Animal models and SARS-CoV-2-induced pulmonary and neurological injuries.

Laboratory animals are essential mainly for experiments aiming to study pathogenesis and evaluate antivirals and vaccines against emerging human infectious diseases. Preclinical studies of coronavirus disease 19 (COVID-19) pathogenesis have used several animal species as models: transgenic human ACE2 mice (K18 mice), inbred BALB/c or C57BL/6N mice, ferrets, minks, domestic cats and dogs, hamsters, and macaques. However, the choice of an animal model relies on several limitations. Besides the host susceptibility, the researcher's experience with animal model management and the correct interpretation of clinical and laboratory records are crucial to succeed in preclinical translational research. Here, we summarise pathological and clinical findings correlated with virological data and immunological changes observed from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experimental infections using different well-established SARS-CoV-2 animal model species. This essay aims to critically evaluate the current state of animal model translation to clinical data, as described in the human SARS-CoV-2 infection.

COVID-19: Understanding the impact of anti-hypertensive drugs and hydroxychloroquine on the ACE1 and ACE2 in lung and adipose tissue in SHR and WKY rats.

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10 mg/kg/day) or captopril (10 mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.

CLEC5A expression can be triggered by spike glycoprotein and may be a potential target for COVID-19 therapy.

The immune response is crucial for coronavirus disease 19 (COVID-19) progression, with the participation of proinflammatory cells and cytokines, inducing lung injury and loss of respiratory function. CLEC5A expression on monocytes can be triggered by viral and bacterial infections, leading to poor outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to induce neutrophil activation by CLEC5A and Toll-like receptor 2, leading to an aggressive inflammatory cascade, but little is known about the molecular interactions between CLEC5A and SARS-CoV-2 proteins. Here, we aimed to explore how CLEC5A expression could be affected by SARS-CoV-2 infection using immunological tools with in vitro, in vivo, and in silico assays. The findings revealed that high levels of CLEC5A expression were found in monocytes from severe COVID-19 patients in comparison with mild COVID-19 and unexposed subjects, but not in vaccinated subjects who developed mild COVID-19. In hamsters, we detected CLEC5A gene expression during 3-15 days of Omicron strain viral challenge. Our results also showed that CLEC5A can interact with SARS-CoV-2, promoting inflammatory cytokine production, probably through an interaction with the receptor-binding domain in the N-acetylglucosamine binding site (NAG-601). The high expression of CLEC5A and high levels of proinflammatory cytokine production were reduced in vitro by a human CLEC5A monoclonal antibody. Finally, CLEC5A was triggered by spike glycoprotein, suggesting its involvement in COVID-19 progression; therapy with a monoclonal antibody could be a good strategy for COVID-19 treatment, but vaccines are still the best option to avoid hospitalization/deaths.

Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces mild or asymptomatic COVID-19 in most cases, but some patients develop an excessive inflammatory process that can be fatal. As the NLRP3 inflammasome and additional inflammasomes are implicated in disease aggravation, drug repositioning to target inflammasomes emerges as a strategy to treat COVID-19. Here, we performed a high-throughput screening using a 2560 small-molecule compound library and identified FDA-approved drugs that function as pan-inflammasome inhibitors. Our best hit, niclosamide (NIC), effectively inhibits both inflammasome activation and SARS-CoV-2 replication. Mechanistically, induction of autophagy by NIC partially accounts for inhibition of NLRP3 and AIM2 inflammasomes, but NIC-mediated inhibition of NAIP/NLRC4 inflammasome are autophagy independent. NIC potently inhibited inflammasome activation in human monocytes infected in vitro, in PBMCs from patients with COVID-19, and in vivo in a mouse model of SARS-CoV-2 infection. This study provides relevant information regarding the immunomodulatory functions of this promising drug for COVID-19 treatment.

Discontinuation of Health Interventions Among Brazilian Older Adults During the Covid-19 Pandemic: REMOBILIZE Study.

The objective of this study was to analyze changes in access to health interventions during the pandemic among Brazilian older adults and to investigate the factors associated with social and health inequalities. We conducted an online survey with Brazilian adults aged 60 + years between May and June 2020. A multidimensional questionnaire was used to investigate access to health interventions during the pandemic and associated factors. Of 1482 participants, 56.5% reported health care before the pandemic, and 36.4% discontinued it during the pandemic. The discontinuation rate was 64.4% (95% CI 61.1-67.6). Participants with higher educational level (nine or more years of education: OR 0.34; 95% CI 0.17-0.70) and higher income (eight or more times the minimum wage: OR 0.54; 95% CI 0.36-0.81) were associated with less probability of discontinuation. Presenting multimorbidity (OR: 1.42; 95% CI 1.06-1.90) and polypharmacy (OR: 0.61; 95% CI 0.46-0.81) were associated with discontinuity in health interventions. Our study showed that structural health inequities in access to health care shaped the rates of discontinuation in health care interventions during the COVID-19 pandemic. Strategic actions should be set up to actively monitor socially vulnerable older adults and strengthen community-based services to mitigate the discontinuation of health care interventions.

Phylogenetic-based inference reveals distinct transmission dynamics of SARS-CoV-2 lineages Gamma and P.2 in Brazil.

The COVID-19 epidemic in Brazil experienced two major lineage replacements until mid-2021. The first was driven by lineage P.2, in late 2020, and the second by lineage Gamma, in early 2021. To understand how these SARS-CoV-2 lineages spread in Brazil, we analyzed 11,724 genomes collected throughout the country between September 2020 and April 2021. Our findings indicate that lineage P.2 probably emerged in July 2020 in the Rio de Janeiro state and Gamma in November 2020 in the Amazonas state. Both states were the main hubs of viral disseminations to other Brazilian locations. We estimate that Gamma was 1.56-3.06 times more transmissible than P.2 in Rio de Janeiro and that the median effective reproductive number (Re) of Gamma varied according to the geographic context (Re = 1.59-3.55). In summary, our findings support that lineage Gamma was more transmissible and spread faster than P.2 in Brazil.

Determinants of endothelial dysfunction in noncritically ill hospitalized COVID-19 patients: A cross-sectional study.

OBJECTIVE: The aim of this study was to identify determinants of endothelial dysfunction in patients hospitalized with acute COVID-19. METHODS: A total of 109 hospitalized COVID-19 patients in noncritical status were cross-sectionally studied. Clinical data (age, sex, comorbidities, and medications) and BMI were assessed. Laboratory tests included serum hemoglobin, leukocytes, lymphocytes, platelets, C-reactive protein, ferritin, D-dimer, and creatinine. Physical status was evaluated using a handgrip dynamometer. Endothelial function was assessed noninvasively using the flow-mediated dilation (FMD) method. RESULTS: The sample average age was 51 years, 51% of patients were male, and the most frequent comorbidity was obesity (62%). Univariate analysis showed association of lower FMD with higher BMI, hypertension, use of oral antihypertensive, higher blood levels of creatinine, and larger baseline artery diameter. After adjusting for confounders, the multivariate analysis showed BMI (95% CI: -0.26 to -0.11; p < 0.001) as the major factor associated with FMD. Other factors associated with FMD were baseline artery diameter (95% CI: -1.77 to -0.29; p = 0.007) and blood levels of creatinine (95% CI: -1.99 to -0.16; p = 0.022). CONCLUSIONS: Increased BMI was the major factor associated with endothelial dysfunction in noncritically hospitalized COVID-19 patients. This may explain one of the pathways in which obesity may increase the risk for severe COVID-19.

The COVID-19 epidemic in Brazil: how statistics education may contribute to unravel the reality behind the charts.

The world is now facing the most severe health, social, and economic event of the last hundred years, which has made the need to acquire statistical thinking to interpret the information disseminated on a daily basis by the media clear to society. This article proposes a discussion on the role that statistics education might play in supporting the acquisition of such knowledge, contributing to the development of critical citizens, aware of their social responsibility. In this context, we present examples of curves and other charts to demonstrate how to use the several levels defined by experts in reading and interpreting the charts. At a more advanced level, these examples will allow discussion on the impacts of this epidemic on the most vulnerable population in Brazil. The charts presented reveal a great regional inequality, suggesting that mortality due to the virus is distinguished by region and micro-region when considering access to hospital beds. The examples signpost ways for educators to be able to develop projects or research based on the discussion on the reality of the pandemic, the necessary public policies, and how political coordination grounded on science and on a humanitarian vision would have mitigated the Brazilian tragedy.

Impact of COVID-19 Pandemic on Life-Space Mobility of Older Adults Living in Brazil: REMOBILIZE Study.

Background: The COVID-19 pandemic hit Brazil in a scenario of substantial socioeconomic and health inequalities. It is unknown the immediate impact of social restriction recommendations (i.e., lockdown, stay-at-home) on the life-space mobility of older people. Objective: To investigate the immediate impact of COVID-19 pandemic on life-space mobility of community-dwelling Brazilian older adults and examine the social determinants of health associated with change in life-space mobility. Design: Baseline data from a prospective cohort study (REMOBILIZE Study). Setting: Community. Subject: A convenience snowball sample of participants aged 60 and older (n = 1,482) living in 22 states in Brazil. Methods: We conducted an online and phone survey using an adapted version of the Life-Space Assessment (LSA). Linear regression models were used to investigate social determinants of health on the change in LSA score. Results: Regardless of their gender and social determinants of health, participants showed a significant reduction in life-space mobility since COVID-19 pandemic outbreak. Life-space mobility reduction was higher among black individuals, those living alone and aged between 70 and 79. Other variables associated with change in life-space mobility, to a lesser extent, were sex, education and income. Conclusion: Social restriction measures due to pandemic caused substantial reduction in older adults' life-space mobility in Brazil. Social inequalities strongly affected vulnerable groups. Concerted actions should be put in place to overcome the deterioration in life-pace mobility amongst these groups. Failure in minimizing health inequalities amplified by the pandemic may jeopardize the desired achievements of the Decade of Healthy Aging.

Risk stratification and geographical mapping of Brazilian inflammatory bowel disease patients during the COVID-19 outbreak: Results from a nationwide survey.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic is still evolving globally, and Brazil is currently one of the most affected countries. It is still debated whether patients with inflammatory bowel disease (IBD) are at a higher risk for developing COVID-19 or its complications. AIM: To assess geographical distribution of IBD patients at the highest risk and correlate these data with COVID-19 mortality rates in Brazil. METHODS: The Brazilian IBD Study Group (Grupo de Estudos da Doença Inflamatória Intestinal do Brasil) developed a web-based survey adapted from the British Society of Gastroenterology guidelines. The included categories were demographic data and inquiries related to risk factors for complications from COVID-19. Patients were categorized as highest, moderate or lowest individual risk. The Spearman correlation test was used to identify any association between highest risk and mortality rates for each state of the country. RESULTS: A total of 3568 patients (65.3% females) were included. Most participants were from the southeastern and southern regions of Brazil, and 84.1% were using immunomodulators and/or biologics. Most patients (55.1%) were at moderate risk, 23.4% were at highest risk and 21.5% were at lowest risk of COVID-19 complications. No association between the proportion of IBD patients at highest risk for COVID-19 complications and higher mortality rates was identified in different Brazilian states (r = 0.146, P = 0.467). CONCLUSION: This study indicates a distinct geographical distribution of IBD patients at highest risk for COVID-19 complications in different states of the country, which may reflect contrasting socioeconomic, educational and healthcare aspects. No association between high risk of IBD and COVID-related mortality rates was identified.

Experiências e desafios da formação médica durante a pandemia da COVID-19

Objective: to report the experience and challenges of medical students in the first semester of medical training during the COVID-19 pandemic. Method: Report of experience and challenges of medical graduation during the pandemic of the new coronavirus in a private higher education institution, from March to July 2020. Results: The University Center (UNIVAG) established measures to face COVID-19, adopting Emergency Home Education. This experience demonstrated great adaptive capacity of those involved in the learning processes of theoretical content, as well as more creative attitudes of students and the inclusion of other active methodologies in the teaching plan of the Community Interaction Program in order to bring the student closer to reality. Conclusion: Given this scenario, adapting to the use of available technologies was a challenge, but essential to add knowledge to medical students and continue the school year. Objetivo: reportar la experiencia y desafíos de los estudiantes de medicina en el primer semestre de formación médica durante la pandemia de COVID-19. Método: Informe de experiencia y desafíos de la graduación médica durante la pandemia del nuevo coronavirus en una institución privada de educación superior, de marzo a julio de 2020. Resultados: El Centro Universitario (UNIVAG) estableció medidas para enfrentar el COVID-19, adoptando la educación de emergencia en el hogar. Esta experiencia demostró una gran capacidad adaptativa de los involucrados en los procesos de aprendizaje de contenidos teóricos, así como actitudes más creativas de los estudiantes y la inclusión de otras metodologías activas en el plan docente del Programa de Interacción Comunitaria con el fin de acercar al estudiante a la realidad. Conclusión: Ante este escenario, adaptarse al uso de las tecnologías disponibles fue un desafío, pero fundamental para sumar conocimientos a los estudiantes de medicina y continuar el curso escolar. Objetivo: relatar a experiência e os desafios dos estudantes de medicina do primeiro semestre da formação médica durante a pandemia da COVID-19. Método: Relato de experiência e desafios da graduação médica durante a pandemia do novo coronavírus em uma instituição de ensino superior privada, no período de março a julho de 2020. Resultados: O Centro Universitário (UNIVAG) estabeleceu medidas para o enfrentamento da COVID-19, adotando a Educação Domiciliar Emergencial. Essa experiência demonstrou grande capacidade adaptativa dos envolvidos nos processos de aprendizagem dos conteúdos teóricos, bem como atitudes mais criativas dos alunos e a inclusão de outras metodologias ativas no plano de ensino do Programa de Interação Comunitária a fim de aproximar o aluno da realidade. Conclusão: Diante deste cenário, a adaptação para a utilização de tecnologias disponíveis foi um desafio, porém essencial para agregar conhecimento aos graduandos de medicina e continuar o ano letivo.

Management and Nursing Education Experiences during the screening of COVID-19 in an Integrated Clinic

Objective: to discuss managerial experience and nursing education in the control of COVID-19. Method: report of experience of management and education in nursing, in an integrated school clinic during the return of the activities of the health courses. Result: management of COVID -19 control measures in the clinical screening sectors and contributions to management training in the nursing course emerged as results. The course participated in the implementation of COVID-19 control measures in the institution and the importance of articulating clinical and managerial knowledge was realized, preserving the teaching and learning process of nursing students and ensuring the safety of all in this confrontation of the pandemic. Conclusion: the management of the education of nursing students made it possible to develop their managerial and clinical skills in the face of the scenario, as well as allowing the concrete application of specific instruments that were previously applied only in theory. Objetivo: discutir la experiencia gerencial y la formación de enfermería en el control de COVID-19. Método: reporte de experiencia de gestión y educación en enfermería, en una clínica escolar integrada durante el retorno de las actividades de los cursos de salud. Resultado: surgieron como resultados la gestión de las medidas de control de COVID -19 en los sectores de cribado clínico y las contribuciones a la formación gerencial en el curso de enfermería. El curso participó en la implementación de las medidas de control de COVID-19 en la institución y se realizó la importancia de articular el conocimiento clínico y gerencial, preservando el proceso de enseñanza y aprendizaje de los estudiantes de enfermería y velando por la seguridad de todos en este enfrentamiento de la pandemia. Conclusión: la gestión de la formación de los estudiantes de enfermería permitió desarrollar sus habilidades gerenciales y clínicas frente al escenario, además de permitir la aplicación concreta de instrumentos específicos que antes solo se aplicaban en teoría. Objetivo: discorrer experiência gerencial e educação em enfermagem no controle da COVID-19. Método: relato de experiência da gestão e educação em enfermagem, em clínica escola integrada durante o retorno das atividades dos cursos da saúde. Resultado: gestão das medidas de controle da COVID -19 nos setores de triagem da clínica e as contribuições na formação para gestão no curso de enfermagem emergiram como resultados. O curso participou da implantação das medidas de controle de COVID-19 na instituição e percebeu-se a importância da articulação de conhecimentos clínicos e gerenciais preservando o processo de ensino e aprendizagem dos discentes de enfermagem e garantindo a segurança de todos neste enfrentamento da pandemia. Conclusão: a gestão da educação dos alunos do curso de enfermagem possibilitou o desenvolvimento de suas competências gerenciais e clínicas diante do cenário, bem como permitiu a aplicação concreta de instrumentos específicos que, antes eram aplicados apenas na teoria.

Multiple Introductions Followed by Ongoing Community Spread of SARS-CoV-2 at One of the Largest Metropolitan Areas of Northeast Brazil.

Multiple epicenters of the SARS-CoV-2 pandemic have emerged since the first pneumonia cases in Wuhan, China, such as Italy, USA, and Brazil. Brazil is the third-most affected country worldwide, but genomic sequences of SARS-CoV-2 strains are mostly restricted to states from the Southeast region. Pernambuco state, located in the Northeast region, is the sixth most affected Brazilian state, but very few genomic sequences from the strains circulating in this region are available. We sequenced 101 strains of SARS-CoV-2 from patients presenting Covid-19 symptoms that reside in Pernambuco. Phylogenetic reconstructions revealed that all genomes belong to the B lineage and most of the samples (88%) were classified as lineage B.1.1. We detected multiple viral introductions from abroad (likely from Europe) as well as six local B.1.1 clades composed by Pernambuco only strains. Local clades comprise sequences from the capital city (Recife) and other country-side cities, corroborating the community spread between different municipalities of the state. These findings demonstrate that different from Southeastern Brazilian states where the epidemics were majorly driven by one dominant lineage (B.1.1.28 or B.1.1.33), the early epidemic phase at the Pernambuco state was driven by multiple B.1.1 lineages seeded through both national and international traveling.