Orogenital and anal infection by Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and other sexually transmitted infections in men who have sex with men in Lisbon.

BACKGROUND: Men who have sex with men (MSM) are at risk for sexually transmitted infections (STIs), but more data on extragenital carriage are needed. AIM: We assessed the genital and extragenital prevalence of bacterial and other STIs in MSM in a Lisbon sexual health clinic. METHODS: We screened oral, anal, and urine samples of MSM visiting the GAT-CheckpointLX clinic June 2017-December 2021 for Chlamydia trachomatis (including lymphogranuloma venereum, LGV), Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, Mycoplasma hominis, Ureaplasma urealyticum, and U. parvum. Ano-oro-genital lesions were tested for LGV, Treponema pallidum, and Herpes Simplex Virus. Blood was tested for HIV and T. pallidum antibodies. RESULTS: N. gonorrhoeae was found in 16.6% of the MSM followed by C. trachomatis (13.2%), M. genitalium (10.3%) and T. vaginalis (0.2%). The most frequent occurrence was anorectal (C. trachomatis, M. genitalium) and oral (N. gonorrhoeae). We found high carriage of U. urealyticum (36.1%) and M. hominis (22.1%). LGV was detected in 21.8% of chlamydia-positive anorectal swabs. Syphilis was detected in 22.6% of tested MSM, while 13.8% had HIV. Gonorrhoea and chlamydia were significantly more prevalent in MSM with concomitant HIV or syphilis. CONCLUSION: The substantial extragenital prevalence of bacterial STIs in MSM, and HIV and syphilis coinfections, suggest screening has value in identifying hidden carriage and in contributing for providing better care.

Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.

Group recommender systems for tourism: how does personality predict preferences for attractions, travel motivations, preferences and concerns?

To travel in leisure is an emotional experience, and therefore, the more the information about the tourist is known, the more the personalized recommendations of places and attractions can be made. But if to provide recommendations to a tourist is complex, to provide them to a group is even more. The emergence of personality computing and personality-aware recommender systems (RS) brought a new solution for the cold-start problem inherent to the conventional RS and can be the leverage needed to solve conflicting preferences in heterogenous groups and to make more precise and personalized recommendations to tourists, as it has been evidenced that personality is strongly related to preferences in many domains, including tourism. Although many studies on psychology of tourism can be found, not many predict the tourists' preferences based on the Big Five personality dimensions. This work aims to find how personality relates to the choice of a wide range of tourist attractions, traveling motivations, and travel-related preferences and concerns, hoping to provide a solid base for researchers in the tourism RS area to automatically model tourists in the system without the need for tedious configurations, and solve the cold-start problem and conflicting preferences. By performing Exploratory and Confirmatory Factor Analysis on the data gathered from an online questionnaire, sent to Portuguese individuals from different areas of formation and age groups (n = 1035), we show all five personality dimensions can help predict the choice of tourist attractions and travel-related preferences and concerns, and that only neuroticism and openness predict traveling motivations.

Deaths by COVID-19 in a hospital from a city from Legal Amazon region: what lessons could be learned? / Mortes por COVID-19 em um hospital de uma cidade da região da Amazônia Legal: que lições podem ser aprendidas?

Objective: Describe the epidemiology of COVID-19 deaths within a hospital in the Amazon region in a period of 64 days, which corresponds to the growth curve of the COVID-19 first-wave pandemic in 2020. Methods: The data were obtained from medical records of 152 deaths registered for adults and elderly hospitalized. The data were also compared with the number of deaths in previous years during the same period studied to assess the impact of the pandemic on this hospital. The study also assesses the impact of intra-hospital transfers, accounting for the number of times patients who died performed transfers between sectors of the hospital. Results: During the period analyzed, there was an increase in deaths compared to the previous years. The majority of dead patients were male, aged between 34 and 96 years. The deaths were associated comorbidities such as arterial hypertension, diabetes mellitus, and kidney disease. The SARS-CoV-2 infection was confirmed in 91 cases. Among them, 15 individuals were admitted without conditions related to SARS-CoV-2 infection; they had a three-fold higher number of hospital transfers than those admitted with SARS-CoV-2 infection symptoms. Sixteen patients with SARS-CoV-2 infection developed respiratory symptoms just after hospitalization. The diagnostic exam for SARS-CoV-2 infection was performed on average 4 (± 6) days after the onset of symptoms and 6 (± 6) days after admission, and the average time from the onset of respiratory symptoms to death was 4 (± 6) days. Conclusions: These data suggest the high presence of hospital infection by SARS-CoV-2 in the Brazilian Amazon region, which may be related to the number of sectorial transfers, delay in confirming the diagnosis, and lack of management. We report a serious public health problem, as it demonstrates the fragility of healthcare institutions in the hospital environmen (AU).

Objetivo: Descrever a epidemiologia de mortes por COVID-19 em um hospital na região da Amazônia em um período de 64 dias, que corresponde à curva de crescimento da primeira onda da pandemia de COVID-19 em 2020. Métodos: Os dados foram obtidos de 152 óbitos registrados em prontuários de adultos e idosos hospitalizados. Os dados foram também comparados com o número de óbitos em anos anteriores, no mesmo período estudado, de forma a avaliar o impacto da pandemia neste hospital. O estudo também avalia o impacto das transferências intra-hospitalares, contabilizando o número de vezes que os pacientes que faleceram realizaram transferências entre setores do hospital. Resultados: No período analisado, houve aumento de óbitos em relação aos anos anteriores. A maioria dos pacientes mortos era do sexo masculino, com idade entre 34 e 96 anos. Os óbitos foram associados a comorbidades como hipertensão arterial, diabetes mellitus e doença renal. A infecção por SARS-CoV-2 foi confirmada em 91 casos. Entre eles, 15 indivíduos foram internados sem condições relacionadas à infecção por SARS-CoV-2; eles tiveram um número três vezes maior de transferências hospitalares do que aqueles admitidos com sintomas de infecção por SARS-CoV-2. Dezesseis pacientes com infecção por SARS-CoV-2 desenvolveram sintomas respiratórios logo após a hospitalização. O exame diagnóstico para infecção por SARS-CoV-2 foi realizado em média 4 (± 6) dias após o início dos sintomas e 6 (± 6) dias após a admissão, e o tempo médio do início dos sintomas respiratórios até o óbito foi de 4 ( ± 6) dias. Conclusões: Esses dados sugerem alta presença de infecção hospitalar por SARS-CoV-2 na região amazônica brasileira, o que pode estar relacionado ao número de transferências setoriais, demora na confirmação do diagnóstico e falta de manejo. Relatamos um grave problema de saúde pública, pois demonstra a fragilidade das instituições de saúde no ambiente hospitalar (AU).

Cellular environment of TTR deposits in an animal model of ATTR-Cardiomyopathy.

Introduction: Cardiac amyloidoses are the most fatal manifestation of systemic amyloidoses. It is believed the number of cases to be greatly underestimated mostly due to misdiagnosis. Particularly, the involvement of TTR V30M in the heart of ATTRV30M amyloidosis has not been completely understood specifically in terms of implicated cellular pathways, heart function and cardiac physiology. In the present work we proposed to characterize TTR V30M cardiac involvement particularly at the tissue cellular level in a mouse model. Methods: HSF ± hTTR V30M mice, a model that expresses human TTRV30M in a Ttr null background, widely used for the characterization and modulation of neurological features of ATTRV30M amyloidosis was used. SDS-PAGE of cardiac homogenates followed by Western blot was performed. Immunohistochemistry and double immunofluorescence analyses were carried out to determine TTR deposition pattern and sub-localization. Results: Western blots were able to detect TTR in its monomeric state at ∼14 kDa. Immunofluorescent images showed TTR was found mostly in the intercellular spaces. Blood contamination was excluded by CD31 staining. Tissues were Congo Red negative. Upon TTR and macrophages (CD68) staining in the cardiac tissue a clear tendency of macrophage convergence to the tissue regions where TTR was more abundant was observed. Moreover, in some instances it was possible to detect co-localization of both fluorophores. Cardiac fibroblasts were stained with PDGFr-alpha, and here the co-localization was not so evident although there was some degree of co-occurrence. The hearts of transgenic mice revealed higher content of Galectin-3. Conclusion: This animal model and associated features observed as result of cardiac TTR deposition provide a promising and invaluable research tool for a better understanding of the implicated pathways that lead to the lethality associated to TTR cardiac amyloidosis. New therapeutic strategies can be tested and ultimately this will lead to improved treatment alternatives capable of increasing patient's quality of life and life expectancy and, hopefully to eradicate a condition that is silently spreading worldwide.

TLR2 and 4 signaling pathways are altered in macrophages from V30M TTR mice with down-regulated expression of chemokines.

Hereditary amyloid transthyretin (ATTRv) amyloidosis is a fatal neurodegenerative disorder, first identified in Portugal. The most common transthyretin (TTR) mutation in ATTRv results from an exchange of a methionine for a valine at position 30 (V30M). ATTRv is characterized by the extracellular deposition of aggregates and fibrils of mutant forms of TTR, particularly in the nerves and ganglia of the peripheral nervous system (PNS). This phenotype is often accompanied by the lack of inflammatory infiltrates, despite the importance of macrophages in removal of TTR deposits in ATTRv patients. The mechanisms underlying this impairment of inflammatory responses in ATTRv patients are poorly understood. Here, we show a significant down-regulation in the expression of several chemokines by bone marrow-derived macrophages (BMDM) generated from V30M TTR mice upon stimulation with toll-like receptor 4 (TLR4) and TLR2 agonists. The phosphorylation of the MAP kinase p38, important for TLR4 and TLR2 signaling pathways, was also down-regulated in V30M macrophages, as compared with wild-type (WT) ones. The present study contributes with new insights to unravel the molecular mechanisms underlying the lack of inflammatory immune responses observed in ATTRv patients and may help in the development of new immune therapeutic strategies for the disease.

Genetic and functional analyses implicate microRNA 499A in bipolar disorder development.

Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (pnom = 0.331) and rs140486571 in MIR499A (pnom = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.

Predictors of physical activity promotion in clinical practice: a cross-sectional study among medical doctors.

BACKGROUND: Physical activity is a major determinant of physical and mental health. International recommendations identify health professionals as pivotal agents to tackle physical inactivity. This study sought to characterize medical doctors' clinical practices concerning the promotion of patients' physical activity, while also exploring potential predictors of the frequency and content of these practices, including doctors' physical activity level and sedentary behaviours. METHODS: A cross-sectional study assessed physical activity promotion in clinical practice with a self-report questionnaire delivered through the national medical prescription software (naturalistic survey). Physical activity and sedentary behaviours were estimated using the International Physical Activity Questionnaire (short form). Indicators of medical doctors' attitudes, knowledge, confidence, barriers, and previous training concerning physical activity promotion targeting their patients were also assessed. Multiple regression analysis was performed to identify predictors of physical activity promotion frequency by medical doctors, including sociodemographic, attitudes and knowledge-related variables, and physical activity behaviours as independent variables. RESULTS: A total of 961 medical doctors working in the Portuguese National Health System participated (59% women, mean age 44 ± 13 years) in the study. The majority of the participants (84.6%) reported to frequently promote patients' physical activity. Five predictors of physical activity promotion frequency emerged from the multiple regression analysis, explaining 17.4% of the dependent variable (p < 0.001): working in primary healthcare settings (p = 0.037), having a medical specialty (p = 0.030), attributing a high degree of relevance to patients' physical activity promotion in healthcare settings (p < 0.001), being approached by patients to address physical activity (p < 0.001), and having higher levels of physical activity (p = 0.001). CONCLUSIONS: The sample of medical doctors approached reported a high level of engagement with physical activity promotion. Physical activity promotion frequency seems to be influenced by the clinical practice setting, medical career position and specialty, attitudes towards physical activity, and perception of patients´ interest on the topic, as well as medical doctors' own physical activity levels.

Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2.

Bipolar disorder (BD) is a chronic mood disorder characterized by manic and depressive episodes. Dysregulation of neuroplasticity and calcium homeostasis are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that miR-499-5p regulates dendritogenesis and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients, as well as in the hippocampus of rats which underwent juvenile social isolation. In rat hippocampal neurons, miR-499-5p impairs dendritogenesis and reduces surface expression and activity of the L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory ß-subunit of Cav1.2, as a direct functional target of miR-499-5p in neurons. miR-499-5p overexpression in the hippocampus in vivo induces short-term memory impairments selectively in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. In humans, miR-499-5p expression is negatively associated with gray matter volumes of the left superior temporal gyrus, a region implicated in auditory and emotional processing. We propose that stress-induced miR-499-5p overexpression contributes to dendritic impairments, deregulated calcium homeostasis, and neurocognitive dysfunction in BD.

The role of common genetic variation in presumed monogenic epilepsies.

BACKGROUND: The developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies which co-present with developmental delay and intellectual disability (ID). DEEs usually occur in people without a family history of epilepsy and have emerged as primarily monogenic, with damaging rare mutations found in 50% of patients. Little is known about the genetic architecture of patients with DEEs in whom no pathogenic variant is identified. Polygenic risk scoring (PRS) is a method that measures a person's common genetic burden for a trait or condition. Here, we used PRS to test whether genetic burden for epilepsy is relevant in individuals with DEEs, and other forms of epilepsy with ID. METHODS: Genetic data on 2,759 cases with DEEs, or epilepsy with ID presumed to have a monogenic basis, and 447,760 population-matched controls were analysed. We compared PRS for 'all epilepsy', 'focal epilepsy', and 'genetic generalised epilepsy' (GGE) between cases and controls. We performed pairwise comparisons between cases stratified for identifiable rare deleterious genetic variants and controls. FINDINGS: Cases of presumed monogenic severe epilepsy had an increased PRS for 'all epilepsy' (p<0.0001), 'focal epilepsy' (p<0.0001), and 'GGE' (p=0.0002) relative to controls, which explain between 0.08% and 3.3% of phenotypic variance. PRS was increased in cases both with and without an identified deleterious variant of major effect, and there was no significant difference in PRS between the two groups. INTERPRETATION: We provide evidence that common genetic variation contributes to the aetiology of DEEs and other forms of epilepsy with ID, even when there is a known pathogenic variant of major effect. These results provide insight into the genetic underpinnings of the severe epilepsies and warrant a shift in our understanding of the aetiology of the DEEs as complex, rather than monogenic, disorders. FUNDING: Science foundation Ireland, Human Genome Research Institute; National Heart, Lung, and Blood Institute; German Research Foundation.

SARS-CoV-2 introductions and early dynamics of the epidemic in Portugal.

Background: Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods: By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARS-CoV-2 introductions and early dissemination in Portugal. Results: We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions: Here we conclude that the earlier implementation of measures could have minimized the number of introductions and subsequent virus expansion in Portugal. This study lays the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlights the need for systematic and geographically-representative genomic surveillance.

Necrotizing fasciitis of the vulva due to carbapenem-resistant Enterobacteriaceae as a complication of acute myeloid leukemia treatment: a case report.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae strains have been reported in healthcare facilities with a rising incidence and are a major concern owing to infections that are often severe and can be potentially fatal, with limited therapeutic options. Klebsiella pneumonia represents the most frequently isolated microorganism. CASE PRESENTATION: We report the case of a Caucasian 52-year old Caucasian woman with acute myeloid leukemia was admitted to the inpatient hematology unit at a university referral hospital in Portugal. This hospital has endemic colonization of Carbapenem-resistant Enterobacteriaceae and contention measures are being implemented to reduce spreading of these multidrug resistant bacteria. After receiving first line chemotherapy according to the intermediate-dose cytarabine regimen, in context of deep medullary aplasia, the patient developed a localized infection of the vulva, which progressed to a necrotizing fasciitis. This is a rare, life-threatening, and fulminant infection. Carbapenem-resistant Klebsiella was isolated in both vulvar exudate and blood cultures. The patient underwent multiple schemes of antimicrobials, but progressed with multiorgan compromise and was admitted to the intensive care unit for a short period for stabilization. Surgical debridement was performed twice with clinical improvement and, after 6 weeks, a skin graft was executed with good response. Reevaluation of the hematologic disease showed a complete response to first cycle of induction therapy. Despite success in resolving this complex infection, decisions regarding antibiotic treatment represented a tremendous challenge for the whole team. The importance of multidisciplinary collaboration was key for the patient's recovery and survival, and therefore, needs to be acknowledged. CONCLUSIONS: This clinical case raises awareness on a clinical entity that can be life threatening and, therefore, requires a high level of suspicion to assure an early integrated approach to avoid complications. Endemic spreading of carbapenem-resistant Enterobacteriaceae is becoming a reality, and health policies need to be urgently undertaken at the national level to decrease morbidity and mortality because of health facilities-related infections.

MiRNA126 - RGS16 - CXCL12 Cascade as a Potential Mechanism of Acute Exercise-Induced Precursor Cell Mobilization.

Acute exercise enhances circulating stem and precursor cells (CPCs) in the peripheral blood. The responsible mechanisms and molecular pathways, however, have not been fully identified. The aim of the present study was to investigate a pathway related to elevated levels of apoptotic peripheral blood mononuclear cells (MNCs) and their secretome. An increased uptake of miRNA126 in MNCs was suggested to lead to reduced levels of RGS16 mRNA and, in turn, an enhanced translation and secretion of CXCL12. Eighteen healthy, young men underwent two identical incremental cycling exercises of which the first served as control while the second was preceded by a 7-day-long antioxidative supplementation. Blood samples were collected at baseline (-10min) and several time points after exercise (0, 30, 90, 180, and 270min). Relative concentrations of miRNA126 in MNCs and CXCL12 levels in plasma were determined at all time points while RGS16 mRNA was assessed in MNCs at baseline and 30min after exercise. CXCL12 increased after exercise and strongly correlated with CPC numbers. MiRNA126 increased 30min and, to a lesser extent, also 180 and 270min after exercise but only with supplementation. RGS16 mRNA decreased 30min after exercise independent of the intervention. The amount of RGS16 mRNA inversely correlated with levels of miRNA126, but not with plasma CXCL12. In conclusion, even though plasma CXCL12 correlated with CPC numbers, the increase in CXCL12 cannot be explained by the increased concentration of miRNA126 and lower RGS16 mRNA in MNCs that would have allowed for an enhanced translation of CXCL12. Clinical Trial Registration: ClinicalTrials.gov, NCT03747913. Registered 20 November 2018, https://clinicaltrials.gov/ct2/show/NCT03747913.

PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice.

The importance of closely observing patients receiving antibiotic therapy, performing therapeutic drug monitoring (TDM), and regularly adjusting dosing regimens has been extensively demonstrated. Additionally, antibiotic resistance is a contemporary concerningly dangerous issue. Optimizing the use of antibiotics is crucial to ensure treatment efficacy and prevent toxicity caused by overdosing, as well as to combat the prevalence and wide spread of resistant strains. Some antibiotics have been selected and reserved for the treatment of severe infections, including amikacin, gentamicin, tobramycin, and vancomycin. Critically ill patients often require long treatments, hospitalization, and require particular attention regarding TDM and dosing adjustments. As these antibiotics are eliminated by the kidneys, critical deterioration of renal function and toxic effects must be prevented. In this work, clinical data from a Portuguese cohort of 82 inpatients was analyzed and physiologically based pharmacokinetic (PBPK) modeling and simulation was used to study the influence of different therapeutic regimens and parameters as biological sex, body weight, and renal function on the biodistribution and pharmacokinetic (PK) profile of these four antibiotics. Renal function demonstrated the greatest impact on plasma concentration of these antibiotics, and vancomycin had the most considerable accumulation in plasma over time, particularly in patients with impaired renal function. Thus, through a PBPK study, it is possible to understand which pharmacokinetic parameters will have the greatest variation in a given population receiving antibiotic administrations in hospital context.

Discriminating Between Premigration and Postmigration HIV Acquisition Using Surveillance Data.

BACKGROUND: Migrant populations are overrepresented among persons diagnosed with HIV in the European Union and the European Economic Area. Understanding the timing of HIV acquisition (premigration or postmigration) is crucial for developing public health interventions and for producing reliable estimates of HIV incidence and the number of people living with undiagnosed HIV infection. We summarize a recently proposed method for determining the timing of HIV acquisition and apply it to both real and simulated data. METHODS: The considered method combines estimates from a mixed model, applied to data from a large seroconverters' cohort, with biomarker measurements and individual characteristics to derive probabilities of premigration HIV acquisition within a Bayesian framework. The method is applied to a subset of data from the European Surveillance System (TESSy) and simulated data. FINDINGS: Simulation study results showed good performance with the probabilities of correctly classifying a premigration case or a postmigration case being 87.4% and 80.4%, respectively. Applying the method to TESSy data, we estimated the proportions of migrants who acquired HIV in the destination country were 31.9%, 37.1%, 45.3%, and 45.2% for those originating from Africa, Europe, Asia, and other regions, respectively. CONCLUSIONS: Although the considered method was initially developed for cases with multiple biomarkers' measurements, its performance, when applied to data where only one CD4 count per individual is available, remains satisfactory. Application of the method to TESSy data, estimated that a substantial proportion of HIV acquisition among migrants occurs in destination countries, having important implications for public health policy and programs.

MicroRNA-dependent control of neuroplasticity in affective disorders.

Affective disorders are a group of neuropsychiatric disorders characterized by severe mood dysregulations accompanied by sleep, eating, cognitive, and attention disturbances, as well as recurring thoughts of suicide. Clinical studies consistently show that affective disorders are associated with reduced size of brain regions critical for mood and cognition, neuronal atrophy, and synaptic loss in these regions. However, the molecular mechanisms that mediate these changes and thereby increase the susceptibility to develop affective disorders remain poorly understood. MicroRNAs (miRNAs or miRs) are small regulatory RNAs that repress gene expression by binding to the 3'UTR of mRNAs. They have the ability to bind to hundreds of target mRNAs and to regulate entire gene networks and cellular pathways implicated in brain function and plasticity, many of them conserved in humans and other animals. In rodents, miRNAs regulate synaptic plasticity by controlling the morphology of dendrites and spines and the expression of neurotransmitter receptors. Furthermore, dysregulated miRNA expression is frequently observed in patients suffering from affective disorders. Together, multiple lines of evidence suggest a link between miRNA dysfunction and affective disorder pathology, providing a rationale to consider miRNAs as therapeutic tools or molecular biomarkers. This review aims to highlight the most recent and functionally relevant studies that contributed to a better understanding of miRNA function in the development and pathogenesis of affective disorders. We focused on in vivo functional studies, which demonstrate that miRNAs control higher brain functions, including mood and cognition, in rodents, and that their dysregulation causes disease-related behaviors.

Empathy and Coping in Allied Health Sciences: Gender Patterns.

This study aimed to examine the patterns of associations between empathy and coping among undergraduate men and women studying at Allied Health Sciences. This cross-sectional study is part of a larger longitudinal study conducted in an Allied Health Sciences School. Participants were 183 undergraduate students from 12 training programs (e.g., Physiotherapy, Occupational Therapy, Speech Therapy). Their mean age was 20.79 years (SD = 2.64), and they were in their first, third, and fourth years of school. The instruments were the Brief-COPE and the Interpersonal Reactivity Index (IRI). Empathy correlated with coping strategies in both genders, though showing different patterns of association. First, distinct coping strategies were associated with the same empathy dimension (perspective taking) among women (positive reframing and self-blame) and among men (active coping). Second, the same three coping strategies appeared in both genders (seeking emotional or instrumental support and resorting to religion) but associated with different empathy dimensions (cognitive empathy among women and mostly emotional empathy among men). Third, among women (but not among men), two coping strategies (positive reframing and behavioral disengagement) were each simultaneously correlated with cognitive and emotional empathy in opposite directions. Fourth, emotional empathy correlated, only among women, with several coping strategies considered to be maladaptive (behavioral disengagement, denial and substance use). Among men, only one significant coping strategy was considered to be maladaptive (behavioral disengagement) and it was negatively correlated with cognitive empathy (perspective taking). Unlike in women, relationships between the empathic dimension of fantasy and coping strategies were non-significant among men. These distinct patterns of associations emerged despite significant differences in empathy by gender (fantasy, personal distress and empathic concern) and in coping strategies (instrumental support, emotional support, religion and venting). These results support the idea that the display of empathy might be associated with gender differences in the underlying empathy dimensions and in the coping strategies used to deal with stress in the undergraduate programs of Allied Health Sciences.

The quiet crossing of ocean tipping points.

Anthropogenic climate change profoundly alters the ocean's environmental conditions, which, in turn, impact marine ecosystems. Some of these changes are happening fast and may be difficult to reverse. The identification and monitoring of such changes, which also includes tipping points, is an ongoing and emerging research effort. Prevention of negative impacts requires mitigation efforts based on feasible research-based pathways. Climate-induced tipping points are traditionally associated with singular catastrophic events (relative to natural variations) of dramatic negative impact. High-probability high-impact ocean tipping points due to warming, ocean acidification, and deoxygenation may be more fragmented both regionally and in time but add up to global dimensions. These tipping points in combination with gradual changes need to be addressed as seriously as singular catastrophic events in order to prevent the cumulative and often compounding negative societal and Earth system impacts.

In Silico Pharmacokinetic Study of Vancomycin Using PBPK Modeling and Therapeutic Drug Monitoring.

BACKGROUND: Vancomycin has been in clinical use for nearly 50 years and remains the first-line treatment option for Gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA). There are multiple strategies to monitor therapy and adjust the dose of this antibiotic. AUC24/MIC ratio has been demonstrated to be the best parameter to predict the effectiveness and safety of vancomycin, and a target ratio of ≥400 is recommended. Still, trough and peak serum levels at steady-state conditions have been used in clinical settings as an accurate and practical method to monitor vancomycin. METHODS: In this work, we collected and analyzed clinical information of patients being treated in a hospital center in Porto (Portugal) and studied the pharmacokinetics of vancomycin in silico, developing several physiologically based pharmacokinetic (PBPK) models using simulation software GastroPlus™. Different dosages and treatment regimens were studied, and the influence of patients' age, weight and renal function was evaluated; a simulation population was also performed. RESULTS: A linear effect of dose and a significant influence of weight and renal function in plasmatic levels of vancomycin was observed. CONCLUSION: The results of this work corroborate the accumulation of vancomycin in plasma and identify some parameters that influence the pharmacokinetics of this antibiotic. The importance of therapeutic monitoring of vancomycin is highlighted, and the usefulness of in silico tools, namely PBPK modeling, is demonstrated.

Massive dissemination of a SARS-CoV-2 Spike Y839 variant in Portugal.

Genomic surveillance of SARS-CoV-2 was rapidly implemented in Portugal by the National Institute of Health in collaboration with a nationwide consortium of >50 hospitals/laboratories. Here, we track the geotemporal spread of a SARS-CoV-2 variant with a mutation (D839Y) in a potential host-interacting region involving the Spike fusion peptide, which is a target motif of anti-viral drugs that plays a key role in SARS-CoV-2 infectivity. The Spike Y839 variant was most likely imported from Italy in mid-late February and massively disseminated in Portugal during the early epidemic, becoming prevalent in the Northern and Central regions of Portugal where it represented 22% and 59% of the sampled genomes, respectively, by 30 April. Based on our high sequencing sampling during the early epidemics [15.5% (1275/8251) and 6.0% (1500/24987) of all confirmed cases until the end of March and April, respectively], we estimate that, between 14 March and 9 April (covering the epidemic exponential phase) the relative frequency of the Spike Y839 variant increased at a rate of 12.1% (6.1%-18.2%, CI 95%) every three days, being potentially associated with 24.8% (20.8-29.7%, CI 95%; 3177-4542 cases, CI 95%) of all COVID-19 cases in Portugal during this period. Our data supports population/epidemiological (founder) effects contributing to the Y839 variant superspread. The potential existence of selective advantage is also discussed, although experimental validation is required. Despite huge differences in genome sampling worldwide, SARS-CoV-2 Spike D839Y has been detected in 13 countries in four continents, supporting the need for close surveillance and functional assays of Spike variants.