Effectiveness of Bivalent mRNA Booster Vaccine Against COVID-19 in Korea.

BACKGROUND: Bivalent booster mRNA vaccines containing the omicron-variant strains have been introduced worldwide in the autumn of 2022. Nevertheless, the omicron subvariants evoked another large coronavirus disease 2019 (COVID-19) pandemic wave in late 2022 and early 2023. METHODS: A retrospective, test-negative, case-control study was conducted to estimate the vaccine effectiveness (VE) of bivalent COVID-19 vaccines in 8 university hospitals between January and February 2023. The case and control groups were divided based on nasopharyngeal COVID-19 real-time polymerase chain reaction results and matched based on age, sex, hospital, and date (week) of the test performed. The VE of the BA.1- or BA.4/BA.5-based mRNA vaccines were estimated. VE was calculated using the 1-adjusted odds ratio from multivariable logistic regression. RESULTS: In total, 949 patients and 947 controls were enrolled in this study. VE for the BA.4/BA.5-based bivalent mRNA vaccine was 43% (95% confidence interval [CI], 17, 61%). In subgroup analysis based on age and underlying medical conditions, BA.4/BA.5-based bivalent mRNA vaccine was effective against old adults aged ≥ 65-years (VE, 55%; 95% CI, 23, 73%) and individuals with comorbidities (VE, 54%; 95% CI, 23, 73%). In comparison, the BA.1-based bivalent mRNA vaccine did not demonstrate statistically significant effectiveness (VE, 25%; 95% CI, -8, 49%). CONCLUSION: The BA.4/BA.5-based bivalent mRNA booster vaccine provided significant protection against COVID-19 in the Korean adults, especially in the older adults aged ≥ 65 years and in individuals with underlying medical conditions.

Interim Estimates of 2023-2024 Seasonal Influenza Vaccine Effectiveness Among Adults in Korea.

In the 2023-2024 season, the influenza epidemic in South Korea peaked earlier than in recent years. In this study, we aimed to estimate the interim vaccine effectiveness (VE) of the influenza vaccination to prevent influenza during the early season. From November 1, 2023, to December 31, 2023, we enrolled 2,632 subjects with influenza-like illness from eight hospitals participating in hospital-based influenza morbidity and mortality surveillance. A retrospective test-negative case-control study was conducted to estimate the VE. The results showed an adjusted VE of 22.5% (95% confidence interval [CI], 6.6 to 35.8) for the total population. The adjusted VE was 22.3% (95% CI, 6.1 to 35.7) for influenza A and 9.4% (95% CI, -51.3 to 45.7) for influenza A/H1N1. Full results of the analysis will be reported.

Functional cooperation of the glycine synthase-reductase and Wood-Ljungdahl pathways for autotrophic growth of Clostridium drakei.

Among CO2-fixing metabolic pathways in nature, the linear Wood-Ljungdahl pathway (WLP) in phylogenetically diverse acetate-forming acetogens comprises the most energetically efficient pathway, requires the least number of reactions, and converts CO2 to formate and then into acetyl-CoA. Despite two genes encoding glycine synthase being well-conserved in WLP gene clusters, the functional role of glycine synthase under autotrophic growth conditions has remained uncertain. Here, using the reconstructed genome-scale metabolic model iSL771 based on the completed genome sequence, transcriptomics, 13C isotope-based metabolite-tracing experiments, biochemical assays, and heterologous expression of the pathway in another acetogen, we discovered that the WLP and the glycine synthase pathway are functionally interconnected to fix CO2, subsequently converting CO2 into acetyl-CoA, acetyl-phosphate, and serine. Moreover, the functional cooperation of the pathways enhances CO2 consumption and cellular growth rates via bypassing reducing power required reactions for cellular metabolism during autotrophic growth of acetogens.

Transdural Revascularization by Multiple Burrhole After Erythropoietin in Stroke Patients With Cerebral Hypoperfusion: A Randomized Controlled Trial.

BACKGROUND: In patients with acute symptomatic stroke, reinforcement of transdural angiogenesis using multiple burr hole (MBH) procedures after EPO (erythropoietin) treatment has rarely been addressed. We aimed to investigate the efficacy and safety of cranial MBH procedures under local anesthesia for augmenting transdural revascularization after EPO treatment in patients with stroke with perfusion impairments. METHODS: This prospective, randomized, blinded-end point trial recruited patients with acute ischemic stroke with a perfusion impairment of grade ≥2 within 14 days of symptom onset, steno-occlusive mechanisms on imaging examinations, and absence of transdural collaterals on transfemoral cerebral angiography. Patients were randomly assigned to receive MBH + EPO or MBH alone. The primary and secondary outcomes were revascularization success (trans-hemispheric and trans-burr hole) at 6 months and adverse events, respectively. RESULTS: We evaluated 42 of the 44 targeted patients, with 2 patients lost to follow-up. The combined and MBH-only (n=21 each) groups showed no differences in demographic characteristics and baseline perfusion parameters. Significantly, more cases of trans-hemispheric (19/21 [90.5%] versus 12/21 [57.1%]) and trans-burr hole (42/58 [72.4%] versus 30/58 [51.7%]) revascularization and significant improvements in perfusion parameters were observed in the combined group relative to the MBH-only group. No differences in treatment-related complications were observed between groups. Even after adjustment for potential covariates, EPO usage was an independent factor of successful hemispheric revascularization in this study (odds ratio, 6.41 [95% CI, 1.08-38.02]). CONCLUSIONS: The combination of MBH and EPO is safe and feasible for reinforcing transdural revascularization in acute steno-occlusive patients with perfusion impairments. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02603406.

Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

BACKGROUND AND PURPOSE: Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. RESULTS: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. CONCLUSIONS: Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

Nelonemdaz for Patients With Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy: A Randomized Phase II Trial.

BACKGROUND: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. METHODS: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks. RESULTS: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported. CONCLUSIONS: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088.

Rosmarinic Acid, as an NHE1 Activator, Decreases Skin Surface pH and Improves the Skin Barrier Function.

Stratum corneum (SC) pH regulates skin barrier functions and elevated SC pH is an important factor in various inflammatory skin diseases. Acidic topical formulas have emerged as treatments for impaired skin barriers. Sodium proton exchanger 1 (NHE1) is an important factor in SC acidification. We investigated whether topical applications containing an NHE1 activator could improve skin barrier functions. We screened plant extracts to identify NHE1 activators in vitro and found Melissa officinalis leaf extract. Rosmarinic acid, a component of Melissa officinalis leaf extract, significantly increased NHE1 mRNA expression levels and NHE1 production. Immunofluorescence staining of NHE1 in 3D-cultured skin revealed greater upregulation of NHE1 expression by NHE1 activator cream, compared to vehicle cream. Epidermal lipid analysis revealed that the ceramide level was significantly higher upon application of the NHE1 activator cream on 3D-cultured skin, compared to application of a vehicle cream. In a clinical study of 50-60-year-old adult females (n = 21), application of the NHE1 activator-containing cream significantly improved skin barrier functions by reducing skin surface pH and transepidermal water loss and increasing skin hydration, compared to patients who applied vehicle cream and those receiving no treatment. Thus, creams containing NHE1 activators, such as rosmarinic acid, could help maintain or recover skin barrier functions.

A fusion of CD63-BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis.

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.

Assessment of antiphospholipid antibodies and calprotectin as biomarkers for discriminating mild from severe COVID-19.

BACKGROUND: To explore the association of thrombo-inflammatory biomarkers with severity in coronavirus disease (COVID-19), we measured antiphospholipid antibodies (aPL) and calprotectin in sera of COVID-19 patients. METHODS: Anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I antibodies were measured using enzyme-linked immunosorbent assay (ELISA) and multiplex flow immunoassay (MFIA) in hospitalized COVID-19 patients (N = 105) and healthy controls (N = 38). Anti-phosphatidylserine/prothrombin antibodies, calprotectin, and C-reactive protein (CRP) levels were also measured. We assessed the potential correlation between calprotectin levels and various laboratory parameters that were measured during the hospitalization period. After stratifying COVID-19 patients into two groups by their oxygenation status or acute respiratory distress syndrome presentation, the discriminatory performance of each biomarker was evaluated. RESULTS: A high proportion of COVID-19 patients (29.5%, 31/105) had low aCL IgM titers that were detectable by ELISA but mostly below the detection limit of MFIA. Calprotectin levels in severe groups of COVID-19 were significantly higher than those in non-severe groups, while CRP levels revealed no significant differences. Serum calprotectin levels showed strong to moderate degree of correlation with other routinely used parameters including peak levels of CRP, ferritin, procalcitonin, BUN, and neutrophil-to-lymphocyte ratio, but a negative correlation with minimal lymphocyte count and CD4+ T cells. The discriminatory performance was highest for calprotectin in discriminating severe groups of COVID-19. CONCLUSIONS: Serum calprotectin levels were significantly elevated in severe COVID-19 cases. The prevalence of clinically significant aPL did not differ. The link between calprotectin and inflammatory pathway in COVID-19 may help improve the management and outcomes of COVID-19 patients.

The Clinical Usefulness of Targeted Temperature Management in Acute Ischemic Stroke with Malignant Trait After Endovascular Thrombectomy.

BACKGROUND/OBJECTIVE: Targeted temperature management (TTM) may be more beneficial after endovascular treatment (EVT) in patients with a large ischemic core. Therefore, we assessed the usefulness of TTM for such patients from a multicenter endovascular registry. METHODS: Anterior circulation stroke patients who underwent endovascular recanalization were included; acute ischemic stroke with malignant traits was designated as (1) baseline Alberta Stroke Program Early CT Score (ASPECTS) below 6 and (2) diffusion-weighted imaging (DWI) lesion volume measurement (> 82 ml) or National Institutes of Health Stroke Scale score > 20 and item Ia > 0. TTM (34.5 °C) was maintained for at least 48 h. RESULTS: We evaluated baseline demographics, risk factors, EVT parameters, and clinical outcomes between the TTM and non-TTM groups. Among the 548 patients, the TTM group (n = 91) significantly had a lower baseline ASPECTS (p < 0.001) and a higher DWI volume (p < 0.001) than the non-TTM group (n = 457). TTM group had a lower prevalence of favorable outcome (0-2 of modified Rankin Scale at 3 months; p = 0.008) than the non-TTM group. In a subgroup analysis of malignant trait patients (n = 80), TTM patients (n = 28) had more favorable outcome (32.1% vs. 7.7% p = 0.009) and less hemorrhagic transformation (none vs. any hemorrhage, p = 0.007) than non-TTM patients (n = 52). After adjusting for potential outcome predictors, TTM (odds ratio [OR] 4.63; confidence interval [CI] 1.20-17.89; p = 0.026) and hypertension (OR 0.18; CI 0.04-0.74; p = 0.018) were found to be independent determinants. CONCLUSIONS: Our data suggest that TTM attenuates impending hemorrhagic transformation and leads to favorable clinical outcomes in EVT patients with malignant trait.