The Korea Cohort Consortium: The Future of Pooling Cohort Studies

ObjectivesWe introduced the cohort studies included in the Korean Cohort Consortium (KCC), focusing on large-scale cohort studies established in Korea with a prolonged follow-up period. Moreover, we also provided projections of the follow-up and estimates of the sample size that would be necessary for big-data analyses based on pooling established cohort studies, including population-based genomic studies.MethodsWe mainly focused on the characteristics of individual cohort studies from the KCC. We developed “PROFAN”, a Shiny application for projecting the follow-up period to achieve a certain number of cases when pooling established cohort studies. As examples, we projected the follow-up periods for 5000 cases of gastric cancer, 2500 cases of prostate and breast cancer, and 500 cases of non-Hodgkin lymphoma. The sample sizes for sequencing-based analyses based on a 1:1 case-control study were also calculated.ResultsThe KCC consisted of 8 individual cohort studies, of which 3 were community-based and 5 were health screening-based cohorts. The population-based cohort studies were mainly organized by Korean government agencies and research institutes. The projected follow-up period was at least 10 years to achieve 5000 cases based on a cohort of 0.5 million participants. The mean of the minimum to maximum sample sizes for performing sequencing analyses was 5917–72 102.ConclusionsWe propose an approach to establish a large-scale consortium based on the standardization and harmonization of existing cohort studies to obtain adequate statistical power with a sufficient sample size to analyze high-risk groups or rare cancer subtypes.     

Epidemiological Trends of Pediatric Inflammatory Bowel Disease in Korea: A Multicenter Study of the Last 3 Years Including the COVID-19 Era

BackgroundStudies on how the coronavirus pandemic has affected pediatric inflammatory bowel disease (PIBD) are lacking. We aimed to investigate the trends in epidemiology, characteristics, initial management, and short-term outcomes of PIBD in South Korea over the recent three years including the era of coronavirus disease 2019 (COVID-19).MethodsThis multicenter study retrospectively investigated temporal trends in the epidemiology of PIBD in Korea. Annual occurrences, disease phenotypes, and initial management at diagnosis were analyzed from January 2018 to June 2021.ResultsA total of 486 patients from 17 institutions were included in this epidemiological evaluation. Analysis of the occurrence trend confirmed a significant increase in PIBD, regardless of the COVID-19 pandemic. In Crohn’s disease, patients with post-coronavirus outbreaks had significantly higher fecal calprotectin levels than those with previous onset (1,339.4 ± 717.04 vs. 1,595.5 ± 703.94, P = 0.001). Patients with post-coronavirus-onset ulcerative colitis had significantly higher Pediatric Ulcerative Colitis Activity Index scores than those with previous outbreaks (48 ± 17 vs. 36 ± 15, P = 0.004). In the initial treatment of Crohn’s disease, the use of 5-aminosalicylic acid (5-ASA) and steroids significantly decreased (P = 0.006 and 0.001, respectively), and enteral nutrition and the use of infliximab increased significantly (P = 0.045 and 0.009, respectively). There was a significant increase in azathioprine use during the initial treatment of ulcerative colitis (P = 0.020).ConclusionRegardless of the COVID-19 pandemic, the number of patients with PIBD is increasing significantly annually in Korea. The initial management trends for PIBD have also changed. More research is needed to establish appropriate treatment guidelines considering the epidemiological and clinical characteristics of Korean PIBD.     

Congenital Heart Surgery Skill Training Using Simulation Models: Not an Option but a Necessity

Congenital heart surgery (CHS) is technically demanding, and its training is extremely complex and challenging. Training of the surgeon’s technical skills has relied on a preceptorship format in which the trainees are gradually exposed to patients in the operating room under the close tutelage of senior staff surgeons. Training in the operating room is an inefficient process and the concept of a learning curve is no longer acceptable in terms of patient outcomes. The benefits of surgical simulation in training of congenital heart surgeons are well known and appreciated. However, adequate surgical simulation models and equipment for training have been scarce until the recent development of three-dimensionally (3D) printed models. Using comprehensive 3D printing and silicone-molding techniques, realistic simulation training models for most congenital heart surgical procedures have been produced. Newly developed silicone-molded models allow efficient CHS training in a stress-free environment with instantaneous feedback from the proctors and avoids risk to patients. The time has arrived when all congenital heart surgeons should consider surgical simulation training before progressing to real-life operating in a similar fashion to the aviation industry where all pilots are required to complete simulation training before flying a real aircraft. It is argued here that simulation training is not an option anymore but should be a mandatory component of CHS training.     

Agreement and Reliability between Clinically Available Software Programs in Measuring Volumes and Normative Percentiles of Segmented Brain Regions

ObjectiveTo investigate the agreement and reliability of estimating the volumes and normative percentiles (N%) of segmented brain regions among NeuroQuant (NQ), DeepBrain (DB), and FreeSurfer (FS) software programs, focusing on the comparison between NQ and DB.Materials and MethodsThree-dimensional T1-weighted images of 145 participants (48 healthy participants, 50 patients with mild cognitive impairment, and 47 patients with Alzheimer’s disease) from a single medical center (SMC) dataset and 130 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset were included in this retrospective study. All images were analyzed with DB, NQ, and FS software to obtain volume estimates and N% of various segmented brain regions. We used Bland–Altman analysis, repeated measures ANOVA, reproducibility coefficient, effect size, and intraclass correlation coefficient (ICC) to evaluate inter-method agreement and reliability.ResultsAmong the three software programs, the Bland–Altman plot showed a substantial bias, the ICC showed a broad range of reliability (0.004–0.97), and repeated-measures ANOVA revealed significant mean volume differences in all brain regions. Similarly, the volume differences of the three software programs had large effect sizes in most regions (0.73–5.51). The effect size was largest in the pallidum in both datasets and smallest in the thalamus and cerebral white matter in the SMC and ADNI datasets, respectively. N% of NQ and DB showed an unacceptably broad Bland–Altman limit of agreement in all brain regions and a very wide range of ICC values (-0.142–0.844) in most brain regions.ConclusionNQ and DB showed significant differences in the measured volume and N%, with limited agreement and reliability for most brain regions. Therefore, users should be aware of the lack of interchangeability between these software programs when they are applied in clinical practice.     

Catechin-7-O-α-L-rhamnopyranoside can reduce α-MSH-induced melanogenesis in B16F10 melanoma cells through competitive inhibition of tyrosinase

Although melanogenesis is a defense mechanism against ultraviolet (UV)-induced skin damage, abnormally excessive melanin production causes pigmentation disorders. Tyrosinase, as a key factor for melanin synthesis, plays an important role in inducing skin pigmentation. Therefore, the inhibition of tyrosinase is crucial in preventing skin pigmentation in the cosmetics and medicine fields. However, the majority of well-known tyrosinase inhibitors have been discontinued due to toxic effects on the skin or lack of selectivity and/or stability. In this study, we evaluated possible anti-melanogenic effects of catechin-7-O-α-L-rhamnopyranoside (C7R) isolated from the stem bark of Ulmus parvifolia, to discover a new tyrosinase inhibitor that has both safety and stability. When C7R was pretreated in B16F10 melanoma cells stimulated by α-melanocyte-stimulating hormone, this compound reduced melanin accumulation and murine tyrosinase activity. In line with these results, C7R inhibits tyrosinase purified from a mushroom in vitro like kojic acid and arbutin. Furthermore, C7R exhibited a competitive inhibition on a Lineweaver-Burk plot. Next, the underlying mechanisms of the C7R-mediated tyrosinase inhibitory effect were sought through docking simulation and pharmacophore analysis between tyrosinase residues and C7R. The results of these analyses showed that C7R had binding energy of -14.5kcal/mol, and indicated that C7R interacts with tyrosinase through an aromatic ring and various hydrophobic and hydrogen bonds. Together, our results suggest that C7R can be applied as a novel natural anti-melanogenic agent that inhibits tyrosinase.     

Preparation and evaluation of immediate release ibuprofen solid dispersions using polyethylene glycol 4000

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared in a relatively easy and simple manner, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), and evaluated for solubility, in-vitro drug release and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and resolidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FT-IR spectra showed the presence of drug crystalline in SDs. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and Cmax, and a significant decrease in Tmax over pure ibuprofen. Preliminary results from this study suggested that the preparation of fast dissolving ibuprofen SDs by low temperature melting method using polyethylene glycol 4000 (PEG 4000) as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and absorption rate of ibuprofen.     

Enchondral cartilage rests collagen-induced autoimmunity: a possible pathogenetic mechanism of otosclerosis

Collagen autoimmunity has been suggested as one etiologic mechanism to otosclerosis. Although substantial studies relating this disease to collagen autoimmunity have been reported, a basic understanding of the pathogenic mechanism involved is lacking. Some otosclerosis patients have a high level of antibody to type II collagen. In addition, complement and antibody were deposited in the stapes from otosclerosis patients. Furthermore, the otic capsule and stapes have been found to contain type II collagen by immunohistologic studies and biochemical analysis. Otospongiosis-like lesions have also been produced in rats by immunizing them with type II collagen. This finding led us to postulate a hypothesis of an autoimmunity to type II collagen as an etiopathogenesis of this illness. Our initial hypothesis has been updated to incorporate new findings in the field of cell biology. The role of interleukin 1, osteoclasts, osteoblasts, bone resorption, and other factors such as minor collagens, calcitonin, vitamin D, parathyroid hormone, collagenase, and prostaglandins are incorporated in this updated hypothesis.     

Long-term outcomes and risk factors for mortality of patients with hypertrophic obstructive cardiomyopathy undergoing septal myectomy

BackgroundWe aimed to evaluate the long-term surgical outcomes of patients with hypertrophic obstructive cardiomyopathy and explore the risk factors for mortality, especially those related to atrial fibrillation.MethodsWe retrospectively reviewed 150 consecutive patients with hypertrophic obstructive cardiomyopathy who underwent surgical treatment between March 2003 and December 2020.ResultsFifty (33.3%, age 53.7±16.1 years) patients underwent isolated septal myectomy (SM), 79 (52.7%, age 52.3±12.6 years) underwent SM with mitral valve intervention (SM + MVI), and 21 (14.0%, age 57.1±13.5 years) underwent SM with mitral valve replacement (SM + MVR). Overall peak left ventricular outflow tract pressure gradient at rest was significantly decreased from 91.9±43.2 to 13.3±13.0 mmHg (P<0.0001). Survival rates were 96.7%, 89.1%, and 81.5% at 30 days, 5 years, and 10 years, respectively. Patients in the SM + MVI group survived longer than those in SM + MVR or isolated SM groups (94.1% vs. 75.4% vs. 88.0%, respectively, at 5 years, P=0.05). Patients with preoperative atrial fibrillation had a worse 5-year survival rate than those without atrial fibrillation (73.4% vs. 92.8%, respectively, P<0.001). Preoperative atrial fibrillation was an independent risk factor for late mortality in multivariable analysis. Notably, those whose atrial fibrillation was successfully eradicated by surgical ablation had a better 5-year survival rate than other patients (87.7% vs. 28.6%, respectively, P<0.001).ConclusionsSurgical outcomes in hypertrophic obstructive cardiomyopathy are favorable in the long-term, except in patients with preoperative atrial fibrillation. Therefore, intraoperative ablation for preoperative atrial fibrillation in hypertrophic obstructive cardiomyopathy should be actively considered to improve patient outcomes.     

Humoral response to vaccination against SARS-CoV-2 in patients undergoing dialysis

Patients undergoing maintenance dialysis have a higher mortality rate associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and response rates to vaccination against SARS-CoV-2 vary from 29.6% to 96.4% in such patients. This study aimed to assess the immunogenicity of SARS-CoV-2 vaccination in Korean patients undergoing dialysis. We enrolled 70 SARS-CoV-2-vaccinated patients undergoing dialysis, with 11 healthcare workers serving as healthy control subjects. Thirty-two patients had received a third vaccination, whereas 38 had received 2 vaccinations. The healthy control subjects completed the second vaccination. Immunoglobulin G (IgG) antibodies targeting the receptor-binding domain of the S1 subunit of the SARS-CoV-2 spike protein were measured The vaccination responder rates were 86% (37/43), 96% (26/27), and 91% (10/11) in the patients undergoing hemodialysis and peritoneal dialysis and healthy controls, respectively. IgG antibody levels were significantly higher when a third dose was administered, independent of the type of vaccine or the time interval between vaccination and the subsequent blood sampling date. When a third dose of vaccine was administered, there was no difference in IgG antibody levels between those receiving cross-vaccination or a single vaccine. There was no significant difference in IgG antibodies between healthy controls and patients undergoing dialysis. Patients on dialysis exhibited a sufficient antibody-related response to vaccination against SARS-CoV-2, even in those receiving cross-vaccination, and the antibody titer was higher after a third vaccination. Therefore, it is necessary to administer a third vaccine dose to Korean patients undergoing dialysis.