that resists the endless cycle of coevolution between phages and the diversified staphylococcal hosts. The endolysin structure is highly conserved regardless the 3 distinct phage morphologies, the 5 endolysin synthesis modes (single gene with and without inter-lytic secondary translation site, two genes spliced by group I intron, two genes adjacent and non- adjacent) and 11 different host genera found in the analysed dataset. We found that staphylococcal phages endolysins have several catalytic domains (AMI2, AMI3, GLUCO, PET-M23, CHAP, being the latter present in 95% of the cases) but only one cell wall binding domain identified (SH3, Src homology 3). Thus, SH3 domain is an intriguing biological marker of Staphylococcus-infecting viruses. Overall, we give a high-resolution and update view of the staphylococcal viral genetic diversity, providing novel insights into their evolution. This analysis included a significant number of phages infecting coagulase-negative species that were limited so far and that have helped to revise previously classifications. The highly conserved endolysin binding domain represents a peculiar evolution pathway to bind the host peptidoglycan at the end of the phage lytic cycle.info:eu-repo/semantics/publishedVersio

a study on perceived effects on health and economic condition

Funding Information: Acknowledgments: We thank all the participants who answered the questionnaire. We extend our thanks to Fundação Ciência e Tecnologia for funding Research 4 COVID-19—Ref. FCT 608. Funding Information: Funding: The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020). Funding Information: The present publication was funded by Funda??o Ci?ncia e Tecnologia, IP national support through CHRC (UIDP/04923/2020). We thank all the participants who answered the questionnaire. We extend our thanks to Funda??o Ci?ncia e Tecnologia for funding Research 4 COVID-19?Ref. FCT 608. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Increasing evidence on the effects of the COVID-19 pandemic suggests that its social and health impacts are being disproportionately shouldered by socioeconomically disadvantaged populations, including migrants. Knowledge of how these populations are experiencing the COVID-19 crisis is scarce. We examined the effects of the pandemic on the perceived individual financial situation and health condition of migrants in Lisbon, Portugal, and described the most affected sub-groups. A cross-sectional survey was conducted with a diverse community-based sample of 1126 migrants. A worsening of their financial situation since the pandemic was reported by 55.6% of the participants and a worsening of their health condition by 19.9%. A worsened financial situation was most often reported by those ≥45 years old and with a lower income (<EUR 650). Likewise, a worsened health condition was most often reported by older and lower-income migrants, as well as by women and those with a lower level of education. Migration-related factors such as length of stay and migration status were not associated with worsened health conditions. Socioeconomic characteristics appear to be more important when assessing differences in perceived effects of the pandemic among migrants. The social impact of the pandemic both exacerbates economic and gender inequalities and may lead to worse health conditions within the population in the medium and long terms.publishersversionpublishe

a mixed-methods approach to explore migrants’ perspectives of access and use of health services during the Covid-19 pandemic

Funding Information: The study was partially supported by Fundo para o Asilo, Migração e Integração (Ref. PT/2021/FAMI/693). Funding Information: The authors wish to thank the study participants for their contribution to the research. The authors thank Ana Rita Pedro for her assistance in revising the draft of the manuscript. The authors extend their thanks to Fundação para a Ciência e a Tecnologia for funding Research 4 COVID-19—Ref. FCT 608. A.S.M. received a grant from the Fundação para a Ciência e a Tecnologia (FCT) [UI/BD/151430/2021], for her PhD. A.G. is supported by FCT/MCTES—CEEC Individual Program Contract (CEECINST/00042/2021). Publisher Copyright: © 2022 by the authors.The COVID-19 pandemic put pressure on health systems, affecting populations’ use of health services, especially those experiencing increased difficulties in healthcare access, as some migrant groups. This study aimed to investigate access and use of health services during the COVID-19 pandemic among migrants in Portugal. A mixed-methods approach was used. A community-based cross-sectional survey was conducted involving migrant communities residing in the Lisbon Metropolitan Area. Analyses of a subsample of participants (n = 929) examined factors associated with perceived worsening of access to health services during the pandemic. Semi-structured interviews with 14 migrants were conducted and thematically analyzed to further understand experiences and difficulties in health services’ use. Around 44% of surveyed participants reported worsening of access to health services since the pandemic, more frequently women, those with lower income, and those who perceived being at moderate or high risk for COVID-19 infection. Digital change in services and lack of formal and informal support during lockdowns were highlighted by interviewers as main barriers in access to healthcare for migrants. The pandemic renewed concerns about inequalities in healthcare access among migrants. It is key that in following years health systems are able to address the potential accumulated burden of disease.publishersversionpublishe

Factors associated with involuntary psychiatric hospitalization in Portugal

Funding This study integrated the research project “Mental Health, Impact Assessment of Local and Economic Constraints—SMAILE”, funded by the Foundation for Science and Technology (PTDC/ATP-GEO/4101/2012). The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020).Background: Identifying which factors contribute to involuntary psychiatric hospitalization may support initiatives to reduce its frequency. This study examines the sociodemographic, clinical, and contextual factors associated with involuntary hospitalization of patients from five Portuguese psychiatric departments in 2002, 2007 and 2012. Methods: Data from all admissions were extracted from clinical files. A Poisson generalized linear model estimated the association between the number of involuntary hospitalizations per patient in one year and sociodemographic, clinical, and contextual factors. Results: An increment of involuntary hospitalizations was associated with male gender [exp(β ^) = 1.31; 95%CI 1.06–1.62, p < 0.05], having secondary and higher education [exp(β ^) = 1.45; 95%CI 1.05–2.01, p < 0.05, and exp(β ^) = 1.89; 95%CI 1.38–2.60, p < 0.001, respectively], a psychiatric diagnosis of psychosis [exp(β ^) = 2.02; 95%CI 1.59–2.59, p < 0.001], and being admitted in 2007 and in 2012 [exp(β ^) = 1.61; 95%CI 1.21–2.16, p < 0.01, and exp(β ^) = 1.73; 95%CI 1.31–2.32, p < 0.001, respectively]. A decrease in involuntary hospitalizations was associated with being married/cohabitating [exp(β ^) = 0.74; 95%CI 0.56–0.99, p < 0.05], having experienced a suicide attempt [exp(β ^) = 0.26; 95%CI 0.15–0.42, p < 0.001], and belonging to the catchment area of three of the psychiatric services evaluated [exp(β ^) = 0.65; 95%CI 0.49–0.86, p < 0.01, exp(β ^) = 0.67; 95%CI 0.49–0.90, p < 0.01, and exp(β ^) = 0.67; 95%CI 0.46–0.96, p < 0.05 for Hospital de Magalhães Lemos, Centro Hospitalar Psiquiátrico de Lisboa and Unidade Local de Saúde do Baixo Alentejo, respectively]. Conclusions: The findings suggest that involuntary psychiatric hospitalizations in Portugal are associated with several sociodemographic, clinical, and contextual factors. This information may help identify high-risk patients and inform the development of better-targeted preventive interventions to reduce these hospitalizations.publishersversionpublishe

Candida tropicalis biofilm is highly influenced by the environmental human pH

In the last decades, the increase of candidiasis has been accompanied by an intensification of infections caused by Candida tropicalis.Indeed, C. tropicalis has been described as able to colonize and infect several anatomically distinct sites, including the skin, gastrointestinal, genitourinary and respiratory tracts. Adaptation to diverse pH that exists in each human niche has been shown to be critical for virulence in many commensal pathogens, but there are no reports concerning C. tropicalis. Biofilm formation ability is one of the most important virulence factors that have important clinical repercussions due to its increased resistance to antifungal therapy. Thus, the aim of the current study was to characterize the influence of pH on C. tropicalis biofilm formation, structure and composition. The effect of pH (3, 4, 7 and 8) on C. tropicalis biofilms was evaluated by enumeration of culturable cells, total biomass quantification and matrix composition. Biofilm structure and the morphology of its cells were analysed through scanning electron microscopic and confocal laser microscopy. The resultsrevealed an intensification of C. tropicalis capacity to form biofilm at neutral and alkaline conditions, with an increased on number of culturable cells and total biomass and in its structural complexity, comparatively to acid conditions. For the first time, we have demonstrated that C. tropicalis biofilm formation is highly influenced by the environmental human pH, which has an important clinical impact, which may partly explain the increase incidence of candidiasis

How did the use of psychotropic drugs change during the Great Recession in Portugal? A follow-up to the National Mental Health Survey

The Portuguese Mental Health Study was funded by the Champalimaud Foundation, the Gulbenkian Foundation, the Foundation for Science and Technology (FCT), and the Ministry of Health. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Nova Medical School, Nova University of Lisbon, with collaboration of the CESOP– Silva et al. BMC Psychiatry (2020) 20:215 Page 7 of 9 Portuguese Catholic University, and in conjunction with the World Health Organization WMH Survey Initiative. The World Health Organization WMH Survey Initiative is supported by the National Institute of Mental Health (NIMH; R01MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the U.S. Public Health Service (R13-MH066849, R01-MH069864 and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, GlaxoSmithKline and Bristol-Myers Squibb. A complete list of funding support and publications can be found at: http://www.hcp.med.harvard.edu/wmh. The National Mental Health Survey Follow-Up was funded by the Public Health Initiatives Programme (PT06), financed by EEA Grants Financial Mechanism 2009–2014. For further information, please visit http//www.eeagrants.gov.pt/. The funding bodies of both surveys were not involved in any aspect of the design of the study and collection, analysis, or interpretation of data and in writing the manuscript.BACKGROUND: Research suggests that economic recessions might be associated with a higher use of psychotropic drugs, but literature is scarce and contradictory in identifying the most vulnerable groups. This study aims to assess possible changes in the use of psychotropic drugs due to the economic recession in Portugal, by comparing self-reported consumption in 2008/09 and 2015/16. METHODS: Data from the World Mental Health Survey Initiative Portugal (2008/09) and the National Mental Health Survey Follow-Up (2015/16) were used (n = 911). McNemar's tests were performed to estimate changes in consumption of any psychotropic drug and of antidepressants, anxiolytics, and hypnotics/sedatives. Multiple Generalised Estimating Equations models with interaction effects were used to estimate the population odds of consuming psychotropic drugs according to year, gender and age. RESULTS: An increase of 6.74% was estimated in the consumption of psychotropic drugs from 2008/09 to 2015/16. Population odds of consuming any psychotropic drugs in 2015/16 were estimated to be 1.5 times higher than in 2008/09 (OR = 1.50;95%CI:1.13-2.01), particularly for hypnotics/sedatives (OR = 1.60;95%CI:1.14-2.25). Women and older individuals presented higher odds of consuming any psychotropic drugs (OR = 2.79;95%CI:2.03-3.84, and OR = 1.80;95%CI:1.28-2.54), after adjusting for year of assessment and education. However, when evaluating the interaction effect of the year with gender and age, men and younger individuals reported higher odds of consuming any psychotropic drugs in 2015/16, when compared to 2008/09 (OR = 1.85;95%CI:1.08-3.17, and OR = 1.95;95%CI:1.32-2.90, respectively). CONCLUSIONS: The findings indicate that the period of economic recession was associated with an increased risk of psychotropic drugs use in Portugal. Consumption of psychotropic drugs remained higher among women and older individuals, but the results suggest that the economic crisis had a disproportionate impact on men and younger individuals. This identification of the most vulnerable population groups is useful to design effective and targeted public health interventions aimed at alleviating the effects of economic recessions.publishersversionpublishe