Association Between Aortic Valve Sclerosis and Clonal Hematopoiesis of Indeterminate Potential.

Background: The mechanism and medical treatment target for degenerative aortic valve disease, including aortic stenosis, is not well studied. In this study, we investigated the effect of clonal hematopoiesis of indeterminate potential (CHIP) on the development of aortic valve sclerosis (AVS), a calcified aortic valve without significant stenosis. Methods: Participants with AVS (valves ≥2 mm thick, high echogenicity, and a peak transaortic velocity of <2.5 m/sec) and an age- and sex-matched control group were enrolled. Twenty-four CHIP genes with common variants in cardiovascular disease were used to generate a next-generation sequencing panel. The primary endpoint was the CHIP detection rate between the AVS and control groups. Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for differences in baseline characteristics. Results: From April 2020 to April 2022, 187 participants (125 with AVS and 62 controls) were enrolled; the mean age was 72.6±8.5 yrs, and 54.5% were male. An average of 1.3 CHIP variants was observed. CHIP detection, defined by a variant allele frequency (VAF) of ≥0.5%, was similar between the groups. However, the AVS group had larger CHIP clones: 49 (39.2%) participants had a VAF of ≥1% (vs. 13 [21.0%] in the control group; P=0.020), and 25 (20.0%) had a VAF of ≥2% (vs. 4 [6.5%]; P=0.028). AVS is independently associated with a VAF of ≥1% (adjusted odds ratio: 2.44, 95% confidence interval: 1.11-5.36; P=0.027). This trend was concordant and clearer in the IPTW cohort. Conclusions: Participants with AVS more commonly had larger CHIP clones than age- and sex-matched controls. Further studies are warranted to identify causality between AVS and CHIP.

Occupational and Psychological Factors Associated With Burnout in Night Shift Nurses.

OBJECTIVE: Providing inpatient nursing care inevitably involves night shift work. However, night shift work nurses often face psychiatric health problems such as burnout. If night shift work is an essential work type for nurses, it is necessary to select personnel suitable for night shift work or establish improvement measures such as psychiatric intervention through psychiatric evaluation. The objective of this study was to identify factors that could be interventional among factors affecting burnout in shift-working nurses. METHODS: A total of 231 night shift female nurses participated in this study. A questionnaire survey was given to assess their general characteristics. To assess burnout, the Maslach Burnout Inventory-General Survey Korean version was adopted. In addition, several mental health scales were used to identify individual psychological characteristics. To identify variables associated with the presence of burnout, odds ratios were calculated using a logistic regression model taking three dimensions of burnout as a dependent variable after adjusting for psychological and occupational factors. RESULTS: High resilience was a significant preventive factor in the three dimensions of burnout. Regarding occupational factor, the longer the duration of employment, the higher depersonalization, but the professional efficacy was good. CONCLUSION: Our results indicate that resilience and social support could be prevention factors for burnout. This study is meaningful in examining items that require active intervention and support for burnout targeting night shift nurses who are indispensable for patient care.

Advancements in Nanogels for Enhanced Ocular Drug Delivery: Cutting-Edge Strategies to Overcome Eye Barriers.

Nanomedicine in gel or particle formation holds considerable potential for enhancing passive and active targeting within ocular drug delivery systems. The complex barriers of the eye, exemplified by the intricate network of closely connected tissue structures, pose significant challenges for drug administration. Leveraging the capability of engineered nanomedicine offers a promising approach to enhance drug penetration, particularly through active targeting agents such as protein peptides and aptamers, which facilitate targeted release and heightened bioavailability. Simultaneously, DNA carriers have emerged as a cutting-edge class of active-targeting structures, connecting active targeting agents and illustrating their potential in ocular drug delivery applications. This review aims to consolidate recent findings regarding the optimization of various nanoparticles, i.e., hydrogel-based systems, incorporating both passive and active targeting agents for ocular drug delivery, thereby identifying novel mechanisms and strategies. Furthermore, the review delves into the potential application of DNA nanostructures, exploring their role in the development of targeted drug delivery approaches within the field of ocular therapy.

Standardized Suicide Prevention Program for Gatekeeper Intervention of North Korean Defectors in South Korea.

OBJECTIVE: North Korean defectors (NKDs) have experienced substantial difficulties during the migration and settlement in South Korea. They have a high prevalence of depression, post-traumatic stress disorder, and suicidal behaviors. The high prevalence of mental disorders among NKDs can lead to a high suicide rate. However, there are no suicide prevention programs for NKDs. This study aims to customize a suicide prevention program with content suitable for NKDs' particular circumstances. METHODS: A multidisciplinary research team developed this program based on domestic and international gatekeeper training programs for suicide prevention and articles related to suicide prevention. RESULTS: We developed a multi-part gatekeeper training program, "Suicide CARE for NKDs." In the "Introduction," trainees learn about the need for the program and its importance. In "Careful observation," trainees learn to recognize linguistic, behavioral, and situational signals of suicide risk. In "Active listening," trainees learn how to ask about suicidal thoughts and to listen empathetically. In "Risk evaluation and expert referral," trainees learn to evaluate suicide risk and to connect NKDs with institutes or services. CONCLUSION: We expect this program to become useful for training gatekeepers to prevent suicide among NKD. A future follow-up study is needed to confirm the efficacy of the program.

Development and validation of sensitive BCR::ABL1 fusion gene quantitation using next-generation sequencing.

BACKGROUND: BCR::ABL1 fusion has significant prognostic value and is screened for chronic myeloid leukemia (CML) disease monitoring as a part of routine molecular testing. To overcome the limitations of the current standard real-time quantitative polymerase chain reaction (RQ-PCR), we designed and validated a next-generation sequencing (NGS)-based assay to quantify BCR::ABL1 and ABL1 transcript copy numbers. METHODS: After PCR amplification of the target sequence, deep sequencing was performed using an Illumina Nextseq 550Dx sequencer and in-house-designed bioinformatics pipeline. The Next-generation Quantitative sequencing (NQ-seq) assay was validated for its analytical performance, including precision, linearity, and limit of detection, using serially diluted control materials. A comparison with conventional RQ-PCR was performed with 145 clinical samples from 77 patients. RESULTS: The limit of detection of the NQ-seq was the molecular response (MR) 5.6 [BCR::ABL1 0.00028% international scale (IS)]. The NQ-seq exhibited excellent precision and linear range from MR 2.0 to 5.0. The IS value from the NQ-seq was highly correlated with conventional RQ-PCR. CONCLUSIONS: We conclude that the NQ-seq is an effective tool for monitoring BCR::ABL1 transcripts in CML patients with high sensitivity and reliability. Prospective assessment of the unselected large series is required to validate the clinical impact of this NGS-based monitoring strategy.

The Effectiveness of Virtual Reality Intervention for COVID-19-Related Psychological Distress: A Systematic Review.

OBJECTIVE: The prolonged coronavirus disease-2019 (COVID-19) pandemic is likely to cause psychological distress in people. This systematic review aimed to identify the effectiveness of virtual reality (VR)-based psychological intervention among individuals with psychological distress during the COVID-19 crisis. PubMed, Ovid MEDLINE, Cochrane Library, Web of Science, Embase, and PsycINFO databases were searched for articles published until July 2022. METHODS: The available citations were deduplicated and screened by two authors using the title and abstract information. Eligibility criteria were constructed according to the PICOT guidelines. Empirical studies of all designs and comparator groups were included if they appraised the impact of an immersive VR intervention on any standardized measure indicative of psychological distress (stress, anxiety, depression, and post-traumatic symptoms) or improvements in quality of life in participants, including COVID-19 patients, medical staff working with COVID-19 patients, and people who had experienced strict social distancing during the COVID-19 pandemic. RESULTS: The results were discussed using a narrative synthesis because of the heterogeneity between studies. Seven of the studies met the inclusion criteria. There were two randomized controlled trials and five uncontrolled studies on VR interventions. CONCLUSION: All studies reported significant improvement in a wide range of psychological distress during COVID-19, ranging from stress, anxiety, depression, and post-traumatic symptoms to quality of life, supporting the efficacy of VR-based psychological intervention. Our results suggest that VR intervention has potential to ameliorate COVID-19-related psychological distress with efficacy and safety.

Applications of molecular barcode sequencing for the detection of low-frequency variants in circulating tumour DNA from hepatocellular carcinoma.

PURPOSE: Liquid biopsy has emerged as a promising tool for minimally invasive and accurate detection of various malignancies. We aimed to apply molecular barcode sequencing to circulating tumour DNA (ctDNA) from liquid biopsies of hepatocellular carcinoma (HCC). STUDY DESIGN: Patients with HCC or benign liver disease were enrolled between 2017 and 2018. Matched tissue and serum samples were obtained from these patients. Plasma cell-free DNA was extracted and subjected to targeted sequencing with ultra-high coverage and molecular barcoding. RESULTS: The study included 143 patients: 102 with HCC, 7 with benign liver tumours and 34 with chronic liver disease. No tier 1/2 or oncogenic mutations were detected in patients with benign liver disease. Among the HCC patients, 49 (48%) had tier 1/2 mutations in at least one gene; detection rates were higher in advanced stages (75%) than in early stages (26%-33%). TERT was the most frequently mutated gene (30%), followed by TP53 (16%), CTNNB1 (14%), ARID2 (5%), ARID1A (4%), NFE2L2 (4%), AXIN1 (3%) and KRAS (1%). Survival among patients with TP53 mutations was significantly worse (p = 0.007) than among patients without these mutations, whereas CTNNB1 and TERT mutations did not affect survival. ctDNA testing combined with α-fetoprotein and prothrombin induced by vitamin K absence-II analyses improved HCC detection, even in early stages. CONCLUSIONS: ctDNA detection using molecular barcoding technology offers dynamic and personalized information concerning tumour biology, such information can guide clinical diagnosis and management. This detection also has the potential as a minimally invasive approach for prognostic stratification and post-therapeutic monitoring.

Ig Gene Clonality Analysis Using Next-Generation Sequencing for Improved Minimal Residual Disease Detection with Significant Prognostic Value in Multiple Myeloma Patients.

Next-generation sequencing (NGS) of rearranged Ig genes is an effective technology for identifying pathologic clonal cells in multiple myeloma (MM) and tracking minimal residual disease. The clinical effect of implementing NGS in Ig gene clonality analysis was evaluated via a retrospective chart review. A total of 312 patients diagnosed with MM were enrolled in the study. Ig gene clonality was determined by fragment analysis using BIOMED-2 multiplex PCR assays and by NGS using the LymphoTrack IGH FR1 Assay and LymphoTrack IGK Assay. The clonality detection rates in diagnostic samples obtained using fragment analysis and NGS were 96.7% and 95.4%, respectively (statistically nonsignificant difference; P = 0.772). Among samples of patients in complete remission, the clonality detection rates obtained using fragment analysis and NGS were 33.3% and 60.3%, respectively (statistically significant difference; P = 0.034). Progression-free survival was significantly longer in negative than positive patients by NGS analysis (P = 0.03). Clonality detection by NGS-based methods using IGH FR1 and IGK assays in routine clinical practice is feasible, provides good clonality detection rates in diagnostic samples, and allows monitoring of samples in MM patients with significant prognostic value.

How COVID-19 Affected Healthcare Workers in the Hospital Locked Down due to Early COVID-19 Cases in Korea.

BACKGROUND: The healthcare workers (HCWs) were exposed to never-experienced psychological distress during the early stage of the coronavirus disease 2019 (COVID-19) pandemic. The aim of this study was to investigate how the COVID-19 pandemic affected the mental health of HCWs during the hospital lockdown period due to mass healthcare-associated infection during the early spread of COVID-19. METHODS: A real-time online survey was conducted between April 14-18, 2020 among HCWs who worked at the university hospital where COVID-19 was confirmed in a patient, and the hospital was shut down for 3 weeks. Along with demographic variables and work-related information, psychological distress was measured using the Generalized Anxiety Disorder-7 (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), the Maslach Burnout Inventory-General Survey scale, and the Stress and Anxiety to Viral Epidemics-9. RESULTS: The HCWs working in the cohort ward and those who have experienced social discrimination had significantly higher level of depression (PHQ-9 score; 5.24 ± 4.48 vs. 4.15 ± 4.38; P < 0.01 and 5.89 ± 4.78 vs. 3.25 ± 3.77; P < 0.001, respectively) and anxiety (GAD-7 score; 3.69 ± 3.68 vs. 2.87 ± 3.73; P < 0.05 and 4.20 ± 4.22 vs. 2.17 ± 3.06; P < 0.001, respectively) compared to other HCWs. Worries regarding the peer relationship and the skepticism about job were associated with depression (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.07-1.79; P < 0.05 and OR, 1.69; 95% CI, 1.31-2.17; P < 0.001, respectively) and anxiety (OR, 1.73; 95% CI, 1.21-2.49; P < 0.01 and OR, 1.54; 95% CI, 1.09-2.17; P < 0.05, respectively), while fear of infection or worsening of health was not. Path analysis showed that work-related stress associated with the viral epidemic rather than anxiety about the viral epidemic mainly contributed to depression. CONCLUSION: The present observational study indicates that mental health problems of HCWs exposed to COVID-19 are associated with distress in work and social relationship. Early intervention programs focusing on these factors are necessary.

Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients.

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.

Analytical validation of the droplet digital PCR assay for diagnosis of spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by homozygote loss of exon 7 on the survival motor neuron 1 (SMN1) gene. The severity of the SMA phenotype is influenced by copies of SMN2, a gene that is highly homologous with SMN1. METHODS: We validated analytical performance of droplet digital polymerase chain reaction (ddPCR) for detection of copy number variation of SMN1 and SMN2 genes for diagnosis of SMA using clinical samples. For accuracy performance evaluation, ddPCR results were compared with those of multiplex ligation-dependent probe amplification (MLPA) as a reference standard. Copy numbers of SMN1/SMN2 exon 7 from 200 clinical samples were concordant between ddPCR and MLPA. RESULTS: For all samples, the copy number of SMN1/SMN2 exon 7 was concordant between MLPA and ddPCR. The ddPCR also showed acceptable degrees of repeatability and total imprecision. CONCLUSION: Therefore, ddPCR is expected to be useful for SMA diagnosis and to predict phenotypic severity of SMA patients by determining the copy number of SMN2 in clinical laboratories.

Clinical utility of targeted NGS panel with comprehensive bioinformatics analysis for patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a genetically complex and heterogeneous disease for which a wide range of genetic variations has been identified. With the need for comprehensive high-throughput analysis, we have designed a comprehensive next-generation sequencing (NGS) assay to detect somatic mutations, translocations, and copy number changes and have evaluated its clinical utility in patients with ALL. The panel reliably detected single nucleotide variations (SNV) and copy number variations (CNV) analysis was exceptionally useful in identifying genic and chromosomal CNV which dominated the genetic abnormalities of ALL. We detected SNVs and CNVs simultaneously in a single assay, which could provide an alternative or supplement for several conventional tests and simplify the testing processes. We applied the genetic information obtained to the risk stratification of patients with high risk mutations and further confirmed the clinical utility of the comprehensive genetic testing with intensive bioinformatics analysis.

Targeted next generation sequencing can serve as an alternative to conventional tests in myeloid neoplasms.

The 2016 World Health Organization classification introduced a number of genes with somatic mutations and a category for germline predisposition syndromes in myeloid neoplasms. We have designed a comprehensive next-generation sequencing assay to detect somatic mutations, translocations, and germline mutations in a single assay and have evaluated its clinical utility in patients with myeloid neoplasms. Extensive and specified bioinformatics analyses were undertaken to detect single nucleotide variations, FLT3 internal tandem duplication, genic copy number variations, and chromosomal copy number variations. This enabled us to maximize the clinical utility of the assay, and we concluded that, as a single assay, it can be a good supplement for many conventional tests, including Sanger sequencing, RT-PCR, and cytogenetics. Of note, we found that 8.4-11.6% of patients with acute myeloid leukemia and 12.9% of patients with myeloproliferative neoplasms had germline mutations, and most were heterozygous carriers for autosomal recessive marrow failure syndromes. These patients often did not respond to standard chemotherapy, suggesting that germline predisposition may have distinct and significant clinical implications.

Clinical Evaluation of Massively Parallel RNA Sequencing for Detecting Recurrent Gene Fusions in Hematologic Malignancies.

The application of next-generation sequencing (NGS) technology in clinical diagnostics should proceed with care. We have evaluated the clinical validity of two commercially available RNA fusion panels, the TruSight RNA fusion panel (Illumina) and FusionPlex Pan-Heme Kit (ArcherDx), to detect recurrent translocations in hematologic malignancies. Twenty-four bone marrow samples taken at the initial diagnosis of patients with acute leukemia and chronic myeloid leukemia were included. To assess the limit of detection, serial dilutions of BCR-ABL1 (e1a2)-positive RNAs were prepared using a commercial reference material. Both NGS panels detected 19 cases with recurrent translocations identified with RT-PCR, as well as a case with KMT2A-AFF1 with false-negative results on RT-PCR. Two rare translocations, DDX3X-MLLT10 and NUP98-HOXC13, were additionally identified using NGS panels. The detection limit ranged from 10-1 to 10-2, which was not satisfactory for samples with low tumor burden. To conclude, RNA fusion panels were suitable for the initial diagnosis; however, for follow-up samples, conventional RT-PCR should be selected.

Differences in Psychopathology between Offspring of Parents with Bipolar I Disorder and Those with Bipolar II Disorder: A Cross-Sectional Study.

OBJECTIVE: The aim of this study was to evaluate differences in psychopathology between offspring of parents with bipolar I disorder (BP-I) and those with bipolar II disorder (BP-II). METHODS: The sample included 201 offspring between 6 and 17 years of age who had at least one parent with BP-I or BP-II. The offspring were diagnostically evaluated using the Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. Psychopathology and Clinical characteristics were evaluated, including lifetime DSM-5 diagnoses, depression, and childhood trauma. Lifetime DSM-5 diagnoses were also compared between schoolchildren aged 6 to 11 years and adolescents aged 12 to 17 years. RESULTS: In lifetime DSM-5 diagnoses, offspring of parents with BP-I had significantly increased risk of developing MDD and BP-I than those with BP-II. Regarding clinical characteristics, ADHD rating scale and childhood trauma scale were significantly higher in offspring of parents with BP-I than that in those with BP-II. CONCLUSION: The present study supports that BP-I may be etiologically distinct from BP-II by a possible genetic liability. Our findings indicate that additional research related to bipolar offspring is needed to enhance understanding of differences between BP-I and BP-II.