On the safety and effectiveness of COVID-19 vaccines, certainties and uncertainties

Introduction: The COVID-19 vaccines in use (inactivaded virus, encapsulated m-RNA, non-replicating adenovirus-vectored DNA) were clinically tested in randomized placebocontrolled phase-3 studies. Objective: To address certainties and uncertainties about safety and effectiveness of COVID-19 vaccines that were approved for use in various countries. Method: The evidence provided by clinical studies on the efficacy and safety of COVID-19 vaccines was critically appraised. Results: COVID-19 vaccines proved to be efficacious and safe in clinical trials. Adverse events were mostly those of minor severity commonly noted with other vaccines such as injection site pain, mild flu-like symptoms, headache and asthenia. Although being very rare, anaphylaxis-like reactions were noted with mRNA vaccines. Uncertainties regarding vaccine effectiveness refer mainly to the (long-term) duration of immunity provided by vaccination, the degree of protection conferred to elderly people, and how effective vaccines are against emerging SARS-CoV-2 variants. There are few uncertainties about vaccine safety including the absence of clinical trial data in pregnant women (and the impact on the unborn child), children and adolescents. Conclusions:  Notwithstanding the knowledge gaps about effectiveness and safety of COVID-19 vaccines (to be further addressed by observational studies), there is overwhelming evidence that public health benefits of vaccination by far outweigh any foreseeable risk.TÍTULO PT: Sobre a segurança e efetividade das vacinas para COVID-19, certezas e incertezas Introdução: As vacinas contra COVID-19 (vírus inativado, m-RNA encapsulado, vetor adenovírus não replicante) foram testadas em ensaios clínicos randomizados (fase-3) controlados com placebo. Objetivo: Abordar as certezas e incertezas sobre segurança e efetividade das vacinas para COVID-19 já aprovadas para uso em vários países. Método: A evidência clínica de eficácia e segurança das vacinas contra COVID-19 foram examinadas criticamente. Resultados: As vacinas (COVID-19) mostraram ser eficazes e seguras nos ensaios clínicos. Os eventos adversos foram predominantemente os de menor  gravidade comumente observados com outras vacinas, tais como dor no  local da injeção, sintomas gripais leves, cefaleia e fraqueza. Embora sejam raras, reações do tipo anafilático foramregistradas com vacinas mRNA. As incertezas sobre efetividade referem-se à duração da imunidade conferida pela vacina, o grau de proteção de idosos, e a efetividade das vacinas contra as novas variantes do SARS-CoV-2. As incertezas sobre segurança são poucas e incluem a ausência de estudos clínicos em grávidas (e sobre o bebê no útero), em crianças e adolescentes. Conclusões: Não obstante as poucas lacunas acerca da efetividade e segurança das vacinas contra COVID-19 (a serem abordadas por estudos observacionais), os previsíveis benefícios da vacinação para a saúde pública excedem de longe quaisquer riscos antecipáveis

Drug repurposing clinical trials in the search for life-saving COVID-19 therapies; research targets and methodological and ethical issues

Introduction: So far, there is no vaccine, nor are there effective drugs to treat COVID-19, an emerging viral respiratory infection deadlier than influenza. Objective: To take a snapshot picture of planned and ongoing clinical research addressing drugs potentially useful for treating SAR-CoV-2 infections. Method: A search was conducted (20 April 2020) in an international registry of clinical studies (https://ClinicalTrials.gov, US NIH). After excluding observational studies and other interventions that fell outside the scope of this study, 294 research protocols (out of 516 retrieved protocols) were selected for analysis. Results: Of 294 included trials, 249 were Randomized Controlled Trials (RCT), 118 of which were double-, triple- or quadruple-blinded studies. The interventions (drug therapies) were compared with “standard-of-care” (SOC) or with the placebo plus SOC, or yet with presumed “active” comparators. RCT focused on the primary treatment of the disease (inhibitors of viral replication) or on the therapy for resolution of hyperinflammation in pneumonia/Acute Respiratory Distress Syndrome (ARDS) and thromboembolism associated with SARS-CoV-2. The trials found in the database involve existing antiviral compounds and drugs with multiple modes of antiviral action. Antiparasitic drugs, which inhibited viral replication in cell-culture assays, are being tested as well. Regarding the adjunctive immunomodulatory, anti-inflammatory and antithrombotic therapies, a number of drugs with distinct pharmacological targets are under investigation in trials enrolling patients with severe COVID-19. Conclusions: Although many clinical studies of drugs for COVID-19 are planned or in progress, only a minority of them are sufficiently large, randomized and placebo-controlled trials with masking and concealment of allocation. Owing to methodological limitations, only a few clinical trials found in the registry are likely to yield robust evidence of effectiveness and safety of drugs repurposable for COVID-19.TÍTULO PT: Ensaios clínicos para reposicionamento de medicamentos para COVID-19 na busca de terapias para salvar vidas; alvos de pesquisa, e questões metodológicas e éticas Introdução: Até agora, não há vacinas ou medicamentos eficazes para tratar COVID-19, uma infecção viral respiratória emergente mais letal do que a gripe. Objetivo: Desenhar um quadro das pesquisas planejadas e em curso sobre medicamentos potencialmente úteis para tratar infecções por SARS-CoV-2. Método: Um levantamento foi realizado (20 de abril de 2020) em um registro internacional de estudos clínicos (https://ClinicalTrials.gov, US NIH). Após excluir estudos observacionais e outras interveções fora do escopo deste estudo, 294 protocolos (de 516 identificados na busca) foram selecionados para análise. Resultados: De 294 ensaios incluídos, 249 eram Ensaios Controlados Randomizados (ECR), dos quais 118 eram estudos duplo-, triplo- ou quadruplo-cego. As intervenções (medicamentos testados) foram comparadas com o “tratamento padrão” (TP) ou com placebo mais TP, ou ainda com comparadores supostamente ativos. ECR abordaram o tratamento primário da doença (inibidores da replicação viral) ou a resolução da super-inflamação na pneumonia e Síndrome do Desconforto Respiratório Agudo (SDRA), e do tromboembolismo associados ao SARS-CoV-2. Os ensaios localizados no registro envolviam fármacos antivirais com múltiplos modos de ação e medicamentos anti-parasitários que inibem a replicação viral em cultura de células. Em relação às terapias imunomodulatória, antiinflamatória e antitrombótica adjuvantes, inúmeros medicamentos com alvos farmacológicos distintos também estão sendo investigados em ensaios envolvendo pacientes graves com COVID-19. Conclusões: Embora muitos ensaios clínicos de medicamentos para COVID-19 tenham sido planejados e estejam em andamento, apenas uma minoria deles são estudos suficientemente grandes, randomizados, controlados com placebo e com mascaramento, e ocultação da alocação. Em virtude das limitações metodológicas apontadas, provavelmente apenas uns poucos ensaios clínicos fornecerão evidências robustas da eficácia e segurança de medicamentos potencialmente redirecionáveis para COVID-19

Outcomes Following Total Hip Arthroplasty for Hip Dysplasia in Older Adults. Are They Comparable to Those with Osteoarthritis?

Background: Total hip arthroplasty (THA) for the treatment of hip dysplasia, which disproportionately impacts the younger population, has been shown to be an effective intervention to restore functionality and improve quality of life. However, it is unclear whether these outcomes can be just as beneficial in treating hip dysplasia when it presents in older patients. Therefore, we sought to investigate and compare the pre-and postoperative outcomes of THA for hip dysplasia in older adults to those with end-stage osteoarthritis (OA). Methods: A prospectively collected database from a single institution was queried from September 1st, 2016 to October 31st, 2021 to identify 323 unilateral THA patients age 50 years or older and separated into 2 groups given a primary diagnosis of hip dysplasia (n = 90 patients) or osteoarthritis (n = 233 patients). Preoperative and minimum 1-year postoperative outcomes were then compared using the Hip Outcome Score (HOS), Hip Disability and Osteoarthritis Outcome Score (HOOS), University of California-Los Angeles (UCLA) activity score, Pain Catastrophizing Score (PCS), and the Depression Anxiety Stress Scale (DASS). Results: The outcomes between the groups showed no significant differences in their pre-and postoperative HOOS (P = 0.22 and P = 0.63 respectively), DASS Anxiety (P = 0.81 and P = 0.29 respectively), and the DASS Stress Score (P = 0.17 and P = 0.28 respectively). Patients with hip dysplasia reported significantly better preoperative (10.1 vs 12.9, P P = 0.01) DASS Depression Scores but scored significantly lower in the pre-operative HOS (35.4 vs 42.2, P P = 0.02), but no significant difference was seen postoperatively (4.6 vs 5.0, P = 0.11). The PCS noted no significant differences preoperatively (23.2 vs 21.0, P = 0.12). However, the hip dysplasia group has significantly better postoperative scores (6.6 vs 10.0, P = 0.02). Conclusion: Our investigation demonstrates THA as an excellent surgical option for treating hip dysplasia when presenting in older adults and can yield comparable outcomes as those noted in THA performed for OA in older adults

Regularidades e dispersões no discurso de Oprah Winfrey

In this paper, we aim to analyze Oprah Winfrey’s discourse at the Golden Globe awards in 2018, in order to understand how the black woman’s place of speech is established from the subject positions constituted by regularities and dispersions in motion. Therefore, our basis is on the theoretical and methodological assumptions of Discourse Analysis allied to Michel Pêcheux’s constructs, with regard to the discursive functioning, and in the archeological studies of Michel Foucault, mobilizing some concepts such as power relations, interdiction, objectification, subjectivation. To this theoretical reference basis, we articulate the conditions of production of Oprah’s discourse, constantly crossed by power relations. We analyze, therefore, the elements that allow us to understand the displacement of black women, regarding marginalization, racial segregation, racism and acts of extreme violence, emphasizing sexual violence. We consider Oprah’s discourse, as a place where the discourse tends to remains by the regularities and rupture by the dispersions.Neste artigo, objetivamos analisar o discurso de Oprah Winfrey na premiação do Globo de Ouro, em 2018, a fim de compreender como se estabelece o lugar de fala da mulher negra a partir das posições-sujeito constituídas pelas regularidades e dispersões em movimento. Para tanto, nosso embasamento é nos pressupostos teórico-metodológicos da Análise de Discurso aliados aos construtos de Michel Pêcheux, no que tange ao funcionamento discursivo, e nos estudos arquegenealógicos de Michel Foucault, mobilizando alguns conceitos como relações de poder, interdição, objetivação, subjetivação. A essa base referencial teórica, articulamos as condições de produção do discurso de Oprah atravessado constantemente pelas relações de poder. Analisamos, portanto, os elementos que nos permitem compreender o deslocamento da mulher negra, no que tange à marginalização, à segregação racial, ao racismo e aos atos de extrema violência, dando ênfase à violência sexual. Consideramos o discurso de Oprah como um lugar do mesmo, pelas regularidades, e da ruptura, pelas dispersões

GAMIFICAÇÃO DE TESTES PSICOLÓGICOS PARA ALFABETIZAÇÃO E COMPETÊNCIAS ESPACIAIS DE CRIANÇAS PORTADORAS DE AUTISMO E SÍNDROME DE DOWN

Assistive technology aids in many different situations. Concerning cognitive disorders, the area of neuro-psychopedagogy lacks of products focused on helping professionals with the treatment. A product that focuses on educational aid is being presented in this article, using psychological tools in order to assist collecting new pieces of information concerning the patient, increasing reading, writing skills as well as self knowledge and promote a better use of the session’s time. The method used was Ergonomizer Intervention with observations of five children’s behavior, which were encompassed in distinctive disorders: Autism Spectrum and Down Syndrome. With this article, it’s expected to promote the use of collaborative design and encourage the search for new treatment solutions.As tecnologias assistivas auxiliam em diversos casos. Considerando as síndromes cognitivas, ainda há uma carência de produtos voltados para estas deficiências que ajudem os profissionais da área de neuropsicopedagogia. Será apresentado neste trabalho um produto voltado para auxílio educacional que utiliza ferramentas psicológicas, a fim de recolher novas informações do paciente, promover o aumento das capacidades de leitura, escrita e autoconhecimento das crianças e estimular o melhor rendimento do tempo de consulta. O método de desenvolvimento utilizado consistiu na Intervenção Ergonomizadora a partir do acompanhamento do tratamento de cinco crianças com síndromes distintas: Transtorno do Espectro Autista (TEA) e Síndrome de Down. Espera-se com este trabalho estimular o uso do design colaborativo e incentivar a busca e elaboração de novas formas de tratamento

The concentrations of heavy metals and the incidence of micronucleated erythrocytes and liver EROD activity in two edible fish from the Paraíba do Sul river basin in Brazil

The Paraíba do Sul river (PSR) basin crosses one of the most populated and industrialized regions of Brazil and receives effluent from the metallurgic, paper mill and agricultural industries. PSR water has multiple uses, including being a supply of potable water and riverine populations which consume some species of its fish. In the present study, we investigated the responses of two biomarkers of aquatic pollution, EROD activity in the liver and micronuclei frequency in peripheral blood, as well as the concentrations of seven heavy metals in the muscle tissue of two species of fish native to the PSR: Geophagus brasiliensis and Hypostomus sp. Sampling was performed in both the wet and dry seasons of 2003, with a total of 339 fish collected from 16 sites along the PSR basin. Fish collected at Levy Gasparian, Barra Mansa and Três Rios both had higher EROD activity and micronuclei frequency. The results also suggested a moderate induction of EROD activity in fish collected from S.L. Paraitinga and Sapucaia. Micronuclei frequency was elevated in fish from S.J. Campos, Além Paraíba, Campos and S.J. Barra. In all cases, heavy metal concentrations did not exceed the maximum considered safe for fish meat consumption.Título PT: Concentração de metais pesados e incidência de eritrócitos micronucleados e atividade de EROD hepática em duas espécies de peixes comestíveis na bacia do Rio Paraíba do Sul, BrasilA bacia do rio Paraíba do Sul (PSR) atravessa uma das regiões mais povoadas e industrializadas do Brasil, recebendo efluentes de indústrias metalúrgicas, de papel e celulose e agrícolas. Os usos das águas do PSR são múltiplos, incluem o fornecimento de água potável, e as populações ribeirinhas consomem algumas de suas espécies de peixes. No presente trabalho foram investigadas as respostas de dois biomarcadores à poluição, a atividade hepática de EROD e a freqüência de micronúcleo em sangue periférico, e medidos os níveis de sete metais pesados no músculo de duas espécies de peixes nativas do PSR, Geophagus brasiliensis and Hypostomus sp.. As amostragens foram realizadas nos períodos de seca e de cheias de 2003. Ao todo foram coletados 339 peixes em 16 regiões ao longo da bacia do PSR. Os peixes coletados em Levy Gasparian, Barra Mansa e Três Rios apresentaram alta atividade de EROD e frequência de micronúcleo. Também foi detectada uma moderada indução de EROD nos peixes coletados em S.L. Paraitinga e Sapucaia. A frequência de micronúcleo foi elevada nos peixes coletados em S.J. Campos, Além Paraíba, Campos e S.J. Barra. Em todos os casos, as concentrações de metais pesados não excederam os valores máximos permitidos para carne de peixes

Enhanced Hyaluronan Signaling and Autophagy Dysfunction by VPS35 D620N

The motor features of Parkinson’s disease (PD) result from the loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. A PD-causing familial mutation in VPS35 (D620N) has been reported to inhibit autophagy. In order to identify signaling pathways responsible for this autophagy defect, we performed an unbiased screen using RNA sequencing (RNA-Seq) of wild-type or VPS35 D620N-expressing retinoic acid-differentiated SH-SY5Y cells. We report that VPS35 D620N-expressing cells exhibit transcriptome changes indicative of alterations in extracellular matrix (ECM)-receptor interaction as well as PI3K-AKT signaling, a pathway known to regulate autophagy. Hyaluronan (HA) is a major component of brain ECM and signals via the ECM receptors CD44, a top RNA-Seq hit, and HA-mediated motility receptor (HMMR) to the autophagy-regulating PI3K-AKT pathway. We find that high (\u3e950 kDa), but not low (15–40 kDa), molecular weight HA treatment inhibits autophagy. In addition, VPS35 D620N facilitated enhanced HA-AKT signaling. Transcriptomic assessment and validation of protein levels identified the differential expression of CD44 and HMMR isoforms in VPS35 D620N mutant cells. We report that knockdown of HMMR or CD44 results in upregulated autophagy in cells expressing wild-type VPS35. However, only HMMR knockdown resulted in rescue of autophagy dysfunction by VPS35 D620N indicating a potential pathogenic role for this receptor and HA signaling in Parkinson’s disease

Developing technologies to assess vascular ageing:a roadmap from VascAgeNet

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges

Developing technologies to assess vascular ageing: a roadmap from VascAgeNet.

Vascular ageing is the deterioration of arterial structure and function which occurs naturally with age, and which can be accelerated with disease. Measurements of vascular ageing are emerging as markers of cardiovascular risk, with potential applications in disease diagnosis and prognosis, and for guiding treatments. However, vascular ageing is not yet routinely assessed in clinical practice. A key step towards this is the development of technologies to assess vascular ageing. In this Roadmap, experts discuss several aspects of this process, including: measurement technologies; the development pipeline; clinical applications; and future research directions. The Roadmap summarises the state of the art, outlines the major challenges to overcome, and identifies potential future research directions to address these challenges