Effect of Paxlovid in COVID-19 treatment during the periods of SARS-CoV-2 Omicron BA.5 and BN.1 subvariant dominance in the Republic of Korea: a retrospective cohort study.

BACKGROUND: This study was conducted to assess the efficacy of nirmatrelvir/ritonavir treatment in patients with coronavirus disease 2019 (COVID-19), particularly those aged 60 years and older. Using real-world data, the period during which the BN.1 Omicron variant was dominant was compared to the period dominated by the BA.5 variant. METHODS: In this retrospective cohort study, data were collected regarding 2,665,281 patients infected with severe acute respiratory syndrome coronavirus 2 between July 24, 2022, and March 31, 2023. Propensity score matching was utilized to match patients who received nirmatrelvir/ ritonavir in a 1:4 ratio between BN.1 and BA.5 variant groups. Multivariable logistic regression analysis was employed to assess the effects of nirmatrelvir/ritonavir within these groups. RESULTS: Compared to the prior period, the efficacy of nirmatrelvir/ritonavir did not significantly differ during the interval of Omicron BN.1 variant dominance in the Republic of Korea. Among patients treated with nirmatrelvir/ritonavir, a significantly lower risk of mortality was observed in the BN.1 group (odds ratio [OR], 0.698; 95% confidence interval [CI], 0.557-0.875) compared to the BA.5 group. However, this treatment did not significantly reduce the risk of severe or critical illness, including death, for those in the BN.1 group (OR, 0.856; 95% CI, 0.728-1.007). CONCLUSION: Nirmatrelvir/ritonavir has maintained its effectiveness against COVID-19, even with the emergence of the BN.1 Omicron subvariant. Consequently, we strongly recommend the administration of nirmatrelvir/ritonavir to patients exhibiting COVID-19-related symptoms, irrespective of the dominant Omicron variant or their vaccination status, to mitigate disease severity and decrease the risk of mortality.

Changes in the intrinsic severity of severe acute respiratory syndrome coronavirus 2 according to the emerging variant: a nationwide study from February 2020 to June 2022, including comparison with vaccinated populations.

BACKGROUND: As the population acquires immunity through vaccination and natural infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the intrinsic severity of coronavirus disease (COVID-19) is becoming challenging. We aimed to evaluate the intrinsic severity regarding circulating variants of SARS-CoV-2 and to compare this between vaccinated and unvaccinated individuals. METHODS: With unvaccinated and initially infected confirmed cases of COVID-19, we estimated the case severity rate (CSR); case fatality rate (CFR); and mortality rate (MR), including severe/critical cases and deaths, stratified by age and compared by vaccination status according to the period regarding the variants of COVID-19 and vaccination. The overall rate was directly standardized with age. RESULTS: The age-standardized CSRs (aCSRs) of the unvaccinated group were 2.12%, 5.51%, and 0.94% in the pre-delta, delta, and omicron period, respectively, and the age-standardized CFRs (aCFRs) were 0.60%, 2.49%, and 0.63% in each period, respectively. The complete vaccination group had lower severity than the unvaccinated group over the entire period showing under 1% for the aCSR and 0.5% for the aCFR. The age-standardized MR of the unvaccinated group was 448 per million people per month people in the omicron period, which was 11 times higher than that of the vaccinated group. In terms of age groups, the CSR and CFR sharply increased with age from the 60 s and showed lower risk reduction in the 80 s when the period changed to the omicron period. CONCLUSIONS: The intrinsic severity of COVID-19 was the highest in the delta period, with over 5% for the aCSR, whereas the completely vaccinated group maintained below 1%. This implies that when the population is vaccinated, the impact of COVID-19 will be limited, even if a new mutation appears. Moreover, considering the decreasing intrinsic severity, the response to COVID-19 should prioritize older individuals at a higher risk of severe disease.

Differential effect of cancer-associated fibroblast-derived extracellular vesicles on cisplatin resistance in oral squamous cell carcinoma via miR-876-3p.

Rationale: Platinum-based chemotherapy is commonly used for treating solid tumors, but drug resistance often limits its effectiveness. Cancer-associated fibroblast (CAF)-derived extracellular vesicle (EV), which carry various miRNAs, have been implicated in chemotherapy resistance. However, the molecular mechanism through which CAFs modulate cisplatin resistance in oral squamous cell carcinoma (OSCC) is not well understood. We employed two distinct primary CAF types with differential impacts on cancer progression: CAF-P, representing a more aggressive cancer-promoting category, and CAF-D, characterized by properties that moderately delay cancer progression. Consequently, we sought to investigate whether the two CAF types differentially affect cisplatin sensitivity and the underlying molecular mechanism. Methods: The secretion profile was examined by utilizing an antibody microarray with conditioned medium obtained from the co-culture of OSCC cells and two types of primary CAFs. The effect of CAF-dependent factors on cisplatin resistance was investigated by utilizing conditioned media (CM) and extracellular vesicle (EVs) derived from CAFs. The impacts of candidate genes were confirmed using gain- and loss-of-function analyses in spheroids and organoids, and a mouse xenograft. Lastly, we compared the expression pattern of the candidate genes in tissues from OSCC patients exhibiting different responses to cisplatin. Results: When OSCC cells were cultured with conditioned media (CM) from the two different CAF groups, cisplatin resistance increased only under CAF-P CM. OSCC cells specifically expressed insulin-like growth factor binding protein 3 (IGFBP3) after co-culture with CAF-D. Meanwhile, IGFBP3-knockdown OSCC cells acquired cisplatin resistance in CAF-D CM. IGFBP3 expression was promoted by GATA-binding protein 1 (GATA1), a transcription factor targeted by miR-876-3p, which was enriched only in CAF-P-derived EV. Treatment with CAF-P EV carrying miR-876-3p antagomir decreased cisplatin resistance compared to control miRNA-carrying CAF-P EV. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, there was a positive correlation between IGFBP3 and GATA1 expression and cisplatin sensitivity in OSCC tissues from patients. Conclusion: These results provide insights for overcoming cisplatin resistance, especially concerning EVs within the tumor microenvironment. Furthermore, it is anticipated that the expression levels of GATA1 and miR-876-3p, along with IGFBP3, could aid in the prediction of cisplatin resistance.

Functional modulation of lysophosphatidic acid type 2 G-protein coupled receptor facilitates alveolar bone formation.

Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.

Sustainable production and degradation of plastics using microbes.

Plastics are indispensable in everyday life and industry, but the environmental impact of plastic waste on ecosystems and human health is a huge concern. Microbial biotechnology offers sustainable routes to plastic production and waste management. Bacteria and fungi can produce plastics, as well as their constituent monomers, from renewable biomass, such as crops, agricultural residues, wood and organic waste. Bacteria and fungi can also degrade plastics. We review state-of-the-art microbial technologies for sustainable production and degradation of bio-based plastics and highlight the potential contributions of microorganisms to a circular economy for plastics.

Using Comparative Proteomics to Identify Protein Signatures in Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIM: Renal cell carcinoma (RCC) is one of the most commonly diagnosed cancers in the world. Approximately 25-30% of patients identified with initial kidney cancer will have metastasized tumors, thus 5-year survival rates for these patients are poor. Therefore, biomarker research is required to identify and predict molecular signatures in RCC. MATERIALS AND METHODS: To address this, we used a mass spectrometry (MS)-based proteomics approach to identify proteins related to clear cell RCC (ccRCC) tissues from patients with T1G2, T1G3, T3G2, T3G3, and metastatic RCC (mRCC) stages. RESULTS: We identified and quantified 2,608 and 2,463 proteins, respectively, in ccRCC tissue and identified 1,449 differentially expressed proteins (DEPs). Bioinformatics analysis revealed that serpin family A member 3 (SERPINA3) qualified as biomarker for ccRCC progression. Using indirect enzyme-linked immunosorbent assay (ELISA), immunoblotting, and immunohistochemistry assays it was found that SERPINA3 expression levels in ccRCC tissues were much higher in stages before metastasis. CONCLUSION: Comparative proteomics analysis of ccRCC tissues provided new evidence of SERPINA3 association with ccRCC progression.

3D simulation of interosseous interference in sagittal split ramus osteotomy for mandibular asymmetry.

BACKGROUND: The purpose of this study was to evaluate the pattern of predicted interosseous interference and to determine the influencing factor to volume of bony interference using a computer-assisted simulation system. This retrospective study recruited 116 patients with mandibular prognathism who had undergone sagittal split ramus osteotomy (SSRO) with or without maxillary osteotomy. The patients were divided into 3 groups according to the amount of menton (Me) deviation: less than 2 mm (Group 1), 2-4 mm (Group 2), and more than 4 mm (Group 3). Changes in the distal segments following BSSRO and the volume of the interosseous interference between the proximal and distal segments were simulated after matching preoperative occlusion and postoperative expected occlusion with the cone-beam computed tomography data. Ramal inclinations and other skeletal measurements were analyzed before surgery, immediately after surgery, and at least 6 months after surgery. RESULTS: The anticipated interosseous interference was more frequently noted on the contralateral side of chin deviation (long side) than the deviated site (short side) in Groups 2 and 3. More interference volume was predicted at the long side (186 ± 343.9 mm3) rather than the short side (54.4 ± 124.4 mm3) in Group 3 (p = 0.033). The bilateral difference in the volume of the interosseous interference of the osteotomized mandible was significantly correlated with the Me deviation (r = - 0.257, p = 0.009) and bilateral ramal inclination (r = 0.361, p < 0.001). The predictor variable that affected the volume of the osseous interference at each side was the amount of Me deviation (p = 0.010). CONCLUSION: By using the 3D simulation system, the potential site of bony collision could be visualized and successfully reduced intraoperatively. Since the osseous interference can be existed on any side, unilaterally or bilaterally, 3D surgical simulation is necessary before surgery to predict the osseous interference and improve the ramal inclination.

Integrative Profiling of Lysine Acylome in Sepsis-Induced Liver Injury.

Sepsis is one of the life-threatening diseases worldwide. Despite the continuous progress in medicine, the specific mechanism of sepsis remains unclear. A key strategy of pathogens is to use post-translational modification to modulate host factors critical for infection. We employed global immunoprecipitation technology for lysine acetylation (Kac), succinylation (Ksu), and malonylation (Kmal) for the first global lysine acylation (Kacy) analysis in a cecum ligation and puncture (CLP) model in mouse. This was performed to reveal the pathogenic mechanism of integrative Kacy and the changes in modification sites. In total, 2230 sites of 1,235 Kac proteins, 1,887 sites of 433 Ksu proteins, and 499 sites of 276 Kmal proteins were quantified and normalized by their protein levels. We focused on 379 sites in 219 upregulated proteins as the integrative Kacy sites of Kac, Ksu, and Kmal on the basis of sirtuins decreased in the CLP group. KEGG pathway analysis of integrative Kacy in 219 upregulated proteins revealed three central metabolic pathways: glycolysis/gluconeogenesis, pyruvate metabolism, and tricarboxylic acid cycle. These findings reveal the key pathogenic mechanism of integrative PTM alteration in terms of the decreased sirtuins level and provide an important foundation for an in-depth study of the biological function of Kacy in sepsis.

Risk Factors for Sudden Death Within 2 Days After Diagnosis of COVID-19 in Korea.

BACKGROUND: We aimed to analyze the risk factors for sudden death after diagnosis of coronavirus disease 2019 (COVID-19) in South Korea and to provide evidence for informing prevention and control interventions for patients at risk of sudden death. METHODS: We included 30,302 COVID-19 related deaths registered in the patient management information system (Central Disease Control Headquarters) between January 1, 2021, and December 15, 2022. We collected their epidemiological data recorded by the reporting city, province, or country. We performed multivariate logistic regression analysis to identify risk factors for sudden death after diagnosis of COVID-19. RESULTS: Among the 30,302 deaths, there were 7,258 (24.0%) and 23,044 (76.0%) sudden and non-sudden deaths, respectively. Sudden death means a person who died within 2 days of diagnosis and who did not receive inpatient treatment. Underlying condition, vaccination status, and place of death were significantly associated with the survival period in all age groups. Moreover, region, sex, and prescription were significantly associated with the survival period only in certain age groups. However, reinfection was not significantly associated with the survival period in any age group. CONCLUSION: To our knowledge, this is the first study on the risk factors for sudden death after a diagnosis of COVID-19, which included age, underlying condition, vaccination status, and place of death. Additionally, individuals aged < 60 years without an underlying condition were at high risk for sudden death. However, this group has relatively low interest in health, as can be seen from the high non-vaccination rate (16.1% of the general population vs. 61.6% of the corresponding group). Therefore, there is a possibility for the presence of an uncontrolled underlying disease in this population. In addition, many sudden deaths occurred due to delayed hospital visits to continue economic activities even after the onset of COVID-19 symptoms (7 days overall vs. 10 days average for the group). In conclusion, 'continued interest in health' is a key factor in avoiding sudden death in the economically active group (under 60 years of age).

Nanotechnologies for the Diagnosis and Treatment of SARS-CoV-2 and Its Variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the global coronavirus disease 2019 (COVID-19) pandemic, has caused well over 750 million infections and 6.8 million deaths. Rapid diagnosis and isolation of infected patients are the primary aims of the concerned authorities to minimize the casualties. The endeavor to mitigate the pandemic has been impeded by the emergence of newly identified genomic variants of SARS-CoV-2. Some of these variants are considered as serious threats because of their higher transmissibility and potential immune evasion, leading to reduced vaccine efficiency. Nanotechnology can play an important role in advancing both diagnosis and therapy of COVID-19. In this review, nanotechnology-based diagnostic and therapeutic strategies against SARS-CoV-2 and its variants are introduced. The biological features and functions of the virus, the mechanism of infection, and currently used approaches for diagnosis, vaccination, and therapy are discussed. Then, nanomaterial-based nucleic acid- and antigen-targeting diagnostic methods and viral activity suppression approaches that have a strong potential to advance both diagnostics and therapeutics toward control and containment of the COVID-19 pandemic are focused upon.

Widespread Household Transmission of SARS-CoV-2 B.1.1.529 (Omicron) Variant from Children, South Korea, 2022.

The role that children play in the transmission of the omicron variant is unclear. Here we report an outbreak that started in young children attending various pediatric facilities, leading to extensive household transmission that affected 75 families with 88 confirmed case-patients in 3 weeks. Tailored social and public health measures directed towards children and pediatric facilities are warranted with the emergence of highly transmissible omicron variant to mitigate the impact of coronavirus diseases 2019 (COVID-19).

Novel Time-dependent Multi-omics Integration in Sepsis-associated Liver Dysfunction.

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease processes. However, it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical outcomes. Here, we conducted a time-dependent multi-omics integration (TDMI) in a sepsis-associated liver dysfunction (SALD) model. We successfully deduced the relation of the toll-like receptor 4 (TLR4) pathway with SALD. Although TLR4 is a critical factor in sepsis progression, it is not specified in single-omics results but only in the TDMI analysis. This result indicates that the TDMI-based approach is more advantageous than single-omics analysis in terms of exploring the underlying pathophysiological mechanism of this disease. Furthermore, this approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology, health, and diseases, thus allowing the identification of promising candidates for therapeutic strategies.

Biohybrid CO2 electrolysis for the direct synthesis of polyesters from CO2.

Converting anthropogenic CO2 to value-added products using renewable energy has received much attention to achieve a sustainable carbon cycle. CO2 electrolysis has been extensively investigated, but the products have been limited to some C1-3 products. Here, we report the integration of CO2 electrolysis with microbial fermentation to directly produce poly-3-hydroxybutyrate (PHB), a microbial polyester, from gaseous CO2 on a gram scale. This biohybrid system comprises electrochemical conversion of CO2 to formate on Sn catalysts deposited on a gas diffusion electrode (GDE) and subsequent conversion of formate to PHB by Cupriavidus necator cells in a fermenter. The electrolyzer and the electrolyte solution were optimized for this biohybrid system. In particular, the electrolyte solution containing formate was continuously circulated through both the CO2 electrolyzer and the fermenter, resulting in the efficient accumulation of PHB in C. necator cells, reaching a PHB content of 83% of dry cell weight and producing 1.38 g PHB using 4 cm2 Sn GDE. This biohybrid system was further modified to enable continuous PHB production operated at a steady state by adding fresh cells and removing PHB. The strategies employed for developing this biohybrid system will be useful for establishing other biohybrid systems producing chemicals and materials directly from gaseous CO2.

Metabolic engineering for sustainability and health.

Bio-based production of chemicals and materials has attracted much attention due to the urgent need to establish sustainability and enhance human health. Metabolic engineering (ME) allows purposeful modification of cellular metabolic, regulatory, and signaling networks to achieve enhanced production of desired chemicals and degradation of environmentally harmful chemicals. ME has significantly progressed over the past 30 years through further integration of the strategies of synthetic biology, systems biology, evolutionary engineering, and data science aided by artificial intelligence. Here we review the field of ME from its emergence to the current state-of-the-art, highlighting its contribution to sustainable production of chemicals, health, and the environment through representative examples. Future challenges of ME and perspectives are also discussed.

Atypical lipomatous tumour/well-differentiated liposarcoma found in the buccal mucosa: A rare case report.

Oral liposarcomas are uncommon diseases, the most predominant histopathological subtype being atypical lipomatous tumour/well-differentiated liposarcoma. In regard to its clinical aspects in the oral cavity, it is challenging to confirm a diagnosis and develop a treatment plan. In this case report, we present a rare case of atypical lipomatous tumour/well-differentiated liposarcoma in the right cheek of a 77-year-old male patient. Conservative surgery was performed considering the histopathological subtype of the neoplasm. Knowledge of the clinical and histopathological characteristics of this rare disease is essential to maintaining function and aesthetics through conservative treatment in older patients.

LDHA Desuccinylase Sirtuin 5 as A Novel Cancer Metastatic Stimulator in Aggressive Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed genital cancer in men worldwide. Around 80% of the patients who developed advanced PCa suffered from bone metastasis, with a sharp drop in the survival rate. Despite great efforts, the detailed mechanisms underlying castration-resistant PCa (CRPC) remain unclear. Sirtuin 5 (SIRT5), an NAD+-dependent desuccinylase, is hypothesized to be a key regulator of various cancers. However, compared to other SIRTs, the role of SIRT5 in cancer has not been extensively studied. Here, we revealed significantly decreased SIRT5 levels in aggressive PCa cells relative to the PCa stages. The correlation between the decrease in the SIRT5 level and the patient's reduced survival rate was also confirmed. Using quantitative global succinylome analysis, we characterized a significant increase in the succinylation at lysine 118 (K118su) of lactate dehydrogenase A (LDHA), which plays a role in increasing LDH activity. As a substrate of SIRT5, LDHA-K118su significantly increased the migration and invasion of PCa cells and LDH activity in PCa patients. This study reveals the reduction of SIRT5 protein expression and LDHA-K118su as a novel mechanism involved in PCa progression, which could serve as a new target to prevent CPRC progression for PCa treatment.

Factors influencing the intention to engage in cervical cancer preventive behavior in human papillomavirus-infected women: a cross-sectional survey.

PURPOSE: This study investigated the influence of cervical cancer knowledge, human papillomavirus (HPV) knowledge, self-efficacy, and uncertainty on the intention to engage in cervical cancer preventive behavior in HPV-infected women. METHODS: This descriptive correlational study was conducted among 129 adult women aged 20 to 65 years who received positive HPV results at a general hospital in Changwon, Korea. The dataset was analyzed using descriptive statistics, the independent t-test, analysis of variance, the Pearson correlation coefficient, and multiple regression. RESULTS: The mean score for the intention to engage in cervical cancer preventive behavior was high (4.43±0.65). This intention was significantly different according to age at first sexual intercourse (F=7.38, p=.001), HPV type (F=4.79, p=.010), vaccination (t=3.19, p=.002), and condom use (t=3.03, p=.003). The intention to engage in cervical cancer preventive behavior showed significant, weak-to-moderate positive correlations with HPV knowledge (r=.22, p=.012) and self-efficacy (r=.42, p<.001). Self-efficacy (ß=.46, p<.001), first sexual intercourse at <20 years (ß=.45, p<.001), first sexual intercourse at 20-24 years (ß=.29, p=. 018), HPV high- and low-risk group infection (ß=.26, p=.019), HPV high-risk group infection (ß=.26, p=.026), and vaccination (ß=.21, p=.007) significantly influenced the intention to engage in cervical cancer preventive behavior. These variables explained 34.6% of variance in intention. CONCLUSION: Study findings support the need to develop a program that effectively conveys accurate information about cervical cancer prevention to HPV-infected women and helps them enhance self-efficacy to boost the intention to engage in cervical cancer preventive behavior.

Multiple HA substitutions in highly pathogenic avian influenza H5Nx viruses contributed to the change in the NA subtype preference.

Novel highly pathogenic avian influenza (HPAI) H5Nx viruses are predominantly circulating worldwide, with an increasing potential threat of an outbreak in humans. It remains largely unknown how the stably maintained HPAI H5N1 suddenly altered its neuraminidase (NA) to other NA subtypes, which resulted in the emergence and evolution of H5Nx viruses. Here, we found that a combination of four specific amino acid (AA) substitutions (S123P-T156A-D183N- S223 R) in the hemagglutinin (HA) protein consistently observed in the H5Nx markedly altered the NA preference of H5N1 viruses. These molecular changes in H5N1 impaired its fitness, particularly viral growth and the functional activities of the HA and NA proteins. Among the AA substitutions identified, the T156A substitution, which contributed to the NA shift, also dramatically altered the antigenicity of H5N1 viruses, suggesting an occurrence of antigenic drift triggered by selective pressure. Our study shows the importance of how HA and NA complement each other and that antigenic drift in HA can potentially cause a shift in the NA protein in influenza A virus evolution.