[Feasibility of using artificial intelligence for screening COVID-19 patients in ParaguayViabilidade do uso de inteligência artificial na triagem de pacientes com COVID-19 no Paraguai]. / Factibilidad de la utilización de la inteligencia artificial para el cribado de pacientes con COVID-19 en Paraguay.

Objective: Study the feasibility of using artificial intelligence as a sensitive and specific method for COVID-19 screening in patients with respiratory conditions, using chest CT scan images and a telemedicine platform. Methods: From March 2020 to June 2021, the authors conducted an observational descriptive multicenter feasibility study based on artificial intelligence (AI) for COVID-19 screening using chest images of patients with respiratory conditions who presented at public hospitals. The AI platform was used to diagnose chest CT scan images; this was then compared with molecular diagnosis (RT-PCR) to determine whether they matched and to analyze the feasibility of AI for screening patients with suspected COVID-19. A telemedicine platform was used to send images and diagnostic results. Results: Screening of 3 514 patients with a suspected COVID-19 diagnosis was performed in 14 hospitals around the country. Most patients were aged 27 to 59 years, followed by those over 60. The average age was 48.6 years; 52.8% were male. The most frequent findings were severe pneumonia, bilateral pneumonia with pleural effusion, bilateral pulmonary emphysema, and diffuse ground glass opacity, among others. There was an average of 93% matching and 7% mismatching between images analyzed by AI and RT-PCR. Sensitivity and specificity of the AI system, obtained by comparing AI and RT-PCR screening results, were 93% and 80% respectively. Conclusions: The use of sensitive and specific AI for stratified rapid detection of COVID-19 in patients with respiratory conditions by using chest CT scan images and a telemedicine platform in public hospitals in Paraguay is feasible.

Objetivo: Examinar a viabilidade do uso de inteligência artificial como um método sensível e específico de triagem de COVID-19 em pacientes com afecções respiratórias, empregando imagens obtidas por exame de tomografia do tórax e uma plataforma de telemedicina. Métodos: Entre março de 2020 e junho de 2021, foi realizado um estudo observacional descritivo multicêntrico sobre a viabilidade do uso de inteligência artificial (IA) para a triagem de COVID-19, empregando imagens do tórax de pacientes com afecções respiratórias atendidos em hospitais da rede pública. O diagnóstico das imagens obtidas em tomografia do tórax foi realizado por meio de uma plataforma de IA e, em seguida, cotejado com o diagnóstico molecular (RT-PCR) para determinar a concordância entre os métodos utilizados e analisar a viabilidade deste processo para a triagem de pacientes com suspeita de COVID-19. As imagens e os resultados do exame diagnóstico foram disponibilizados em uma plataforma de telemedicina. Resultados: Foi realizada a triagem de 3 514 pacientes com suspeita de COVID-19 atendidos em 14 hospitais de todo o país. Os pacientes, na sua maioria, tinham entre 27 e 59 anos de idade ou pertenciam à faixa etária acima de 60 anos, com média de idade de 48,6 anos, sendo que 52,8% eram do sexo masculino. Os achados mais comuns foram pneumonia grave, pneumonia bilateral com derrame pleural, enfisema pulmonar bilateral e opacidade difusa em vidro fosco, entre outros. Verificou-se, em média, 93% de concordância e 7% de discordância entre as imagens analisadas com uso de IA e os resultados do exame de RT-PCR, com uma sensibilidade de 93% e especificidade de 80% desse sistema de triagem. Conclusões: Demonstrou-se que o uso de um sistema de IA sensível e específico é viável nos hospitais públicos do Paraguai para a detecção rápida estratificada de COVID-19 em pacientes com afecções respiratórias, empregando imagens de exame de tomografia do tórax e uma plataforma de telemedicina.

Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults.

BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.

Tracking the emergence of disparities in the subnational spread of COVID-19 in Brazil using an online application for real-time data visualisation: A longitudinal analysis.

BACKGROUND: Brazil is one of the countries worst affected by the COVID-19 pandemic with over 20 million cases and 557,000 deaths reported by August 2021. Comparison of real-time local COVID-19 data between areas is essential for understanding transmission, measuring the effects of interventions, and predicting the course of the epidemic, but are often challenging due to different population sizes and structures. METHODS: We describe the development of a new app for the real-time visualisation of COVID-19 data in Brazil at the municipality level. In the CLIC-Brazil app, daily updates of case and death data are downloaded, age standardised and used to estimate the effective reproduction number (Rt ). We show how such platforms can perform real-time regression analyses to identify factors associated with the rate of initial spread and early reproduction number. We also use survival methods to predict the likelihood of occurrence of a new peak of COVID-19 incidence. FINDINGS: After an initial introduction in São Paulo and Rio de Janeiro states in early March 2020, the epidemic spread to northern states and then to highly populated coastal regions and the Central-West. Municipalities with higher metrics of social development experienced earlier arrival of COVID-19 (decrease of 11·1 days [95% CI:8.9,13.2] in the time to arrival for each 10% increase in the social development index). Differences in the initial epidemic intensity (mean Rt ) were largely driven by geographic location and the date of local onset. INTERPRETATION: This study demonstrates that platforms that monitor, standardise and analyse the epidemiological data at a local level can give useful real-time insights into outbreak dynamics that can be used to better adapt responses to the current and future pandemics. FUNDING: This project was supported by a Medical Research Council UK (MRC-UK) -São Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0).

Role Of Artificial Intelligence In Improving Access To COVID-19 Diagnosis During Pandemic

IntroductionThe evolution of advances in informatics, technology in medicine, and artificial intelligence (AI) offers opportunities to enhance health care during the coronavirus disease 2019 (COVID-19) pandemic. The challenge for biomedical engineers is to implement these developments in clinical practice to improve global health. Populations living in low-income countries do not have access to specialist care and quality diagnostic services for COVID-19. Therefore, an AI system based on a telemedicine platform for diagnosing COVID-19 could help mitigate the lack of highly trained radiologists at regional hospitals and serve as a triage system for rationalizing the use of reverse transcription polymerase chain reaction (RT-PCR) testing and other health resources in low-income countries. Thus, the utility of an AI system for diagnosing COVID-19 in Paraguay was investigated.MethodsThis is a descriptive multicenter observational feasibility study of an AI tool for the rapid detection of COVID-19 in chest computed tomography (CT) images of patients with respiratory difficulties who attended public hospitals across the country.ResultsBetween March 2020 and August 2021, 3,514 rapid diagnostic tests were carried out on patients with respiratory disorders to rule out COVID-19 in 14 hospitals nationwide. The average age of the patients was 48.6 years (52.8% were men);the most common age ranges were 27 to 59 years, followed by older than 60 years and 19 to 26 years. The most frequent findings on the CT images were severe pneumonia, bilateral pneumonia with pleural effusion, bilateral pulmonary emphysema, diffuse ground glass opacity, hemidiaphragmatic paresis, calcified granuloma in the lower right lobe, bilateral pleural effusion, sequelae of tuberculosis, bilateral emphysema, and fibrotic changes. Overall, there was 93 percent agreement and 7 percent discordance between the AI system and the RT-PCR test results. Compared with RT-PCR testing, the AI system had a sensitivity of 93 percent and a specificity of 80 percent.ConclusionsParaguay has an AI-based telemedicine screening system for the rapid detection of COVID-19 that uses chest CT images of patients with respiratory conditions.

Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial.

Background: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. Methods: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. Results: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4+ T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion. Conclusions: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. Funding: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial number: NCT04651790.

Rapid screening for COVID-19 by applying artificial intelligence to chest computed tomography images: A feasibility study

Aim: The aim of the study was to present the results and impact of the application of artificial intelligence (AI) in the rapid diagnosis of COVID-19 by telemedicine in public health in Paraguay. Methods: This is a descriptive, multi-centered, observational design feasibility study based on an AI tool for the rapid detection of COVID-19 in chest computed tomography (CT) images of patients with respiratory difficulties attending the country’s public hospitals. The patients’ digital CT images were transmitted to the AI diagnostic platform, and after a few minutes, radiologists and pneumologists specialized in COVID-19 downloaded the images for evaluation, confirmation of diagnosis, and comparison with the genetic diagnosis (reverse transcription polymerase chain reaction (RT-PCR)). It was also determined the percentage of agreement between two similar AI systems applied in parallel to study the viability of using it as an alternative method of screening patients with COVID-19 through telemedicine. Results: Between March and August 2020, 911 rapid diagnostic tests were carried out on patients with respiratory disorders to rule out COVID-19 in 14 hospitals nationwide. The average age of patients was 50.7 years, 62.6% were male and 37.4% female. Most of the diagnosed respiratory conditions corresponded to the age group of 27–59 years (252 studies), the second most frequent corresponded to the group over 60 years, and the third to the group of 19–26 years. The most frequent findings of the radiologists/pneumologists were severe pneumonia, bilateral pneumonia with pleural effusion, bilateral pulmonary emphysema, diffuse ground glass opacity, hemidiaphragmatic paresis, calcified granuloma in the lower right lobe, bilateral pleural effusion, sequelae of tuberculosis, bilateral emphysema, and fibrotic changes, among others. Overall, an average of 86% agreement and 14% diagnostic discordance was determined between the two AI systems. The sensitivity of the AI system was 93% and the specificity 80% compared with RT-PCR. Conclusion: Paraguay has an AI-based telemedicine screening system for the rapid stratified detection of COVID-19 from chest CT images of patients with respiratory conditions. This application strengthens the integrated network of health services, rationalizing the use of specialized human resources, equipment, and inputs for laboratory diagnosis.

A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern.

CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.

Distal Consequences of Mucosal Infections in Intestinal and Lung Inflammation.

Infectious diseases are one of the leading causes of morbidity and mortality worldwide, affecting high-risk populations such as children and the elderly. Pathogens usually activate local immune responses at the site of infection, resulting in both protective and inflammatory responses, which may lead to local changes in the microbiota, metabolites, and the cytokine environment. Although some pathogens can disseminate and cause systemic disease, increasing evidence suggests that local infections can affect tissues not directly invaded. In particular, diseases occurring at distal mucosal barriers such as the lung and the intestine seem to be linked, as shown by epidemiological studies in humans. These mucosal barriers have bidirectional interactions based mainly on multiple signals derived from the microbiota, which has been termed as the gut-lung axis. However, the effects observed in such distal places are still incompletely understood. Most of the current research focuses on the systemic impact of changes in microbiota and bacterial metabolites during infection, which could further modulate immune responses at distal tissue sites. Here, we describe how the gut microbiota and associated metabolites play key roles in maintaining local homeostasis and preventing enteric infection by direct and indirect mechanisms. Subsequently, we discuss recent murine and human studies linking infectious diseases with changes occurring at distal mucosal barriers, with particular emphasis on bacterial and viral infections affecting the lung and the gastrointestinal tract. Further, we discuss the potential mechanisms by which pathogens may cause such effects, promoting either protection or susceptibility to secondary infection.

Reduced Immune Response to Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Cohort of Immunocompromised Patients in Chile.

BACKGROUND: Inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been widely implemented in low- and middle-income countries. However, immunogenicity in immunocompromised patients has not been established. Herein, we aimed to evaluate immune response to CoronaVac vaccine in these patients. METHODS: This prospective cohort study included 193 participants with 5 different immunocompromising conditions and 67 controls, receiving 2 doses of CoronaVac 8-12 weeks before enrollment. The study was conducted between May and August 2021, at Red de Salud UC-CHRISTUS, Santiago, Chile. Neutralizing antibody (NAb) positivity, total anti-SARS-CoV-2 immunoglobulin G antibody (TAb) concentrations, and T-cell responses were determined. RESULTS: NAb positivity and median neutralizing activity were 83.1% and 51.2% for the control group versus 20.6% and 5.7% (both P < .001) in the solid organ transplant group, 41.5% and 19.2% (both P < .0001) in the autoimmune rheumatic diseases group, 43.3% (P < .001) and 21.4% (P<.01 or P = .001) in the cancer with solid tumors group, 45.5% and 28.7% (both P < .001) in the human immunodeficiency virus (HIV) infection group, 64.3% and 56.6% (both differences not significant) in the hematopoietic stem cell transplant group, respectively. TAb seropositivity was also lower for the solid organ transplant (20.6%; P < .0001), rheumatic diseases (61%; P < .001), and HIV groups (70.9%; P = .003), compared with the control group (92.3%). On the other hand, the number of interferon γ spot-forming T cells specific for SARS-CoV-2 tended to be lower in all immunocompromising conditions but did not differ significantly between groups. CONCLUSIONS: Diverse immunocompromising conditions markedly reduce the humoral response to CoronaVac vaccine. These findings suggest that a boosting vaccination strategy should be considered in these vulnerable patients. CLINICAL TRIALS REGISTRATION: NCT04888793.

BCG-Based Vaccines Elicit Antigen-Specific Adaptive and Trained Immunity against SARS-CoV-2 and Andes orthohantavirus.

Background:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis (M. tb). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb, other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus. Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 108 CFU or one dose of 1 × 105 CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4+ and CD8+ T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response.

Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile.

BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial. METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity. RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2. CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.

Tracking the emergence of disparities in the subnational spread of COVID-19 in Brazil using an online application for real-time data visualisation: A longitudinal analysis

Background Brazil is one of the countries worst affected by the COVID-19 pandemic with over 20 million cases and 557,000 deaths reported by August 2021. Comparison of real-time local COVID-19 data between areas is essential for understanding transmission, measuring the effects of interventions, and predicting the course of the epidemic, but are often challenging due to different population sizes and structures. Methods We describe the development of a new app for the real-time visualisation of COVID-19 data in Brazil at the municipality level. In the CLIC-Brazil app, daily updates of case and death data are downloaded, age standardised and used to estimate the effective reproduction number (Rt). We show how such platforms can perform real-time regression analyses to identify factors associated with the rate of initial spread and early reproduction number. We also use survival methods to predict the likelihood of occurrence of a new peak of COVID-19 incidence. Findings After an initial introduction in São Paulo and Rio de Janeiro states in early March 2020, the epidemic spread to northern states and then to highly populated coastal regions and the Central-West. Municipalities with higher metrics of social development experienced earlier arrival of COVID-19 (decrease of 11·1 days [95% CI:8.9,13.2] in the time to arrival for each 10% increase in the social development index). Differences in the initial epidemic intensity (mean Rt) were largely driven by geographic location and the date of local onset. Interpretation This study demonstrates that platforms that monitor, standardise and analyse the epidemiological data at a local level can give useful real-time insights into outbreak dynamics that can be used to better adapt responses to the current and future pandemics. Funding This project was supported by a Medical Research Council UK (MRC-UK) -São Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0)

Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible of the current pandemic ongoing all around the world. Since its discovery in 2019, several circulating variants have emerged and some of them are associated with increased infections and death rate. Despite the genetic differences among these variants, vaccines approved for human use have shown a good immunogenic and protective response against them. In Chile, over 70% of the vaccinated population is immunized with CoronaVac, an inactivated SARS-CoV-2 vaccine. The immune response elicited by this vaccine has been described against the first SARS-CoV-2 strain isolated from Wuhan, China and the D614G strain (lineage B). To date, four SARS-CoV-2 variants of concern described have circulated worldwide. Here, we describe the neutralizing capacities of antibodies secreted by volunteers in the Chilean population immunized with CoronaVac against variants of concern Alpha (B.1.1.7), Beta (B.1.351) Gamma (P.1) and Delta (B.617.2). Methods: Volunteers enrolled in a phase 3 clinical trial were vaccinated with two doses of CoronaVac in 0-14 or 0-28 immunization schedules. Sera samples were used to evaluate the capacity of antibodies induced by the vaccine to block the binding between Receptor Binding Domain (RBD) from variants of concern and the human ACE2 receptor by an in-house ELISA. Further, conventional microneutralization assays were used to test neutralization of SARS-CoV-2 infection. Moreover, interferon-γ-secreting T cells against Spike from variants of concern were evaluated in PBMCs from vaccinated subjects using ELISPOT. Results: CoronaVac promotes the secretion of antibodies able to block the RBD of all the SARS-CoV-2 variants studied. Seropositivity rates of neutralizing antibodies in the population evaluated were over 97% for the lineage B strain, over 80% for Alpha and Gamma variants, over 75% for Delta variant and over 60% for the Beta variant. Geometric means titers of blocking antibodies were reduced when tested against SARS-CoV-2 variants as compared to ancestral strain. We also observed that antibodies from vaccinated subjects were able to neutralize the infection of variants D614G, Alpha, Gamma and Delta in a conventional microneutralization assay. Importantly, after SARS-CoV-2 infection, we observed that the blocking capacity of antibodies from vaccinated volunteers increased up to ten times for all the variants tested. We compared the number of interferon-γ-secreting T cells specific for SARS-CoV-2 Spike WT and variants of concern from vaccinated subjects and we did not detect significant differences. Conclusion: Immunization with CoronaVac in either immunization schedule promotes the secretion of antibodies able to block SARS-CoV-2 variants of concern and partially neutralizes SARS-CoV-2 infection. In addition, it stimulates cellular responses against all variants of concern.

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study.

PURPOSE: Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. METHODS: After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 µg/kg/day. RESULTS: In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Innovative Screening System For COVID-19 Using Application Of Artificial Intelligence For Telemedicine

IntroductionArtificial intelligence (AI) and innovative technology offer opportunities for enhanced health care during the COVID-19 pandemic. Populations living in low-income countries do not have access to reverse transcription polymerase chain reaction (RT-PCR) testing for COVID-19 and, thus, depend on the scarce resources of their health system. In this context, an automated screening system for COVID-19 based on AI for a telemedicine platform could be directed towards alleviating the current lack of trained radiologists who can interpret computed tomography images at countryside hospitals.MethodsThis descriptive study was carried out in Paraguay by the Telemedicine Unit of the Ministry of Public Health and Social Welfare in collaboration with the Department of Biomedical Engineering and Imaging of the Health Science Research Institute and the University of the Basque Country. The utility of the screening system for COVID-19 was analyzed by dividing the results from two tailored AI systems implemented in 14 public hospitals into four likelihood levels for COVID-19.ResultsBetween March and October 2020, 911 COVID-19 diagnoses were performed in 14 regional hospitals (62.6% were men and 37.4% were women). The average age of the patients diagnosed with COVID-19 was 50.7 years;59.1% were aged 19 to 59 years. The two AI systems used have different background information for detecting COVID-19. The most common findings were severe pneumonia and bilateral pneumonia with pleural effusions. The role of computed tomography was to find lesions and evaluate the effects of treatment. The sensitivity of AI for detecting COVID-19 was 93%.ConclusionsAI technology could help in developing a screening system for COVID-19 and other respiratory pathologies. It could speed up medical imaging diagnosis at regional hospitals for patients with suspected infection during the COVID-19 pandemic and rationalize scarce RT-PCR and specialized human resources in low-income countries. These results must be contextualized with the local or regional epidemiological profile before widespread implementation.

Immune Profile and Clinical Outcome of Breakthrough Cases After Vaccination With an Inactivated SARS-CoV-2 Vaccine.

Constant efforts to prevent infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are actively carried out around the world. Several vaccines are currently approved for emergency use in the population, while ongoing studies continue to provide information on their safety and effectiveness. CoronaVac is an inactivated SARS-CoV-2 vaccine with a good safety and immunogenicity profile as seen in phase 1, 2, and 3 clinical trials around the world, with an effectiveness of 65.9% for symptomatic cases. Although vaccination reduces the risk of disease, infections can still occur during or after completion of the vaccination schedule (breakthrough cases). This report describes the clinical and immunological profile of vaccine breakthrough cases reported in a clinical trial in progress in Chile that is evaluating the safety, immunogenicity, and efficacy of two vaccination schedules of CoronaVac (clinicaltrials.gov NCT04651790). Out of the 2,263 fully vaccinated subjects, at end of June 2021, 45 have reported symptomatic SARS-CoV-2 infection 14 or more days after the second dose (1.99% of fully vaccinated subjects). Of the 45 breakthrough cases, 96% developed mild disease; one case developed a moderate disease; and one developed a severe disease and required mechanical ventilation. Both cases that developed moderate and severe disease were adults over 60 years old and presented comorbidities. The immune response before and after SARS-CoV-2 infection was analyzed in nine vaccine breakthrough cases, revealing that six of them exhibited circulating anti-S1-RBD IgG antibodies with neutralizing capacities after immunization, which showed a significant increase 2 and 4 weeks after symptoms onset. Two cases exhibited low circulating anti-S1-RBD IgG and almost non-existing neutralizing capacity after either vaccination or infection, although they developed a mild disease. An increase in the number of interferon-γ-secreting T cells specific for SARS-CoV-2 was detected 2 weeks after the second dose in seven cases and after symptoms onset. In conclusion, breakthrough cases were mostly mild and did not necessarily correlate with a lack of vaccine-induced immunity, suggesting that other factors, to be defined in future studies, could lead to symptomatic infection after vaccination with CoronaVac.

Impact of non-pharmaceutical interventions against COVID-19 in Europe in 2020: a quasi-experimental non-equivalent group and time series design study.

IntroductionThe current pandemic of coronavirus disease (COVID-19) is unparalleled in recent history as are the social distancing interventions that have led to a considerable halt on the economic and social life of so many countries.AimWe aimed to generate empirical evidence about which social distancing measures had the most impact in reducing case counts and mortality.MethodsWe report a quasi-experimental (observational) study of the impact of various interventions for control of the outbreak through 24 April 2020. Chronological data on case numbers and deaths were taken from the daily published figures by the European Centre for Disease Prevention and Control and dates of initiation of various control strategies from the Institute of Health Metrics and Evaluation website and published sources. Our complementary analyses were modelled in R using Bayesian generalised additive mixed models and in STATA using multilevel mixed-effects regression models.ResultsFrom both sets of modelling, we found that closure of education facilities, prohibiting mass gatherings and closure of some non-essential businesses were associated with reduced incidence whereas stay-at-home orders and closure of additional non-essential businesses was not associated with any independent additional impact.ConclusionsOur findings are that schools and some non-essential businesses operating 'as normal' as well as allowing mass gatherings were incompatible with suppressing disease spread. Closure of all businesses and stay at home orders are less likely to be required to keep disease incidence low. Our results help identify what were the most effective non-pharmaceutical interventions in this period.

Rapid screening for COVID-19 by applying artificial intelligence to chest computed tomography images: A feasibility study.

Aim: The aim of the study was to present the results and impact of the application of artificial intelligence (AI) in the rapid diagnosis of COVID-19 by telemedicine in public health in Paraguay. Methods: This is a descriptive, multi-centered, observational design feasibility study based on an AI tool for the rapid detection of COVID-19 in chest computed tomography (CT) images of patients with respiratory difficulties attending the country's public hospitals. The patients' digital CT images were transmitted to the AI diagnostic platform, and after a few minutes, radiologists and pneumologists specialized in COVID-19 downloaded the images for evaluation, confirmation of diagnosis, and comparison with the genetic diagnosis (reverse transcription polymerase chain reaction (RT-PCR)). It was also determined the percentage of agreement between two similar AI systems applied in parallel to study the viability of using it as an alternative method of screening patients with COVID-19 through telemedicine. Results: Between March and August 2020, 911 rapid diagnostic tests were carried out on patients with respiratory disorders to rule out COVID-19 in 14 hospitals nationwide. The average age of patients was 50.7 years, 62.6% were male and 37.4% female. Most of the diagnosed respiratory conditions corresponded to the age group of 27-59 years (252 studies), the second most frequent corresponded to the group over 60 years, and the third to the group of 19-26 years. The most frequent findings of the radiologists/pneumologists were severe pneumonia, bilateral pneumonia with pleural effusion, bilateral pulmonary emphysema, diffuse ground glass opacity, hemidiaphragmatic paresis, calcified granuloma in the lower right lobe, bilateral pleural effusion, sequelae of tuberculosis, bilateral emphysema, and fibrotic changes, among others. Overall, an average of 86% agreement and 14% diagnostic discordance was determined between the two AI systems. The sensitivity of the AI system was 93% and the specificity 80% compared with RT-PCR. Conclusion: Paraguay has an AI-based telemedicine screening system for the rapid stratified detection of COVID-19 from chest CT images of patients with respiratory conditions. This application strengthens the integrated network of health services, rationalizing the use of specialized human resources, equipment, and inputs for laboratory diagnosis.