Purpose: Sustained cell proliferation and cell cycle acceleration in cancer cells inherently increase DNA damage, which interferes with homeostatic replication and transcription. Ataxia telangiectasia and Rad3-related (ATR) is crucial for initiation of the DNA damage response, and ATR inhibitors, such as elimusertib, induce increased replication stress and DNA damage. We investigated the anti-tumor effects of elimusertib and its mechanism of action in relation to replication stress. Materials and Methods: Anti-tumor effects were evaluated by MTT assay and colony formation assay in breast cancer cell lines in vitro, in breast cancer cell xenografts in vivo, and in patient-derived xenograft models. Cell cycle was assessed by flow cytometry and BrdU assay was used to measure replicating cells and S-phase progression. Alkaline and neutral comet assay was used to measure single and double-stranded DNA damages, respectively. Results: Elimusertib delayed S-phase progression in MDA-MB-453 and MDA-MB-231 cells and induced caspase-7–dependent apoptosis. Furthermore, the increase in sub-G1 population in the fluorescence-activated cell sorting analysis and Annexin V assay also confirmed apoptotic cell death. In the BrdU assay, single-stranded DNA (ssDNA) increased in sensitive cells and aberrant ssDNA induced DNA damage in S-phase and eventually caused replication catastrophe. Finally, these anti-tumor effects were proven in in vivo xenograft and patient-derived xenograft models. Conclusion Elimusertib had anti-tumor effects and induced replication catastrophe in breast cancer cells with a high replication rate. Moreover, cells under high DNA replication stress were sensitive to elimusertib. Further studies and treatment strategies with elimusertib are warranted for cancers with a high replication rate.

Background: and Purpose Treatments for neuromyelitis optica spectrum disorder (NMOSD) such as eculizumab, ravulizumab, satralizumab, and inebilizumab have significantly advanced relapse prevention, but they remain expensive. Rituximab is an off-label yet popular alternative that offers a cost-effective solution, but its real-world efficacy needs better quantification for guiding the application of newer approved NMOSD treatments (ANTs). This study aimed to determine real-world rituximab failure rates to anticipate the demand for ANTs and aid in resource allocation. Methods: We conducted a nationwide retrospective study involving 605 aquaporin-4-antibody-positive NMOSD patients from 22 centers in South Korea that assessed the efficacy and safety of rituximab over a median follow-up of 47 months. Results: The 605 patients treated with rituximab included 525 (87%) who received continuous therapy throughout the follow-up period (median=47 months, interquartile range=15–87 months). During this period, 117 patients (19%) experienced at least 1 relapse. Notably, 68 of these patients (11% of the total cohort) experienced multiple relapses or at least 1 severe relapse.Additionally, 2% of the patients discontinued rituximab due to adverse events, which included severe infusion reactions, neutropenia, and infections. Conclusions This study has confirmed the efficacy of rituximab in treating NMOSD, as evidenced by an 87% continuation rate among patients over a 4-year follow-up period. Nevertheless, the occurrence of at least one relapse in 19% of the cohort, including 11% who experienced multiple or severe relapses, and a 2% discontinuation rate due to adverse events highlight the urgent need for alternative therapeutic options.

Background: and Purpose Treatments for neuromyelitis optica spectrum disorder (NMOSD) such as eculizumab, ravulizumab, satralizumab, and inebilizumab have significantly advanced relapse prevention, but they remain expensive. Rituximab is an off-label yet popular alternative that offers a cost-effective solution, but its real-world efficacy needs better quantification for guiding the application of newer approved NMOSD treatments (ANTs). This study aimed to determine real-world rituximab failure rates to anticipate the demand for ANTs and aid in resource allocation. Methods: We conducted a nationwide retrospective study involving 605 aquaporin-4-antibody-positive NMOSD patients from 22 centers in South Korea that assessed the efficacy and safety of rituximab over a median follow-up of 47 months. Results: The 605 patients treated with rituximab included 525 (87%) who received continuous therapy throughout the follow-up period (median=47 months, interquartile range=15–87 months). During this period, 117 patients (19%) experienced at least 1 relapse. Notably, 68 of these patients (11% of the total cohort) experienced multiple relapses or at least 1 severe relapse.Additionally, 2% of the patients discontinued rituximab due to adverse events, which included severe infusion reactions, neutropenia, and infections. Conclusions This study has confirmed the efficacy of rituximab in treating NMOSD, as evidenced by an 87% continuation rate among patients over a 4-year follow-up period. Nevertheless, the occurrence of at least one relapse in 19% of the cohort, including 11% who experienced multiple or severe relapses, and a 2% discontinuation rate due to adverse events highlight the urgent need for alternative therapeutic options.

Background: and Purpose Treatments for neuromyelitis optica spectrum disorder (NMOSD) such as eculizumab, ravulizumab, satralizumab, and inebilizumab have significantly advanced relapse prevention, but they remain expensive. Rituximab is an off-label yet popular alternative that offers a cost-effective solution, but its real-world efficacy needs better quantification for guiding the application of newer approved NMOSD treatments (ANTs). This study aimed to determine real-world rituximab failure rates to anticipate the demand for ANTs and aid in resource allocation. Methods: We conducted a nationwide retrospective study involving 605 aquaporin-4-antibody-positive NMOSD patients from 22 centers in South Korea that assessed the efficacy and safety of rituximab over a median follow-up of 47 months. Results: The 605 patients treated with rituximab included 525 (87%) who received continuous therapy throughout the follow-up period (median=47 months, interquartile range=15–87 months). During this period, 117 patients (19%) experienced at least 1 relapse. Notably, 68 of these patients (11% of the total cohort) experienced multiple relapses or at least 1 severe relapse.Additionally, 2% of the patients discontinued rituximab due to adverse events, which included severe infusion reactions, neutropenia, and infections. Conclusions This study has confirmed the efficacy of rituximab in treating NMOSD, as evidenced by an 87% continuation rate among patients over a 4-year follow-up period. Nevertheless, the occurrence of at least one relapse in 19% of the cohort, including 11% who experienced multiple or severe relapses, and a 2% discontinuation rate due to adverse events highlight the urgent need for alternative therapeutic options.

Background: The effectiveness of electronic medical record-based alert systems, response protocols for sepsis diagnosis, and treatment in hospitalized patients remains unclear. This study aimed to determine whether the introduction of an electronic medical record-based sepsis response protocol (SRP) along with a 24/7 operating rapid response system affects the prognosis for patients with hospital-onset sepsis. Methods: In August 2022, a SRP based on the National Early Warning Score was implemented in the electronic medical record system at Asan Medical Center. We retrospectively analyzed patients screened by the detection system for 1 year after the SRP implementation. Patients of the first 6 months (preliminary group) and those of the second 6 months (SRP group) were matched 1:1 based on propensity scores. The primary outcome was 30-day mortality. Results: Of the 608 hospitalized patients screened by the system, 176 were assigned to each group after 1:1 propensity score matching. Patients in the SRP group were significantly more likely to receive blood cultures (58.5%) compared with the preliminary group (45.5%) (P=0.019). The SRP group showed a lower 30-day mortality risk (hazard ratio, 0.56; 95% CI, 0.36–0.86; P=0.017) compared to the preliminary group. A restricted cubic spline curve showed that SRP survival benefit began to manifest after the first 4 months (P=0.036). Conclusions Alongside an existing rapid response system, the National Early Warning Score-based SRP in the electronic medical record reduced mortality for hospital-onset sepsis within 1 year.

Objective: This study aimed to determine the safety and efficacy of the RKP00156 vaginal tablet, a CDK9 inhibitor, in healthy women and patients with cervical intraepithelial neoplasia grade 2 (CIN2). Methods: We conducted a phase 1/2a clinical trial of RKP00156. In step 1, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered transvaginally to 24 healthy women.In step 2, RKP00156 at a dose of 10, 25, or 50 mg or a placebo tablet was administered once daily for 4 weeks in 62 patients with CIN2. The primary endpoints of this trial were the safety of RKP00156 and the change in the human papillomavirus (HPV) viral load. Results: A total of 86 patients were enrolled and randomized. RKP00156 administration did not cause serious drug-associated adverse events (AEs). Although no significant difference in the HPV viral load was found between the experimental and placebo groups, a reduction in the HPV viral load was observed in the 25 mg-dose group (−98.61%; 95% confidence interval=−99.83%, 4.52%; p=0.046) after treatment completion in patients with a high HPV viral load, despite a lack of statistical power. No differences in histologic regression and HPV clearance were observed. Conclusion The safety of RKP00156 was proved with no serious AEs. Although the study did not show any significance in histologic regression and HPV clearance, our findings indicate that RKP00156 may have a possibility of short-term inhibitory effect on HPV replication in patients with higher viral loads.

Background: Precautionary allergen labeling (PAL) is mandatory and legally regulated in Korea. This study aims to investigate the frequency of PAL use in food products, evaluate its competence, and seek direction for improvement. Methods: Cow’s milk (CM) and hen’s egg white (EW) protein concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The results validated PAL using the Voluntary Incidental Trace Allergen Labeling ® 3.0 program. A survey was conducted on guardians to compare preferences and understanding of the current and the arbitrarily revised PAL. Results: PAL was used in 91.8% (280/305) of baby food products. ELISA results using randomly selected baby food products showed that only 16.7% (5/30; No PAL with no contamination, n = 4; PAL with real-contamination risk, n = 1) were validated to PAL. A detectable CM was found in two products (2/26, 7.7%), with one product exceeding the reference dose (10.3 ± 0.17 ppm). EW was not detected at all (0/16). A total of 207 surveys from guardians were collected and categorized into three groups: food allergy (FA, n = 103), diseases other than food allergies (Others, n = 52), and no disease (Control, n = 52). The FA group exhibited the highest frequency of checking food allergen labeling (“always”: 78.6%, “often”: 9.7%), with a similar PAL adherence (“always”: 58.3%, “often”: 10.4%). None of the groups were satisfied with the current PAL. The ‘allergen-free’ statement was mostly preferred across all groups. The FA group notably preferred PAL with concentration statements. Conclusion PAL is excessively prevalent and insufficient in ensuring the safety of children with FAs, necessitating a revision towards a more patient-friendly, evidence-based system for affected individuals and their families.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. Methods: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. Results: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. Conclusion This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

This study aimed to analyze the correlation between smoking and coronavirus disease 2019 (COVID-19) severity by region and gross domestic product (GDP). The regions were categorized by continent and GDP rankings. Studies conducted between June 3, 2020 and March 27, 2023 were searched to compare the severity of COVID-19 between smokers and non-smokers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Compared with never-smokers, the smokers’ COVID-19 severity scores were 1.48 (confidence interval [CI]: 1.25–1.75) in Asia, 1.24 (CI: 1.05–1.46) in the Middle East, 1.32 (1.21–1.45) in Europe, 1.39 (1.30–1.49) in North America, 1.69 (1.22–2.34) in South America, and 2.87 (1.82–4.53) in Africa. By GDP, the smokers’ COVID-19 severity scores were higher than those of never-smokers: 1.42 (1.32–1.53) in high-GDP countries, 1.33 (1.25–1.41) in middle-GDP countries (11th–50th), and 1.53 (0.85–2.76) in low-GDP countries. The COVID-19 severity in smokers was significantly higher in low-GDP countries than in high- and middle-income countries. The high COVID-19 death rate among smokers in the African continent and low-GDP countries is thought to stem from the lack of medical management systems compared with other countries. In addition to medical treatment, environmental or socioeconomic factors can increase the severity.

Background: Precautionary allergen labeling (PAL) is mandatory and legally regulated in Korea. This study aims to investigate the frequency of PAL use in food products, evaluate its competence, and seek direction for improvement. Methods: Cow’s milk (CM) and hen’s egg white (EW) protein concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). The results validated PAL using the Voluntary Incidental Trace Allergen Labeling ® 3.0 program. A survey was conducted on guardians to compare preferences and understanding of the current and the arbitrarily revised PAL. Results: PAL was used in 91.8% (280/305) of baby food products. ELISA results using randomly selected baby food products showed that only 16.7% (5/30; No PAL with no contamination, n = 4; PAL with real-contamination risk, n = 1) were validated to PAL. A detectable CM was found in two products (2/26, 7.7%), with one product exceeding the reference dose (10.3 ± 0.17 ppm). EW was not detected at all (0/16). A total of 207 surveys from guardians were collected and categorized into three groups: food allergy (FA, n = 103), diseases other than food allergies (Others, n = 52), and no disease (Control, n = 52). The FA group exhibited the highest frequency of checking food allergen labeling (“always”: 78.6%, “often”: 9.7%), with a similar PAL adherence (“always”: 58.3%, “often”: 10.4%). None of the groups were satisfied with the current PAL. The ‘allergen-free’ statement was mostly preferred across all groups. The FA group notably preferred PAL with concentration statements. Conclusion PAL is excessively prevalent and insufficient in ensuring the safety of children with FAs, necessitating a revision towards a more patient-friendly, evidence-based system for affected individuals and their families.