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Objectives: On November 5, 2021, Pfizer Inc. announced Paxlovid (nirmatrelvir+ritonavir) as a treatment method that could reduce the risk of hospitalization or death for patients with confirmed coronavirus disease 2019 (COVID-19).Methods: From February 6, 2022 to April 2, 2022, the incidence of COVID-19 and the effects of treatment with Paxlovid were analyzed in 2,241 patients and workers at 5 long-term care facilities during the outbreak of the Omicron variant of severe acute respiratory syndrome coronavirus 2 in South Korea.Results: The rate of severe illness or death in the group given Paxlovid was 51% lower than that of the non-Paxlovid group (adjusted risk ratio [aRR], 0.49; 95% confidence interval [CI], 0.24−0.98). Compared to unvaccinated patients, patients who had completed 3 doses of the vaccine had a 71% reduced rate of severe illness or death (aRR, 0.29; 95% CI, 0.13−0.64) and a 65% reduced death rate (aRR, 0.35; 95% CI, 0.15−0.79).Conclusion: Patients given Paxlovid showed a lower rate of severe illness or death and a lower fatality rate than those who did not receive Paxlovid. Patients who received 3 doses of the vaccine had a lower rate of severe illness or death and a lower fatality rate than the unvaccinated group.

Pathogen effectors can suppress various plant immune responses, suggesting that they have multiple targets in the host. To understand the mechanisms underlying plasma membrane-associated and effector-mediated immunity, we screened the Phytophthora capsici RxLR cell death-inducer suppressing immune system (CRISIS). We found that the cell death induced by the CRISIS2 effector in Nicotiana benthamiana was inhibited by the irreversible plasma membrane H+-ATPase (PMA) activator fusicoccin. Biochemical and gene-silencing analyses revealed that CRISIS2 physically and functionally associated with PMAs and induced host cell death independent of immune receptors. CRISIS2 induced apoplastic alkalization by suppressing PMA activity via its association with the C-terminal regulatory domain. In planta expression of CRISIS2 significantly enhanced the virulence of P. capsici, whereas host-induced gene-silencing of CRISIS2 compromised the disease symptoms and the biomass of the pathogen. Thus, our study has identified a novel RxLR effector that plays multiple roles in the suppression of plant defense and in the induction of cell death to support the pathogen hemibiotrophic life cycle in the host plant.

In clinical studies or trials comparing survival times between two treatment groups, the restricted mean lifetime (RML), defined as the expectation of the survival from time 0 to a prespecified time-point, is often the quantity of interest that is readily interpretable to clinicians without any modeling restrictions. It is well known that if the treatments are not randomized (as in observational studies), covariate adjustment is necessary to account for treatment imbalances due to confounding factors. In this article, we propose a simple doubly-robust pseudo-value approach to effectively estimate the difference in the RML between two groups (akin to a metric for estimating average causal effects), while accounting for confounders. The proposed method combines two general approaches: (a) group-specific regression models for the time-to-event and covariate information, and (b) inverse probability of treatment assignment weights, where the RMLs are replaced by the corresponding pseudo-observations for survival outcomes, thereby mitigating the estimation complexities in presence of censoring. The proposed estimator is double-robust, in the sense that it is consistent if at least one of the two working models remains correct. In addition, we explore the potential of available machine learning algorithms in causal inference to reduce possible bias of the causal estimates in presence of a complex association between the survival outcome and covariates. We conduct extensive simulation studies to assess the finite-sample performance of the pseudo-value causal effect estimators. Furthermore, we illustrate our methodology via application to a dataset from a breast cancer cohort study. The proposed method is implementable using the R package drRML, available in GitHub.

Primary cilia are non-motile cilia that function as antennae for cells to sense signals. Deficits of primary cilia cause ciliopathies, leading to the pathogenesis of various developmental disorders; however, the contribution of primary cilia to neurodevelopmental disorders is largely unknown. Fragile X syndrome (FXS) is a genetically inherited disorder and is the most common known cause of autism spectrum disorders. FXS is caused by the silencing of the fragile X mental retardation 1 (FMR1) gene, which encodes for the fragile X mental retardation protein (FMRP). Here, we discovered a reduction in the number of primary cilia and the Sonic hedgehog (Shh) signaling in cerebellar Bergmann glia of Fmr1 KO mice. We further found reduced granule neuron precursor (GNP) proliferation and thickness of the external germinal layer (EGL) in Fmr1 KO mice, implicating that primary ciliary deficits in Bergmann glia may contribute to cerebellar developmental phenotypes in FXS, as Shh signaling through primary cilia in Bergmann glia is known to mediate proper GNP proliferation in the EGL. Taken together, our study demonstrates that FMRP loss leads to primary ciliary deficits in cerebellar Bergmann glia which may contribute to cerebellar deficits in FXS.

To quantify the dose-response relationship between moderate to vigorous physical activity and primary cardiac arrest (PCA).There were 504,840 participants older than 18 years who underwent the Korean National Health Screening Program, including a self-administered questionnaire for physical activity from January 1, 2009, through December 31, 2014. Physical activity levels were converted into metabolic equivalent tasks (METs) per week and categorized to correspond with multiples of public health recommendations. We evaluated the quantitative and categorical dose-response relationship between physical activity and PCA.A curvilinear dose-response relationship between physical activity and PCA was observed; the benefits started at two-thirds (5 MET-hour/week) of the United States and World Health Organization guidelines-recommended minimum (7.5 MET-hour/week) and continued to 5 times (40 MET-hour/week) the recommended minimum (P nonlinearity.001). The largest benefit was noted at a level of 2 to 3 times the recommended minimum (hazard ratio, 0.6; 95% CI, 0.4 to 0.8). In addition, there was no evidence of an increased PCA risk at a level more than 5 times the recommended minimum (hazard ratio, 0.7; 95% CI, 0.5 to 1.1). These associations were consistent regardless of age, sex, body mass index, comorbid conditions, and estimated 10-year risk for cardiovascular disease.The beneficial effect of physical activity on PCA started at two-thirds of the recommended minimum and continued to 5 times the recommended minimum. No excess risk for PCA was present among individuals with activity levels more than 5 times the recommended minimum regardless of cardiovascular disease or lifestyle risk factor presence.

To clarify transmissibility of the severe acute respiratory syndrome coronavirus 2 Omicron variant, we determined serial intervals and secondary attack rates among household contacts in South Korea. Mean serial interval for 12 transmission pairs was 2.9 days, and secondary attack rate among 25 households was 50.0%, raising concern about a rapid surge in cases.

Phosphorylation state-dependent interactions of the phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) components with transcription factors play a key role in carbon catabolite repression (CCR) by glucose in bacteria. Glucose inhibits the PTS-dependent transport of fructose and is preferred over fructose in Vibrio cholerae, but the mechanism is unknown. We have recently shown that, contrary to Escherichia coli, the fructose-dependent transcriptional regulator FruR acts as an activator of the fru operon in V. cholerae and binding of the FruR–fructose 1-phosphate (F1P) complex to an operator facilitates RNA polymerase (RNAP) binding to the fru promoter. Here we show that, in the presence of glucose, dephosphorylated HPr, a general PTS component, binds to FruR. Whereas HPr does not affect DNA-binding affinity of FruR, regardless of the presence of F1P, it prevents the FruR–F1P complex from facilitating the binding of RNAP to the fru promoter. Structural and biochemical analyses of the FruR–HPr complex identify key residues responsible for the V. cholerae-specific FruR–HPr interaction not observed in E. coli. Finally, we reveal how the dephosphorylated HPr interacts with FruR in V. cholerae, whereas the phosphorylated HPr binds to CcpA, which is a global regulator of CCR in Bacillus subtilis and shows structural similarity to FruR.

Background Skeletal muscle wasting related to aging or pathological conditions is critically associated with the increased incidence and prevalence of secondary diseases including cardiovascular diseases, metabolic syndromes, and chronic inflammations. Much effort is made to develop agents to enhance muscle metabolism and function. Inonotus obliquus (I. obliquus; IO) is a mushroom popularly called chaga and has been widely employed as a folk medicine for inflammation, cardiovascular diseases, diabetes, and cancer in Eastern Europe and Asia. However, its effect in muscle health has not been explored. ObjectiveHere, we aimed to investigate the beneficial effect of IO extract in muscle regeneration and metabolism. MethodsThe effect of I. obliquus extract was investigated on myogenesis and myotube atrophy models of C2C12 myoblasts and muscle regeneration model of mice. The muscle stem cell proliferation and regeneration post muscle injury were employed to further confirm the effect of I. obliquus. The underlying mechanism of I. obliquus was also investigated by the mitochondrial content and oxidative muscle metabolism as well as the activation of AKT and PGC-1α expression. Results The treatment of IO in C2C12 myoblasts led to increased myogenic differentiation and alleviation of dexamethasone-induced myotube atrophy. Network pharmacological analysis using the identified specific chemical constituents of IO extracts predicted protein kinase B (AKT)-dependent mechanisms to promote myogenesis and muscle regeneration. Consistently, IO treatment resulted in the activation of AKT, which suppressed muscle-specific ubiquitin E3 ligases induced by dexamethasone. IO treatment in mice improved the regeneration of cardiotoxin-injured muscles accompanied by elevated proliferation and differentiation of muscle stem cells. Furthermore, it elevated the mitochondrial content and muscle oxidative metabolism accompanied by the induction of peroxisome proliferator-activated receptor γ coactivator α (PGC-1α). Conclusions Our current data suggest that I. obliquus is a promising natural agent in enhancing muscle regenerative capacity and oxidative metabolism thereby preventing muscle wasting.

SUMMARYTransient, rapid increase of cytosolic Ca2+upon pathogen infection is essential for plant pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). Several cyclic nucleotide-gated channels (CNGCs) have been implicated; however, their regulatory mechanisms remain elusive. Here, thePhytophthora infestansRXLR effector AVRblb2 family targeted NbCNGC18–20 at the plasma membrane, inhibiting Ca2+influx and PTI. AVRblb2 required calmodulin (CaM) and calmodulin-like (CML) proteins as co-factors to interact withN. benthamianaCNGCs (NbCNGCs), forming the AVRblb2-CaM/CML-NbCNGCs complex. After recognizing PAMPs, NbCNGC18 formed active heteromeric channels with other CNGCs, potentially providing selectivity for diverse signals to fine-tune cytosolic Ca2+levels and responses. AVRblb2 suppressed the Ca2+influx and oxidative burst induced by NbCNGC18 heteromeric complexes. Silencing CNGC18, CNGC20, and CNGC25 compromised the effect of AVRblb2 onP. infestansvirulence, confirming that AVRblb2 contributed to virulence by targeting CNGCs. Our findings delineated the regulatory mechanism and role of effector-targeted Ca2+channels in plant innate immunity.

Objectives: The purpose of this study was to identify the relevant factors between the completion of continuing education that is required for license registration and license registration awareness.Methods: The data were conducted an online questionnaire survey on 330 dental hygienists working in dental clinic in Daegu. Data were analyzed using frequency, logistic regression, multiple regression with the SPSS 25.0 program.Results: It was revealed that 83.4% of the subjects of this study completed continuing education. The variables that were statistically significant in multivariate analysis with license registration awareness as a dependent variable were marital status, education level, number of dental hygienists, main duty, annual, monthly leave, route of information, and experience of getting official documents. Finally, when continuing education was completed, license registration awareness was found to have a positive correlation compared to those who did not complete continuing education (p< 0.001).Conclusions: The role and responsibility of the Korean Dental Hygienists Association is more important for practical alternatives and improvements leading to license registration by increasing the completion of continuing education and license registration awareness.

Background Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States. DILI is mainly caused by painkillers and fever reducers, and it is often characterized by the type of hepatic injury (hepatocellular or cholestatic). This report presents a case of fenofibrate-induced severe jaundice in a 65-year-old Korean male with no prior history of liver disease. We offer a strategy for patients who present signs of severe liver injury with jaundice and high elevations in serum transaminases. Case summary A 65-year-old male visited the gastroenterology outpatient clinic of a tertiary hospital due to increased levels of liver enzyme and total bilirubin which were incidentally detected through a preoperative screening test. Abdominal ultrasound and computed tomography showed no biliary obstruction or non-specific findings in the liver. Liver biopsy was performed and the patient was finally diagnosed with acute cholestatic hepatitis. Following the biopsy, steroid therapy was initiated and after 3 wk of treatment, the total bilirubin level was reduced to 7.22 mg/dL. Conclusion In patients with hyperlipidemia, treatment including fenofibric acid induces rare complications such as severe jaundice and acute cholestatic hepatitis, warranting clinical attention.

The objective of this study was to determine the effects of supercritical carbon dioxide (SC-CO2) extracts from red pepper (RP) or pine needles (PN) on the physicochemical properties of perilla oil (PO). Subsequently, the physicochemical properties of the perilla oil containing SC-CO2 extract at 0.1% and PO without extract were compared. Oxidative stability was measured based on viscosity, acid value (AV), peroxide value (POV), antioxidant (2,2-diphenyl-1-picrahydrazyl) activity, p-anisidine value (p-AV), and fatty acid composition. All the samples were studied under medium temperature (65°C) accelerated oxidation conditions for 24 h. The viscosities of PO with PN extract and PO without extract significantly increased with increasing storage time, but that of PO added with RP extract was not significantly different (p

Background Although regular physical activity benefits cardiovascular health, there is a concern that intense exercise is linked to the promotion of atrial fibrillation (AF) and coronary plaque rupture. However, the impact of physical activity on the outcomes of patients with concomitant AF and coronary artery disease (CAD) remains unclear. This study aimed to evaluate the association with clinical outcomes according to the level of physical activity in patients with concomitant AF and CAD. Methods We assessed 551 patients with AF and CAD (mean age, 67.1 ± 9.8 years) who completed a self-reported questionnaire for physical activity from 2015 to 2020 in a single tertiary-care hospital. Physical activity levels were converted into metabolic equivalent of task (MET) per week and categorized to correspond with multiple public health recommendations. We examined the association between physical activity, all-cause mortality, and major adverse cardiac and cerebrovascular events (MACCE). Results The risks of all-cause mortality (P for linear trend = 0.017) and MACCE (P for linear trend = 0.05) appeared inverse trend with a greater level of physical activity. Compared with inactive patients, patients who met the recommended target range of physical activity (500–1,000 MET-min/week: unadjusted hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.36–0.99) and highly active patients who exceeded the minimum recommended level (≥ 1,000 MET-min/week: unadjusted HR = 0.47, 95% CI = 0.25–0.88) had a lower risk of all-cause mortality in the unadjusted model; however, these associations did not remain significant after adjusting for the model. There was no evidence of increased risk of all-cause mortality and MACCE at levels of physical activity above the recommended target range, even with vigorous-intensity physical activity exceeding the recommended target range. Conclusions There appears to be an inverse trend between physical activity levels and all-cause mortality and MACCE in patients with concomitant AF and CAD. No excess risk of mortality or MACCE was found at exercise levels above the recommended target range. Further large-scale studies are warranted to create an improved evidence base concerning the effects of physical activity in patients with AF and CAD.

On 22 June, a man who returned to South Korea from Germany tested positive for the monkeypox virus using real-time polymerase chain reaction. We identified 49 contacts concerning the first monkeypox case and classified them into two groups based on risk exposure levels. Through active monitoring of eight people in the medium-risk group and passive monitoring of 41 people in the low-risk group, we identified that no secondary transmission occurred over 21 days. The prompt active or passive monitoring of the index case of imported monkeypox could prevent community transmission in Korea.

This study aimed to determine the effect of Gyeongsangnam-do fire department officilas’ organizational culture on organizational performance, including job satisfaction and organizational commitment, and to verify the mediated effect of organizational culture and organizational performance through the parameters of trust. According to an online survey of fire service workers, paramedics, and rescue workers from 18 locations in the Gyeongsangnam-do Fire Department, only the clan culture had a significant effect on job satisfaction, and functioned as a mediator between organizational and peer trust, showing mediation effects. Furthermore, we confirmed that only clan culture had a significant influence on organizational commitment, and that it also acted as a mediator in organizational and supervisor trust. Finally, the organizational culture that most positively influenced organizational performance and trust among fire service officials in Gyeongsangnam-do was found to be clan culture. Therefore, a clan culture that is centered on human relationships based on trust, and that is suited to the characteristics of each organization, should be established.

This study describes the epidemiological characteristics of coronavirus disease 2019 (COVID-19) based on reported cases from long-term care facilities. As of April 20th, 2020, 3 long-term care facilities in a metropolitan area of South Korea had reported cases of COVID-19. These facilities’ employees were presumed to be the sources of infection. There were 2 nursing hospitals that did not report any additional cases. One nursing home had a total of 25 cases, with an attack rate of 51.4% (95% CI 35.6–67.0), and a fatality rate of 38.9% (95% CI 20.3–61.4) among residents. The results from this study suggest that early detection and maintenance of infection control minimizes the risk of rapid transmission.

Summary The primary cilium is the non-motile cilium present in most mammalian cell types and functions as an antenna for cells to sense signals. Ablating primary cilia in postnatal newborn neurons of the dentate gyrus (DG) results in both reduced dendritic arborization and synaptic strength, leading to hippocampal-dependent learning and memory deficits. Fragile X syndrome (FXS) is a common form of inheritance for intellectual disabilities with a high risk for autism spectrum disorders, and Fmr1 KO mice, a mouse model for FXS, demonstrate deficits in newborn neuron differentiation, dendritic morphology, and memory formation in the DG. Here, we found that the number of primary cilia in Fmr1 KO mice is reduced, specifically in the DG of the hippocampus. Moreover, this cilia loss was observed postnatally mainly in newborn neurons generated from the DG, implicating that these primary ciliary deficits may possibly contribute to the pathophysiology of FXS., Graphical Abstract, Highlights • Primary cilia are significantly reduced in the DG of Fmr1 KO mice • Fmr1 KO mice show age-dependent primary cilia deficits • Neuronal ciliogenesis defects are shown in the DG of Fmr1 KO mice • Primary cilia deficits are observed in newborn neurons from SGZ, but not from DNe, In this article, Lee and colleagues show that Fmr1 KO mice, a mouse model for fragile X syndrome, have primary cilia deficits in the dentate gyrus (DG) found specifically in newborn neurons originating from the subgranular zone (SGZ) of the DG, but not in other hippocampal brain regions or from neurons originating from the dentate neuroepithelium (DNe).

Neurological conditions like neurodevelopmental disorders and neurodegenerative diseases are quite complex and often exceedingly difficult for patients. Most of these conditions are due to a mutation in a critical gene. There is no cure for the majority of these neurological conditions and the availability of disease-modifying therapeutics is quite rare. The lion’s share of the treatments that are available only provide symptomatic relief, as such, we are in desperate need of an effective therapeutic strategy for these conditions. Considering the current drug development landscape, gene therapy is giving us hope as one such effective therapeutic strategy. Consistent efforts have been made to develop gene therapy strategies using viral and non-viral vectors of gene delivery. Here, we have discussed both of these delivery methods and their properties. We have summarized the relative advantages and drawbacks of viral and non-viral vectors from the perspectives of safety, efficiency, and productivity. Recent developments such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene editing and its use in vivo have been described here as well. Given recent advancements, gene therapy shows great promise to emerge as a next-generation therapeutic for many of the neurodevelopmental and neurodegenerative conditions.

To determine optimal quarantine duration, we evaluated time from exposure to diagnosis for 107 close contacts of severe acute respiratory syndrome coronavirus 2 Omicron variant case-patients. Average time from exposure to diagnosis was 3.7 days; 70% of diagnoses were made on day 5 and 99.1% by day 10, suggesting 10-day quarantine.

Pathogen effectors can suppress various plant immune responses, suggesting their multiple targets in the host. To understand the mechanisms underlying plasma membrane-associated and effector-mediated immunity, we performed Phytophthora capsici CRISIS screening. In Nicotiana benthamiana, cell death induced by the RxLR effector CRISIS2 is inhibited by irreversible plasma membrane H+-ATPase (PMA) activator fusicoccin. Biochemical and gene silencing analyses revealed that CRISIS2 physically and functionally associates with PMAs and induces cell death independent of immune receptors. CRISIS2 induces apoplastic alkalization by suppressing PMA activity by association with the C-terminal regulatory domain of PMA. In planta expression of CRISIS2 significantly enhanced virulence of P. capsici, whereas host-induced gene silencing of CRISIS2 compromised disease symptom and biomass of P. capsici. Furthermore, co-immunoprecipitation assays revealed CRISIS2 associates with BAK1, the co-receptor of PRRs. CRISIS2 interferes with the FLS2-BAK1 complex induced by flagellin perception and impairs downstream signaling from PRR complex. Proteomics and gene silencing assays identified putative PRRs negatively regulate the virulence of P. capsici in N. benthamiana as interactors of CRISIS2 and BAK1. Our study identified a novel RxLR effector playing multiple roles in suppression of plant defense and induction of cell death to support the pathogen hemibiotrophic life cycle in the host plant.

Inflammation plays an important role in the progression of peripheral artery disease (PAD). We investigated the predictive value of the C-reactive protein-to-albumin ratio (CAR) on the severity of PAD and outcomes after endovascular therapy (EVT). Patients (n = 307) with PAD who underwent EVT were retrospectively reviewed and categorized according to CAR tertiles. The groups were compared for the prevalence of complex lesions and multilevel involvement as well as the incidence of major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). The rates of complex lesions and multilevel involvement increased with increasing CAR tertiles (all P < .001). These associations remained significant even after adjustment for other confounders (complex lesion odds ratio, 1.22 [1.03-1.50]; P = .036; multilevel disease odds ratio, 1.20 [1.01-1.44]; P = .041). The third CAR tertile showed a significantly higher incidence of MACEs and MALEs than the second and first tertiles within a year (log-rank P < .001). A higher CAR as a continuous variable was also independently associated with the 4-year rate of MACE (hazard ratio, 1.20 [1.04-1.38]; P = .015). Elevated CAR was a powerful surrogate marker of severe PAD and worse outcomes. Thus, CAR might become a predictor of poor prognosis in patients with PAD.

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.