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Purpose: We investigated the consistent efficacy and safety of eflapegrastim, a novel long-acting granulocyte-colony stimulating factor (G-CSF), in Koreans and Asians compared with the pooled population of two global phase 3 trials., Materials and Methods: Two phase 3 trials (ADVANCE and RECOVER) evaluated the efficacy and safety of fixed-dose eflapegrastim (13.2 mg/0.6 mL [3.6 mg G-CSF equivalent]) compared to pegfilgrastim (6 mg based on G-CSF) in breast cancer patients who received neoadjuvant or adjuvant docetaxel/cyclophosphamide. The primary objective was to demonstrate non-inferiority of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN) in cycle 1, in Korean and Asian subpopulations., Results: Among a total of 643 patients randomized to eflapegrastim (n=314) or pegfilgrastim (n=329), 54 Asians (29 to eflapegrastim and 25 to pegfilgrastim) including 28 Koreans (14 to both eflapegrastim and pegfilgrastim) were enrolled. The primary endpoint, DSN in cycle 1 in the eflapegrastim arm was non-inferior to the pegfilgrastim arm in Koreans and Asians. The DSN difference between the eflapegrastim and pegfilgrastim arms was consistent across populations: -0.120 days (95% confidence interval [CI], -0.227 to -0.016), -0.288 (95% CI, -0.714 to 0.143), and -0.267 (95% CI, -0.697 to 0.110) for pooled population, Koreans and Asians, respectively. There were few treatment-related adverse events that caused discontinuation of eflapegrastim (1.9%) or pegfilgrastim (1.5%) in total and no notable trends or differences across patient populations., Conclusion: This study may suggest that eflapegrastim showed non-inferior efficacy and similar safety compared to pegfilgrastim in Koreans and Asians, consistently with those of pooled population.

To explore the clinical significance of anti-cytosolic 5'-nucleoditase 1A (NT5c1A) antibody seropositivity in inflammatory myopathies, we measured anti-NT5c1A antibodies and analyzed their clinical features. Anti-NT5c1A antibodies were measured in the sera of 103 patients with inflammatory myopathies using an enzyme-linked immunosorbent assay. Positivity for anti-NT5c1A antibody was found in 13 (12.6%) of 103 patients with inflammatory myopathy. Anti-NT5c1A antibody was most frequently identified in patients with inclusion body myositis (IBM) (8/20, 40%), followed by dermatomyositis (2/13, 15.4%), immune-mediated necrotizing myopathy (2/28, 7.1%), and polymyositis (1/42, 2.4%). In eight patients with the anti-NT5c1A antibody-seropositive IBM, the median age at symptom onset was 54 years (interquartile range [IQR]: 48-57 years), and the median disease duration was 34 months (IQR: 24-50 months]. Knee extension weakness was greater than or equal to hip flexion weakness in eight (100%) patients, and finger flexion strength was less than shoulder abduction in three (38%) patients. Dysphagia symptoms were found in three (38%) patients. The median serum CK level was 581 IU/l (IQR: 434-868 IU/L]. Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment. Although anti-NT5c1A antibody is known to be associated with IBM, seropositivity has also been noted in non-IBM inflammatory myopathies, and is insufficient to have clinical significance by itself. These findings have important implications for interpreting anti-NT5c1A antibody test results as the first study in Korea., Competing Interests: All authors certify that there are no affiliations with or involvement in any organization or entity with direct financial interest in the subject matter or materials discussed in the manuscript. All authors have approved the final version of the manuscript and have no potential conflicts of interest to declare., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bethlem myopathy is one of the collagens VI-related muscular dystrophies caused by mutations in the collagen VI genes. The study was designed to analyze the gene expression profiles in the skeletal muscle of patients with Bethlem myopathy. Six skeletal muscle samples from 3 patients with Bethlem myopathy and 3 control subjects were analyzed by RNA-sequencing. 187 transcripts were significantly differentially expressed, with 157 upregulated and 30 downregulated transcripts in the Bethlem group. Particularly, 1 (microRNA-133b) was considerably upregulated, and 4 long intergenic non-protein coding RNAs, LINC01854, MBNL1-AS1, LINC02609, and LOC728975, were significantly downregulated. We categorized differentially expressed gene using Gene Ontology and showed that Bethlem myopathy is strongly associated with the organization of extracellular matrix (ECM). Kyoto Encyclopedia of Genes and Genomes pathway enrichment reflected themes with significant enrichment of the ECM-receptor interaction (hsa04512), complement and coagulation cascades (hsa04610), and focal adhesion (hsa04510). We confirmed that Bethlem myopathy is strongly associated with the organization of ECM and the wound healing process. Our results demonstrate transcriptome profiling of Bethlem myopathy, and provide new insights into the path mechanism of Bethlem myopathy associated with non-protein coding RNAs., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The decision to perform percutaneous mitral commissurotomy (PMC) on asymptomatic patients requires careful weighing of the potential benefits against the risks of PMC, and we conducted a multicentre, randomised trial to compare long-term outcomes of early PMC and conventional treatment in asymptomatic, severe mitral stenosis (MS)., Methods: We randomly assigned asymptomatic patients with severe MS (defined as mitral valve area between 1.0 and 1.5 cm 2 ) to early PMC (84 patients) or to conventional treatment (83 patients). The primary endpoint was a composite of major cardiovascular events, including PMC-related complications, cardiovascular mortality, cerebral infarction and systemic thromboembolic events. The secondary endpoints were death from any cause and mitral valve (MV) replacement during follow-up., Results: In the early PMC group, there were no PMC-related complications. During the median follow-up of 6.4 years, the composite primary endpoint occurred in seven patients in the early PMC group (8.3%) and in nine patients in the conventional treatment group (10.8%) (HR 0.77; 95% CI 0.29 to 2.07; p=0.61). Death from any cause occurred in four patients in the early PMC group (4.8%) and three patients in the conventional treatment group (3.6%) (HR 1.30; 95% CI 0.29 to 5.77). Ten patients (11.9%) in the early PMC group and 17 patients (20.5%) in the conventional treatment group underwent MV replacement (HR 0.59; 95% CI 0.27 to 1.29)., Conclusions: Compared with conventional treatment, early PMC did not significantly reduce the incidence of cardiovascular events among asymptomatic patients with severe MS during the median follow-up of 6 years., Trial Registration Number: NCT01406353., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Vitamin B12 (B12) is involved as a cofactor in the synthesis of myelin. A lack of B12 impairs peripheral nerve production, which can contribute to sarcopenia. In this cross-sectional study, we aimed to investigate the relationship between B12 insufficiency and sarcopenia in community-dwelling older Korean adults. A total of 2325 (1112 men; 1213 women) adults aged 70-84 years were recruited. The tools used for sarcopenia were based on the Asian Working Group for Sarcopenia (AWGS) guidelines. Individuals with low appendicular skeletal muscle mass index (ASMI) (<7.0 kg/m 2 for men; <5.4 kg/m 2 for women) and low hand grip strength (HGS) (<28 kg for men; <18 kg for women) were defined as the sarcopenia group. Among this group, those who showed low physical performance (≤9 points on the Short Physical Performance Battery (SPPB)) were defined as the severe sarcopenia group. B12 concentrations were classified into insufficient (<350 pg/mL) and sufficient (≥350 pg/mL). Univariate and multivariate logistic regression analyses were used to evaluate the relationship between sarcopenia and B12 levels. Low ASMI showed a high incidence in the B12-insufficient group. However, HGS, SPPB, and the severity of sarcopenia showed no correlation with B12. Further, insufficient B12 may affect muscle quantity rather than muscle strength or physical performance.

The purpose of this study was to demonstrate the reliability and validity of the Korean version of the Caregiver Burden Inventory (CBI). The study was conducted as a multicenter cross-sectional survey for caregivers caring for patients with disabilities in outpatient or inpatient rehabilitation clinics. Sociodemographic characteristics and health-related quality of life were collected via questionnaires. The CBI and Burden Interview (BI) were administered, after which internal consistency and factor analysis of the CBI and correlation between the CBI and BI were explored. A total of 151 caregivers participated. The mean age of caregivers was 53.7 ± 12.4 years, and 80.8 % were women. The majority of caregivers were the main caregivers of stroke, spinal cord injury or traumatic brain injury. The factor analysis confirmed its five factorial structure. The time-dependence and physical burden scores of CBI were higher than those of other factors. All five-dimensional and total scores of CBI showed high internal consistency and were well correlated with BI. In conclusion, the CBI has proven its reliability, construct validity and concurrent validity for caregivers of disabled people and has shown its advantage as a multidimensional measure., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Dystrophinopathy is a group of inherited phenotypes arising from pathogenic variants in DMD. We evaluated the clinical and genetic characteristics of Korean patients with genetically confirmed dystrophinopathy. We retrospectively reviewed medical records (January 2004-September 2020) from the myopathy database maintained at the study hospital and found 227 patients from 218 unrelated families with dystrophinopathy. Clinical phenotypes included 120 (53%) Duchenne muscular dystrophy (DMD) cases, 20 (9%) intermediate phenotype muscular dystrophy (IMD) cases, 65 (29%) Becker muscular dystrophy (BMD) cases, 18 (8%) undetermined phenotypes, and 4 (2%) symptomatic carriers. The median ages at symptom onset and diagnosis were 5.0 years (interquartile range [IQR]: 3.8-8.0) and 12.0 years (IQR: 7.0-21.0), respectively. Total manual muscle test (MMT) scores decreased annually in patients with DMD, IMD, and BMD. Overall, when age increased by 1 year, total MMT scores decreased on average by -1.978, -1.681, and -1.303 in patients with DMD (p<0.001), IMD (p<0.001), and BMD (p<0.001), respectively. Exonic deletion and duplication were reported in 147 (67%) and 31 (14%) of the 218 unrelated probands, respectively. A total of 37 different small sequence variants were found in 40 (18%) of the 218 probands. The reading frame rule was applicable to 142 (94%) of the 151 probands. The present results highlight the long-term natural history and genetic spectrum of dystrophinopathy in a large-scale Korean cohort., Competing Interests: Go Hun Seo is employed by the company 3billion. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Altogether, 81% of Korean college students experience halitosis and concomitant psychosocial problems such as depression and lowered self-esteem, as well as poor oral-health-related quality of life. Although halitosis causes many social and psychological problems among college students, there have been no reports of improvement interventions. This study aimed to identify the effects of ingesting tablets of the oral probiotic Weissella cibaria CMU (Chonnam Medical University, Gwangju, Korea) on halitosis and examine its effects on psychosocial indicators. This was a randomized, double-blind, placebo-controlled trial. The participants were randomly assigned to the experimental group or the control group. They ingested W. cibaria CMU or the placebo, depending on which group they belonged to, before going to bed daily for eight weeks. The measured indicators were subjective halitosis, subjective oral-health status, depression, self-esteem, and oral-health-related quality of life. Measurements were at baseline and eight weeks later. The participants showed statistically significant differences in subjective halitosis and oral-health-related quality of life. For college students with halitosis, intake of the oral probiotic for eight weeks could be a useful nursing intervention for reducing halitosis and improving oral-health-related quality of life.

There is limited data regarding the association between sarcopenia and clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI). From the prospective ASAN-TAVI registry, we evaluated a total of 522 patients with severe aortic stenosis who underwent TAVI between March 2010 and November 2018. Routine pre-TAVI computed tomography scan was used to calculate the skeletal muscle index (SMI), which was defined as skeletal muscle area at the L3 level divided by height squared; subject patients were classified into the gender-specific tertile groups of SMI. The patients' mean age was 79 years and 49% were men. Mean SMI values were 41.3 ± 6.7 cm 2 /m 2 in men and 34.1 ± 6.5 cm 2 /m 2 in women. The Kaplan-Meier estimates of all-cause mortality at 12 months were higher in the low-tertile group than in the mid- and high-tertile groups (15.5%, 7.1%, and 6.2%, respectively; p = 0.036). In multivariate analysis, low-tertile of SMI was an independent predictor of mortality (vs high-tertile of SMI, hazard ratio 2.69; 95% confidence interval, 1.18 to 6.12; p = 0.019). The all-cause mortality was substantially higher in the groups with high-surgical risk plus low SMI tertile. The risk assessment with addition of SMI on conventional STS-PROM score was significantly improved by statistical measures of model reclassification and discrimination. In patients who underwent TAVI, sarcopenia measured by SMI was significantly associated with an increased risk of 1-year mortality. The prognostic impact of SMI-measured sarcopenia was more prominent in patients with high surgical risks., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study aimed to investigate whether trunk fat mass measured using dual-energy X-ray absorptiometry (DEXA) correlates with balance and physical performance.This study utilized 2-year baseline data pertaining to 3014 participants from the database of the Korean frailty and aging cohort study. The trunk lean mass and fat mass were measured by DEXA. Trunk fat mass index (tFMI) was established using the following standard equation: Trunk fat mass (Kg)/height (m). The clinical balance tests were performed using the timed up and go test (TUG), total balance score in short physical performance battery (SPPB). We performed SPPB and evaluated independence of daily living using activities of daily living, instrumental activities of daily living (IADL), sarcopenia screening tool (SARC-F) and both hand grip power. In our study, we tried to check the correlation of tFMI with balance and physical performance and to determine the factors associated with tFMI.The tFMI was positively correlated with mean values of 4 m gait speed, repeat chair stand time in SPPB, TUG, and SARC-F and negatively correlated with hand grip, IADL, total balance test score in SPPB, total SPPB score, and age. The results of the multiple generalized linear model analysis that assessed the factors associated with balance and physical performance indicated that tFMI had a significant correlation with repeat chair stand time in SPPB (seconds) (Beta estimate [B]: 0.252), TUG (seconds) (B: 0.25), 4 m gait speed (seconds) (B: 0.055), and total balance score in SPPB (B: -0.035).Higher tFMI using DEXA was correlated with low physical performance and balance, indicating that trunk fat mass was associated with balance and physical performance in community-dwelling older people.

The asymmetry in lower extremity strength is known to be related to the functional mobility in older adults living in the community. However, little is known about the association between lower extremity lean mass asymmetry and functional mobility in this patient group. Hence, this study aimed to determine whether asymmetry in lower extremity muscle mass has a significant relationship with functional mobility in older adults living in the community.This cross-sectional study analyzed the pre-existing data from the Korean Frailty and Aging Cohort Study. A total of 435 older people (aged 70-84 years) were divided into the following groups according to their Limb Asymmetry Index (LAsI): low, intermediate, and high asymmetric groups. LAsI is calculated using lower extremity lean mass, and comparisons between groups were conducted. The participants were also further divided into better and worse mobility groups based on their physical performance test results (Timed Up and Go and Short Physical Performance Battery), and comparisons between groups were conducted. Comparisons between fallers and non-fallers were also conducted. In addition, this study investigated the factors that had a significant effect on gait speed and fall experience within the past year among older adults living in the community.The LAsI was significantly associated with gait speed in older adults living in the community. Older adults in the highest tertile of the LAsI had a slower gait speed than those in the lowest tertile of the LAsI. However, no significant difference was observed in the LAsI between the better mobility group and worse mobility group. Moreover, the LAsI was not a significant predictor of falls.Asymmetry in lower extremity lean mass was significantly associated with gait speed in older adults living in the community.

Rationale: Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome is a very rare multisystem disorder, which shows malformations of the central nervous system, ears, eyes, teeth, and skeleton that was first reported in 1991. Only a few cases that sporadically occurred have been reported worldwide. The research investigating the pathogenesis and patterns of CODAS inheritance is still ongoing. There is no satisfactory treatment for this rare genetic disease yet. Due to the lack of curative medical treatment, rehabilitation could play a major role in treatment for genetic disease., Patient Concerns: To our best knowledge, the 2 children described in this study are the only CODAS syndromes siblings reported in the world so far. These Korean siblings show highly distinctive features consisting of developmental delay, cataracts, vulnerability to tooth decay, epiphyseal dysplasia, and anomalous ears., Diagnoses: CODAS syndrome., Interventions: Comprehensive long-term rehabilitation treatment during 5 years., Outcomes: We report on the progress of the comprehensive long-term rehabilitation treatment at 5-year follow-up. Their fine motor and language skills development improved similarly to that of same-aged children. We observed the positive effect of rehabilitation on the quality of life., Lessons: The therapy of genetic disorders is challenging for pediatric neurologists and pediatric physiatrists. We suggest that rehabilitation is the best treatment currently available for this genetic disease that yields satisfactory therapeutic effect.

Aortic valve (AV) replacement (AVR) is the only effective treatment for severe aortic stenosis (AS). However, survival benefits by performing AVR in asymptomatic AS patients with preserved left ventricular (LV) function remains controversial. This study included 468 patients (aged 64.2 ± 13.0 years, 232 women) with preserved LV function (≥50%) and severe AS (AV area ≤1.0 cm 2 , peak trans-AV velocity [V max ] ≥4.0 m/s, or mean AV pressure gradient ≥40 mm Hg) between 2000 and 2015. AVR was performed in 221 (47.2%) patients early (within 3 months; n = 130, 27.8%) or during follow-up (n = 91, 19.4%), whereas the remainder (n = 247) received medical treatment. Time-dependent Cox regression analyses were performed to determine the impact of AVR on long-term survival outcomes. During a median follow-up of 60.9 months (quartile 1 to 3, 29.9 to 107.0 months), 72 (15.4%) patients developed AS-related symptoms and 146 (31.2%) died. On time-dependent Cox models, AVR was associated with a significant risk reduction in all-cause death (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40 to 0.97; p = 0.036) and cardiac death (HR, 0.59; 95% CI, 0.35 to 0.995; p = 0.048) after adjusting for significant contributors to mortality. Survival benefits by performing AVR were manifested in most risk subgroups. In conclusion, AVR in asymptomatic severe AS patients with preserved LV function resulted in significant survival benefits, suggesting that early recruitment for AVR may be warranted before ventricular dysfunction or symptom development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aims: Currently, office blood pressure (OBP) is the most widely used method of measuring blood pressure (BP) in daily clinical practice. However, data on the diagnostic accuracy of OBP in reference to ambulatory blood pressure (ABP) are scarce in Korea., Methods: In retrospective and prospective cohorts, manual OBP and ABP measurements were compared among ambulatory hypertensive patients. Hypertension was defined as systolic OBP ≥ 140 mmHg and/or diastolic OBP ≥ 90 mmHg, and systolic ABP ≥ 130 mmHg and/or diastolic ABP ≥ 80 mmHg., Results: In the retrospective cohort (n = 903), the mean OBP1 (before ABP measurement) was higher than ABP in both systolic (138 ± 17 mmHg vs. 123 ± 13 mmHg, p < 0.001) and diastolic (84 ± 12 mmHg vs. 78 ± 11 mmHg, p < 0.001) measurements. Interestingly, there was only a weak correlation between OBP and ABP ( r 2 = 0.038, p < 0.001). The overall discordance rate of OBP compared to ABP, which is the reference method for measuring BP, was 43.9%. The prospective cohort (n = 57) showed similar results. In a subgroup analysis, male patients had higher false negative results (masked or under-treated hypertension) than did female patients (26.1% vs. 17.8%, p = 0.003), whereas female patients had a higher false positive rate (white-coat or over-treated hypertension) than did male patients (28.7% vs. 15.2%, p < 0.001)., Conclusions: The diagnostic accuracy of manual OBP is low in reference to ABP. Men and women have different patterns of discordance. These findings indicate that management of hypertensive patients with manual OBP measurements may be suboptimal and encourages the use of ABP in ambulatory hypertensive patients.

To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS.

Purpose: The prognosis of breast cancer has been consistently improving. We analyzed our cohort of breast cancer patients with a long-term follow up at a single center over time., Materials and Methods: A total of 1889 patients with known cancer stages were recruited and analyzed between January 1991 and December 2005. Patients were classified according to the time periods (1991-1995; 1996-2000; 2001-2005). To determine intrinsic subtypes, 858 patients whose human epidermal growth receptor-2 status and Ki67 were reported between April 2004 and December 2008 were also analyzed., Results: At a median follow up of 9.1 years, the 10-year overall survival (OS) rate was 80.5% for the entire cohort. On multivariate analysis for OS and recurrence-free survival (RFS), the time period was demonstrated to be a significant factor independent of conventional prognostic markers. In the survival analysis performed for each stage (I to III), OS and RFS significantly improved according to the time periods. Adoption of new agents in adjuvant chemotherapy and endocrine therapy was increased according to the elapsed time. In the patients with known subtypes, OS and RFS significantly differed among the subtypes, and the triple-negative subtype showed the worst outcome in stages II and III., Conclusion: In the Korean breast cancer cohort with a long-term follow up, our data show an improved prognosis over the past decades, and harbor the contribution of advances in adjuvant treatment. Moreover, we provided new insight regarding comparison of the prognostic impact between the tumor burden and subtypes.

Background: We performed this analysis to investigate the clinical presentation of trastuzumab-associated cardiac toxicity in Korean women., Method: 124 patients treated in a single institute from January 2006 to November 2011 with adjuvant trastuzumab therapy following primary surgery were identified from a database. We evaluated the cumulative incidence of cardiac toxicity, associated risk factors, and changes in cardiac function during trastuzumab treatment., Results: The median age of patients was 50 years (range 27-73). After 12 months of follow-up, the cumulative incidence of cardiac toxicity was 12.1% (grade I: 8.1%, grade II: 0.8%, grade III: 3.2%). In total, 4% of patients discontinued treatment due to cardiac dysfunction. The left ventricular ejection fraction (LVEF) recovered in all patients who discontinued or delayed treatment due to cardiac dysfunction following treatment discontinuation. The degree of the decrease in LVEF was large at 6 months after the initiation of treatment. A lower LVEF at baseline (<65%) was associated with cardiac toxicity., Conclusions: The low incidence of cardiac toxicity and the reversibility of cardiac dysfunction may validate the safety of trastuzumab treatment in Korean women with an acceptable baseline LVEF., (© 2013 S. Karger AG, Basel.)