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Abstract Background Occupational biomonitoring is essential for assessing health risks linked to workplace exposures. The use of ‘omics’ technologies, such as metabolomics and proteomics, has become crucial in detecting subtle biological alterations induced by occupational hazards, thereby opening novel avenues for biomarker discovery. Aims This systematic review aims to evaluate the application of metabolomics and proteomics in occupational health. Methods Following the PRISMA guidelines, we conducted a comprehensive search on PubMed, Scopus, and Web of Science for original human studies that use metabolomics or proteomics to assess occupational exposure biomarkers. The risk of bias was assessed by adapting the Cochrane Collaboration tool and the Newcastle-Ottawa Quality Assessment Scale. Results Of 2311 initially identified articles, 85 met the eligibility criteria. These studies were mainly conducted in China, Europe, and the United States of America, covering a wide range of occupational exposures. The findings revealed that metabolomics and proteomics approaches effectively identified biomarkers related to chemical, physical, biomechanical, and psychosocial hazards. Analytical methods varied, with mass spectrometry-based techniques emerging as the most prevalent. The risk of bias was generally low to moderate, with specific concerns about exposure measurement and confounding factors. Conclusions Integrating metabolomics and proteomics in occupational health biomonitoring significantly advances our understanding of exposure effects and facilitates the development of personalized preventive interventions. However, challenges remain regarding the complexity of data analysis, biomarker specificity, and the translation of findings into preventive measures. Future research should focus on longitudinal studies and biomarker validation across diverse populations to improve the reliability and applicability of occupational health interventions.

Drug abuse represents a significant public health problem with a growing tendency. As a way of circumventing the strict national and international control of psychoactive substances by regulatory agencies, there is a market release of new substances with psychoactive activity, called New Psychoactive Substances (NPSs). This group of substances encompasses a diverse range of synthetic compounds designed to mimic the effects of traditional illicit substances. As NPSs show stronger psychoactive effects than classical drugs, they pose unique challenges to public health and regulatory frameworks. Additionally, some substances are considered NPSs in some countries but not in others. Therefore, based on a given legal definition, manufacturers can create an NPS that does not fall under that definition and thus is not prohibited. This review critically explores the multifaceted dimensions of the criminal and legal contexts associated with NPSs. It examines the trends of abuse, the intricate network of criminal and legal aspects surrounding these substances, and the crucial warning signs that indicate their emergence, highlighting the health risks posed by these substances. In conclusion, this manuscript addresses the intricate interplay between the pharmacology, risks, and regulatory responses. These multifaceted challenges associated with NPSs will likely provide valuable insights for future research.

Ovarian cancer (OC) patients develop ascites, an accumulation of ascitic fluid in the peritoneal cavity anda sign of tumour dissemination within the peritoneal cavity. This body fluid is under-researched, mainly regarding the ascites formed during tumour progression that have no diagnostic value and, therefore, are discarded. We performed a discovery proteomics study to identify new biomarkers in the ascites supernatant of OC patients. In this preliminary study, we analyzed a small amount of OC ascites to highlight the importance of not discarding such biological material during treatment, which could be valuable for OC management. Our findings reveal that OC malignant ascitic fluid (MAF) displays a proliferative environment that promotes the growth of OC cells that shift the metabolic pathway using alternative sources of nutrients, such as the cholesterol pathway. Also, OC ascites drained from patients during treatment showed an immunosuppressive environment, with up-regulation of proteins from the signaling pathways of IL-4 and IL-13 and down-regulation from the MHC-II. This preliminary study pinpointed a new protein (Transmembrane Protein 132A) in the OC context that deserves to be better explored in a more extensive cohort of patients’ samples. The proteomic profile of MAF from OC patients provides a unique insight into the metabolic kinetics of cancer cells during disease progression, and this information can be used to develop more effective treatment strategies.

Antimicrobial resistance (AMR), frequently considered a major global public health threat, requires a comprehensive understanding of its emergence, mechanisms, advances, and implications. AMR’s epidemiological landscape is characterized by its widespread prevalence and constantly evolving patterns, with multidrug-resistant organisms (MDROs) creating new challenges every day. The most common mechanisms underlying AMR (i.e., genetic mutations, horizontal gene transfer, and selective pressure) contribute to the emergence and dissemination of new resistant strains. Therefore, mitigation strategies (e.g., antibiotic stewardship programs—ASPs—and infection prevention and control strategies—IPCs) emphasize the importance of responsible antimicrobial use and surveillance. A One Health approach (i.e., the interconnectedness of human, animal, and environmental health) highlights the necessity for interdisciplinary collaboration and holistic strategies in combating AMR. Advancements in novel therapeutics (e.g., alternative antimicrobial agents and vaccines) offer promising avenues in addressing AMR challenges. Policy interventions at the international and national levels also promote ASPs aiming to regulate antimicrobial use. Despite all of the observed progress, AMR remains a pressing concern, demanding sustained efforts to address emerging threats and promote antimicrobial sustainability. Future research must prioritize innovative approaches and address the complex socioecological dynamics underlying AMR. This manuscript is a comprehensive resource for researchers, policymakers, and healthcare professionals seeking to navigate the complex AMR landscape and develop effective strategies for its mitigation.

This technical note aims to characterize and contextualize the creation of a new collection of identified skeletons stored in the University Institute of Health Sciences—CESPU. This project presents unique and innovative pedagogical opportunities, with students actively involved in the cleaning and processing of the bones and antemortem/postmortem information gathering, as well as in anthropology research projects. This XXI Century Identified Skeletal Collection is composed of 98 complete adult skeletons of both sexes and is still expanding, being the 10th contemporary collection available in Portugal. The skeletons consist exclusively of Portuguese nationals who died between 1946 and 2007, and the 42% that have been processed so far are in good preservation. Comparative learning outcomes after implementing this active learning strategy are not yet available. Improvements are expected since more participation and enthusiasm in classes and research were perceived.

Tramadol and tapentadol are chemically related opioids prescribed for the analgesia of moderate to severe pain. Although safer than classical opioids, they are associated with neurotoxicity and behavioral dysfunction, which arise as a concern, considering their central action and growing misuse and abuse. The hippocampal formation is known to participate in memory and learning processes and has been documented to contribute to opioid dependence. Accordingly, the present study assessed molecular and cellular alterations in the hippocampal formation of Wistar rats intraperitoneally administered with 50 mg/kg tramadol or tapentadol for eight alternate days. Alterations were found in serum hydrogen peroxide, cysteine, homocysteine, and dopamine concentrations upon exposure to one or both opioids, as well as in hippocampal 8-hydroxydeoxyguanosine and gene expression levels of a panel of neurotoxicity, neuroinflammation, and neuromodulation biomarkers, assessed through quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of hippocampal formation sections showed increased glial fibrillary acidic protein (GFAP) and decreased cluster of differentiation 11b (CD11b) protein expression, suggesting opioid-induced astrogliosis and microgliosis. Collectively, the results emphasize the hippocampal neuromodulator effects of tramadol and tapentadol, with potential behavioral implications, underlining the need to prescribe and use both opioids cautiously.

No início do ano de 2024, fazemos o balanço do percurso científico da RevSALUS – Revista Científica Internacional da Rede Académica das Ciências da Saúde da Lusofonia, prestamos o nosso agradecimento a todos quantos tiveram um papel fundamental para mais um ano de sucesso da revista, e perspetivamos as metas que pretendemos alcançar. À semelhança do ano anterior, em 2023 a RevSALUS publicou três números regulares, além de dois números suplementares, traduzindo-se num total de 22 artigos e 236 resumos das diversas áreas das ciências da vida e da saúde. Ao longo do ano de 2023, a RevSALUS recebeu através da sua plataforma de gestão editorial um total de 40 artigos, dos quais 14 foram aceites para publicação. Com o crescente reconhecimento científico da RevSALUS no espaço internacional, em particular, da Lusofonia, continuamos o caminho para alcançar a indexação às mais prestigiadas bases das ciências da saúde e da vida. A trajetória até aqui tem sido marcada pelo compromisso inabalável com a excelência científica, e continuaremos a contemplar a promoção do conhecimento numa base de integridade científica.

On 19 March 2020, a “state of emergency” was declared in Portugal due to the manifestation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with an exponential rate of infection and high mortality and morbidity rates. Since then, the state of emergency was declared a further fifteen times until 30 April 2021, during which a total of 16,974 deaths associated with COVID-19 were acknowledged in the country. Over the aforementioned period, guidelines were followed regarding the handling of suspected cases in autopsy rooms, mortuaries, and cemeteries. However, no procedures have been established regarding the handling of human remains during and after cemeterial exhumations. Furthermore, little is known about the virus survival and its spatial distribution in postmortem human tissues. Given that the minimum Portuguese legal period of inhumation is ending and cemeteries have been facing limited burial space and soon will start exhuming buried individuals, the authors believe it is important to reflect on the matter.

Forensic sciences aggregate a series of scientific and technological domains that aid the judiciary and judicial system. Despite the highly specialized and qualified professionals taking a role in forensic practice, this paradigmatic integration of law, science, and technology often leads them to face significant ethical challenges. Indeed, forensic sciences hold a unique position due to the social and legal implications inherent to forensic expertise. The potential interference with personal rights and freedoms requires the professional practice of the forensic specialist to be guided by alignment with scientific-technical competence under the seal of the highest ethical principles. However, the absence of a specific statutory regulation blurs the performance of the forensic professional and may harm the professional credibility but also the scientific domain as a whole. The existence of ethical pillars is essential to support professional practice, following international recommendations in this regard. Herein, we propose a framework for a code of ethics and conduct that is based on the professional particularities characterizing the forensic practice but also considers the ethical issues that are mandatory to ensure high levels of reliability and credibility of forensic specialists.

Summary: Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38).

Ovarian cancer metastization is accompanied by the development of malignant ascites, which are associated with poor prognosis. The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.

Ao iniciar o percurso científico para o ano de 2023 da RevSALUS – Revista Científica Internacional da Rede Académica das Ciências da Saúde da Lusofonia, fazemos um balanço do passado, agradecemos a todos quantos contribuíram para mais um ano de sucesso da revista, e perspetivamos novas metas. Pela primeira vez desde a sua constituição em 2019, a RevSALUS publicou em 2022 três números regulares, além de dois números suplementares, o que se traduz num total de 35 artigos e mais de cinco centenas de resumos das diversas áreas das ciências da vida e da saúde. Durante o ano de 2022, a RevSALUS recebeu através da sua plataforma eletrónica de gestão do processo editorial Open Journal System um total de 40 artigos, dos quais 11 foram aceites para publicação. Ainda que o seu reconhecimento internacional e maturação tenham sido notáveis neste último ano, as dores do “crescimento” obrigam a reflexões e tomadas de decisão que permitam uma evolução equilibrada. Afirmando-se cada vez mais como revista científica internacional da e para a Lusofonia, pretendemos caminhar no sentido de alcançar a indexação às mais prestigiadas bases das ciências da saúde e da vida.

Clinical and forensic toxicology are critically involved in the acquisition of basic skills to correctly suspect intoxication, collect biological and non-biological materials for toxicological analysis, comprehend the complexities inherent to laboratory activity, and understand the fundamentals of toxicokinetics and toxicodynamics that underlie the interpretation of results. This works presents a pedagogical innovation proposal for the teaching of clinical and forensic toxicology based on a compilation of more than 3 000 cases where the image was fulcra for suspicion. The experience in this article follows the model practiced in bachelors, masters, and PhD degrees, as well as in other continuing training courses, where we are teaching toxicology for more than 15 years. All these levels of education are considered fundamental to the sound development of this science. This approach aims also to offer strength to the intervention of the true toxicologist in all the toxicological phases, besides the classic analytical chemistry. Indeed, it is impossible to provide effective clinical and forensic toxicological interpretations without a proper and broad education, and not thinking exclusively in terms of laboratory techniques. In the future, it will be interesting to evaluate knowledge retention and to propose a database of videos of signs related to intoxications.KEY POINTSA pedagogical innovation proposal for the teaching of forensic and clinical toxicology is presented.A universal and never-ending atlas of phtotographs related to signs of intoxications have been compile.Offering to our students an integrated teaching of clinical and forensic toxicology is crucial since both are grounded in analogous toxicological principles and are mutually dependent.

The relevance of postmortem microbiological examinations has been controversial for decades, but the boom in advanced sequencing techniques over the last decade is increasingly demonstrating their usefulness, namely for the estimation of the postmortem interval. This comprehensive review aims to present the current knowledge about the human postmortem microbiome (the necrobiome), highlighting the main factors influencing this complex process and discussing the principal applications in the field of forensic sciences. Several limitations still hindering the implementation of forensic microbiology, such as small-scale studies, the lack of a universal/harmonized workflow for DNA extraction and sequencing technology, variability in the human microbiome, and limited access to human cadavers, are discussed. Future research in the field should focus on identifying stable biomarkers within the dominant Bacillota and Pseudomonadota phyla, which are prevalent during postmortem periods and for which standardization, method consolidation, and establishment of a forensic microbial bank are crucial for consistency and comparability. Given the complexity of identifying unique postmortem microbial signatures for robust databases, a promising future approach may involve deepening our understanding of specific bacterial species/strains that can serve as reliable postmortem interval indicators during the process of body decomposition. Microorganisms might have the potential to complement routine forensic tests in judicial processes, requiring robust investigations and machine-learning models to bridge knowledge gaps and adhere to Locard’s principle of trace evidence.

The emergence of the Internet has transformed all areas of society. This includes the universe of scientific publications, with several publishers now exclusively focusing on the electronic format and open access model while expanding to a megajournal scope. In this context, the pandemic of predatory open access journals (POAJs) and meetings are of grave concern to the academic and research community. This new shift within academia produces a variety of new victims; namely, the authors themselves. In turn, scientific knowledge is often discredited, with the public placing less trust in science. Now more than ever, performing research with integrity and selecting a journal in which to publish requires close attention and expertise. The “predatory movement” has developed increasingly sophisticated techniques for misleading people into believing what seem to be credible professional layouts and legitimate invitations. Initiatives such as the Jeffrey Beall’s list, the Cabell’s Scholarly Analytics and Think.Check.Submit offer some guidance to uncover the “parasitic” intervention of predatory journals and meetings, but specific education in this field is sorely needed. This work aims to review the main characteristics of predatory journals and meetings and to analyze this topic in the context of forensic and legal medicine research.

This work presents an odd historical record obtained through more than 14 years of research regarding one of the first major European forensic cases. The presumed homicide of Mário Guilherme Augusto de Sampaio in 1890 was allegedly perpetrated by his uncle, the prestigious doctor Vicente Urbino de Freitas. This famous poisoning had international repercussions for decades, with the participation of several forensic experts that made the history of forensic sciences, namely forensic toxicology and pathology. This third work aims to collect, restore, and analyse all the forensic evidence, particularly from the autopsy, toxicological, and psychiatric forensic reports. Facts regarding the life of Vicente Urbino de Freitas during his exile in Brazil were also recovered, along with a vast and outstanding assortment of forensic medicine photographs from the 19th century.

Epigenetic mechanisms are potential mediators of the physiological response to abuse by altering the genetic predisposition of the cellular response to the environment, leading to changes in the regulation of multiple organ systems. This study was established to review the epigenetic mechanisms associated with childhood abuse as well as the long-term determinants that these epigenetic changes may have on future illness. We retrospectively analysed the effect of exposure to adverse childhood experiences (ACEs, specifically those relating to childhood maltreatment) between the ages of 0 and 16 years on the human epigenome, as well as possible clinical associations. After meeting inclusion and exclusion criteria, 36 articles were included in this systematic review. Eight of these studies did not find a relationship between childhood maltreatment and DNA methylation. Of the remaining 28 studies, nine were genome-wide association studies, whereas the rest were candidate gene studies, mainly studying effects on neuroendocrine, serotoninergic and immunoregulatory systems. Meta-analysis of correlation coefficients from candidate gene studies estimated an association of childhood adversity and DNA methylation variation at r = 0.291 (P

The crime possibly perpetrated by a doctor named Vicente Urbino de Freitas in 1890 is one of the most famous cases of poisoning, and it had echoes in the Portuguese and foreign press for several decades. This prestigious doctor was convicted of the fatal poisoning of his nephew. He also attempted the homicide of two nieces and his mother-in-law, who only escaped because they obstinately refused to comply with the “therapeutics” prescribed by the family doctor. The motive of the crime should have been Vicente Urbino de Freitas’ ambition to receive the family inheritance of his wife, the daughter of the well-known merchant José António Sampaio of Flores Street in Porto. Vicente Urbino de Freitas was convicted but doubt about his guilt persists for more than a century. This second work aimed to collect and analyse all the relevant and contradictory testimonial evidence of the prosecution and defence witnesses. This case represents an odd historical record obtained through more than 12 years of research on the first major significant Portuguese forensic case. Rare and unprecedented testimonial evidence and photographs were obtained from different countries and then repaired, since these also provide an important historical record of the medical photography.

Scientific integrity is a learned skill. When researchers and students learn integrity in laboratories or in the classroom, they are empowered to use similar principles in other aspects of their lives. This commentary reviews the concepts related to scientific integrity at a time when science faces important challenges related to the increase number of articles produced regarding research on coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ignited another parallel viral pandemic, with science ranging from robust studies to dishonest studies being conducted, posted, and shared at an unprecedented rate. A balance is needed between the benefits of the rapid access to new scientific data and the threat of causing panic or erroneous clinical decisions based on mistakes or misconduct. The truth is that the “scientific research has changed the world” but now, and more than ever, “it needs to change itself”. A pandemic with a “paperdemic” will be even more complicated to manage if it progresses in an uncontrolled manner and is not properly scrutinized.

É no início do percurso científico para 2022 da RevSALUS – Revista Científica Internacional da Rede Académica das Ciências da Saúde da Lusofonia, que olhamos o passado, agradecemos os contributos e perspetivamos o futuro. Durante o ano de 2021, a RevSALUS recebeu através da sua plataforma eletrónica de gestão do processo editorial Open Journal System um total de 68 artigos, dos quais 19 foram aceites para publicação, correspondendo a uma taxa de aceitação de aproximadamente 28%. É já uma grande prova de maturidade científica e da afirmação na Lusofonia. Queremos dar agora passos de gigantes na indexação às mais prestigiadas bases das ciências da saúde e da vida.

Tramadol and tapentadol, synthetic opioids commonly prescribed for moderate-to-severe pain, have a unique pharmacology that optimizes their analgesia and safety. However, they are not devoid of risks, presenting addictive, abuse, and dependence potential. While tramadol-reinforcing properties have been documented by various studies with human and animal models, including conditioned place preference (CPP) assays, no similar studies have been performed with tapentadol. In the present study, we performed CPP assays by intraperitoneally administering Wistar rats with a tramadol/tapentadol therapeutic dose. Animal permanence and the number of entries in the CPP compartments were recorded in the preconditioning phase and then 1 (T1), 7 (T7), and 14 (T14) days after conditioning. Both opioids induced a change in place preference (T1), suggesting that they have short-term reinforcing properties. However, only tramadol was associated with place preference retention (T7 and T14), with an increase in the number of entries in the opioid-paired compartment (T1 and T7), showing that it causes rewarding memory and incubation of craving. The results indicate that at therapeutic doses: (1) both drugs cause short-term rewarding effects and (2) as opposed to tramadol, tapentadol does not cause CPP retention, despite its higher central nervous system activity and stricter scheduling.

Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.

The “Crime of Flores Street” is one of the most famous cases of poisoning to divide public opinion in Portugal in the late 19th century, and it also demonstrated the weaknesses of the Portuguese medicolegal system and attested to the importance of toxicological analysis. Vicente Urbino de Freitas was a prominent doctor, graduating from the Faculty of Medicine of the University of Coimbra in 1875. He later became Professor of Physiology at the Porto Medical-Surgical School and author of a number of books on leprosy. In 1877, he married Maria das Dores Basto Sampaio Freitas, and this was followed by the death of a number of her close relatives in suspicious circumstances, notably her brother José António Sampaio Junior and nephew Mário Guilherme Augusto de Sampaio. This review aims to retell the story of Portugal’s first significant medicolegal case as well as the accompanying judicial drama that gave birth to Forensic Toxicology in Portugal and prompted the medicolegal organization that exists today. This research was carried out over a 10-year period and represents undeniable historical value given the rarity of the facts compiled. At the heart of this forensic case was the use of toxicological analyses in court for which the Chemist António Joaquim Ferreira da Silva played a key role. This toxicological report revealed high concentrations of morphine, delphinine and narceine in viscera and in Mario’s urine. The Mario’s cause of death was attributed to poisoning by opium alkaloids. Despite the strong judicial evidence, doubts still remains as to whether Vicente Urbino de Freitas was a “monster” or a victim of circumstances and a hapless martyr.

The use of in vitro human skin permeation tests is of value when addressing the quality and equivalence of topical drug products in Europe and the US. Human skin is the membrane of choice for these studies. The use of human skin as a membrane is hindered by limited access, high variability of results, and limited applicability for drugs with low skin permeability. Reconstructed human epidermis (RhE) models are validated as skin surrogates for safety tests and have been explored for percutaneous absorption testing. Clotrimazole poorly permeates human skin and is widely available for topical treatments. In this study, clotrimazole creams were used to test the ability of RhE to be used as biological membrane for bioequivalence testing, based on the Draft Guideline on Quality and Equivalence of Topical Products (CHMP/QWP/708282/2018) using a discriminative and modified in vitro permeation test (IVPT). To fulfill the validation of a discriminatory method, Canesten® 10 mg/g cream was compared with a test product with the same drug strength, along with two “negative controls” dosed at a 50% and 200% drug strength. Products were compared in finite dose conditions, regarding maximal flux (Jmax) and the total amount of drug permeated (Atotal). The results showed the discriminatory power of the method among the three drug strengths with no interference of the placebo formulation. The study design and validation complied with the requirements established in the guideline for a valid IVPT. This new test system allowed for the equivalence comparison between test and comparator product. Higher permeability of the RhE compared to human skin could be observed. This arose as a strength of the model for this modified IVPT bioequivalence testing, since comparing permeation profiles among products is envisaged instead of drawing absolute conclusions on skin permeation extent. These results may support the acceptance of RhE as biological membranes for modified IVPT in bioequivalence testing of topical products.

Durante o ano de 2020 a RevSALUS continuou a trilhar o seu caminho de afirmação como revista científica para a Lusofonia. A RevSALUS recebeu através da sua plataforma eletrónica de gestão do processo editorial Open Journal System um total de 33 artigos, dos quais 17 foram publicados nos Volume 2: Números 1 e 2, lançados em junho e dezembro de 2020, respetivamente. Viu também reconhecido o seu projeto científico através da sua aceitação pela Publons Reviewer Recognition e passou a integrar no seu processo de revisão editorial dos artigos o serviço de iThenticate: plagiarism detection. Este primeiro editorial de 2021 da RevSALUS e dedicado a autoria de artigos científicos e como a RevSALUS se revê neste domínio, nomeadamente quanto ao cumprimento dos critérios definidos pelo International Commitee of Medical Journals Editors (ICMJE).

A crescente competição e cultura de “publicar ou perecer” na academia, combinada com o peso cada vez maior dos referenciais bibliométricos está a conflituar com a objetividade e integridade na investigação científica. Este editorial é dedicado à importância crescente dada aos resultados científicos negativos e para os quais surge já na literatura revistas dedicadas e com a missão de os publicar. Estas revistas advogam, que mesmo sendo inconclusivos, os resultados não merecem ficar escondidos na “gaveta do laboratório”. Provavelmente a vantagem mais óbvia, será o impedir que vários outros grupos de investigação despendam tempo e recursos na mesma linha científica. Mas neste editorial, outras vantagens e limitações são discutidas e comparadas com os resultados positivos em ciência.

Introduction: Heart failure (HF) is a clinical syndrome caused by structural and functional cardiac abnormalities resulting in the impairment of cardiac function, entailing significant mortality. The prevalence of HF has reached epidemic proportions in the last few decades, mainly in the elderly, but recent evidence suggests that its epidemiology may be changing. Objective: Our objective was to estimate the prevalence of HF and its subtypes, and to characterize HF in a population of integrated care users. Material and Methods: A non-interventional cross-sectional study was performed in a healthcare center that provides primary, secondary and tertiary health cares. Echocardiographic parameters (left ventricle ejection fraction (LVEF) and evidence of structural heart disease) and elevated levels of natriuretic peptides were used to define two HF phenotypes: (i) HF with a reduced ejection fraction (HFrEF, LVEF ≤ 40% and either NT-proBNP ≥ 400 pg/mL (≥600 pg/mL if atrial fibrillation (AF)/flutter) or BNP ≥ 100 pg/mL (≥125 pg/mL if AF/flutter)) and (ii) HF with a non-reduced ejection fraction (HFnrEF), which encompasses both HFpEF (LVEF ≥ 50% and either NT-proBNP ≥ 200 pg/mL (≥600 pg/mL if AF/flutter) or BNP ≥ 100 pg/mL (≥125 pg/mL if AF/flutter) in the presence of at least one structural cardiac abnormality) and HF with a mildly reduced fraction (HFmrEF, LVEF within 40–50% and either NT-proBNP ≥ 200 pg/mL (≥600 pg/mL if AF/flutter) or BNP ≥ 100 pg/mL (≥125 pg/mL if AF/flutter) in the presence of at least one structural cardiac abnormality). The significance threshold was set at p ≤ 0.001. Results: We analyzed 126,636 patients with a mean age of 52.2 (SD = 18.3) years, with 57% (n = 72,290) being female. The prevalence of HF was 2.1% (n = 2700). The HF patients’ mean age was 74.0 (SD = 12.1) years, and 51.6% (n = 1394) were female. Regarding HF subtypes, HFpEF accounted for 65.4% (n = 1765); 16.1% (n = 434) had HFmrEF and 16.3% (n = 439) had HFrEF. The patients with HFrEF were younger (p < 0.001) and had a history of myocardial infarction more frequently (p < 0.001) compared to HFnrEF, with no other significant differences between the HF groups. The HFrEF patients were more frequently prescribed CV medications than HFnrEF patients. Type 2 Diabetes Mellitus (T2D) was present in 44.7% (n = 1207) of the HF patients. CKD was more frequently present in T2D vs. non-T2D HF patients at every stage (p < 0.001), as well as stroke, peripheral artery disease, and microvascular disease (p < 0.001). Conclusions: In this cohort, considering a contemporary definition, the prevalence of HF was 2.1%. HFrEF accounted for 16.3% of the cases, with a similar clinical–epidemiological profile having been previously reported in the literature. Our study revealed a high prevalence of patients with HFpEF (65.4%), raising awareness for the increasing prevalence of this entity in cardiology practice. These results may guide local and national health policies and strategies for HF diagnosis and management.

Editorial do Prof. Doutor Ricardo Jorge Dinis-Oliveira, Editor Chefe da RevSALUS.

Summary: Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α−/− macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells. : Mesquita et al. show that genetic deficiency of HIF-1α in the myeloid compartment promotes de novo lipogenesis through the BNIP3/mTOR/SREBP-1c axis. This is associated with higher susceptibility to Leishmania donovani infection, which is reduced upon pharmacological inhibition of fatty acid synthesis. Keywords: HIF-1α, visceral leishmaniasis, macrophages, lipogenesis, SREBP-1c, FASN, acetate, myeloid cells