Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells.

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.

SARS-CoV-2 productively infects primary human immune system cells in vitro and in COVID-19 patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.

Long-Term Symptoms among COVID-19 Survivors in Prospective Cohort Study, Brazil.

We conducted a prospective cohort study in a population with diverse ethnic backgrounds from Brazil to assess clinically meaningful symptoms after surviving coronavirus disease. For most of the 175 patients in the study, clinically meaningful symptoms, including fatigue, dyspnea, cough, headache, and muscle weakness, persisted for >120 days after disease onset.

Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.

OBJECTIVE: To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes. DESIGN: We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate. RESULTS: Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0-6.0) days for the colchicine group and 6.5 (4.0-9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0-9.0) days for the colchicine group and 9.0 (7.0-12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26). CONCLUSION: Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19. TRIAL REGISTRATION NUMBER: RBR-8jyhxh.

Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients.

Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1ß, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.

Infection of human lymphomononuclear cells by SARS-CoV-2.

Although SARS-CoV-2 severe infection is associated with a hyperinflammatory state, lymphopenia is an immunological hallmark, and correlates with poor prognosis in COVID-19. However, it remains unknown if circulating human lymphocytes and monocytes are susceptible to SARS-CoV-2 infection. In this study, SARS-CoV-2 infection of human peripheral blood mononuclear cells (PBMCs) was investigated both in vitro and in vivo . We found that in vitro infection of whole PBMCs from healthy donors was productive of virus progeny. Results revealed that monocytes, as well as B and T lymphocytes, are susceptible to SARS-CoV-2 active infection and viral replication was indicated by detection of double-stranded RNA. Moreover, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from COVID-19 patients, and less frequently in CD4 + T lymphocytes. The rates of SARS-CoV-2-infected monocytes in PBMCs from COVID-19 patients increased over time from symptom onset. Additionally, SARS-CoV-2-positive monocytes and B and CD4+T lymphocytes were detected by immunohistochemistry in post mortem lung tissue. SARS-CoV-2 infection of blood circulating leukocytes in COVID-19 patients may have important implications for disease pathogenesis, immune dysfunction, and virus spread within the host.

Author Correction: Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Clinical Manifestations and Ophthalmic Outcomes of Ocular Syphilis at a Time of Re-Emergence of the Systemic Infection.

Recent reports from different world regions suggest ocular syphilis is re-emerging, in parallel with an increasing incidence of the systemic infection globally. We conducted a large observational study of 127 persons consecutively treated for ocular syphilis at public medical centers in Brazil over a 2.5-year period ending July 2015. Of 104 individuals serologically tested for human immunodeficiency virus (HIV), 34.6% were positive. Ophthalmological evaluations included measurement of Snellen visual acuity and intraocular pressure, and assessment of inflammation by slit lamp examination and dilated posterior eye examination. Involvements in 214 eyes were anterior (6.1%), intermediate (8.4%), posterior (76.2%) and pan- (8.4%) uveitis, and scleritis (0.9%). Multiple anterior and posterior eye complications were observed, including cataract in the anterior eye (incidence rate, 0.18/eye-year) and epiretinal membrane in the posterior eye (incidence rate, 0.09/eye-year); incidence rates of reduction in best-corrected visual acuity to ≤20/50 and ≤20/200 were 0.10 and 0.06/eye-year, respectively. Rates of complications and visual acuity loss did not differ significantly between HIV- positive and negative individuals. In an era of re-emergence, syphilis has ocular complications that may compromise vision, despite treatment with appropriate anti-microbial drugs.

Lipodystrophy diagnosis in people living with HIV/AIDS: prediction and validation of sex-specific anthropometric models.

BACKGROUND: Body composition alterations, or lipodystrophy, can lead to serious health problems in people living with HIV/AIDS (PLWHA). The objectives of this study are to predict and validate sex-specific anthropometric predictive models for the diagnosis of lipodystrophy in PLWHA. METHODS: A cross-sectional design was employed to recruit 106 PLWHA (men = 65 and women = 41) in Brazil during 2013-2014. They were evaluated using dual-energy X-ray absorptiometry, and 19 regions of body perimeters and 6 skinfold thicknesses were taken. Sex-specific predictive models for lipodystrophy diagnosis were developed through stepwise linear regression analysis. Cross-validations using predicted residual error sum of squares was performed to validate each predictive model. RESULTS: Results support the use of anthropometry for the diagnosis of lipodystrophy in men and women living with HIV/AIDS. A high power of determination with a small degree of error was observed for lipodystrophy diagnosis for men in model six (r2 = 0.77, SEE = 0.14, r2PRESS = 0.73, SEE PRESS = 0.15), that included ratio of skinfold thickness of subscapular to medial calf, skinfold thickness of thigh, body circumference of waist, formal education years, time of diagnosis to HIV months, and type of combined antiretroviral therapy (cART) (with protease inhibitor "WI/PI = 1" or without protease inhibitor "WO/PI = 0"); and model five for women (r2 = 0.78, SEE = 0.11, r2PRESS = 0.71, SEE PRESS = 0.12), that included skinfold thickness of thigh, skinfold thickness of subscapular, time of exposure to cART months, body circumference of chest, and race (Asian) ("Yes" for Asian race = 1; "No" = 0). CONCLUSIONS: The proposed anthropometric models advance the field of public health by facilitating early diagnosis and better management of lipodystrophy, a serious adverse health effect experienced by PLWHA.

Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital.

INTRODUCTION: Few studies have evaluated the factors involved in the spontaneous HBsAg seroclearance in patients with chronic hepatitis B (HBV) followed up on a long-term basis from areas with a low prevalence of HBV infection. We aimed to determine the rate of spontaneous HBsAg seroclearance and the factors related to it in patients with chronic HBV infection followed up at the Hepatitis Outpatient Clinic of HCFMRP from 1992-2008. MATERIALS AND METHODS: A total of 548 patients with chronic HBV infection (366 with chronic hepatitis B and 182 inactive carriers) were followed for 15 years and 9 months with an annual measurement of HBV-DNA, ALT, AST and GGT (average of 4 annual determinations) and serology (HBsAg, HBeAg, Anti-HBeAg and Anti-HBsAg). RESULTS: Spontaneous HBsAg seroclearance occurred in 40 patients (7.3%) with a mean age of 46.0 ± 14.4 years, corresponding to an annual rate of 0.7%.The factors related to spontaneous HBsAg seroclearance were inactive carrier status (67.5 vs. 32.5%, p = 0.000191) and age of more than 40 years (p = 0.0007). There was no difference in the rate of spontaneous HBsAg seroclearance when comparing males and females (p = 0.383). Patients with spontaneous HBsAg seroclearance did not progress to more severe forms of the disease during follow-up. CONCLUSION: Spontaneous HBsAg seroclearance has a favorable long-term prognosis in patients with chronic HBV infection. HBsAg seroclearance occurred at rates compatible with low prevalence areas and was associated with low serum HBV-DNA levels and an age older than 40 years.

Avaliação formativa e feedback como ferramenta de aprendizado na formação de profissionais da saúde / Formative assessment and feedback as learning tools in health professions education

As diferentes formas de avaliação são elementos centrais do processo de ensino-aprendizagem de qualquer programa educacional, e devem ser bem planejadas e implementadas em todas as propostas curriculares,especialmente na formação de profissionais na área da saúde. Uma avaliação do estudante adequada e de qualidade guarda estreita relação com a competência e capacitação do profissional que será entregue à sociedade. Neste contexto, a avaliação formativa e a capacitação dos professores para prover feedback efetivo, frequente, e de qualidade são fundamentais na formação dos futuros profissionais da saúde. Este artigo faz uma revisão sobre avaliação formativa, feedback e debriefing.

The different assessment forms are major elements of any teaching and learning process in educational programs, and should be considered as a core component to be planned and implemented in all curriculums, especially in the health professions education. A regular and qualified students’ assessment is closely related to competence and skills of the professionals that will be delivered to society. In this context, formative assessment and well-trained staff to provide effective and regular feedback are essentials in the formation of the future generation of health professionals. This article focuses primarily on formative assessment, feedback and debriefing.