Characterization of Unique Pathological Features of COVID-Associated Coagulopathy: Studies with AC70 hACE2 Transgenic Mice Highly Permissive to SARS-CoV-2 Infection (preprint)

COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS-CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as [~] 3 and [~] 0.5 TCID50 of SARS-CoV-2, respectively. Mice infected with 105 TCID50 of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and many inflammatory mediators could be readily detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio. Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy, including significantly elevated levels of D-dimer, t-PA, PAI-1, and circulating NETs, along with activated platelet/endothelium marker. Immunohistochemical staining with anti-PF4 antibody revealed profound platelet aggregates especially within blocked veins of the lungs. ANXA2 is known to interact with S100A10 to form heterotetrametric complexes, serving as coreceptors for t-PA to regulate membrane fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated de novo ANXA2/S100A10 synthesis, and reduced AnxA2/S100A10 association in infected mice support an important role of this protein in the pathogenesis of acute COVID-19. In summary, we showed that acute SARS-CoV-2 infection of AC70 hACE2 Tg mice triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis, accompanied by dysregulation of ANXA2 system, which might serve as druggable targets for development of antithrombotic and/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19. Author SummaryAccumulating evidence strongly suggests that COVID-associated coagulopathy characterized by dysregulation of the coagulation cascade, fibrinolysis system and pulmonary microvascular immune-thrombosis during different stages of SARS-CoV-2 infection may have a "yet-to-be fully defined" impact on the development of post-acute sequela of COVID-19. Herein we initially reported a comprehensively characterized AC70 hACE2 Tg mouse model for SARS-CoV-2 infection and disease. We next demonstrated the subsequent onset of imbalanced coagulation and fibrinolysis pathways in infected Tg mice, focusing on dysregulated formation of ANXA2/S100A10 complexes, key coreceptors for t-PA that regulates membrane fibrinolysis, in which elevated production of autoantibodies against ANXA2 induced by SARS-CoV-2 might play an intriguing role. Taken together, we demonstrated that AC70 hACE2 Tg mice lethally challenged with SARS-CoV-2 recapitulated several features of COVID-associated coagulopathy observed in patients and highlighted the potential role of ANXA2 in this phenomenon. Thus, ANXA2 might serve as a potentially novel druggable target to attenuate COVID-19-associated thrombotic events.

Evaluating Take 5: Virtual Learning Sessions on Trauma Informed Care for Healthcare Staff During COVID-19

In 2018, CAI, an organization that provides national level training and capacity-building developed a TIC implementation model, now delivered in HIV and primary care agencies throughout the United States to integrate TIC into their culture, environment, and service delivery. In 2018, an organization that provides national level training and capacity-building, Cicatelli Associates, Inc. (CAI), developed a TIC implementation model, now delivered in HIV and primary care agencies throughout the United States to integrate TIC into their culture, environment, and service delivery. PWH who have experienced trauma are 58% less likely to adhere to their antiretroviral treatment compared to PHW who have not experienced trauma (Brown. Since 2018, CAI, a national training and technical assistance organization, has developed and implemented a TIC implementation model to build the capacity of primary care agencies and their healthcare staff to integrate TIC throughout their cultures, environments, and service delivery. The motivation for this model is based on the understanding that primary care providers play a critical role in identifying and addressing past trauma with clients, as opposed to simply relying on referrals to external mental health services to support these needs. CAI technical assistance providers offer capacity building and training to staff at these agencies to implement components of the model to ensure successful integration of TIC into agency culture, environment, and service delivery.

Mahusay! (Beautiful!): Assessing a community-based festival management in the antecedent and subsequent COVID-19 pandemic – the case of Daramsiyao Festival in Daram, Samar, Philippines

This analysis of festival management before and during the COVID-19 pandemic focused on the Daramsiyao Festival, a local event in Daram, Samar, Philippines. Utilizing a qualitative phenomenological approach, the study identified the role and impact of the festival on its stakeholders and how management processes changed during the pandemic. To gather data, a content analysis of written festival documentation and Hybrid Focus Group Discussion (HFGD) with twelve (n = 12) Daram stakeholders were conducted, utilizing tabular reconnaissance and a semi-structured aide-mémoire. The information was assessed through a Repertory Grid and Thematic Network Analysis. Upon analyzing the stakeholders' collective and individual experiences, the findings suggested themes that explored the implications of the changing management practices, leading to the development of the SAYAW Framework on Sustainable Community-based Festival Management. The proposed intervention program titled: "Tayo'y MagSAYAW! (Let's Dance!)” was conceptualized to develop the festival management for future celebrations of the Daramsiyao Festival. The framework introduces five (5) main themes: Substratum, Adaptation, Yare Governance, Acclimation, and Workmanship. Through the comprehensive analysis of the festival subject, primary and secondary stakeholders could adapt to improve the related projects and activities. It also leads to strengthening collaboration and partnership between stakeholders. [ FROM AUTHOR] Copyright of Journal of Convention & Event Tourism is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

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.

Antidepressant Advisor (ADeSS): a decision support system for antidepressant treatment for depression in UK primary care - a feasibility study.

OBJECTIVES: To develop and probe the first computerised decision-support tool to provide antidepressant treatment guidance to general practitioners (GPs) in UK primary care. DESIGN: A parallel group, cluster-randomised controlled feasibility trial, where individual participants were blind to treatment allocation. SETTING: South London NHS GP practices. PARTICIPANTS: Ten practices and eighteen patients with treatment-resistant current major depressive disorder. INTERVENTIONS: Practices were randomised to two treatment arms: (a) treatment-as-usual, (b) computerised decision support tool. RESULTS: Ten GP practices participated in the trial, which was within our target range (8-20). However, practice and patient recruitment were slower than anticipated and only 18 of 86 intended patients were recruited. This was due to fewer than expected patients being eligible for the study, as well as disruption resulting from the COVID-19 pandemic. Only one patient was lost to follow-up. There were no serious or medically important adverse events during the trial. GPs in the decision tool arm indicated moderate support for the tool. A minority of patients fully engaged with the mobile app-based tracking of symptoms, medication adherence and side effects. CONCLUSIONS: Overall, feasibility was not shown in the current study and the following modifications would be needed to attempt to overcome the limitations found: (a) inclusion of patients who have only tried one Selective Serotonin Reuptake Inhibitor, rather than two, to improve recruitment and pragmatic relevance of the study; (b) approaching community pharmacists to implement tool recommendations rather than GPs; (c) further funding to directly interface between the decision support tool and self-reported symptom app; (d) increasing the geographic reach by not requiring detailed diagnostic assessments and replacing this with supported remote self-report. TRIAL REGISTRATION NUMBER: NCT03628027.

Effectiveness of SinergiAPS, an intervention based on Patient Feedback to Improve Patient Safety in Primary Care: a randomized clinical trial in Spain

Aims: To evaluate the effectiveness of SinergiAPS (a patient-centred audit and feedback intervention) in improving patient safety in primary healthcare (PHC) centres. Method(s): We conducted a cluster randomized controlled clinical trial in 59 PHC centres in Spain. We audited all the participant centres, assessing their level of patient safety based on the administration of the Patient Reported Experiences and Outcomes of Safety in Primary Care (PREOS-PC) questionnaire to 75 patients/centre. Then, PHC centres were randomly allocated to receive the SinergiAPS intervention or usual care. Only the intervention centres were fed back with the audit results. They received: (1) a bespoke feedback report with quantitative (scale and item level scores) and qualitative (free text) results;(2) a set of educational materials (based on available evidence-based strategies for addressing patient safety problems);and (3) a structured template to record and monitor their safety improvement plans. The intervention was remotely delivered using a bespoke web tool. The primary outcome was patient safety culture among professionals (MOSPSC questionnaire). Secondary outcomes were patient-reported patient safety (mean scores of five PREOS-PC questionnaire scales), and rate of avoidable hospital admissions. After 12 months follow-up, we conducted 14 semi-structured qualitative interviews with PHC professionals to explore their perceptions of the intervention and to identify implementation barriers. Result(s): We successfully recruited 1053 professionals out of 1971 (53%) invited professionals (81% women;mean (SD) age 49 (10) years). The post-intervention followup rate was 75% (793/1053). No significant differences were observed at 12 months between groups in patient safety culture score (intervention: 3.60 [95%CI 3.55-3.64] vs. control: 3.64 [95%CI 3.60-3.68]), or in any of the secondary outcomes. The qualitative interviews revealed that the response to the COVID-19 pandemic (which in Spain started 6 weeks after starting to deliver feedback reports) severely limited the ability of PHC centres to use the intervention resources as planned. Despite its low ''reach'', the intervention presented high acceptability and perceived utility. Conclusion(s): In the context of a health emergency, SinergiAPS did not improve patient safety in Spanish PHC centres. Future studies are needed to evaluate its effectiveness in contexts more consistent with usual practice.

The Greifswald Post COVID Rehabilitation Study and Research (PoCoRe)-Study Design, Characteristics and Evaluation Tools.

(1) Background: COVID-19 is often associated with significant long-term symptoms and disability, i.e., the long/post-COVID syndrome (PCS). Even after presumably mild COVID-19 infections, an increasing number of patients seek medical help for these long-term sequelae, which can affect various organ systems. The pathogenesis of PCS is not yet understood. Therapy has so far been limited to symptomatic treatment. The Greifswald Post COVID Rehabilitation Study (PoCoRe) aims to follow and deeply phenotype outpatients with PCS in the long term, taking a holistic and comprehensive approach to the analysis of their symptoms, signs and biomarkers. (2) Methods: Post-COVID outpatients are screened for symptoms in different organ systems with a standardized medical history, clinical examination, various questionnaires as well as physical and cardiopulmonary function tests. In addition, biomaterials are collected for the analysis of immunomodulators, cytokines, chemokines, proteome patterns as well as specific (auto)antibodies. Patients are treated according to their individual needs, adhering to the current standard of care. PoCoRe's overall aim is to optimize diagnostics and therapy in PCS patients.

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.

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.

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

The SARS-CoV-2 Omicron variant has challenged the control of the COVID-19 pandemic even in highly vaccinated countries. While a second booster of mRNA vaccines improved the immunity against SARS-CoV-2, the humoral and cellular responses induced by a second booster of an inactivated SARS-CoV-2 vaccine have not been studied. In the context of a phase 3 clinical study, we report that a second booster of CoronaVac increased the neutralizing response against the ancestral virus yet showed poor neutralization against the Omicron variant. Additionally, isolated PBMCs displayed equivalent activation of specific CD4+ T lymphocytes and IFN-{gamma} production when stimulated with a mega-pool of peptides derived from the spike protein of the ancestral virus or the Omicron variant. In conclusion, a second booster dose of CoronaVac does not improve the neutralizing response against the Omicron variant compared with the first booster dose, yet it helps maintain a robust spike-specific CD4+ T cell response.

Anti-neuronal antibodies against brainstem antigens are associated with COVID-19.

BACKGROUND: Understanding how SARS-CoV-2 affects respiratory centres in the brainstem may help to preclude assisted ventilation for patients in intensive care setting. Viral invasion appears unlikely, although autoimmunity has been implicated, the responsible antigens remain unknown. We previously predicted the involvement of three epitopes within distinct brainstem proteins: disabled homolog 1 (DAB1), apoptosis-inducing-factor-1 (AIFM1), and surfeit-locus-protein-1 (SURF1). METHODS: Here, we used microarrays to screen serum from COVID-19 patients admitted to intensive care and compared those with controls who experienced mild course of the disease. FINDINGS: The results confirm the occurrence of IgG and IgM antibodies against the hypothesised epitopes in COVID-19 patients. Importantly, while IgM levels were similar in both groups, IgG levels were significantly elevated in severely ill patients compared to controls, suggesting a pathogenic role of IgG. INTERPRETATION: The newly discovered anti-neuronal antibodies might be promising markers of severe disease and the targeted peptide epitopes might be used for targeted immunomodulation. Further work is needed to determine whether these antibodies may play a role in long-COVID. FUNDING: AF, CF and PR received support from the German Research Foundation (grants FL 379/22-1, 327654276-SFB 1315, FR 4479/1-1, PR 1274/8-1). SH, DR, and DB received support from the Ministry of Economy, State of Mecklenburg Western Pomerania, Germany (grant COVIDPROTECT: "Optimisation of diagnostic and therapeutic pathways for COVID-19 patients in MV"). SH received support from the Research Group Molecular Medicine University of Greifswald (FVMM, seed funding FOVB-2021-01). AV received support from the Else Kröner Fresenius Foundation and the Alzheimer Research Initiative.

Differential immune response induced by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial (preprint)

BackgroundThe development of vaccines to control the COVID-19 pandemic progression is a worldwide priority. CoronaVac(R) is an inactivated SARS-CoV-2 vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. MethodsThis study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged [≥]18 years. Volunteers received two doses of CoronaVac(R) separated by two (0-14 schedule) or four weeks (0-28 schedule). 2,302 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. ResultsBoth 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 between schedules. Stimulation of PBMCs with MPs induced the secretion of IFN-{gamma} and the expression of activation induced markers for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-{gamma} secretion. ConclusionsImmunization with CoronaVac(R) 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. FundingMinistry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial numberNCT04651790. summaryTwo immunization schedules were evaluated for the inactivated SARS-CoV-2 vaccine, Coronavac(R), with two doses of the vaccine separated by two or four weeks. We compared humoral and cellular immune responses, showing they are mostly similar, with differences in neutralization capacities.

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.

Parents and school-aged children's mental well-being after prolonged school closures and confinement during the COVID-19 pandemic in Mexico: a cross-sectional online survey study.

OBJECTIVE: This study aimed to determine parents' and school-aged children's mental well-being after experiencing confinement and prolonged school closures during the COVID-19 pandemic. DESIGN: Using a cross-sectional design, an online survey was applied to parents of school-aged children inquiring about their mental well-being and COVID-19 pandemic changes in their home and working lives. To assess the presence of depression, anxiety and stress in parents, the participants responded to the Depression, Anxiety and Stress Scale - 21 scale. To assess psychosocial dysfunction and sleep disturbances in children, participants responded to the Pediatric Symptom Checklist and the Children Sleep Habits Questionnaire. RESULTS: A total of 209 parents answered the questionnaire, most of them were female (87.1%) with a mean age of 40 years. The prevalence of anxiety, stress and parental depression symptoms were 35.9%, 28.2% and 25.4%, respectively. Children's mean age was 8.9 years, the prevalence of children's psychosocial dysfunction was 12%, while their sleep disturbance symptoms were 59.8%. 10.5% of children were suffering both outcomes. We found a bidirectional relationship between parents' and children's mental health outcomes. Parental depression symptoms were associated with experiencing COVID-19 infection within the household, having children with pre-existing medical diagnoses, children's psychosocial dysfunction and sleep disturbances. Children's psychosocial dysfunction was associated with parental depression and changes in their school routine. Children's sleep disturbances were associated with parental anxiety, younger age, increased use of electronic devices, night-time awakenings and shorter sleep time. CONCLUSION: Our results support the impact of long confinement and school closure due to the COVID-19 pandemic in Mexican children and parents' mental well-being. We advocate for specific mental health interventions tailored to respond to parents and children at risk of mental well-being distress.

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.

An inactivated SARS-CoV-2 vaccine is safe and induces humoral and cellular immunity against virus variants in healthy children and adolescents in Chile (preprint)

BackgroundMultiple vaccines against SARS-CoV-2 have been evaluated in clinical trials, but very few include the pediatric population. The inactivated vaccine CoronaVac(R) has shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. This study is an interim safety and immunogenicity report of a phase 3 clinical trial for CoronaVac(R) in healthy children and adolescents in Chile. MethodsParticipants aged 3 to 17 years old received two doses of CoronaVac(R) in a four-week interval. Local and systemic adverse reactions were registered in 699 participants that received the first dose and 381 that received the second dose until December 31st, 2021. Whole blood samples were collected from 148 participants for humoral and cellular immunity analyses. ResultsThe primary adverse reaction reported after the first and second dose was pain at the injection site. The adverse reactions observed were primarily mild and local, and no severe adverse events were reported. Four weeks after the second dose, a significant increase in the levels of total and neutralizing antibodies was observed. Increased activation of specific CD4+ T cells was also observed four weeks after the second dose. Although antibodies induced by vaccination neutralize variants Delta and Omicron, titers were lower than the D614G variant. Importantly, comparable T cell responses were detected against these variants of concern. ConclusionsCoronaVac(R) is safe and immunogenic in subjects aged 3-17 years old and is thus likely to confer protection against infection caused by SARS-CoV-2 variants in this target population.