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<title>20 April, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Social identification and risk dynamics: how perceptions of (inter)personal and collective risk impact the adoption of COVID-19 preventative behaviours</strong> -
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Public adoption of preventative behaviours to reduce the transmission of COVID-19 is crucial to managing the pandemic, and so it is vital to determine what factors influence the uptake of those behaviours. Previous studies have identified COVID-19 risk perceptions as a key factor, but this work has typically been limited both in assuming that risk means risk to the personal self, and in being reliant on self-reported data. Drawing on the social identity approach (Reicher, Spears and Haslam, 2010), we conducted two online studies in which we investigated the effects of two different types of risk on preventative measure taking: risk to the personal self and risk to the collective self (i.e. members of a group with which one identifies). Both studies involved behavioural measures using innovative interactive tasks. In Study 1 (n = 199; data collected 27 May 2021), we investigated the effects of (inter)personal and collective risk on physical distancing. In Study 2 (n = 553; data collected 20 September 2021), we investigated the effects of (inter)personal and collective risk on the speed at which tests are booked as COVID-19 symptoms develop. In both studies, we find that perceptions of collective risk, but not perceptions of (inter)personal risk, influence the extent to which preventative measures are adopted. We discuss the implications both conceptually (as they relate to both the conceptualisation of risk and social identity processes) and also practically (in terms of the implications for public health communications).
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🖺 Full Text HTML: <a href="https://osf.io/vw7ze/" target="_blank">Social identification and risk dynamics: how perceptions of (inter)personal and collective risk impact the adoption of COVID-19 preventative behaviours</a>
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<li><strong>An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy</strong> -
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COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where the human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.18.537373v1" target="_blank">An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy</a>
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<li><strong>COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator</strong> -
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Silent hypoxemia, or `happy hypoxia’, is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation (SaO280%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model (Diekman et al., 2017, J. Neurophysiol) of the respiratory neural network can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or the nucleus tractus solitarii are responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.19.536507v1" target="_blank">COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator</a>
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<li><strong>Frequency Of pRenatal CAre viSiTs (FORCAST): study protocol to develop a core outcome set for prenatal care schedules</strong> -
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Abstract Background: Prenatal care, one of the most common preventive care services in the United States, endeavors to improve pregnancy outcomes through evidence-based screenings and interventions. Despite the prevalence of prenatal care and its importance to maternal and infant health, there are several debates about the best methods of prenatal care delivery, including the most appropriate schedule frequency and content of prenatal visits. Current U.S. national guidelines recommend that low-risk individuals receive a standard schedule of 12 to 14 in-office visits, a care delivery model that has remained unchanged for almost a century. Objectives: In early 2020, to mitigate individuals exposure to the SARS-CoV-2 virus, prenatal care providers implemented new paradigms that altered the schedule frequency, interval, and modality (e.g., telemedicine) of how prenatal care services were offered. In this manuscript, we describe development of a core outcome set (COS) that can be used to evaluate the effect of the frequency of prenatal care schedules on maternal and infant outcomes. Methods: We will systematically review the literature to identify previously reported outcomes important to individuals who receive prenatal care and the people who care for them. Stakeholders with expertise in prenatal care delivery (i.e., patients/family members, healthcare providers, and public health professionals and policymakers) will rate the importance of identified outcomes in an online survey using a three-round Delphi process. A virtual consensus meeting will be held for a group of stakeholder representatives to discuss and vote on the outcomes to include in the final COS. Results: The Delphi survey was initiated in July 2022 with 71 stakeholders invited. A virtual consensus conference was conducted on October 11, 2022. Data is currently under analysis. Conclusions: More research about the optimal schedule frequency and modality for prenatal care delivery is needed. Standardizing outcomes that are measured and reported in evaluations of the recommended prenatal care schedules will assist evidence synthesis and results reported in systematic reviews and meta-analyses. Overall, this COS will expand the consistency and patient-centeredness of reported outcomes for various prenatal care delivery schedules and modalities, hopefully improving the overall efficacy of recommended care delivery for pregnant people and their families.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.17.23288705v1" target="_blank">Frequency Of pRenatal CAre viSiTs (FORCAST): study protocol to develop a core outcome set for prenatal care schedules</a>
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<li><strong>A Perspective on Mature Gratitude as a Way of Coping with COVID-19</strong> -
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Aim and Method: This perspective searches presents evidence of mature gratitude as a way of coping with the threats and boundaries of COVID-19. This narrative, non-systematic review will be based on studies from the COVID-19 period in association with more general literature on the characteristics of mature gratitude related to good mental health. Results: The results from the literature suggest that a confrontation with our existential vulnerability during a pandemic is not only a crisis but also an opportunity to view our lives in a different way. Mature gratitude, as proposed in this perspective, can help us in coping with the threats and boundaries that are part of our lives due to the COVID-19 pandemic. This time of crisis gives us the opportunity to self-reflect on our current life and plans for the future and to reframe them through a positive lens which can encourage individuals to actively strengthen their psychological resilience and coping skills. Conclusion: Cultivating an attitude of mature gratitude through actions of kindness, expressing being thankful for life and God, and enjoying all the small things in life helps in coping with the current threats of COVID-19 and building lifelong resilience for the future Knowledge about these associations can help psychologists, counselors, and coaches to support people who experience psychological issues due to the current pandemic and all crises to come.
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🖺 Full Text HTML: <a href="https://psyarxiv.com/b9zq4/" target="_blank">A Perspective on Mature Gratitude as a Way of Coping with COVID-19</a>
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<li><strong>Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants</strong> -
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Among the multiple SARS-CoV-2 variants recently reported, the Delta variant has generated most perilous and widespread effects. Another variant, Omicron, has been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations and in numbers much larger than those of its predecessor variants. In this report we discuss some essential structural aspects and time-based structure changes of a selected set of spike protein mutations within the Delta and Omicron variants. The expected impact of multiple-point mutations within the spike protein’s receptor-binding domain (RBD) and S1 of these variants are examined. Additionally, RBD of the more recently emerged subvariants BA.4, BA.5 and BA.2.12.1 are discussed. Within the latter group, BA.5 represents globally, the most prevalent form of SARS-CoV-2 at the present time. Temporal mutation profile for the subvariant BF.7 and currently circulating variants of interest (VOI) and variants under monitoring (VUMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB and XBF are computationally explored here briefly with the expectation that these structural data will be helpful to identify drug targets and to neutralize antibodies for the evolving variants/subvariants of SARS-CoV-2.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.25.493484v5" target="_blank">Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants</a>
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<li><strong>Post-COVID-19 syndrome and insulin resistance 20 months after a mild COVID-19</strong> -
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Objective SARS-CoV-2 infection is associated with impaired glucose metabolism. Although the mechanisms are not fully understood, insulin resistance (IR) appears to be a central factor. Patients who had a severe acute phase, but even asymptomatic or with mild COVID-19, have an increased risk of T2DM. After the acute phase, post-COVID-19 syndrome (PCS) also seems to be related to this metabolic disturbance, but there is a paucity of studies. This study aims to evaluate a possible relationship between PCS and IR after mild COVID-19 and, if confirmed, whether there are differences by sex. Subjects and methods Retrospective observational cohort study including subjects who had mild COVID-19 between April and September 2020 in a community setting. None had been vaccinated against SARS-CoV-2 at inclusion, and previous T2DM and liver disease were exclusion criteria. Patients who met NICE criteria were classified as PCS+. Epidemiological and laboratory data were analysed. Three assessments were performed: 1E (pre-COVID-19, considered baseline and reference for comparisons), 2E (approximately 3 months after the acute phase), and 3E (approximately 20 months after the acute phase). A triglyceride-to-glucose (TyG) index ≥8.74 was considered IR. Albumin-to-globulin ratio (AGR) and lactate dehydrogenase (LDH) were assessed as inflammatory markers. Bivariate analyses were performed, using nonparametric and repeated measures tests. A subsample without metabolic disorder or CVD (age< median, BMI<25 kg/m^2, elevated AGR, TyG index=7.80 [0.5]) was generated to reasonably rule out prior baseline IR that could bias the results. The relationships between PCS and TyG in 3E (TyG3) were modeled in 8 multiple regressions, stratifying by sex and BMI combinations. Results A total of 112 subjects (median [IQR] of age= 44 [20] years; 65 women) were analysed. Up to 14.3% was obese and 17% was hypertensive. Significant increases between 1E and 3E were registered regarding (i) basal glycemia (BG), 87 [14] mg/dL vs. 89 [14]; p=0.014, (ii) TyG index (8.25 [0.8] vs. 8.32 [0.7]; p=0.002), and (iii) LDH in 3rd tertile (16.1% vs 32.1%; p=0.007). A total of 8 previously normoglycemic subjects, showed BG2 or BG3 >126 mg/dL. The subgroups with IR highest prevalence at 3E were those of BMI ≥25 kg/m^2 and PCS+. The subgroup without CVD presented a significant increase in the TyG index (TyG1=7.80 [0.1] vs. TyG3= 8.28 [0.1]; p=0.017). LDH1 was significantly correlated with TyG3 in both sexes (rho=0.214 in women, rho=0.298 in men); in contrast, LDH2 and LDH3 did not present such an association. In multivariable analysis, PCS has shown to be an independent and predictive variable of TyG index in women with BMI<25 kg/m^2, after adjustment for age, hypertension, BMI, Charlson comorbidity index, AGR1, AGR2, LDH1, number of symptoms of acute COVID-19, and number of days of the acute episode (beta coefficient=0.350; p=0.039). Conclusions PCS has played a secondary role in predicting IR, showing a modest effect compared to BMI or prior hypertension. A significant increase in IR has been noted 20 months after mild COVID-19, both in cases of previous baseline IR and in those without previous IR. Basal serum LDH has shown to be predictive of current TyG, regardless of elevated LDH after SARS-CoV-2 infection. There were profound differences between women and men, confirming the need for a sex-stratified analysis when addressing the relation between PCS and glycemic alterations.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.17.23288637v1" target="_blank">Post-COVID-19 syndrome and insulin resistance 20 months after a mild COVID-19</a>
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<li><strong>Infection Risk Shifts of Protests During Pandemics</strong> -
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This research article examines the dual impact of protests on COVID-19 spread, a challenge for policymakers balancing public health and the right to assemble. Using a game theoretical model, it shows that protests can shift infection risks between counties, creating a dilemma for regulators. The empirical study analyzes two German protests in November 2020 using proprietary data from a bus-shuttle service, finding evidence to support the assumption that protests can shift infection risks. The article concludes by discussing the implications of these findings for policymakers, highlighting that regulators9 individually rational strategic decisions may lead to inefficient outcomes.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.15.23288618v1" target="_blank">Infection Risk Shifts of Protests During Pandemics</a>
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<li><strong>Bivalent mRNA-1273.214 vaccine effectiveness in Qatar</strong> -
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Qatar introduced COVID-19 bivalent vaccination for persons ≥12 years old using the 50-μg mRNA-1273.214 vaccine combining SARS-CoV-2 ancestral and omicron BA.1 strains. We estimated effectiveness of this bivalent vaccine against SARS-CoV-2 infection using a matched, retrospective, cohort study. Matched cohorts included 10,886 persons in the bivalent cohort and 53,901 persons in the no-recent-vaccination cohort. During follow-up, 36 infections were recorded in the bivalent cohort and 211 were recorded in the no-recent-vaccination cohort. None progressed to severe, critical, or fatal COVID-19. Cumulative incidence of infection was 0.53% (95% CI: 0.35-0.79%) in the bivalent cohort and 0.55% (95% CI: 0.47-0.65%) in the no-recent-vaccination cohort, 105 days after the start of follow-up. Incidence during follow-up was dominated by omicron XBB* subvariants including XBB, XBB.1, XBB.1.5, XBB.1.9.1, and XBB.1.9.2. The adjusted hazard ratio comparing incidence of infection in the bivalent cohort to that in the no-recent-vaccination cohort was 0.75 (95% CI: 0.53-1.08). Bivalent vaccine effectiveness against infection was 24.7% (95% CI: -7.0-47.2%). Effectiveness was 16.4% (95% CI: -24.6-47.3%) among persons with no prior infection and 35.3% (95% CI: -12.6-63.4%) among persons with prior infection. mRNA-1273.214 reduced incidence of SARS-CoV-2 infection, but the protection was modest at only ~25%. The modest protection may have risen because of XBB* immune evasion or immune imprinting effects, or combination of both.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.15.23288612v1" target="_blank">Bivalent mRNA-1273.214 vaccine effectiveness in Qatar</a>
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<li><strong>Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants</strong> -
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Anosmia was identified as a hallmark of COVID-19 early in the pandemic, however, with the emergence of variants of concern, the clinical profile induced by SARS-CoV-2 infection has changed, with anosmia being less frequent. Here, we assessed the clinical, olfactory and neuroinflammatory conditions of golden hamsters infected with the original Wuhan SARS-CoV-2 strain, its isogenic ORF7-deletion mutant and three variants: Gamma, Delta, and Omicron/BA.1. We show that infected animals developed a variant-dependent clinical disease including anosmia, and that the ORF7 of SARS-CoV-2 contributes to the induction of olfactory dysfunction. Conversely, all SARS-CoV-2 variants were found to be neuroinvasive, regardless of the clinical presentation they induce. Taken together, this confirms that neuroinvasion and anosmia are independent phenomena upon SARS-CoV-2 infection. Using newly generated nanoluciferase-expressing SARS-CoV-2, we validated the olfactory pathway as a major entry point into the brain in vivo and demonstrated in vitro that SARS-CoV-2 travels retrogradely and anterogradely along axons in microfluidic neuron-epithelial networks.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.08.31.505985v2" target="_blank">Neuroinvasion and anosmia are independent phenomena upon infection with SARS-CoV-2 and its variants</a>
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<li><strong>Exploring Physical and Biological Manifestations of Burnout and Post-Traumatic Stress Disorder Symptoms in Healthcare Workers: A Scoping Review Protocol</strong> -
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Introduction: The COVID-19 pandemic has strained the mental and physical well-being of healthcare workers (HCW). Increased work-related stress and limited resources has increased symptoms of anxiety, depression, insomnia, and post-traumatic stress disorder (PTSD) in this population. Stress-related disorders have been strongly associated with long-term consequences including cardiometabolic disorders, endocrine disorders and premature mortality. This scoping review aims to explore available literature on burnout, PTSD, and other mental health-associated symptoms in HCW to synthesize relationships with physiological and biological biomarkers that may be associated with increased risk of disease, creating an opportunity to summarize current biomarker knowledge and identify gaps in this literature. Methods and Analysis: This scoping review uses the Arksey and O,Malley six-step scoping review methodology framework. The research team will select appropriate primary sources using a search strategy developed in collaboration with a health sciences librarian. Three reviewers will initially screen the title and abstracts obtained from the literature searches, and two reviewers will conduct independent reviews of full-text studies for inclusion. The research team will be reviewing literature focusing on which burnout and/or PTSD-associated physiological and biological biomarkers have been studied, the methodologies used to study them and the correlations between the biomarkers and HCW experiencing burnout/PTSD. Data extraction forms will be completed by two reviewers for included studies and will guide literature synthesis and analysis to determine common themes. Ethics and Dissemination: This review does not require ethical approval. We expect results from this scoping review to identify gaps in the literature and encourage future research regarding improving biologic and physiologic biomarker research in HCW. Preliminary results and general themes will be communicated back to stakeholders. Results will be disseminated through peer-reviewed publications, policy briefs, and conferences, as well as presented to stakeholders to an effort to invest in HCW mental and physical health.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.16.23288657v1" target="_blank">Exploring Physical and Biological Manifestations of Burnout and Post-Traumatic Stress Disorder Symptoms in Healthcare Workers: A Scoping Review Protocol</a>
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<li><strong>Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations</strong> -
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SARS-CoV-2 antibody levels associated with reduced hospitalization risk remain undefined. Our outpatient COVID-19 convalescent plasma (CCP), placebo-controlled trial observed SARS-CoV-2 antibody levels decreasing 22-fold from matched donor units into post-transfusion seronegative recipients. Unvaccinated recipients were jointly stratified by a) early or late transfusion (< 5 or >5 days from symptom onset) and b) high or low post-transfusion SARS-CoV-2 antibody levels (< or > geometric mean). Early treatment with high post-transfusion antibody levels reduced hospitalization risk-0/102 (0%) compared to all other CCP recipients-17/370 (4.6%; Fisher exact-p-0.03) and to all control plasma recipients-35/461 (7.6%; Fisher exact p-0.001). A similar donor upper/lower half antibody level and early late transfusion stratified analyses indicated significant hospital risk reduction. Pre-transfusion nasal viral loads were similar in CCP and control recipients regardless of hospitalization outcome. Therapeutic CCP should comprise the upper 30% of donor antibody levels to provide effective outpatient use for immunocompromised and immunocompetent outpatients.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.13.23288353v1" target="_blank">Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations</a>
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<li><strong>Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial</strong> -
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Background: Empagliflozin has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory, metabolic and haemodynamic effects. Methods: In this randomised, controlled, open-label trial, several possible treatments are compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus empagliflozin 10mg once daily for 28 days or until discharge using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. On 3 March the independent data monitoring committee recommended that the investigators review the data and recruitment was consequently stopped on 7 March. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936). Findings: Between 8 July 2021 and 6 March 2023, 4271 patients were randomly allocated to receive either empagliflozin (2113 patients) or usual care alone (2158 patients). Overall, 289 (14%) patients allocated to empagliflozin and 307 (14%) patients allocated to usual care died within 28 days (rate ratio 0.96; 95% confidence interval [CI] 0.82-1.13; p=0.64). There was no evidence of significant differences in duration of hospitalisation (median 8 days vs. 8 days) or the proportion of patients discharged from hospital alive within 28 days (79% vs. 78%; rate ratio 1.03; 95% CI 0.96-1.10; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no evidence of a significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (16% vs. 17%; risk ratio 0.95; 95% CI 0.84-1.08; p=0.44). Interpretation: In adults hospitalised with COVID-19, empagliflozin was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.13.23288469v1" target="_blank">Empagliflozin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial</a>
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<li><strong>VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis</strong> -
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The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.17.537186v1" target="_blank">VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis</a>
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<li><strong>Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury</strong> -
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Background and Aims: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and Results: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe non-integrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. Conclusions: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.17.537197v1" target="_blank">Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effectiveness and Safety of Quinine Sulfate as add-on Therapy for COVID-19 in Hospitalized Adults in Indonesia ( DEAL-COVID19 )</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Standard of Care + Quinine Sulfate; Drug: Standard of Care<br/><b>Sponsors</b>: Universitas Padjadjaran; National Research and Innovation Agency of Indonesia; Prodia Diacro Laboratories P.T.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Exosomes in Treating Chronic Cough After COVID-19</strong> - <b>Condition</b>: Long COVID-19 Syndrome<br/><b>Intervention</b>: Biological: MSC-derived exosomes<br/><b>Sponsors</b>: Huazhong University of Science and Technology; REGEN-αGEEK (SHENZHEN) MEDICAL TECHNOLOGY CO., LTD.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy and Safety of Nirmatrelvir/Ritonavir for Treating Omicron Variant of COVID-19</strong> - <b>Condition</b>: Omicron Variant of COVID-19<br/><b>Intervention</b>: Drug: Nirmatrelvir/Ritonavir<br/><b>Sponsor</b>: Xiangao Jiang<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study of mRNA-1283.222 Injection Compared With mRNA-1273.222 Injection in Participants ≥12 Years of Age to Prevent COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: mRNA-1283.222; Biological: mRNA-1273.222<br/><b>Sponsor</b>: ModernaTX, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>To Evaluate the Safety and Efficacy of Meplazumab in Treatment of COVID-19 Sequelae</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Meplazumab for injection; Other: Normal saline<br/><b>Sponsor</b>: Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluation of the RD-X19 Treatment Device in Individuals With Mild COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Device: RD-X19; Device: Sham<br/><b>Sponsor</b>: EmitBio Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clinical Study for the Efficacy and Safety of Ropeginterferon Alfa-2b in Adult COVID-19 Patients With Comorbidities</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Ropeginterferon alfa-2b; Procedure: SOC<br/><b>Sponsor</b>: National Taiwan University Hospital<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Assessment of Immunogenicity, Safety and Reactogenicity of a Booster Dose of Various COVID-19 Vaccine Platforms in Individuals Primed With Several Regimes.</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: SCB-2019/Clover; Biological: AstraZeneca/Fiocruz; Biological: Pfizer/Wyeth<br/><b>Sponsors</b>: D’Or Institute for Research and Education; Bill and Melinda Gates Foundation<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Postoperative Sugammadex After COVID-19</strong> - <b>Conditions</b>: General Anesthesia; COVID-19<br/><b>Interventions</b>: Drug: Sugammadex Sodium; Drug: neostigmine 50µg/kg + glycopyrollate 0.01mg/kg<br/><b>Sponsor</b>: Korea University Ansan Hospital<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study to Determine the Safety and Effectiveness of Azeliragon in the Treatment of Patients Hospitalized for Coronavirus Disease 2019 (COVID-19)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Azeliragon; Drug: Placebo<br/><b>Sponsor</b>: Salim S. Hayek<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Tailored COVID-19 Testing Support Plan for Francophone African Born Immigrants</strong> - <b>Condition</b>: COVID19 Testing<br/><b>Interventions</b>: Behavioral: FABI tailored COVID-19 testing pamphlet; Behavioral: Standard COVID-19 home-based test kit<br/><b>Sponsors</b>: Texas Woman’s University; National Institutes of Health (NIH)<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Cognitive-behavioral Therapy for Mental Disorder in COVID-19 Survivors</strong> - <b>Condition</b>: Post Acute COVID-19 Syndrome<br/><b>Intervention</b>: Behavioral: mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT)<br/><b>Sponsor</b>: Azienda Socio Sanitaria Territoriale di Lecco<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy of Lactobacillus Paracasei PS23 for Patients With Post-COVID-19 Syndrome</strong> - <b>Condition</b>: Post-COVID-19 Syndrome<br/><b>Intervention</b>: Dietary Supplement: PS23 heat-treated<br/><b>Sponsors</b>: Mackay Memorial Hospital; Bened Biomedical Co., Ltd.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Inpatient COVID-19 Lollipop Study</strong> - <b>Conditions</b>: COVID-19; Diagnostic Test<br/><b>Intervention</b>: Device: Lollipop<br/><b>Sponsor</b>: University of Wisconsin, Madison<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Exploring the Effect of Video Interventions on Intentions for Continued COVID-19 Vaccination</strong> - <b>Conditions</b>: Vaccine Refusal; COVID-19<br/><b>Interventions</b>: Behavioral: Informational Video; Behavioral: Altruistic Video; Behavioral: Individualistic Video<br/><b>Sponsor</b>: Sir Mortimer B. Davis - Jewish General Hospital<br/><b>Not yet recruiting</b></p></li>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Kinetics and ability of binding antibody and surrogate virus neutralization tests to predict neutralizing antibodies against the SARS-CoV-2 Omicron variant following BNT162b2 booster administration</strong> - CONCLUSIONS: This study showed a significant drop in humoral immunity 6 months after booster administration. Anti-RBD IgG and Omicron sVNT assays were highly correlated and could predict neutralizing activity with moderate performance.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Synthesis of SARS-CoV-2 M<sup>pro</sup> inhibitors bearing a cinnamic ester warhead with <em>in vitro</em> activity against human coronaviruses</strong> - COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 M^(pro) is considered the most appealing one due to its essential role in viral replication. However, the inhibition of M^(pro) activity is an interesting…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Diosmetin alleviates acute lung injury caused by lipopolysaccharide by targeting barrier function</strong> - Acute lung injury (ALI) is an acute and devastating disease caused by systemic inflammation e.g. patients infected with bacteria and viruses such as SARS-CoV-2 have an unacceptably high mortality rate. It has been well documented that endothelial cell damage and repair play a central role in the pathogenesis of ALI because of its barrier function. Nevertheless, the leading compounds that effectively accelerate endothelial cell repair and improve barrier dysfunction in ALI are largely unknown. In…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Molecular Networking Accelerated Discovery of Biflavonoid Alkaloids from Cephalotaxus sinensis</strong> - Four undescribed biflavonoid alkaloids, sinenbiflavones A-D, were isolated from Cephalotaxus sinensis using a MS/MS-based molecular networking guided strategy. Their structures were elucidated by series of spectroscopic methods (HRESIMS, UV, IR, 1D, and 2D NMR). Sinenbiflavones A-D are the first examples of amentoflavone-type (C-3’-C-8’’) biflavonoid alkaloids. Meanwhile, sinenbiflavones B and D are the unique C-6-methylated amentoflavone-type biflavonoid alkaloids. Sinenbiflavone D showed weak…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results</strong> - CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with HF and LVEF ≥40%. Efficacy findings were exploratory due to early termination but warrant further clinical investigation of AZD4831.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Awareness raising and dealing with methanol poisoning based on effective strategies</strong> - Intoxication with methanol most commonly occurs as a consequence of ingesting, inhaling, or coming into contact with formulations that include methanol as a base. Clinical manifestations of methanol poisoning include suppression of the central nervous system, gastrointestinal symptoms, and decompensated metabolic acidosis, which is associated with impaired vision and either early or late blindness within 0.5-4 h after ingestion. After ingestion, methanol concentrations in the blood that are…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ferrocenoyl-substituted quinolinone and coumarin as organometallic inhibitors of SARS-CoV-2 3CLpro main protease</strong> - The 3-chymotrypsin-like protease 3CLpro from SARS-CoV-2 is a potential target for antiviral drug development. In this work, three organometallic ferrocene-modified quinolinones and coumarins were compared to their benzoic acid ester analogues with regard to inhibition of 3CLpro using a HPLC-based assay with a 15mer model peptide as the substrate. In contrast to FRET-based assays, this allows direct identification of interference of buffer constituents with the inhibitors, as demonstrated by the…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Transcription factor <em>Dmrt1</em> triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility</strong> - Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Selective translational control of cellular and viral mRNAs by RPS3 mRNA binding</strong> - RPS3, a universal core component of the 40S ribosomal subunit, interacts with mRNA at the entry channel. Whether RPS3 mRNA-binding contributes to specific mRNA translation and ribosome specialization in mammalian cells is unknown. Here we mutated RPS3 mRNA-contacting residues R116, R146 and K148 and report their impact on cellular and viral translation. R116D weakened cap-proximal initiation and promoted leaky scanning, while R146D had the opposite effect. Additionally, R146D and K148D displayed…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors</strong> - Among the various genes and proteins encoded by all coronaviruses, one particularly “druggable” or relatively easy-to-drug target is the coronavirus Main Protease (3CLproor Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Omicsynin B4 potently blocks coronavirus infection by inhibiting host proteases cathepsin L and TMPRSS2</strong> - The emergence of SARS-CoV-2 variants represents a major threat to public health and requires identification of novel therapeutic agents to address the unmet medical needs. Small molecules impeding viral entry through inhibition of spike protein priming proteases could have potent antiviral effects against SARS-CoV-2 infection. Omicsynin B4, a pseudo-tetrapeptides identified from Streptomyces sp. 1647, has potent antiviral activity against influenza A viruses in our previous study. Here, we found…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19</strong> - The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 PLpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 infection. In…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Esculin alleviates LPS-induced acute lung injury via inhibiting neutrophil recruitment and migration</strong> - CONCLUSIONS: Esculin inhibits β(2) integrin-dependent neutrophil migration and chemotaxis, blocks the cytoskeletal remodeling process required for neutrophil recruitment, thereby contributing to its protective effect against ALI. This study demonstrates the new therapeutic potential of esculin as a novel lead compound.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>FDA approved drugs with antiviral activity against SARS-CoV-2: From structure-based repurposing to host-specific mechanisms</strong> - The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>4’-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses</strong> - Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4’-Fluorouridine (4’-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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