Longitudinal transcriptional changes reveal genes from the natural killer cell-mediated cytotoxicity pathway as critical players underlying COVID-19 progression (preprint)

Patients present a wide range of clinical severities in response SARS-CoV-2 infection, but the underlying molecular and cellular reasons why clinical outcomes vary so greatly within the population remains unknown. Here, we report that negative clinical outcomes in severely ill patients were associated with divergent RNA transcriptome profiles in peripheral immune cells compared with mild cases during the first weeks after disease onset. Protein-protein interaction analysis indicated that early-responding cytotoxic NK cells were associated with an effective clearance of the virus and a less severe outcome. This innate immune response was associated with the activation of select cytokine-cytokine receptor pathways and robust Th1/Th2 cell differentiation profiles. In contrast, severely ill patients exhibited a dysregulation between innate and adaptive responses affiliated with divergent Th1/Th2 profiles and negative outcomes. This knowledge forms the basis of clinical triage that may be used to preemptively detect high-risk patients before life-threatening outcomes ensue. Highlights- Mild COVID-19 patients presented an early compromise with NK cell function, whereas severe patients do so with neutrophil function. - The identified co-expressed genes give insights into a coordinated transcriptional program of NK cell cytotoxic activity being associated with mild patients. - Key checkpoints of NK cell cytotoxicity that were enriched in mild patients include: KLRD1, CD247, and IFNG. - The early innate immune response related to NK cells connects with the Th1/Th2 adaptive immune responses, supporting their relevance in COVID-19 progression.

COVID-19 vaccines reduce mortality in hospitalized patients with oxygen requirements: Differences between vaccine subtypes. A multicontinental cohort study.

The aim of this study was to analyze whether the coronavirus disease 2019 (COVID-19) vaccine reduces mortality in patients with moderate or severe COVID-19 disease requiring oxygen therapy. A retrospective cohort study, with data from 148 hospitals in both Spain (111 hospitals) and Argentina (37 hospitals), was conducted. We evaluated hospitalized patients for COVID-19 older than 18 years with oxygen requirements. Vaccine protection against death was assessed through a multivariable logistic regression and propensity score matching. We also performed a subgroup analysis according to vaccine type. The adjusted model was used to determine the population attributable risk. Between January 2020 and May 2022, we evaluated 21,479 COVID-19 hospitalized patients with oxygen requirements. Of these, 338 (1.5%) patients received a single dose of the COVID-19 vaccine and 379 (1.8%) were fully vaccinated. In vaccinated patients, mortality was 20.9% (95% confidence interval [CI]: 17.9-24), compared to 19.5% (95% CI: 19-20) in unvaccinated patients, resulting in a crude odds ratio (OR) of 1.07 (95% CI: 0.89-1.29; p = 0.41). However, after considering the multiple comorbidities in the vaccinated group, the adjusted OR was 0.73 (95% CI: 0.56-0.95; p = 0.02) with a population attributable risk reduction of 4.3% (95% CI: 1-5). The higher risk reduction for mortality was with messenger RNA (mRNA) BNT162b2 (Pfizer) (OR 0.37; 95% CI: 0.23-0.59; p < 0.01), ChAdOx1 nCoV-19 (AstraZeneca) (OR 0.42; 95% CI: 0.20-0.86; p = 0.02), and mRNA-1273 (Moderna) (OR 0.68; 95% CI: 0.41-1.12; p = 0.13), and lower with Gam-COVID-Vac (Sputnik) (OR 0.93; 95% CI: 0.6-1.45; p = 0.76). COVID-19 vaccines significantly reduce the probability of death in patients suffering from a moderate or severe disease (oxygen therapy).

Wearable Temperature Sensor and Artificial Intelligence to Reduce Hospital Workload

Patient sensing and data analytics provide information that plays an important role in the patient care process. Patterns identified from data and Machine Learning (ML) algorithms can identify risk/abnormal patients' data. Due to automatization this process can reduce workload of medical staff, as the algorithms alert for possible problems. We developed an integrated approach to monitor patients' temperature applied to COVID-19 elderly patients and an ML process to identify abnormal behavior with alerts to physicians. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

IgG targeting distinct seasonal coronavirus- conserved SARS-CoV-2 spike subdomains correlates with differential COVID-19 disease outcomes.

Despite SARS-CoV-2 being a "novel" virus, early detection of anti-spike IgG in severe COVID-19 patients may be caused by the amplification of humoral memory responses against seasonal coronaviruses. Here, we examine this phenomenon by characterizing anti-spike IgG responses in non-hospitalized convalescent individuals across a spectrum of COVID-19 severity. We observe that disease severity positively correlates with anti-spike IgG levels, IgG cross-reactivity against other betacoronaviruses (ß-CoVs), and FcγR activation. Analysis of IgG targeting ß-CoV-conserved and non-conserved immunodominant epitopes within the SARS-CoV-2 spike protein revealed epitope-specific relationships: IgG targeting the conserved heptad repeat (HR) 2 region significantly correlates with milder disease, while targeting the conserved S2'FP region correlates with more severe disease. Furthermore, a lower HR2-to-S2'FP IgG-binding ratio correlates with greater disease severity, with ICU-hospitalized COVID-19 patients showing the lowest HR2/S2'FP ratios. These findings suggest that HR2/S2'FP IgG profiles may predict disease severity and offer insight into protective versus deleterious humoral recall responses.

Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence.

The coronavirus disease 2019 (COVID19) pandemic has left researchers scrambling to identify the humoral immune correlates of protection from COVID-19. To date, the antibody mediated correlates of virus neutralization have been extensively studied. However, the extent that non-neutralizing functions contribute to anti-viral responses are ill defined. In this study, we profiled the anti-spike antibody subtype/subclass responses, along with neutralization and antibody-dependent natural killer cell functions in 83 blood samples collected between 4 and 201 days post-symptoms onset from a cohort of COVID-19 outpatients. We observed heterogeneous humoral responses against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Overall, anti-spike profiles were characterized by a rapid rise of IgA and sustained IgG titers. In addition, strong antibody-mediated natural killer effector responses correlated with milder disease and being female. While higher neutralization profiles were observed in males along with increased severity. These results give an insight into the underlying function of antibodies beyond neutralization and suggest that antibody-mediated natural killer cell activity is a key function of the humoral response against the SARS-CoV-2 spike protein.

COVID Crisis and the Impact on Smart Tourism, Sustainable Development and Local Communities

Tourism is one of the industries most affected by the coronavirus-19 (COVID-19) crisis worldwide. Because tourism makes the largest contribution of any industry to Spain and Portugal’s gross domestic product, the crisis’s impact on local communities needs to be analysed in greater depth. This chapter details on how these communities have been affected by the pandemic and identifies which positive and negative factors influence residents’ wellbeing. The state-of-the-art of research on smart and sustainable tourism is examined, as well as on local communities’ resilience. Secondary data were gathered on Spain and Portugal to develop a fuller understanding of the phenomena under study, and the ways the COVID-19 crisis has affected these two countries’ vision of tourism. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Domestic violence during the CoviD-19 pandemic in Portugal

The measures implemented to combat the COVID-19 pandemic led populations to confinement at home, with increased risk of domestic violence due to extended shared time between victims and offenders. Evidence on domestic violence in times of pandemic is lacking. This study examines the occurrence of domestic violence, associated factors and help seeking during the COVID-19 pandemic. An online survey was conducted in Portugal between April and October 2020 by NOVA National School of Public Health. The survey was disseminated through partner networks, media, and institutions working within the scope of violence. Data were collected on the experience of domestic violence, and help seeking during the pandemic. In a total of 1,062 respondents, 146 (13.7%) reported having suffered domestic violence during the pandemic, including psychological (13.0%, n = 138), sexual (1.0%, n = 11), and physical (0.9%, n = 10) abuse. Overall, the lower the age, the more the reported domestic violence. Also, a higher proportion of participants who perceived difficulties to make ends meet during the pandemic reported domestic violence. Differences between women and men and across educational levels on reported domestic violence were not statistically significant. Bivariate logistic analyses showed that, among women, reported domestic violence was more likely among those with up to secondary education compared to higher education. Most of the victims did not seek help (62.3%), the main reasons being considering it unnecessary, that help would not change anything, and feeling embarrassed about what had happened. Only 4.3% of the victims sought police help. The most common reasons for not coming forward to form a complaint were considering the abuse was not severe and believing the police would not do anything. Our findings indicate that domestic violence during the COVID-19 pandemic was experienced by both sexes and across different age groups. There is a need for investing in specific support systems for victims of domestic violence to be applied to pandemic contexts, especially targeting those in more vulnerable situations and potentially underserved. © 2021 The Author(s). Published by S. Karger AG, Basel.

Abnormal Liver Function Test in Patients Infected with Coronavirus (SARS-CoV-2): A Retrospective Single-Center Study from Spain.

The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.

Heme oxygenase-1 inducer hemin does not inhibit SARS-CoV-2 virus infection.

Antiviral agents with different mechanisms of action could induce synergistic effects against SARS-CoV-2 infection. Some reports suggest the therapeutic potential of the heme oxygenase-1 (HO-1) enzyme against virus infection. Given that hemin is a natural inducer of the HO-1 gene, the aim of this study was to develop an in vitro assay to analyze the antiviral potency of hemin against SARS-CoV-2 infection. A SARS-CoV-2 infectivity assay was conducted in Vero-E6 and Calu-3 epithelial cell lines. The antiviral effect of hemin, and chloroquine as a control, against SARS-CoV-2 virus infection was quantified by RT-qPCR using specific oligonucleotides for the N gene. Chloroquine induced a marked reduction of viral genome copies in kidney epithelial Vero-E6 cells but not in lung cancer Calu-3 cells. Hemin administration to the culture medium induced a high induction in the expression of the HO-1 gene that was stronger in Vero-E6 macaque-derived cells than in the human Calu-3 cell line. However, hemin treatment did not modify SARS-CoV-2 replication, as measured by viral genome quantification 48 h post-infection for Vero-E6 and 72 h post-infection for the Calu-3 lineages. In conclusion, although exposure to hemin induced strong HO-1 up-regulation, this effect was unable to inhibit or delay the progression of SARS-CoV-2 infection in two epithelial cell lines susceptible to infection.

Disease spreading with social distancing: A prevention strategy in disordered multiplex networks.

The frequent emergence of diseases with the potential to become threats at local and global scales, such as influenza A(H1N1), SARS, MERS, and recently COVID-19 disease, makes it crucial to keep designing models of disease propagation and strategies to prevent or mitigate their effects in populations. Since isolated systems are exceptionally rare to find in any context, especially in human contact networks, here we examine the susceptible-infected-recovered model of disease spreading in a multiplex network formed by two distinct networks or layers, interconnected through a fraction q of shared individuals (overlap). We model the interactions through weighted networks, because person-to-person interactions are diverse (or disordered); weights represent the contact times of the interactions. Using branching theory supported by simulations, we analyze a social distancing strategy that reduces the average contact time in both layers, where the intensity of the distancing is related to the topology of the layers. We find that the critical values of the distancing intensities, above which an epidemic can be prevented, increase with the overlap q. Also we study the effect of the social distancing on the mutual giant component of susceptible individuals, which is crucial to keep the functionality of the system. In addition, we find that for relatively small values of the overlap q, social distancing policies might not be needed at all to maintain the functionality of the system.