Aging shapes infection profiles of influenza A virus and SARS-CoV-2 in human lung slices (preprint)

The recent coronavirus disease 2019 (COVID-19) outbreak revealed the susceptibility of elderly patients to respiratory virus infections, showing cell senescence or subclinical persistent inflammatory profiles and favouring the development of severe pneumonia. In our study, we evaluated the potential influence of lung aging on the efficiency of replication of influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), as well as determined the pro-inflammatory and antiviral responses of the distal lung tissue. Using precision-cut lung slices (PCLS) from donors of different ages, we found that pandemic H1N1 and avian H5N1 IAV replicated in the lung parenchyma with high efficacy. In contrast to these IAV strains, SARS-CoV-2 early isolate and Delta variant of concern (VOC) replicated less efficiently in PCLS. Interestingly, both viruses showed reduced replication in PCLS from older compared to younger donors, suggesting that aged lung tissue represents a sub optimal environment for viral replication. Regardless of the age-dependent viral loads, PCLS responded to infection with both viruses by an induction of IL-6 and IP-10/CXCL10 mRNAs, being highest for H5N1. Finally, while SARS-CoV-2 infection was not causing detectable cell death, IAV infection caused significant cytotoxicity and induced significant early interferon responses. In summary, our findings suggest that aged lung tissue might not favour viral dissemination, pointing to a determinant role of dysregulated immune mechanisms in the development of severe disease.

Managing Patients with Immune-Mediated Inflammatory Diseases on Disease-Modifying Antirheumatic Drug Therapy in a COVID-19 Endemic World: A Narrative Review and Expert Insights (preprint)

During the coronavirus disease 2019 (COVID-19) pandemic, individuals with immune-mediated inflammatory diseases (IMIDs), such as systemic lupus erythematosus and rheumatoid arthritis, face a heightened risk of infection and severe outcomes due to immunological alterations resulting from their underlying conditions and immunosuppressive treatments. Even as the pandemic has transitioned to an endemic state, it remains crucial to recognize that these patients continue to be at risk. In this narrative review, we analyzed existing literature to explore the impact of IMIDs, clinical risk factors, and the influence of immunosuppressive therapies on COVID-19-related risks and outcomes. Notably, certain disease-modifying antirheumatic drugs (DMARDs), like rituximab, are associated with worse COVID-19 outcomes, and rituximab-treated patients show impaired immune responses to COVID-19 vaccination. Additionally, we outline the diverse effects of glucocorticoids on COVID-19 outcomes and management. To highlight real-life challenges faced by clinicians caring for patients with IMIDs, we present an illustrative scenario that underscores the importance of effective vaccination, timely boosting, and additional mitigation strategies against COVID-19. Given the clinical heterogeneity and diverse disease states within IMIDs, it is crucial to understand the ongoing implications and risks associated with COVID-19 in these patients, to guide the implementation of appropriate measures and optimize care and outcomes in the current endemic era.

Perceptions of COVID-19 Vaccination among Organ Transplant Recipients (preprint)

Understanding vaccine hesitancy in organ transplant recipients (OTR) is critical, given clear, alt-hough attenuated, benefits from vaccination. Adult OTR were surveyed regarding vaccine-related values and a novel outcome variable called Vaccine Acceptance Composite Score (VACS) was built as the average Likert score of 7 domains of vaccination confidence. Of 46 OTR included (93.5% kidney transplant recipients), 32.6% were female, 13.3% Black, 6.77% Hispan-ic/Latino/a/x; median age was 58 years. Patients were most concerned about COVID-19 vac-cine-associated risks (46.3%), its potential effect on allograft (47.6%) and motives of government officials involved with vaccine policy (55.6%). Politically conservative patients were likely to have a significantly lower VACS, while those who lived with someone ≥65 had a higher VACS. The VACS was not significantly associated with race, income, religious beliefs, comorbidities, COVID-19 history, or influenza vaccination status. Higher VACS was significantly associated with ≥3 and ≥4 COVID-19 immunizations. This study highlighted political beliefs and elderly household members as correlates of vaccine acceptance among OTR. The VACS may be a useful tool to help standardize multifaceted analyses in vaccination-focused behavioral research, as well as identify individuals and groups at risk for vaccine hesitancy, who may benefit from tai-lored outreach and educational interventions.

Post-COVID-19: Time to Change Our Way of Life for a Better Future (preprint)

Rationale - From the year 1 anno Domini until 1855 with the third Plague, major pandemics occurred on average every 348 years. Since then, they have occurred on average every 33 years, with Coronavirus disease 2019 (COVID-19) now underway.Even though current technologies have greatly improved the way of life of human beings, COVID-19, with more than 700 000 000 cases and 6 950 000 deaths worldwide by the end of 2023, reminds us that much remains to be done. Objective - Given the frequency and duration of recent pandemics, it might be wise to start thinking about preventative methods to minimize the impact of future pandemics. This report looks back at 18 months of COVID-19, from March 2020 to August 2021, with the aim of highlighting potential solutions that could prove practical, or even essential, for the future. Material - COVID-19 data, including case and death reports, were extracted daily from the Worldometer platform to build a database for macroscopic analysis of the spread of the virus around the world. Demographic data were integrated into the COVID-19 database for a better understanding of the spatial spread of the SARS-CoV-2 virus in cities/municipalities. Method - Without loss of generality, we only analyzed data from the top 30 (out of 200 and above) countries ranked by total number of COVID-19 cases. Statistics (regression, t-test (p < 0.05), correlation, mean ± std, etc.) were carried out with Excel software. Spectral analysis, using Matlab software, was also used to try to better understand the temporal spread of COVID-19. Results - A good linear correlation was observed between the number of cases and the respective number of deaths depending on the country, i.e. y = 0.0121x + 19559 with R² = 0.8042. The analysis then focused mainly on the number of cases.This study showed that COVID-19 mainly affects G20 countries. The most interesting result is that cities/municipalities with high population density are a powerful activator of the spread of the virus. The current demographic context seems to be becoming a societal problem that must be addressed adequately.Spectral analysis highlighted that the very first months of spread of COVID-19 were the most notable with a strong expansion of the SARS-CoV-2 virus. On the other hand, the following six months showed a certain stability due mainly to multiple preventive measures such as confinement, closure of non-essential services, wearing of masks, distancing of 2 meters, etc. Discussion - Analysis of case and death data showed that COVID-19 mainly affects G20 countries. Nevertheless, the most interesting result of this study is that cities and municipal areas with population densities of several thousand inhabitants per square kilometer largely favored the spread of the SARS-CoV-2 virus. It is believed that such a demographic context is becoming a societal problem that developed countries around the world will sooner or later face and therefore needs to be adequately addressed. Conclusion - COVID-19 has made us understand that it is time to act both preventatively and curatively. Phenomenological insights suggest that the next pandemic could occur in less than 50 years. It may be time to launch new societal projects aimed at relieving congestion in densely populated regions.

Burnout in Medical Specialists Redeployed to Emergency Care During the COVID-19 Pandemic (preprint)

Burnout represents a concern for all healthcare providers, particularly those specializing in emergency medical care for whom burnout outcomes have been well-documented. What remains unknown is the effect of burnout on redeployed medical specialists during the COVID-19 pandemic from an appointment-centered practice to emergency care directed by public health considerations. This research aims to identify and assess the burnout responses of fourteen medical specialties noted in searched returns of the four most cited articles published since 2020 about non-emergency physicians regarding their burnout brought on by the unanticipated need for them to provide emergency care during the recent pandemic. The hypothesis is that medical specialists accustomed to planning for emergency possibilities in their appointment-centered practice would demonstrate the least burnout regarding COVID-19-related emergencies. Considering coping as a process based on Lazarus's research, comparing and ranking the COVID-19 emergency responses across the various normally appointment-centered medical specialties in their employed coping strategies determines the outcome. With the hypothesis supported, suggested interventions for future pandemics—when these specialists are, again, redeployed to emergency care directed by public health considerations—are those coping strategies identified as most effective in reducing burnout while maintaining the viability of the medical specialty and excellent patient care.

Uncovering Latent Arguments in Social Media Messaging by Employing LLMs-in-the-Loop Strategy (preprint)

The widespread use of social media has led to a surge in popularity for automated methods of analyzing public opinion. Supervised methods are adept at text categorization, yet the dynamic nature of social media discussions poses a continual challenge for these techniques due to the constant shifting of the focus. On the other hand, traditional unsupervised methods for extracting themes from public discourse, such as topic modeling, often reveal overarching patterns that might not capture specific nuances. Consequently, a significant portion of research into social media discourse still depends on labor-intensive manual coding techniques and a human-in-the-loop approach, which are both time-consuming and costly. In this work, we study the problem of discovering arguments associated with a specific theme. We propose a generic LLMs-in-the-Loop strategy that leverages the advanced capabilities of Large Language Models (LLMs) to extract latent arguments from social media messaging. To demonstrate our approach, we apply our framework to contentious topics. We use two publicly available datasets: (1) the climate campaigns dataset of 14k Facebook ads with 25 themes and (2) the COVID-19 vaccine campaigns dataset of 9k Facebook ads with 14 themes. Furthermore, we analyze demographic targeting and the adaptation of messaging based on real-world events.

The Psychological Ability to Cope Reduced Infections During the Pandemic: A Two-Year Population-Based Study of The Determinants of 123 Million COVID-19 Test Results in Denmark (preprint)

During the COVID-19 pandemic, a key concern for authorities was to identify and activate the psychological states most likely to motivate the public to engage in protective behavior such as physical distancing and hygienic protection. While feelings of fear and threat were rampant during the pandemic, theories of health psychology have highlighted appraisals related to the ability to cope (e.g., the feeling of being able to cost-effectively adhere to government advice) and argued that coping appraisals are superior predictors of motivations to protect the self against risks. In this study, we provide a massive population-based comparison of the association between, on the one hand, threat appraisals, and coping appraisals and, on the other hand, protection against actual infection during the COVID-19 pandemic. To this end, we utilize a unique data infrastructure from Denmark that couple surveys of 8 % of the adult Danish population (N= 386.633) with the individual results of all 123 million COVID-19 tests performed in Denmark during 23 months of the COVID-19 pandemic. Overall, controlling for a comprehensive range of sociodemographic measures and employing panel data to bolster internal validity, we observe that stronger coping appraisals are consistently associated with lower individual probability of COVID-19 infection risk. We find no con-sistent evidence for a similar association for threat appraisals. Threat appraisals rather seem to index – to some extent, accurately – individual feelings of infection exposure. As appeals to fear also have unintended negative consequences (includ-ing anxiety, fatigue, and stigmatization), the findings provide strong empirical support for relying on coping-oriented public health communication in future societal crises in the domain of health and beyond.

Retrospective Analysis of Clostridioides difficile Infection Rates in Hospitalized Patients during COVID-19 Pandemic. A Unicenter Study in Reus, Spain (preprint)

.Background: Clostridioides difficile infections (CDI) vary in severity from mild diarrhea to life-threatening conditions like pseudomembranous colitis or toxic megacolon, often leading to sepsis and death. The COVID-19 pandemic prompted changes in healthcare practices, potentially affecting CDI incidence, though reported data are inconclusive. We studied factors influencing CDI incidence and outcomes at a university hospital throughout the COVID-19 pandemic years. Methods: We conducted a retrospective study on all adult hospitalized CDI cases from January 1, 2020, to December 31, 2022. We collected demographic information, comorbid conditions, and concurrent infections. Results: While overall CDI and COVID-19 rates decreased in 2022, a nota-ble increase in CDI infections was observed among oncological patients and those undergoing some aggressive treatments, such as colon or gastroscopies. The prevalence of comorbidities remained unmodified, and there were declines in prior gastrointestinal surgeries and proton pump inhibitor prescriptions. Factors associated with patient fatality or prolonged hospitaliza-tion included older age, cancer, chronic kidney disease, higher Charlson and McCabe indices, elevated C-reactive protein, and low albumin concentrations. Conclusion: Our study shows the evolving landscape of CDI during the COVID-19 pandemic and emphasizes the impact of de-layed diagnoses and treatments exacerbated by telemedicine adoption. Identified risk factors for CDI-related mortality or prolonged hospital stays underscore the importance of targeted inter-ventions in high-risk populations.

Saving High-Risk Patients from COVID-19 Severity and Death Mainly with Plant-Based Diets and Supplements (preprint)

Our report presents the findings from a treatment program that involved plant-based diets (PBDs) and supplements for 1,750 elderly cardiology patients diagnosed with COVID-19 between April 2020 and June 2023. At the start of the program, there was no published data supporting the use of PBDs for COVID-19 patients. However, after 18 months, studies were released that indicated the effectiveness of PBDs in decreasing the incidence and severity of COVID-19. Our treatment protocol differed from these studies in several ways. We carefully controlled the quality, quantity, and processing method of the foods we provided, opting for raw instead of cooked vegetables. Additionally, we incorporated supplementation that complemented the nutrients lacking in a PBD and enhanced the anti-viral, anti-inflammatory, antioxidant, antithrombotic, and immunomodulatory properties of a PBD. Our patients recovered faster (12±1.4 days vs. 20.9±4.3 days), with lower severity (2% vs. 10-20%), hospitalizations (0 vs. 5-10%), and deaths (0 vs. 15-17%) compared to the general population. These favorable outcomes are particularly noteworthy given Indonesia's high COVID-19 morbidity and mortality rates, among the highest in Asia. The findings of this report provide valuable insights for practitioners in managing high-risk elderly COVID-19 patients, particularly in avoiding severity and mortality.

SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike S2-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike S2 were found to have increased cell viability as compared to control cells. Further observations on gamma-H2AX expression in spike S2-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics.