Background: As nationwide government-led whole-genome sequencing (WGS) projects progress, optimizing the clinical integration of large-scale WGS results is crucial. We explored how the initial analysis from Korea’s First WGS Pilot Study for Rare Diseases was applied in clinical practice, and then we reanalyzed the data comprehensively at Samsung Medical Center (SMC) Seoul, Korea. Methods: A prospective cohort study designed to collect WGS data under a Korean national initiative was conducted from August 2020 to December 2021. We focused on patients with rare diseases recruited from 16 university hospitals. The participants included 5,000 individuals (2,200 probands and 2,800 family members). The initial WGS data and diagnostic reference reports (from 682 probands and 484 family members), generated based on the First Korean WGS Pilot Study for Rare Diseases, were subsequently reanalyzed by SMC. Results: The initial analysis of the First Korean WGS Pilot Study data revealed a diagnostic rate of 17%. Upon receiving these results, the SMC conducted two rounds of reanalysis, increasing the diagnostic rate from 15% in the first analysis, to 18% in the second, and finally to 24% in the third (P = 1.6 × 10 −5 ). Key factors in improving the genetic diagnosis included increased detection of novel (likely) pathogenic variants (P = 1.0 × 10 −4 ), improved diagnostic rates with larger family recruitment (P = 0.004), and refined clinical information for more precise genotype–phenotype correlation analysis (40%). Conclusions Although national WGS projects lay a foundation for rare disease diagnosis, hospital-level reanalysis and multidisciplinary collaborations are crucial for optimizing diagnostic outcomes.

Background: We compared the immunoglobulin (IG) heavy chain (IGH) leader and FR1 primer sets to measure clone sizes and detect immunoglobulin heavy chain variable (IGHV) region somatic hypermutations (SHMs) in Korean patients with chronic lymphocytic leukemia (CLL). We also analyzed IGH and immunoglobulin kappa (IGK) to identify Korean-specific IGs in CLL. Methods: Next-generation sequencing (NGS)–based gene rearrangements and IGHV SHMs were assessed in 40 patients using IGH leader, IGH FR1, and IGK primers. Flow cytometry, karyotyping, interphase FISH, and NGS-based variant analyses were performed for 165 genes. Results: Clonal IGH and IGK rearrangements were detected in 100.0% and 97.5% of patients, respectively. Clonal size was generally smaller per NGS than per flow cytometry, particularly when using the IGH leader (median: 52.5%) versus the IGH FR1 primer set (73.2%). IGHV SHMs occurred in approximately 70% of patients; 10% showed primer set discrepancies. The incidence of IGHV SHMs was low in patients at high risk (i.e., with TP53 abnormalities; complex karyotypes; and ATM, NOTCH1, SF3B1, or BIRC3 variants). IGHV3 was the most common IGHV (58.3%), and IGHV4-34 was most frequently identified (14.6%). IGHV1 and IGHV1-69 usage differed significantly between Koreans and westerners. IGHJ4 was the most common IGHJ (56.3%). A single IGKV–IGKJ gene rearrangement was most frequently observed (18.9%), whereas intron-KDE was the most common rearrangement (30.6%). Conclusions NGS may underestimate CLL clonal size, particularly when using the IGH leader primer set. IGHV SHMs were inversely associated with negative prognostic factors.Our data suggest ethnic differences in CLL pathogenesis.

Background: Fusion genes are major drivers of acute leukemia. Conventional diagnostics are limited in detecting the diverse fusions included in recently updated acute leukemia classifications. We evaluated the fusion detection performance of RNA sequencing (RNAseq) compared with that of conventional diagnostics in patients with acute leukemia. Methods: We retrospectively obtained the data of 101 patients with acute leukemia who underwent conventional diagnostics (i.e., karyotyping, FISH, or multiplex reverse transcription PCR) at diagnosis at Samsung Medical Center, Seoul, Korea, between September 2022 and September 2023. Whole RNA-seq was performed using the Illumina Stranded mRNA Prep kit (Illumina, San Diego, CA, USA). The concordance, sensitivity, and specificity of RNA-seq for fusion gene detection were compared with those of conventional diagnostics. Results: RNA-seq helped identify 52 fusion genes in 51 (50.5%) of 101 patients, with detection rates of 40.7%, 70.3%, 37.5%, and 50% in acute myeloid leukemia, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia, respectively. RNA-seq showed 83.3% sensitivity and 80.8% concordance with conventional diagnostics; it missed eight fusions, likely because of low transcript abundance or enhancer hijacking. RNA-seq also helped clarify three previously unspecified rearrangements and detected 12 fusions (21.4%) in 56 cases that tested negative with conventional diagnostics, including four novel (KMT2A::THAP12 , RUNX1::PRPF19 , MLLT10::UBE2L6, and FUS::ZNF362) and three rare (HNRNPH1::ERG, RUNX1::USP42, and ETV6::NCOA2) fusions. Conclusions This was the first study to evaluate the performance of whole RNA-seq in fusion detection in patients with acute leukemia in Korea. Incorporating RNA-seq into diagnostic workflows may facilitate earlier and more precise therapeutic decisions and improve prognostic assessment in patients with acute leukemia.

Purpose: Drainage fluid may serve as a biologically informative indicator of immune and infectious status during postsurgical recovery after trauma. However, microbiome shifts in drainage fluid associated with clinical resilience have not yet been characterized. This study aimed to investigate microbial dynamics in drainage fluid across the intensive care unit (ICU) and ward recovery phases in Korean trauma patients. Methods: A total of 25 drainage and 10 stool samples were collected from 10 trauma patients who underwent abdominal surgery at a regional trauma center. Microbial composition was analyzed using 16S ribosomal RNA amplicon sequencing.Alpha and beta diversity were compared between sample types and recovery stages. Linear mixed-effects models were used to identify recovery-associated taxa while adjusting for clinical variables, and predicted metabolic pathways were assessed using PICRUSt2. Results: Drainage fluid harbored distinct microbial communities independent of the intestinal microbiota. Shared taxa between drainage and stool increased significantly in patients with bowel injury, suggesting microbial translocation.Seven genera and 5 species showed significantly decreased abundance during the ward stage, with Modestobacter and Blastococcus tunisiensis demonstrating the highest discriminative ability between recovery stages (area under the curve = 0.721). Predicted metabolic pathways related to fatty acid degradation, amino acid degradation, and pro-inflammatory processes were more active during the ICU stage. Conclusion These findings provide preliminary evidence that drainage fluid microbiome profiles may reflect recovery dynamics following trauma, supporting its potential utility for microbiome-based monitoring and biomarker discovery in trauma surgery.

Background: Left bundle branch block (LBBB) significantly increases the risk of left ventricular systolic dysfunction (LVSD) due to cardiac dyssynchrony. Although artificial intelligence–enabled electrocardiography (AI-ECG) mod‑ els show promise in detecting LVSD, their performance in LBBB patients remains underexplored. We hypothesized that an AI-ECG model clinically validated for detecting LVSD would accurately detect LVSD and predict future clinical outcomes in LBBB patients. Methods: In this retrospective multicenter study, 5,689 expert-validated LBBB ECGs collected from 2,813 patients between 2016 and 2024 were analyzed using a previously developed and validated AI-ECG model. LVSD was defined as an ejection fraction of ≤ 40%. Model performance was assessed using the area under the receiver operating char‑ acteristic curve (AUROC), the area under the precision-recall curve (AUPRC), sensitivity, and specificity. Patients were stratified into high- and low-risk groups based on a threshold that achieved 90% sensitivity. A Kaplan–Meier analysis was used to compare clinical outcomes. Results: Among the 2,813 LBBB patients (mean age, 70.7 years; male sex, 43.7%), hypertension and a history of heart failure were common. The AiTiALVSD model showed strong diagnostic performance for LVSD (AUROC, 0.930 [95% CI, 0.924–0.937]; AUPRC, 0.913 [95% CI, 0.902–0.923]; sensitivity, 0.979; specificity, 0.473). During the mean follow-up of 4.1 years, high-risk patients had significantly higher hazards than low-risk patients for all-cause mortality (adjusted hazard ratio [HR], 1.87; 95% CI, 1.53–2.28), implantable cardioverter defibrillator/cardiac resynchronization therapy implantation (adjusted HR, 15.2; 95% CI, 7.51–30.77), and cardiovascular hospitalization (adjusted HR, 1.11; 95% CI, 0.96–1.28). Conclusions AiTiALVSD effectively detects LVSD and stratifies long-term cardiovascular risk in LBBB patients, support‑ ing its clinical utility for early detection and patient management.

Olanzapine is a second-generation antipsychotic drug associated with the development of type 2 diabetes. However, the development and remission of diabetes with glutamic acid decarboxylase (GAD) antibody (Ab) positivity related to olanzapine treatment have not been reported. Here, we present the case of a 33-year-old man taking olanzapine who was diagnosed with diabetes with GAD Ab positivity complicated by diabetic ketoacidosis (DKA). After discontinuation of the drug and tight glycemic control, his diabetes remitted, and the GAD Ab became negative spontaneously after 18 months. The classification of diabetes is challenging because of overlapping autoimmune and metabolic features. Olanzapine may have contributed to pancreatic β-cell apoptosis, which could potentially trigger autoimmunity and the development of type 1 diabetes-like features (DKA as the initial presentation, a low C-peptide level, and GAD Ab positivity). The rapid amelioration of hyperglycemia and weight reduction may be responsible for the remission of diabetes after the discontinuation of olanzapine.

Objective: This study aimed to develop a reliable and valid Mixed State Severity Index (MSSI) to assess mood instability in patients with mood disorders and determine cutoff scores. Methods: Twenty-one items were selected based on Koukopoulos’ criteria for mixed depressive episode, historically referred to as agitated depression, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision mixed features criteria. The MSSI was administered to 242 patients (major depressive disorder [n=92], bipolar disorder [BD] I [n=78], and BD II [n=72]) and 726 controls. Results: The MSSI demonstrated high internal consistency (α=0.78–0.90). Exploratory factor analysis revealed a stable four-factor structure. Based on receiver operating characteristic analysis, optimal cutoff scores were identified to distinguish mood disorder groups from controls, ranging from 19.5 to 27.5 depending on diagnosis. Conclusion The MSSI is a reliable and valid instrument for assessing the severity of mixed features in patients with mood disorders. The established cutoff scores enhance its clinical utility, providing robust diagnosis and treatment planning support.

Purpose: Current guidelines recommend vaccination at least 2 weeks before chemotherapy initiation to optimize the immune response despite limited evidence. Our previous study indicated no differences in short-term immune response for the 13-valent pneumococcal conjugate vaccine (PCV13) according to the vaccination timing. This study aims to investigate the long-term efficacy of PCV13 and clinical factors associated with the respective antibody response. Materials and Methods: Patients with gastric or colorectal cancer who received adjuvant chemotherapy were enrolled and divided into two groups: vaccinated 2 weeks before chemotherapy (arm A) and vaccinated concurrently with chemotherapy (arm B). Serum samples were collected before vaccination and in one month, 3 years, and 5 years. Immune responses were measured using enzyme-linked immunosorbent assay and multiplex opsonophagocytosis assay. Results: Including 63 patients, both groups showed an initial increase in the geometric mean titers of opsonophagocytic activity and the geometric mean concentrations of serotype-specific IgG levels after one month, followed by a decline at 3 and 5 years, particularly for serotypes 1, 14, 18C, and 19A. Despite the decline, global protection was maintained for 5 years, although global response decreased. The two arms did not show significant differences in immunogenicity nor in factors such as vaccination timing, age, cancer type, or chemotherapy regimen. Conclusion Vaccination timing is not a significant factor for the immunogenicity of PCV13 in cancer patients undergoing adjuvant chemotherapy. Global protection against pneumococcal infection was sustained for > 5 years, and global response remained in over half of patients.

Background: With the aging population and advancements in medical care worldwide, the number of older patients with end-stage kidney disease continues to rise. This study aimed to identify factors associated with osteoporosis and osteopenia in older patients undergoing incident hemodialysis and assess their impact on mortality. Methods: We analyzed a large multicenter retrospective cohort of patients aged ≥70 years undergoing incident hemodialysis to identify factors associated with osteoporosis using logistic regression analysis and to assess the association of death with osteoporosis and osteopenia using Cox multivariable analysis. Results: Among 710 patients, 39.0% and 19.6% had osteoporosis and osteopenia, respectively. Osteoporosis was significantly associated with female sex, a history of fractures, and the absence of phosphate binder use. During a median follow-up of 36.8 months, 348 participants (58.8%) died. Mortality rates were the highest in the osteoporosis group (79.8%), followed by the osteopenia (77.2%) and normal bone mineral density (BMD) groups (35.2%). Cox regression analysis revealed that even after adjusting for covariates, the osteoporosis group was significantly associated with a higher mortality risk than the normal BMD group. Osteoporosis at the start of hemodialysis was significantly associated with higher mortality. Conclusion We should consider the importance of bone health in patients undergoing incident hemodialysis and pay attention to the use of phosphate binders and fracture prevention.

Background: Obesity is a well-known risk factor for chronic kidney disease and its progression. However, the impact of obesity on the renal function of the elderly population is uncertain. We investigated the association between obesity and renal outcomes in the elderly. Methods: We analyzed 130,504 participants from the Korean National Health Insurance Service-Senior cohort. Obesity was classified according to body mass index (BMI), sex-specific waist circumference (WC), and the presence of metabolic syndrome. The primary outcome was renal function decline, defined as a decline in the estimated glomerular filtration rate (eGFR) of at least 50% from baseline or new-onset end-stage renal disease. Results: During a follow-up period of 559,531.1 person-years (median, 4.3 years), 2,486 participants (19.0%; incidence rate of 4.44 per 1,000 person-years) showed renal function decline. A multivariate Cox proportional hazards model revealed that BMI/WC was not associated with renal function decline. However, the group with metabolic syndrome had a significantly increased risk of renal function decline compared to the group without metabolic syndrome (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.13–1.36). Compared with the non-metabolic syndrome group, the adjusted HRs (95% CI) for participants with one through five components were 0.96 (0.84–1.11), 1.10 (0.96–1.27), 1.24 (1.06–1.45), 1.37 (1.12–1.66), and 1.99 (1.42–2.79), respectively (p for trend < 0.001). Conclusion In elderly Korean adults, metabolic syndrome and the number of its components were associated with a higher risk of renal function decline, but BMI or WC was not significant.