Effectiveness of Paxlovid, an Oral Antiviral Drug, Against the Omicron BA.5 Variant in Korea: Severe Progression and Death Between July and November 2022.

BACKGROUND: Paxlovid is an oral antiviral drug that received emergency use authorization in South Korea for the treatment of patients with mild-to-moderate coronavirus disease 2019 (COVID-19) on January 14, 2022. Since the onset of the severe acute respiratory syndrome coronavirus 2 pandemic, the virus has continued to evolve. The emergence of new variants has raised concerns about possible reductions in the effectiveness of vaccines and drugs. The effectiveness of Paxlovid in patients infected with the omicron variant and subvariants has not yet been determined. This study assessed the effectiveness of Paxlovid at reducing the risk of severe/critical illness or death and death in patients with mild-to-moderate COVID-19 caused by omicron subvariant BA.5. METHODS: In this nationwide retrospective cohort study, data on 8,902,726 patients were collected from four sources (the Drug Utilization Review database, COVID-19 Patient Information Management System, confirmed patient information, and basic epidemiological investigation data) between July 1 and November 30, 2022. Multivariable logistic regression analysis was conducted, with adjustment for age, sex, severe acute respiratory syndrome coronavirus 2 immunity (vaccination), and comorbidities. RESULTS: A total of 1,936,925 patients with COVID-19 were included in the analysis, including 420,996 patients treated with Paxlovid, and 1,515,959 patients not treated with Paxlovid. Paxlovid treatment in patients aged ≥ 60 years of age was associated with significantly reduced risk of severe/critical illness or death (46.0%), and death rate (32.5%), and its effectiveness was high, regardless of vaccination status. CONCLUSION: Paxlovid is effective at reducing the risk of death due to COVID-19 in patients with omicron BA.5 infection, especially in older patients, regardless of vaccination status. This suggests that older patients with COVID-19-related symptoms should be administered Paxlovid, regardless of their vaccination status, to reduce severity and risk of death.

Community Transmission of SARS-CoV-2 Omicron Variant, South Korea, 2021.

In South Korea, a November 2021 outbreak caused by severe acute respiratory syndrome coronavirus 2 Omicron variant originated from 1 person with an imported case and spread to households, kindergartens, workplaces, restaurants, and hospitals, resulting in 11 clusters within 3 weeks. An epidemiologic curve indicated rapid community transmission of the Omicron variant.

SARS-CoV-2 Delta Variant Breakthrough Infection and Onward Secondary Transmission in Household.

BACKGROUND: Despite the extraordinary speed of mass vaccination efforts, an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant in a vaccinee with coronavirus disease 2019 (COVID-19) mRNA vaccine was identified in an adult day service center (ADSC) of Jeju, South Korea. The primary objective of this study was to investigate the epidemiologic features in infection-vulnerable facilities with a high vaccination rate of BNT162b2 mRNA COVID-19 vaccine. The second was to estimate the secondary transmission prevention effect of the vaccine in the household members by vaccination status. METHODS: We included all ADSC participants, staff and their household members. All COVID-19 infected cases were confirmed by reverse transcriptase polymerase chain reaction. We calculated attack rate in ADSC and the secondary attack rate (SAR) in household members by vaccination status. RESULTS: Among a total of 42 participants and 16 staff, of which 96.6% were fully vaccinated with BNT162b2 mRNA COVID-19 vaccine, 12 symptomatic cases and 13 asymptomatic confirmed cases of COVID-19 were found. The attack rate was 43.1%, with 13 isolates identified as SARS-CoV-2 virus, delta variant. The SAR in unvaccinated and partially vaccinated household members were 27.8% (5/18) and 25.0% (5/20), respectively, while the SAR in fully vaccinated household members was 12.5% (1/8). CONCLUSION: We describe a SARS-CoV-2 delta variant outbreak in ADSC with high vaccine coverage rate, characterized by high infection rate, high transmissibility, and low clinical severity. The outbreak proceeded to unvaccinated or partially vaccinated household members, emphasizing the need for immunizing close contacts of high-risk groups.

Importation and Transmission of SARS-CoV-2 B.1.1.529 (Omicron) Variant of Concern in Korea, November 2021.

In November 2021, 14 international travel-related severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant of concern (VOC) patients were detected in South Korea. Epidemiologic investigation revealed community transmission of the omicron VOC. A total of 80 SARS-CoV-2 omicron VOC-positive patients were identified until December 10, 2021 and 66 of them reported no relation to the international travel. There may be more transmissions with this VOC in Korea than reported.

AKT-independent Reelin signaling requires interactions of heterotrimeric Go and Src.

Reelin, a large secreted extracellular matrix glycoprotein, plays a key role in neuronal migration during cortical development and promotes neuronal maturation. The signaling pathway regulating neuronal maturation in the postnatal period are relatively less well understood. In this study, we demonstrated that a heterotrimeric G protein, Go, is a novel target of Reelin-induced signaling to promote neurite outgrowth. In primary hippocampal neurons of Reelin-deficient reeler mice, neurite outgrowth was significantly reduced and rescued upon addition of Reelin. Pertussis toxin (PTX) treatment or transfection with Gαo-siRNA suppressed Reelin-mediated neurite outgrowth in wild-type neurons. Additionally, Reelin treatment led to increased phosphorylation of AKT, GSK3ß, and JNK, which were all effectively blocked by the PI3K inhibitor, LY294002. By comparison, PTX specifically blocked JNK activation, but not AKT and GSK3ß. Immunoprecipitation assays disclosed that Reelin increases the active forms of both Src and Gαo and promotes their direct association. Notably, Dab1, a cytoplasmic adaptor molecule that mediates Reelin signaling, did not interact with Gαo. Neurite outgrowth by Reelin was induced via activating Src kinase, which directly stimulated Gαo, activity, leading to JNK activation. Based on the collective findings, we suggest that Reelin-dependent signaling mechanisms may be split into Src-AKT-dependent and Src-Go-dependent pathways. Our results additionally provide evidence that Reelin receptors cross-communicate with heterologous G protein-coupled receptors (GPCR) independently of the cognate ligands of GPCR.

Comparative life cycle assessment of various hydrogen supply methods from Australia to the Republic of Korea in environmental and economic aspects.

With the increasing importance of decarbonization to prevent global climate change, hydrogen supply has received considerable attention from several countries, including Korea and Japan, due to the growing demand for the implementation of a hydrogen economy. This study conducted a comprehensive analysis on hydrogen supply methods from Australia to the Republic of Korea in environmental and economic aspects using a life cycle assessment (LCA). The blue hydrogen produced in Australia was considered for import to the Republic of Korea via ocean shipping. The study analyzed the holistic environmental effects in the life cycle of hydrogen ocean transport for various types of hydrogen storage methods (CH2, LH2, LOHC, LNH3, and LNG), as well as alternative marine fuels (MGO, LNG, LPG, CH2, LH2, LNG-LH2, MeOH, and LNH3) for ship transportation. Environmental impact performance was presented in terms of global warming potential (GWP), acidification potential (AP), photochemical ozone creation potential (POCP), eutrophication potential (EP), and particulate matter (PM). For the environmental results, sensitivity studies were conducted to analyze the effects of operating distance and cargo tank size when shipping hydrogen via ocean transport. Additionally, the GWP results of the transportation of green hydrogen and ammonia were compared with those of blue hydrogen and ammonia transport. A cost analysis was performed for the overall processes of hydrogen ocean transport, and the results were included in the study with the estimated hydrogen price for each transportation method.

Effectiveness of Molnupiravir Treatment in Patients with COVID-19 in Korea: A Propensity Score Matched Study.

BACKGROUND: The MOVe-OUT (efficacy and safety of molnupiravir [MK-4482] in non-hospitalized adult participants with COVID-19 [MK-4482-002]) trial reported that the administration of molnupiravir in unvaccinated patients with coronavirus disease 2019 (COVID-19) before the Omicron epidemic showed a preventive effect of 31% against hospitalization and death. However, studies on the preventive effect of molnupiravir against progression to severe disease and death in patients with COVID-19 during the Omicron epidemic are limited. This study aimed to evaluate the preventive effect of molnupiravir against severe/critical illness or death and death in Korean patients with COVID-19 who were vaccinated mostly during the Omicron epidemic. MATERIALS AND METHODS: This study used large-scale retrospective cohort data to select patients with COVID-19 who were either treated or not treated with molnupiravir, between August 2022 and March 2023, at a ratio of 1 : 4 using the propensity score matching method. In total, 762,768 patients comprised the non- administered group, and 190,692 patients comprised the molnupiravir-administered group. The preventive effect of molnupiravir against severe/critical illness or death and death was analyzed using logistic regression analysis. RESULTS: The preventive effect of molnupiravir against severe/critical illness or death and death, represented by the odds ratio (OR) and 95% confidence interval (CI), in the molnupiravir-administered and non-administered group was (OR: 0.714; CI: 0.667 - 0.764) and (OR: 0.749; CI: 0.682 - 0.823), respectively. As age increased, the preventive effect against severe/critical illness or death and death increased. The preventive effect against severe/critical illness or death at ≥60 years was (OR: 0.669; CI: 0.624 - 0.717), at ≥70 years was (OR: 0.614; CI: 0.570 - 0.661), and at ≥80 years was (OR: 0.563; CI: 0.515 - 0.615). The preventive effect against death at ≥60 years was (OR: 0.729; CI: 0.663 - 0.802), at ≥70 years was (OR: 0.676; CI: 0.612 - 0.747), and at ≥80 years was (OR: 0.622; CI: 0.554 - 0.698). CONCLUSION: Although molnupiravir showed a relatively weak preventive effect against severe/critical illness or death (29%) and death (25%) among patients with COVID-19, it exhibited a stronger protective effect in older patients than in younger patients. In particular, the preventive effect against severe/critical illness or death (44%) and death (38%) in those aged ≥80 years was pronounced. This study strongly suggests that molnupiravir administration can alleviate the burden on the medical system, and treat patients with COVID-19 effectively by reducing its progression to severe disease and death.

Early countermeasures to COVID-19 at long-term care facilities in Gwangju Metropolitan City, Republic of Korea.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has continued since its first detection in the Republic of Korea on January 20, 2020. This study describes the early countermeasures used to minimize the risk of COVID-19 outbreaks during cohort quarantine and compares the epidemiological characteristics of 2 outbreaks in long-term care facilities (LTCFs) in Gwangju Metropolitan City in summer 2020. METHODS: An epidemiological investigation was conducted via direct visits. We investigated epidemiological characteristics, including incidence, morbidity, and mortality rates, for all residents and staff members. Demographic characteristics were analyzed using a statistical program. Additionally, the method of managing infection in LTCFs is described. RESULTS: Residents and caregivers had high incidence rates in LTCF-A and LTCF-B, respectively. LTCF-B had a longer quarantine period than LTCF-A. The attack rate was 20.02% in LTCF-A and 27.9% in LTCF-B. The mortality rate was 2.3% (1/43) in LTCF-B, the only facility in which a COVID-19 death occurred. CONCLUSIONS: Extensive management requires contact minimization, which involves testing all contacts to mitigate further transmission in the early stages of LTCF outbreaks. The findings of this study can help inform and prepare public health authorities for COVID-19 outbreaks, particularly for early control in vulnerable facilities.

Evaluation of COVID-19 vaccine effectiveness in different high-risk facility types during a period of Delta variant dominance in the Republic of Korea: a cross-sectional study.

BACKGROUND: We evaluated the effectiveness of coronavirus disease 2019 vaccination in high-risk facilities in the Republic of Korea during the period when the highly transmissible Delta variant was prevalent. Additionally, we aimed to explore any disparities in vaccine effectiveness (VE) across various types of institutions, specifically distinguishing between non-medical and medical establishments. METHODS: We examined 8 outbreak clusters covering 243 cases and 895 contacts from 8 high-risk facilities divided into 2 groups: group A (4 non-medical institutions) and group B (4 medical institutions). These clusters were observed from July 27, 2021 to October 16, 2021 for the attack rate (AR) and VE with respect to disease severity. A generalized linear model with a binomial distribution was used to determine the odds ratio (OR) for disease severity and death. RESULTS: AR was notably lower in group B (medical institutions). Furthermore, VE analysis revealed that group A exhibited higher effectivity for disease severity and death than group B. The OR for disease severity was 0.24 (95% confidence interval [CI], 0.03-2.16) for group A and 0.27 (95% CI, 0.12-0.64) for group B, with the OR for death at 0.12 (95% CI, 0.01-1.32) in group A and 0.34 (95% CI, 0.14-0.87) in group B. CONCLUSION: Although VE may vary across institutions, our findings underscore the importance of implementing vaccinations in high-risk facilities. Customized vaccination programs, tailored response plans, and competent management personnel are essential for effectively addressing and mitigating public health challenges.

A Seroprevalence Study on Residents in a Senior Care Facility with Breakthrough SARS-CoV-2 Omicron Infection.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began spreading rapidly in the community in November 2021, becoming the dominant variant in the Republic of Korea in 2022. Although its pathogenesis in healthy individuals was low, the severity and hospitalization rate was higher in the elderly and immunocompromised patients. We aimed to investigate the immunogenicity in acute and convalescent phases of breakthrough infection by Omicron in elderly individuals. Serological data were assessed by electrochemiluminescence immunoassay, enzyme-linked immunosorbent assay, and plaque-reduction neutralization tests. SARS-CoV-2-specific antibody and immunoglobulin G levels in the acute phase were higher in third dose-vaccinated elderly than in first and second dose-vaccinated patients. The neutralization antibody titer was detected only in third dose-vaccinated patients, and the titer was higher for the Delta than the Omicron variant. In the convalescent phase of Omicron infection, the neutralization antibody titer of vaccinated patients was higher for the Delta than the Omicron variant except in unvaccinated individuals. We demonstrated that the cause of the vulnerability to Omicron variant infection in third dose-vaccinated elderly was due to the low neutralization antibody level against Omicron. A fourth dose of vaccination is required in the elderly to reduce hospitalization and mortality caused by the Omicron variant.

Re-transmissibility of mouse-adapted ME7 scrapie strain to ovine PrP transgenic mice.

Scrapie is a mammalian transmissible spongiform encephalopathy or prion disease that predominantly affects sheep and goats. Scrapie has been shown to overcome the species barrier via experimental infection of other rodents. To confirm the re-transmissibility of the mouse-adapted ME7 scrapie strain to ovine prion protein (PrP) transgenic mice, mice of an ovinized transgenic mouse line carrying the Suffolk sheep PrP gene that contained the A136 R154 Q171/ARQ allele were intracerebrally inoculated with brain homogenates obtained from terminally ill ME7-infected C57BL/6J mice. Herein, we report that the mouse-adapted ME7 scrapie strain was successfully re-transmitted to the transgenic mice expressing ovine PrP. In addition, we observed changes in the incubation period, glycoform profile, and pattern of scrapie PrP (PrPSc) deposition in the affected brains. PrPSc deposition in the hippocampal region of the brain of 2nd-passaged ovine PrP transgenic mice was accompanied by plaque formation. These results reveal that the mouse-adapted ME7 scrapie strain has the capacity to act as a template for the conversion of ovine normal monomeric precursors into a pathogenic form in ovine PrP transgenic mice. The change in glycoform pattern and the deposition of plaques in the hippocampal region of the brain of the 2nd-passaged PrP transgenic mice are most likely cellular PrP species dependent rather than being ME7 scrapie strain encoded.

Fas-associated factor 1 promotes in neurofibrillary tangle-mediated cell death of basal forebrain cholinergic neurons in P301L transgenic mice.

Dysfunction of the cholinergic system of the basal forebrain complex is one of the major contributors toward cognitive impairment in Alzheimer's disease (AD). In AD, degeneration of cholinergic fibers that project to the cerebral cortex and hippocampus may be attributed to the development of neurofibrillary tangles (NFT). Here, we evaluated the relationship between neurofibrillary changes and degeneration of septal cholinergic neurons in P301L tau transgenic mice. The number of cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB) in the basal forebrain was significantly reduced in P301L mice compared with age-matched wild-type mice. The phospho-tau levels and NFT formation in these P301L mice were higher than those in wild-type mice. However, it is still unknown how the development of NFT is caused in AD and AD-like pathology. Our results show that Fas-associated factor 1 (FAF1) expression as well as caspase-3 activation were increased in AT8-positive MS/VDB cholinergic neurons. Furthermore, the formation of AT8-positive paired helical filaments increased in proportion to FAF1 expression and caspase-3 activation in MS/VDB cholinergic neurons. On the basis of the collective findings, we suggest that increased FAF1 expression triggers caspase-3 cleavage and activation, leading to hyperphosphorylated tau aggregation and subsequent NFT formation, in turn initiating apoptosis in MS/VDB cholinergic neurons.

Gene expression profiling using DNA microarray analysis of the cerebellum of mice treated with methylmercury.

To elucidate the molecular mechanism involved in methylmercury-induced cerebellar disorder, we performed DNA microarray analysis of the cerebellum of methylmercury-treated mice. The expression levels of 21 genes were elevated 2-fold or higher in response to methylmercury, including many genes encoding proteins involved in inflammatory reactions associated with chemokines. The expression levels of 11 genes were reduced by half or more in response to methylmercury.

Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway.

The mechanism by which E-prostanoid (EP) receptor is critically involved in PGE(2)-induced mucin 5AC (MUC5AC) gene expression in the airway has been unclear. Furthermore, there have been little reports regarding the negative regulatory mechanism and/or proteins that affect PGE(2)-induced MUC5AC overproduction. In the present study, we found that PGE(2) induced MUC5AC gene expression in a dose-dependent manner (EC(50): 73.31 +/- 3.13 nM) and that the EP(2/4)-specific agonist, misoprostol, increased MUC5AC mRNA level, whereas the EP(1/3)-specific agonist, sulprostone, had no effect. Interestingly, the cAMP concentration (685.1 +/- 14.9 pM) of the EC(50) value of EP(4)-mediated cAMP production was much higher than that of EP(2) (462.33 +/- 23.79 pM), suggesting that EP(4) has higher sensitivity to PGE(2) compared with EP(2). Moreover, PGE(2)-induced Muc5ac overproduction was much increased in regulator of G protein signaling (Rgs) 4 knockout (KO) mice compared with wild-type mice at both transcriptional and translational levels, and it was dramatically suppressed in Rgs4 KO mice that had been infected with lentivirus expressing RGS4 (lenti::RGS4) compared with lentivirus expressing enhanced green fluorescent protein (lenti::eGFP). Finally, we demonstrate that PGE(2) can induce MUC5AC overproduction via the EP(4) receptor and that RGS4 may have suppressive effects in controlling MUC5AC overexpression in the airway. These findings may provide a molecular paradigm for the development of novel drugs for respiratory diseases.