Neural Network-Assisted Humanization of COVID-19 Hamster scRNAseq Data Reveals Matching Severity States in Human Disease (preprint)

Translating findings from animal models to human disease is essential for dissecting disease mechanisms, developing and testing precise therapeutic strategies. The coronavirus disease 2019 (COVID-19) pandemic has highlighted this need, particularly for models showing disease severity-dependent immune responses. Single-cell transcriptomics (scRNAseq) is well poised to reveal similarities and differences between species at the molecular and cellular level with unprecedented resolution. However, computational methods enabling detailed matching are still scarce. Here, we provide a structured scRNAseq-based approach that we applied to scRNAseq from blood leukocytes originating from humans and hamsters affected with moderate or severe COVID-19. Integration of COVID-19 patient data with two hamster models that develop moderate (Syrian hamster, Mesocricetus auratus) or severe (Roborovski hamster, Phodopus roborovskii) disease revealed that most cellular states are shared across species. A neural network-based analysis using variational autoencoders quantified the overall transcriptomic similarity across species and severity levels, showing highest similarity between neutrophils of Roborovski hamsters and severe COVID-19 patients, while Syrian hamsters better matched patients with moderate disease, particularly in classical monocytes. We further used transcriptome-wide differential expression analysis to identify which disease stages and cell types display strongest transcriptional changes. Consistently, hamsters response to COVID-19 was most similar to humans in monocytes and neutrophils. Disease-linked pathways found in all species specifically related to interferon response or inhibition of viral replication. Analysis of candidate genes and signatures supported the results. Our structured neural network-supported workflow could be applied to other diseases, allowing better identification of suitable animal models with similar pathomechanisms across species. Key PointsO_LINeural networks can successfully match disease states between animal models and humans using single-cell data as shown for COVID-19 C_LIO_LIModerately diseased patients best matched Syrian hamster cells; severely diseased patients best matched Roborovski hamster neutrophils C_LI

Transient anti-interferon autoantibodies in the airways are associated with efficient recovery from COVID-19 (preprint)

Pre-existing anti-interferon alpha (anti-IFN-) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN- autoantibodies in the airways - the initial site of infection - can also determine disease outcomes. In this study, we developed a new multiparameter technology, flowBEAT, to quantify and profile the isotypes of anti-IFN- and anti-SARS-CoV-2 antibodies in longitudinal samples collected over 20 months from the airway and matching blood of 129 donors with mild, moderate, and severe COVID-19. We found unexpectedly that nasal anti-IFN- autoantibodies were induced post-infection onset in more than 70% of mild to moderate COVID-19 cases and associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN- autoantibodies followed the peak of host IFN- production and waned with disease recovery, revealing a regulated balance between IFN- and anti-IFN- response. Notably, only a subset of mild to moderate patients progressed to develop systemic anti-IFN-, which correlated with systemic inflammation and worsened symptoms. In contrast, patients with life-threatening COVID-19 sustained elevated anti-IFN- in both airways and blood, coupled with uncontrolled viral load and IFN- production. Our studies thereby reveal a novel protective role for nasal anti-IFN- autoantibodies in the immunopathology of COVID-19 and, more broadly, suggest that anti-IFN- may serve an important regulatory function to restore homeostasis following viral invasion of the respiratory mucosa.

Developing a Video Game as an Awareness and Research Tool Based on SARS-CoV-2 Epidemiological Dynamics and Motivational Perspectives

In mid-2020, the University of Liège (ULiège, Belgium) commissioned the ULiège Video Game Research Laboratory (Liège Game Lab) and the AR/VR Lab of the HEC-Management School of ULiège to create a serious game to raise awareness of preventive measures for its university community. This project has its origins in two objectives of the institutional policy of ULiège in response to the crisis caused by SARS-CoV-2 to raise awareness among community members of various preventive actions that can reduce the spread of the virus and to inform about the emergence and progression of a pandemic. After almost two years of design, the project resulted in the creation of SARS Wars, a decision-making management game for browsers and smartphones. This article presents the creative process of the game, specifically the integration of an adapted SEIR (susceptible-exposed-infectious-recovered) model, as well as the modeling of intercompartmental circulation dynamics in the game's algorithm, and the various limitations observed regarding the game's original missions and possibilities for future work. The SARS-CoV-2 video game project may be considered an innovative way to translate epidemiology into a language that can be used in the scope of citizen sciences. On the one hand, it provides an engaging tool and encourages active participation of the audience. On the other hand, it allows us to have a better understanding of the dynamic changes of a pandemic or an epidemic (crisis preparedness, monitoring, and control) and to anticipate potential consequences in the given parameters at set time (emerging risk identification), while offering insights for impact on some parameters on motivation (social science aspect).

Transcriptional reprogramming of infiltrating neutrophils drives lung disease in severe COVID-19 despite low viral load

Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. Nevertheless, targeted studies within this vulnerable population are scant. Here, we applied multi-omics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, led to a persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of a transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to ARDS in a well-defined patient population disproportionally affected by severe COVID-19.

KEEPING COMMUNITY DURING A PANDEMIC: LGBTQ+ OLDER ADULTS AND THE VIRTUAL SENIOR CENTER

During the initial stages of the pandemic, 96% of all senior centers ceased in-person programming, leaving many older adults without resources for meals, socialization, and critical services (NCOA, 2020). As a result of this shutdown, risk factors such as being a member of the underserved LGBTQ+ community, identifying as part of a racial or ethnic minoritized group, and/or experiencing poverty contributed to an increased likelihood of experiencing difficulties in meeting basic needs, reduced immunity to COVID and experiencing isolation (Berg-Weger and Morley, 2020;Kuehn, 2021). Despite the closure of many senior centers, some organizations were well positioned to strategically utilize pre-existing resources to help the community (Pendergrast, 2021). One organization, SAGE Advocacy and Services for LGBTQ+ Elders, the first publicly funded senior advocacy organization for LGBTQ+ older adults in the US, was one of the first to effectively transition to becoming a virtual senior center within days after the start of the pandemic (NYC DOA, 2020). Having a group of front-line workers who were highly embedded in their community, helped facilitate effective organizational adaptation and transition to a virtual senior center. This presentation seeks to describe how staff and program facilitators became vital resources for maintaining connection to the community of LGBTQ+ older adults. Focus groups with SAGE senior center employees and program facilitators were conducted in summer of 2021. Data identified resiliencies and barriers for maintaining community, providing vital services, and mitigating isolation with LGBTQ+ elders. Lessons learned and implications for organizations facing crises will be shared.

Utilizing SEM-RFC to predict factors affecting online shopping cart abandonment during the COVID-19 pandemic.

Online shopping has accelerated during to the pandemic and an increase in online shopping cart abandonment (SCA) was also evident. The growth of online shopping is contributed by the rising middle class, high consumer spending, millennials, and a tech-savvy population which is valuable to the growth of e-commerce. This study aimed to predict the factors that affect SCA during the COVID-19 Pandemic utilizing the SEM-RFC hybrid. Several factors such as self-efficacy, attribute conflicts, hesitation at checkout, emotional ambivalence, choice process satisfaction, attitude, subjective norms, and perceived behavioral control were analyzed simultaneously. This study integrated the cognition-affect-behavior paradigm with the Theory of Planned Behavior to provide a conceptual framework measured through an online survey questionnaire answered by 1015 valid responses collected by convenience sampling. Results showed that Attitude, Attribute Conflict, Self-Efficacy, and Emotional Ambivalence are the primary significant factors affecting SCA. Amidst the pandemic, consumers still value the ease of use, convenience and safety of the mobile online shopping applications that they have, which they do not positively experience at this time. The findings of this study may be applied and extended by researchers, online retailers, and businesses to understand consumer's abandonment intentions. Moreover, the results and framework of this study may be capitalized on by the business sector to create marketing strategies and develop business models for a sustainable online shopping business worldwide.

Air leak syndromes (Pneumomediastinum, pneumothorax, and subcutaneous emphysema) in critically ill COVID-19 patients - Prevalence, risk factors, and outcome

Background: A high incidence of air leak syndromes (ALSs) has been reported in critically ill coronavirus disease 2019 (COVID-19) patients, which affects disease outcome. Objective: To evaluate the incidence, outcome, and risk factors associated with ALSs in critically ill COVID-19 patients receiving invasive or non-invasive positive pressure ventilation. Result: Out of 79 patients, 16 (20.2%) patients had ALS. The mean age of the ALS group was 48.6 ± 13.1 years as compared to 52.8 ± 13.1 (p = 0.260) years in the non-ALS group. The study group had a lower median body mass index (25.9 kg/m 2 vs 27.6 kg/m 2, P = 0.096), a higher D-dimer value (1179.5 vs 762.0, P = 0.024), lower saturation (74% vs 88%, P = 0.006), and a lower PF ratio (134 vs 189, P = 0.028) at presentation as compared to the non-ALS group. Patients with ALS had received a higher median positive end-expiratory pressure (PEEP) (10 cm vs 8 cm of water, P = 0.005). The pressure support, highest driving pressure, and peak airway pressure were not significantly different in the two groups. The ALS group had a significantly longer duration of hospital stay (17.5 vs 9 days, P = 0.003). Multiple logistic regression analyses indicated that patients who received inj. dexamethasone were less likely to develop ALS (OR: 12.6 (95% CI 1.6-95.4), P = 0.015). Conclusion: A high incidence of ALS is present in critically ill COVID-19 patients. High inflammatory parameters, severe hypoxia at presentation, and use of high PEEP are significant risk factors associated with ALS. The risk of developing ALS was lower in patients who received inj. dexamethasone. © Medical Journal of Dr. D.Y. Patil Vidyapeeth 2022.

The impact of the COVID-19 pandemic on medical conditions and medication adherence in people with chronic diseases.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted primary health care and pharmacy services, posing a challenge in people with chronic diseases who receive routine care. Currently, there exists limited literature on the indirect impact of the pandemic on chronic disease management, particularly related to accessibility to medications and health care resources. OBJECTIVES: To determine the prevalence of medical- and medication-related problems reported by people with chronic diseases during the pandemic. The secondary objective was to identify the barriers and contributing factors related to these medical- and medication-related problems. METHODS: The anonymous and voluntary, Web-based survey was filled out by interested adult respondents with chronic disease(s) across Michigan between September 1, 2020, and January 1, 2021. The primary outcome included self-reported medical- and medication-related problems during the pandemic. Secondary outcomes included potential risk factors for medical- and medication-related problems. Descriptive statistics was used to describe respondents' demographics, chronic disease characteristics, medication adherence, medical- and medication-related problems, and COVID-19-related factors. The multivariable Firth logistic regression was used to analyze correlations between potential risk factors associated with medical- and medication-related problems. RESULTS: A total of 1103 respondents completed the survey and were included in the analysis. Approximately, 51% of respondents reported a medication-related problem with 19.6% reported problems obtaining medication(s) and 31.7% reported forgetting or not taking their medication(s). The top reason for problems obtaining medication(s) was doctor's office being closed for in-person visit(s). In addition, of all responses, more than half reported worsening symptoms of their chronic disease(s) during the pandemic especially with psychiatric disorders (79.5%) and inflammatory bowel disease (60%). Respondents with a significantly higher risk of medication-related problems included those who were younger, were female, and had psychiatric disorder(s), diabetes, arthritis, or lupus, and respondents with a significantly higher risk of medical-related problems included those with multiple chronic diseases, psychiatric disorder(s), and heart failure. CONCLUSION: Understanding the consequences of the pandemic, such as medical- and medication-related problems, in this population is critical to improving health care accessibility and resources through potential outpatient pharmacy services during this and future pandemics.

Baricitinib attenuates the proinflammatory phase of COVID-19 driven by lung-infiltrating monocytes.

SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.

Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol.

INTRODUCTION: More than 1 million elective total hip and knee replacements are performed annually in the USA with 2% risk of clinical pulmonary embolism (PE), 0.1%-0.5% fatal PE, and over 1000 deaths. Antithrombotic prophylaxis is standard of care but evidence is limited and conflicting. We will compare effectiveness of three commonly used chemoprophylaxis agents to prevent all-cause mortality (ACM) and clinical venous thromboembolism (VTE) while avoiding bleeding complications. METHODS AND ANALYSIS: Pulmonary Embolism Prevention after HiP and KneE Replacement is a large randomised pragmatic comparative effectiveness trial with non-inferiority design and target enrolment of 20 000 patients comparing aspirin (81 mg two times a day), low-intensity warfarin (INR (International Normalized Ratio) target 1.7-2.2) and rivaroxaban (10 mg/day). The primary effectiveness outcome is aggregate of VTE and ACM, primary safety outcome is clinical bleeding complications, and patient-reported outcomes are determined at 1, 3 and 6 months. Primary data analysis is per protocol, as preferred for non-inferiority trials, with secondary analyses adherent to intention-to-treat principles. All non-fatal outcomes are captured from patient and clinical reports with independent blinded adjudication. Study design and oversight are by a multidisciplinary stakeholder team including a 10-patient advisory board. ETHICS AND DISSEMINATION: The Institutional Review Board of the Medical University of South Carolina provides central regulatory oversight. Patients aged 21 or older undergoing primary or revision hip or knee replacement are block randomised by site and procedure; those on chronic anticoagulation are excluded. Recruitment commenced at 30 North American centres in December 2016. Enrolment currently exceeds 13 500 patients, representing 33% of those eligible at participating sites, and is projected to conclude in July 2024; COVID-19 may force an extension. Results will inform antithrombotic choice by patients and other stakeholders for various risk cohorts, and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants. TRIAL REGISTRATION: NCT02810704.

P2P-COVID-GAN: Classification and Segmentation of COVID-19 Lung Infections From CT Images Using GAN

Early and automatic segmentation of lung infections from computed tomography images of COVID-19 patients is crucial for timely quarantine and effective treatment. However, automating the segmentation of lung infection from CT slices is challenging due to a lack of contrast between the normal and infected tissues. A CNN and GAN-based framework are presented to classify and then segment the lung infections automatically from COVID-19 lung CT slices. In this work, the authors propose a novel method named P2P-COVID-SEG to automatically classify COVID-19 and normal CT images and then segment COVID-19 lung infections from CT images using GAN. The proposed model outperformed the existing classification models with an accuracy of 98.10%. The segmentation results outperformed existing methods and achieved infection segmentation with accurate boundaries. The Dice coefficient achieved using GAN segmentation is 81.11%. The segmentation results demonstrate that the proposed model outperforms the existing models and achieves state-of-the-art performance.

Monoclonal Antibodies for Early Treatment of COVID-19 in a World of Evolving SARS-CoV-2 Mutations and Variants.

Monoclonal antibodies targeting the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 spike protein are important outpatient treatment options in coronavirus disease 2019 to mitigate progression of disease and prevent hospitalization. The impact of different RBD mutations on the efficacy of the available monoclonal antibodies and processes for incorporating this impact into treatment algorithms are ill defined. Herein, we synthesize the data surrounding the impact of key RBD mutations on the efficacy of US Food and Drug Administration Emergency Use Authorized monoclonal antibodies and describe our approach at Michigan Medicine at monitoring mutation frequency in circulating virus and developing an algorithm that incorporates these data into outpatient treatment pathways.

Propofol-Associated Hypertriglyceridemia in Coronavirus Disease 2019 Versus Noncoronavirus Disease 2019 Acute Respiratory Distress Syndrome.

OBJECTIVES: To characterize the incidence and characteristics of propofol-associated hypertriglyceridemia in coronavirus disease 2019 versus noncoronavirus disease 2019 acute respiratory distress syndrome. DESIGN: Single-center prospective, observational cohort study. SETTING: Medical ICU and regional infectious containment unit. PATIENTS: Patients with acute respiratory distress syndrome admitted from April 7, 2020, to May 15, 2020, requiring continuous propofol administration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 50 patients enrolled, 54% had coronavirus disease 2019 acute respiratory distress syndrome. Median Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 35.5 (interquartile range, 30.2-41) and 8 (interquartile range, 6-9). Pao2/Fio2 ratio was 130.5 (interquartile range, 94.5-193.8). Patients with coronavirus disease 2019-associated acute respiratory distress syndrome experienced a higher rate of hypertriglyceridemia (triglyceride ≥ 500 mg/dL) than noncoronavirus disease 2019-associated acute respiratory distress syndrome (9 [33.3%] vs 1 [4.3%]; p = 0.014). Those with coronavirus disease 2019, compared with those without, received more propofol prior to becoming hypertriglyceridemic (median, 5,436.0 mg [interquartile range, 3,405.5-6,845.5 mg] vs 4,229.0 mg [interquartile range, 2,083.4-4,972.1 mg]; p = 0.027). After adjustment for propofol dose with logistic regression (odds ratio, 5.97; 95% CI, 1.16-59.57; p = 0.031) and propensity score matching (odds ratio, 8.64; 95% CI, 1.27-149.12; p = 0.025), there remained a significant difference in the development of hypertriglyceridemia between coronavirus disease 2019-associated acute respiratory distress syndrome and noncoronavirus disease 2019-associated acute respiratory distress syndrome. There was no difference between groups in time to hypertriglyceridemia (p = 0.063). Serum lipase was not different between those who did or did not develop hypertriglyceridemia (p = 0.545). No patients experienced signs or symptoms of pancreatitis. CONCLUSIONS: Patients with coronavirus disease 2019 acute respiratory distress syndrome experienced a higher rate of propofol-associated hypertriglyceridemia than noncoronavirus disease 2019 acute respiratory distress syndrome patients, even after accounting for differences in propofol administration.

COVID-19 response measures - a Singapore Neurosurgical Academic Medical Centre experience segregated team model to maintain tertiary level neurosurgical care during the COVID-19 outbreak.

AIM: This article aims to inform and share the experience of a Singaporean tertiary level neurosurgical unit in an academic medical centre during the COVID-19 outbreak. METHOD: This is a descriptive study of our segregation team model which is designed with the aim of optimizing manpower and ensuring the safety and welfare of the neurosurgical unit, while maintaining and prioritizing excellent patient care. RESULT: We describe our method of team segregation, rostering, and outline some principles that we adhere to in its design. We also summarise the restructuring of our inpatient and outpatient service, including the operating theatre and protocols for specific procedures, intensive care and general wards, as well as clinic services and multidisciplinary meetings. CONCLUSION: We end with a commentary on residency training and anticipated challenges. Given the likely protracted course of the pandemic, it is key to account for sustainability of such measures and the conservation of resource via the reduction of pateint volume, upkeep of staff emotional and physical health and harnessing technologies such as telemedicine.