Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Unveiling nurses' end-of-life care experiences: Moral distress and impacts.

BACKGROUND: Nurses providing care to patients with end-of-life or terminal illnesses often encounter ethically challenging situations leading to moral distress. However, existing quantitative studies have examined moral distress using instruments that address general clinical situations rather than those specific to end-of-life care. Furthermore, qualitative studies have often been limited to participants from a single unit or those experiencing moral distress-induced circumstances. A comprehensive and integrated understanding of the overarching process of moral distress is vital to discern the unique circumstances surrounding end-of-life care and its consequential impacts. RESEARCH OBJECTIVES: To explore the moral distress experiences of nurses who are frequently involved in caring for patients with end-of-life or terminal illnesses and apply it to two existing theories: the model of moral distress and the ecological model. RESEARCH DESIGN: A qualitative descriptive approach was employed. PARTICIPANTS AND RESEARCH CONTEXT: Seven focus group interviews involving 30 nurses were performed. The subsequent transcriptions underwent rigorous content analysis. ETHICAL CONSIDERATIONS: We obtained Institutional Review Board approval from a university. Focus group interviews were conducted with nurses who agreed to participate and signed the consent form. FINDINGS: The moral distress-inducing factors and nurses' perceived impact of moral distress were identified and categorized based on moral distress theories and ecological models. A total of 15 categories and 30 subcategories across the following 4 domains were derived: (1) intrapersonal, (2) interpersonal, (3) organizational, and (4) structural factors. CONCLUSIONS: End-of-life-specific circumstances induced moral distress among nurses, with both negative and positive impacts identified. Effective organizational and policy support is essential to manage conflicts, form a healthy organizational culture, provide training, and prevent unnecessary expenses due to the negative consequences of moral distress.

Long-term outcomes of very low birth weight infants with intraventricular hemorrhage: a nationwide population study from 2011 to 2019.

BACKGROUND: Advancements in neonatal care have increased preterm infant survival but paradoxically raised intraventricular hemorrhage (IVH) rates. This study explores IVH prevalence and long-term outcomes of very low birth weight (VLBW) infants in Korea over a decade. METHODS: Using Korean National Health Insurance data (NHIS, 2010-2019), we identified 3372 VLBW infants with IVH among 4,129,808 live births. Health-related claims data, encompassing diagnostic codes, diagnostic test costs, and administered procedures were sourced from the NHIS database. The results of the developmental assessments  are categorized into four groups based on standard deviation (SD) scores. Neonatal characteristics and complications were compared among the groups. Logistic regression models were employed to identify significant changes in the incidence of complications and to calculate odds ratios with corresponding 95% confidence intervals for each risk factor associated with mortality and morbidity in IVH. Long-term growth and development were compared between the two groups (years 2010-2013 and 2014-2017). RESULTS: IVH prevalence was 12% in VLBW and 16% in extremely low birth weight (ELBW) infants. Over the past decade, IVH rates increased significantly in ELBW infants (P = 0.0113), while mortality decreased (P = 0.0225). Major improvements in certain neurodevelopmental outcomes and reductions in early morbidities have been observed among VLBW infants with IVH. Ten percent of the population received surgical treatments such as external ventricular drainage (EVD) or a ventriculoperitoneal (VP) shunt, with the choice of treatment methods remaining consistent over time. The IVH with surgical intervention group exhibited higher incidences of delayed development, cerebral palsy, seizure disorder, and growth failure (height, weight, and head circumference) up to 72 months of age (P < 0.0001). Surgical treatments were also significantly associated with abnormal developmental screening test results. CONCLUSIONS: The neurodevelopmental outcomes of infants with IVH, especially those subjected to surgical treatments, continue to be a matter of concern. It is imperative to prioritize specialized care for patients receiving surgical treatments and closely monitor their growth and development after discharge to improve developmental prognosis. Supplementary file2 (MP4 77987 kb).

First Report of Leaf Spot on Eriobotrya japonica Caused by Alternaria alternata in Southwest Korea.

Loquat (Eriobotrya japonica) is a crop cultivated in Southwest Korea, covering an area of 101 ha and yielding 120 tons at harvest (KASS, 2024). Due to its high-income potential, the cultivation area is gradually expanding. In May 2023, 30% of leaf brown spots were observed on all three trees in the Suncheonman National Garden, Suncheon (3488'57.97" N, 12750'92.83" E). As the disease progressed, the brown spot gradually enlarged, turning greyish-ivory inside and forming concentric circles. Three leaf lesions from each tree were cut into 5 x 5 mm pieces, surface-sterilized with 70% ethanol for 1 min, and washed in sterile water three times to isolate the pathogen potentially responsible for these symptoms. The samples obtained were subsequently cultured on 1.5% water agar and then incubated in the dark at 25℃. A total of nine isolates were obtained, with three isolates from each of the three trees through single-spore isolation, namely SYP-1202-1 to 3, SYP-1202-4 to 6, and SYP-1202-7 to 9. The colonies reached 90 mm in diameter after 10 days on potato dextrose agar (PDA), initially dark green, and turned sooty gray after 2 weeks. The hyphae grown on a 0.6% KCl medium for 3 days produced long chains containing three to twelve conidia. The conidia were ellipsoidal or obpyriform in shape and light brown. The conidiophores were straight or curved, measuring 12.1-75.3 x 1.6-4.8 µm (n = 100). The primary and secondary conidia measured length × width of 19.1-60.6 × 6.1-14.4 µm and 8.4-27.8 × 3.5-9.5 µm (n = 100), respectively. The conidia had 1 to 7 transverse and 0 to 3 vertical septa. The morphology of the nine isolates was identical and consistent with Alternaria species (van der Waals et al., 2011; Woudenberg et al., 2015). For molecular identification, ITS (OR844500 to OR844508), GAPDH (OR866383 to OR866391), TEF1 (OR866392 to OR866400), RPB2 (OR866401 to OR866409), Alt a1 (OR866410 to OR866418), endoPG (OR866419 to OR866427), and OPA10-2 (OR866428 to OR866436) sequences from SYP-1202-1 to 9 showed a 100% (515 bp/515 bp), 100% (579/579), 100% (240/240), 100% (753/753), 95.1% (449/472), 100% (448/448), and 100% (634/634) identity with that of type strain A. alternata CBS 115152 (KP124348, KP124202, KP125124, KP124816, KP123896, KP124049, and KP124658, respectively). A pathogenicity test was conducted on three 5-year-old E. japonica cultivar Daebang trees in pots. The surface of the five leaves per tree was sterilized with 70% ethanol for 1 min. Before inoculation, the leaves were wounded with sterile needles and sprayed with the conidial suspension (1×106 conidia/ml) produced from a 1-week-old culture grown on PDA. In contrast, control leaves were sprayed with sterile distilled water. The inoculated leaves were wrapped with black plastic bags and kept at 100% relative humidity for two days. At seven days post-inoculation, symptoms were observed on the wounded leaves, whereas the nonwounded and control leaves did not exhibit any symptoms. The experiment was performed three times in the greenhouse. For each experiment, pathogens were reisolated from the two symptomatic leaves per plant. The identity of the reisolated pathogens was then confirmed via analysis of ITS and RPB2 genes, thereby confirming adherence to Koch's postulates. To the best of our knowledge, this is the first report of E. japonica being infected by A. alternata in Korea. This report provides important information to support effective disease control strategies for E. japonica in orchards in southern Korea.

MoNOT3 Subunit Has Important Roles in Infection-Related Development and Stress Responses in Magnaporthe oryzae.

The multifunctional carbon catabolite repression negative on TATA-box-less complex (CCR4-NOT) is a multi-subunit complex present in all eukaryotes, including fungi. This complex plays an essential role in gene expression; however, a functional study of the CCR4-NOT complex in the rice blast fungus Magnaporthe oryzae has not been conducted. Seven genes encoding the putative CCR4-NOT complex were identified in the M. oryzae genome. Among these, a homologous gene, MoNOT3, was overexpressed during appressorium development in a previous study. Deletion of MoNOT3 in M. oryzae resulted in a significant reduction in hyphal growth, conidiation, abnormal septation in conidia, conidial germination, and appressorium formation compared to the wild-type. Transcriptional analyses suggest that the MoNOT3 gene affects conidiation and conidial morphology by regulating COS1 and COM1 in M. oryzae. Furthermore, Δmonot3 exhibited a lack of pathogenicity, both with and without wounding, which is attributable to deficiencies in the development of invasive growth in planta. This result was also observed in onion epidermal cells, which are non-host plants. In addition, the MoNOT3 gene was involved in cell wall stress responses and heat shock. Taken together, these observations suggest that the MoNOT3 gene is required for fungal infection-related cell development and stress responses in M. oryzae.

Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06).

BACKGROUND: Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies. METHODS: The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria. RESULTS: A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03). CONCLUSIONS: In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response. TRIAL REGISTRATION NUMBER: NCT04761744.

Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib. METHODS: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1. RESULTS: The median age was 60 years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively. CONCLUSION: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.

First Report of Anthracnose Caused by Colletotrichum gloeosporioides on Cinnamomum camphora in Korea.

Cinnamomum camphora, known as the camphor tree, is an evergreen tree widely cultivated in Asia as an ornamental plant (Singh and Jawaid, 2012). In June 2023, several leaves on a total of 10 trees planted on a street in Suncheon, Jeonnam Province, Korea showed black spots. Disease incidence was observed in at least 15% of the 10 trees. The symptoms included circular spots with a light ash-colored center and dark brown borders. The size of lesions varied depending on the progress of the disease. The disease progressed by 30% on the tree leaves. To isolate the pathogen, we cut out the lesions on the leaf surface sterilized with 70% ethanol for one minute, washed three times with sterilized distilled water, dried, and placed on water agar. Then, it was incubated at 25°C for three days. Emerging hyphae from the samples were subcultured on potato dextrose agar (PDA), resulting in three independent isolates (SYP-F1226-1 to SYP-F1226-3) after single spore isolation from 3 independent trees. The isolates exhibited grayish fluffy mycelium in the center of the colony, while the edges were white on PDA. Conidia had rounded cylindrical shape and were 4.9 to 8.4 µm  1.4 to 3.1 µm (avg. 5.9  2.1 µm, n = 100) in size. Appressoria were round, dark gray, produced at the tip of the germ tube after a septum formed the conidium. The morphological characteristics matched those of Colletotrichum species complexes. (Damm et al., 2012; Weir et al., 2012). For molecular identification, ITS (OR647338 to 40), GAPDH (OR657042 to 44), CHS-1 (OR657045 to 47), ACT (OR657048 to 50), and CAL (OR657051 to 53) sequences from isolates SYP-F1226-1~3 showed a 99.65%, 98.56%, 99.00%, 99.28%, and 99.52% identity with that of type strain C. gloeosporioides ICMP 17821 (JX010152, JX010056, JX009818, JX009531, and JX010445, respectively). Using the MEGA X program (Kumar et al. 2018), maximum likelihood analysis based on the concatenated sequences placed the isolates within a clade comprising C. gloeosporioides. Pathogenicity of SYP-F1226-1 was tested using three leaves from a 1-year-old branch of three independent healthy C. camphora plants. The leaf surfaces were sterilized by rubbing a cotton pad soaked in 70% ethanol and then wiping them with a sterilized cotton pad. The leaves per plant were inoculated with 5 mL of a conidial suspension (1 × 105 conidia/mL), both with and without wounding. Another three control leaves were inoculated with sterile distilled water, both with and without wounding. The inoculated leaves were wrapped in a plastic bag for 48 hours under conditions of 100% relative humidity. Spot symptoms were observed on both wounded and non-wounded leaves 21 days after inoculation. No symptoms were observed in the control on either of the wounded leaves. Pathogenicity tests were performed three times. The pathogen was re-isolated from the lesion after treatment, and its identity was confirmed using the five genes and morphological characteristics. This confirms the fulfillment of Koch's postulates. C. fioriniae (Liu et al, 2022) and C. siamens (Liu et al, 2022; Khoo et al, 2023) have been reported as the causal pathogen of anthracnose in C. camphora, but C. gloeosporioides has not been reported as a pathogen in C. camphora. To our knowledge, this is the first report of anthracnose caused by C. gloeosporioides on C. camphora in Korea. This study will provide symptomatic, mycological, and molecular biological information for the early detection of anthracnose disease in C. camphora plants.

Isolation and Identification of Alternaria alternata from Potato Plants Affected by Leaf Spot Disease in Korea: Selection of Effective Fungicides.

Brown leaf spot disease caused by Alternaria spp. is among the most common diseases of potato crops. Typical brown spot symptoms were observed in commercial potato-cultivation areas of northern Korea from June to August 2020-2021. In total, 68 isolates were collected, and based on sequence analysis of the internal transcribed spacer (ITS) region, the collected isolates were identified as Alternaria spp. (80.9%). Phylogenetic analysis revealed that a majority of these isolates clustered within a clade that included A. alternata. Additionally, the ITS region and rpb2 yielded the most informative sequences for the identification of A. alternata. Pathogenicity tests confirmed that the collected pathogens elicited symptoms identical to those observed in the field. In pathogenicity tests performed on seven commercial cultivars, the pathogens exhibited strong virulence in both wound and non-wound inoculations. Among the cultivars tested, Arirang-1ho, Arirang-2ho, and Golden Ball were resistant to the pathogens. Furthermore, among the fungicides tested in vitro, mancozeb and difenoconazole were found to be effective for inhibiting mycelial growth. In summary, our findings suggest that A. alternata plays a critical role in leaf disease in potato-growing regions and emphasise the necessity of continuous monitoring and management to protect against this disease in Korea.

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study.

PURPOSE: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC). PATIENTS AND METHODS: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cß inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety. RESULTS: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08). CONCLUSION: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Second-line chemoimmunotherapy with nivolumab and paclitaxel in immune-related biomarker-enriched advanced gastric cancer: a multicenter phase Ib/II study.

BACKGROUND: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC). METHODS: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m2 or dose level 2, 80 mg/m2) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis. RESULTS: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival. CONCLUSIONS: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.

The effects of fucoidan-rich polysaccharides extracted from Sargassum horneri on enhancing collagen-related skin barrier function as a potential cosmetic product.

BACKGROUND: Sargassum horneri came ashore after flowing from the South China Sea to Jeju Island a few years ago. This caused a significant environmental impact on coastal areas where S. horneri has accumulated because of decomposition and the release of toxic substances, such as hydrogen sulfide. AIMS: In this study, we evaluated a biological ingredient prepared from fucoidan-rich S. horneri and demonstrated its antiwrinkle effects on ultraviolet B (UVB)-induced fibroblast cells. MATERIALS AND METHODS: Fucoidan samples from S. horneri were prepared according to a previously published process with modifications. The compositional analysis of S. horneri fucoidan extract (SHFE) as well as its effects on antiaging were examined to determine its utility as a functional material. RESULTS: SHFE exhibited antioxidant properties using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Treatment of UVB-induced fibroblasts with SHFE significantly increased the synthesis of procollagen compared with adenosine treatment and inhibited MMP-1 and MMP-3 expression. In a clinical study, SHFE lotion improved skin barrier effects in forearms and transepidermal water loss (TEWL) values were reduced after 3 weeks of use compared with a placebo. CONCLUSION: SHFE has utility as an additive with functional antiaging effects for a range of cosmetic products as it restores skin hydration in the epidermal barrier.

Impact of Patient Sex on Adverse Events and Unscheduled Utilization of Medical Services in Cancer Patients Undergoing Adjuvant Chemotherapy: A Multicenter Retrospective Cohort Study.

PURPOSE: The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex. MATERIALS AND METHODS: This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea. RESULTS: A total of 1,170 patients with colorectal, gastric, or non-small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits. CONCLUSION: Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.

Prediction of Postnatal Growth Failure in Very Low Birth Weight Infants Using a Machine Learning Model.

Accurate prediction of postnatal growth failure (PGF) can be beneficial for early intervention and prevention. We aimed to develop a machine learning model to predict PGF at discharge among very low birth weight (VLBW) infants using extreme gradient boosting. A total of 729 VLBW infants, born between 2013 and 2017 in four hospitals, were included. PGF was defined as a decrease in z-score between birth and discharge that was greater than 1.28. Feature selection and addition were performed to improve the accuracy of prediction at four different time points, including 0, 7, 14, and 28 days after birth. A total of 12 features with high contribution at all time points by feature importance were decided upon, and good performance was shown as an area under the receiver operating characteristic curve (AUROC) of 0.78 at 7 days. After adding weight change to the 12 features-which included sex, gestational age, birth weight, small for gestational age, maternal hypertension, respiratory distress syndrome, duration of invasive ventilation, duration of non-invasive ventilation, patent ductus arteriosus, sepsis, use of parenteral nutrition, and reach at full enteral nutrition-the AUROC at 7 days after birth was shown as 0.84. Our prediction model for PGF performed well at early detection. Its potential clinical application as a supplemental tool could be helpful for reducing PGF and improving child health.

Agrobacterium tumefaciens-Mediated Transformation of the Aquatic Fungus Phialemonium inflatum FBCC-F1546.

Phialemonium inflatum is a useful fungus known for its ability to mineralise lignin during primary metabolism and decompose polycyclic aromatic hydrocarbons (PAHs). However, no functional genetic analysis techniques have been developed yet for this fungus, specifically in terms of transformation. In this study, we applied an Agrobacterium tumefaciens-mediated transformation (ATMT) system to P. inflatum for a functional gene analysis. We generated 3689 transformants using the binary vector pSK1044, which carried either the hygromycin B phosphotransferase (hph) gene or the enhanced green fluorescent protein (eGFP) gene to label the transformants. A Southern blot analysis showed that the probability of a single copy of T-DNA insertion was approximately 50% when the co-cultivation of fungal spores and Agrobacterium tumefaciens cells was performed at 24-36 h, whereas at 48 h, it was approximately 35.5%. Therefore, when performing gene knockout using the ATMT system, the co-cultivation time was reduced to ≤36 h. The resulting transformants were mitotically stable, and a PCR analysis confirmed the genes' integration into the transformant genome. Additionally, hph and eGFP gene expressions were confirmed via PCR amplification and fluorescence microscopy. This optimised transformation system will enable functional gene analyses to study genes of interest in P. inflatum.

Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy.

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.

Diagnostic performance of synthetic relaxometry for predicting neurodevelopmental outcomes in premature infants: a feasibility study.

OBJECTIVES: To investigate the predictability of synthetic relaxometry for neurodevelopmental outcomes in premature infants and to evaluate whether a combination of relaxation times with clinical variables or qualitative MRI abnormalities improves the predictive performance. METHODS: This retrospective study included 33 premature infants scanned with synthetic MRI near or at term equivalent age. Based on neurodevelopmental assessments at 18-24 months of corrected age, infants were classified into two groups (no/mild disability [n = 23] vs. moderate/severe disability [n = 10]). Clinical and MRI characteristics associated with moderate/severe disability were explored, and combined models incorporating independent predictors were established. Ultimately, the predictability of relaxation times, clinical variables, MRI findings, and a combination of the two were evaluated and compared. The models were internally validated using bootstrap resampling. RESULTS: Prolonged T1-frontal/parietal and T2-parietal periventricular white matter (PVWM), moderate-to-severe white matter abnormality, and bronchopulmonary dysplasia were significantly associated with moderate/severe disability. The overall predictive performance of each T1-frontal/-parietal PVWM model was comparable to that of individual MRI finding and clinical models (AUC = 0.71 and 0.76 vs. 0.73 vs. 0.83, respectively; p > 0.27). The combination of clinical variables and T1-parietal PVWM achieved an AUC of 0.94, sensitivity of 90%, and specificity of 91.3%, outperforming the clinical model alone (p = 0.049). The combination of MRI finding and T1-frontal PVWM yielded AUC of 0.86, marginally outperforming the MRI finding model (p = 0.09). Bootstrap resampling showed that the models were valid. CONCLUSIONS: It is feasible to predict adverse outcomes in premature infants by using early synthetic relaxometry. Combining relaxation time with clinical variables or MRI finding improved prediction. CLINICAL RELEVANCE STATEMENT: Synthetic relaxometry performed during the neonatal period may serve as a biomarker for predicting adverse neurodevelopmental outcomes in premature infants. KEY POINTS: • Synthetic relaxometry based on T1 relaxation time of parietal periventricular white matter showed acceptable performance in predicting adverse outcome with an AUC of 0.76 and an accuracy of 78.8%. • The combination of relaxation time with clinical variables and/or structural MRI abnormalities improved predictive performance of adverse outcomes. • Synthetic relaxometry performed during the neonatal period helps predict adverse neurodevelopmental outcome in premature infants.

Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.

Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.

Genotypic shift in rotavirus associated with neonatal outbreaks in Seoul, Korea.

BACKGROUND: Rotavirus group A (RVA) is a causative agent of acute gastroenteritis among young children worldwide, despite the global expansion of rotavirus vaccination. In Korea, although the prevalence of RVA has been reduced among young children owing to vaccination, nosocomial infections still occur among neonates. OBJECTIVES: The aim of this study was to investigate the molecular epidemiology of RVA strains associated with several neonatal outbreaks in Seoul from 2017 to 2020. STUDY DESIGN: Clinical and environmental samples were collected and screened for the presence of RVA using ELISA and PCR targeting VP6, respectively. RVA-positive strains were genotyped via RT-PCR and subsequent sequencing of VP4 and VP7 and were phylogenetically compared with RVA strains from other countries. RESULTS: During 2017-2020, a total of 15 RVA outbreaks occurred at neonatal facilities (six in hospital neonatal wards and nine in postpartum care centers) in Seoul, and only two RVA genotypes were detected: G4P[6] and G8P[6]. G8P[6] emerged in Seoul November 2018 and immediately became the predominant genotype among neonates, at least up to 2020. Phylogenetic analysis revealed that the G8P[6] genotype in this study was closely related to G8P[6] strains first identified in Korea in 2017, but differed from G8P[6] strains detected in Africa. CONCLUSIONS: A novel G8P[6] genotype of RVA strains has emerged and caused outbreaks among neonates in Seoul. Continued surveillance for circulating RVA genotypes is imperative to monitor genotype changes and their potential risks to public health.

Research Trends of Lifestyle Intervention for Women With Obesity: A Text Network Analysis.

Background: While the number of lifestyle intervention studies for women with obesity continues to increase, the research trends related to this topic should be evaluated through text network analysis. Methods: A total of 231 relevant studies published in international journals between 2011 and 2021 were identified. Semantic morphemes of the abstracts were refined, and a co-occurrence matrix with 117 keywords was generated using the text network analysis program NetMiner 4.3. Results: The core keywords were determined as the top 25 in degree centrality, closeness centrality, or betweenness centrality. 'Lifestyle', 'Intervention', 'Diet', 'Exercise', 'Diabetes mellitus', 'Body', 'Composition', 'Quality of life', 'Obesity', 'Gain', 'Diet', and 'Loss' were the most frequently used keywords. Conclusion: The findings of this study provide a general overview of the research trends in lifestyle interventions for women with obesity and may be used as reference for future research.