Associations of Perioperative Red Blood Cell Transfusion With Outcomes of Kidney Transplantation in Korea Over a 16-Year Period.

BACKGROUND: This study investigated the associations between transfusion of different types of red blood cell (RBC) preparations and kidney allograft outcomes after kidney transplantation (KT) over a 16-year period in Korea using a nationwide population-based cohort. METHODS: We investigated the reported use of RBCs during hospitalization for KT surgery, rejection, and graft failure status using nationwide data from the National Health Information Database (2002-2017). The associations between the type of perioperative RBC product and transplant outcomes were evaluated among four predefined groups: no RBC transfusion, filtered RBCs, washed RBCs, and packed RBCs (pRBCs). RESULTS: A total of 17,754 KT patients was included, among which 8,530 (48.0%) received some type of RBC transfusion. Of the patients who received RBC transfusion, 74.9%, 19.7%, and 5.4% received filtered RBCs, pRBCs, or washed RBCs, respectively. Regardless of the type of RBC products, the proportions of acute rejection and graft failure was significantly greater in patients receiving transfusion (P < 0.001). Cox proportional hazards regression analyses showed that the filtered RBC and pRBC groups were significantly associated with both rejection and graft failure. The washed RBC group also had hazard ratios greater than 1.0 for rejection and graft failure, but the association was not significant. Rejection-free survival of the pRBC group was significantly lower than that of the other groups (P < 0.001, log-rank test), and graft survival for the no RBC transfusion group was significantly greater than in the other groups (P < 0.001, log-rank test). CONCLUSION: Perioperative RBC transfusion was associated with poor graft outcomes. Notably, transfusion of pRBCs significantly increased transplant rejection. Therefore, careful consideration of indications for RBC transfusion and selection of the appropriate type of RBCs is necessary, especially for patients at high risk of rejection or graft failure.

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol.

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol (1) with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar Ki. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.

Temperature as a risk factor of emergency department visits for acute kidney injury: a case-crossover study in Seoul, South Korea.

BACKGROUND: Previous studies show that escalations in ambient temperature are among the risk factors for acute kidney injury (AKI). However, it has not been adequately studied in our location, Seoul, South Korea. In this study, we aimed to examine the association between ambient temperatures and AKI morbidity using emergency department (ED) visit data. METHODS: We obtained data on ED visits from the National Emergency Medical Center for 21,656 reported cases of AKI from 2010 to 2014. Time-stratified case-crossover design analysis based on conditional logistic regression was used to analyze short-term effects of ambient temperature on AKI after controlling for relevant covariates. The shape of the exposure-response curve, effect modification by individual demographic characteristics, season, and comorbidities, as well as lag effects, were investigated. RESULTS: The odds ratio (OR) per 1 °C increase at lag 0 was 1.0087 (95% confidence interval [CI]: 1.0041-1.0134). Risks were higher during the warm season (OR = 1.0149; 95% CI: 1.0065-1.0234) than during the cool season (OR = 1.0059; 95% CI: 1.0003-1.0116) and even higher above 22.3 °C (OR = 1.0235; 95% CI: 1.0230-1.0239). CONCLUSIONS: This study provides evidence that ED visits for AKI were associated with ambient temperature. Early detection and treatment of patients at risk is important in both clinical and economic concerns related to AKI.

The effect of missing teeth on dementia in older people: a nationwide population-based cohort study in South Korea.

BACKGROUND: To determine the effect of missing teeth on the risk of dementia onset among individuals who received tooth extractions and those who did not, based on the number of missing teeth. METHODS: We selected individuals who had not been diagnosed or treated for dementia between 2002 to 2011 from the National Health Insurance Service-Elderly Cohort Database (NHIS-ECD). We divided participants into two cohorts, a tooth extraction and non-extraction cohort, based on tooth loss from 2002 to 2011. After propensity score matching, there were 104,903 individuals in each cohort, and we included a total of 209,806 individuals in this study. Each cohort was grouped by sex, age, residential area, health insurance eligibility, income level, history of dental caries, history of periodontal treatment, and number of extracted teeth. We analyzed the relationship between dementia onset and these variables using logistic regression analysis. RESULTS: Individuals with tooth loss had a higher risk for dementia than those without tooth loss (odds ratio [OR] = 1.18; 95% confidence interval [CI]: 1.146-1.215). Regarding the incidence of dementia, the OR increased as the number of missing teeth and age increased, and the OR was higher for women (OR = 1.33; 95% CI: 1.286-1.367) than for men, and this difference was statistically significant (P < 0.01). The incidence of dementia decreased with periodontal treatment (OR = 0.96; 95% CI: 0.932-0.992) and increased with dental caries (OR = 1.07; 95% CI: 1.035-1.101). CONCLUSIONS: These results suggest that it is important to delay tooth loss and preserve the stable remaining teeth to help prevent dementia.

Analysis of red blood cell use in elective surgeries over 12 years in Korea.

BACKGROUND: Red blood cell (RBC) transfusion is a lifesaving process for patients with perioperative bleeding, but transfusion can cause adverse events. Effective utilization and management of blood products as a limited resource is essential when considering cost-efficiency and patient safety. STUDY DESIGN AND METHODS: We analyzed the number of RBC units used during the hospitalization of patients who had undergone surgical procedures from 2002 to 2013 using National Health Insurance Service-National Sample Cohort data, which include a total of 487,238 cases for 206 selected operations. RESULTS: RBC units were used in 39,637 (8.1%) cases. A total of 60,815 RBC units were transfused with a mean of 0.13 units per patient overall and a mean of 1.53 units per case receiving RBC transfusion. In addition, 56.7% of the RBC units were transfused for females, and 60.1% of RBC units were transfused into patients aged 60 or older. RBC units were used most often in orthopedic surgeries (33.8%), followed by general surgeries (12.0%) and vascular surgeries (11.8%). The number of operations performed in the cohort increased from 27,690 in 2002 to 49,473 in 2013, and the mean number of RBC units used per operation also increased from 0.08 units in 2002 to 0.15 units in 2013. CONCLUSION: Continuous management for blood preparation and transfusion is needed for efficient utilization of blood. Periodic investigation on the use of blood products through nationwide studies could suggest data applicable to blood product preparation for various elective surgical operations.

Arsenic Compromises Both p97 and Proteasome Functions.

Exposure to arsenic is a worldwide problem that affects more than 200 million people. The underlying mechanisms of arsenic toxicity have been difficult to ascertain due to arsenic's pleotropic effects. A number of recent investigations have shown that arsenic can compromise protein quality control through the ubiquitin proteasome system (UPS) or the endoplasmic reticulum associated protein degradation (ERAD) pathway. In this article, a link between arsenic and protein quality control is reported. Biochemical and cellular data demonstrate a misregulation of the ATPase cycle of the ATPase associated with various cellular activities (AAA+) chaperone, p97. Interestingly, the loss of p97 activity is due to the increased rate of ATP hydrolysis, which mimics a collection of pathogenic genetic p97 lesions. Cellular studies, using a well characterized reporter of both the proteasome and p97, show the proteasome to also be compromised. This loss of both p97 and proteasome functions can explain the catastrophic protein quality control issues observed in acute, high level arsenic exposures.

The Impact of In-Home Services Utilization on the Institutionalization of Older People in Korea.

As a result of aging populations, institutionalization of older people is creating an increasing financial burden in many countries. The purpose of the present study was to explore the impact of in-home service utilization on institutionalization. The subjects were newly certified as eligible for long-term care insurance between January and February 2009 in Korea. The follow-up period was 40 months, to April 2012. We used logistic regression models to identify factors influencing the transition to institutional service, adjusting for gender, age, living status, income level, activities of daily living, and chronic disease. The institutionalization rate was estimated to be 17.3% over 40 months. The interval from transitional living to institutionalization was 36 ± 8 months. Risk factors of transition to institutional services are being female, having advanced age, living with friends or cousins, getting dementia, and not using in-home services. We determined that institutionalization is mitigated by use of in-home services. Therefore, supplying appropriate in-home services to current nonusers would help to greatly reduce the rate of institutionalization of older people.

Dual Unnatural Amino Acid Incorporation and Click-Chemistry Labeling to Enable Single-Molecule FRET Studies of p97 Folding.

Many cellular functions are critically dependent on the folding of complex multimeric proteins, such as p97, a hexameric multidomain AAA+ chaperone. Given the complex architecture of p97, single-molecule (sm) FRET would be a powerful tool for studying folding while avoiding ensemble averaging. However, dual site-specific labeling of such a large protein for smFRET is a significant challenge. Here, we address this issue by using bioorthogonal azide-alkyne chemistry to attach an smFRET dye pair to site-specifically incorporated unnatural amino acids, allowing us to generate p97 variants reporting on inter- or intradomain structural features. An initial proof-of-principle set of smFRET results demonstrated the strengths of this labeling method. Our results highlight this as a powerful tool for structural studies of p97 and other large protein machines.

Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin.

The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity. Interestingly, cellular studies revealed both DHC and its monochloro analogue interfere with both the proteasome and p97, whereas its dichloro analogue showed p97 specificity.

Metabolic perturbation of an essential pathway: evaluation of a glycine precursor of coenzyme A.

Pantetheine and its corresponding disulfide pantethine play a key role in metabolism as building blocks of coenzyme A (CoA), an essential cofactor utilized in ~4% of primary metabolism and central to fatty acid, polyketide, and nonribosomal peptide synthases. Using a combination of recombinant engineering and chemical synthesis, we show that the disulfide of N-pantoylglycyl-2-aminoethanethiol (GlyPan), with one fewer carbon than pantetheine, can rescue a mutant E. coli strain MG1655ΔpanC lacking a functional pantothenate synthetase. Using mass spectrometry, we show that the GlyPan variant is accepted by the downstream CoA biosynthetic machinery, ultimately being incorporated into essential acyl carrier proteins. These findings point to further flexibility in CoA-dependent pathways and offer the opportunity to incorporate orthogonal analogues.

Spirohexenolide A targets human macrophage migration inhibitory factor (hMIF).

Spirohexenolides A and B comprise a unique family of spirotetronate natural products. We report on the identification of their binding to and modulation of human macrophage migration inhibitor factor (hMIF). Using an immunoaffinity-fluorescent labeling method, the properties of this interaction are detailed and evidence is provided that hMIF plays a key role in the cytostatic activity of the spirohexenolides.

The Risk of Major Depressive Disorder Due to Cataracts among the Korean Elderly Population: Results from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2016 and 2018.

Cataracts and major depressive disorder (MDD) both have high prevalence, representing for major health burdens globally. In this study, we examined the risk of MDD due to cataracts. Data from the 2016 to 2018 Korea National Health and Nutrition Examination Survey (KNHANES) were used, including 4122 participants. Logistic regression analysis was performed to evaluate the odds ratio for MDD in association with cataracts. Controlled variables were age, gender, smoking, dyslipidemia and mobility. Subgroup analysis was performed with stratification by gender. The results reveal that cataracts are significantly correlated with MDD. Elderly people with cataracts were found to be more likely to develop MDD compared to those without cataracts (adjusted odds ratio: 1.654; 95% CI = 1.197-2.286). In subgroup analysis, men (adjusted odds ratio: 2.631; 95% CI = 1.247-5.551) were found to be more likely to develop MDD than women (adjusted odds ratio: 1.510; 95% CI = 1.061-2.150). Cataracts may be a risk factor for MDD in the elderly, especially among the male population.

Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.

Genetic hearing loss is the most common hereditary sensorial disorder. Though more than 120 genes associated with deafness have been identified, unveiled causative genes and variants of diverse types of hearing loss remain. Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration. CEP250 encodes C-Nap1 protein belonging to the CEP protein family, comprising 30 proteins that play roles in centrosome aggregation and cell cycle progression. The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol. In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response. In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.

Production of human spinal-cord organoids recapitulating neural-tube morphogenesis.

Human spinal-cord-like tissues induced from human pluripotent stem cells are typically insufficiently mature and do not mimic the morphological features of neurulation. Here, we report a three-dimensional culture system and protocol for the production of human spinal-cord-like organoids (hSCOs) recapitulating the neurulation-like tube-forming morphogenesis of the early spinal cord. The hSCOs exhibited neurulation-like tube-forming morphogenesis, cellular differentiation into the major types of spinal-cord neurons as well as glial cells, and mature synaptic functional activities, among other features of the development of the spinal cord. We used the hSCOs to screen for antiepileptic drugs that can cause neural-tube defects. hSCOs may also facilitate the study of the development of the human spinal cord and the modelling of diseases associated with neural-tube defects.

Outcomes of kidney transplantation over a 16-year period in Korea: An analysis of the National Health Information Database.

BACKGROUND: This study investigated the outcomes of kidney transplantation (KT) over a 16-year period in Korea and identified risk factors for graft failure using a nationwide population-based cohort. METHODS: We investigated the Korean National Health Insurance Service-National Health Information Database. Health insurance claims for patients who underwent KT between 2002 and 2017 were analyzed. RESULTS: The data from 18,331 patients who underwent their first KT were reviewed. The percentage of antithymocyte globulin (ATG) induction continuously increased from 2.0% in 2002 to 23.5% in 2017. Rituximab began to be used in 2008 and had increased to 141 patients (9.6%) in 2013. Acute rejection occurred in 17.3% of all patients in 2002 but decreased to 6.3% in 2017. The rejection-free survival rates were 78.8% at 6 months after KT, 76.1% after 1 year, 67.5% after 5 years, 61.7% after 10 years, and 56.7% after 15 years. The graft survival rates remained over 80% until 12 years after KT, and then rapidly decreased to 50.5% at 16 years after KT. In Cox's multivariate analysis, risk factors for graft failure included being male, more recent KT, KT from deceased donor, use of ATG, basiliximab, or rituximab, tacrolimus use as an initial calcineurin inhibitor, acute rejection history, and cytomegalovirus infection. CONCLUSIONS: ATG and rituximab use has gradually increased in Korea and more recent KT is associated with an increased risk of graft failure. Therefore, meticulous preoperative evaluation and postoperative management are necessary in the case of recent KT with high risk of graft failure.

Perioperative blood usage and therapeutic plasma exchange in kidney transplantation during a 16-year period in South Korea.

BACKGROUND: The frequency of kidney transplantation (KT) is increasing. Blood transfusion plays an important role in the success of KT. Therapeutic plasma exchange (TPE) is also used for desensitisation in ABO-incompatible KT and treatment of antibody-mediated rejection. MATERIALS AND METHODS: We analysed red blood cell (RBC), platelet, and fresh frozen plasma (FFP) usage and the number of TPE procedures performed during the hospitalisation of KT patients from 2002 to 2017 using the Korean National Health Insurance Service-National Health Information Database. RESULTS: A total of 18,331 KT patients were included in this study. The number of transfused RBCs continued to increase from 4,806 units in 2002-2005 to 12,390 units in 2014-2017. However, the average number of RBCs transfused per patient decreased from 2.17 to 1.79 units. Estimated platelet usage increased from 4,259 units in 2002-2005 to 11,519 units in 2014-2017, and the proportion of filtered platelets increased from 72.6% to 83.4% during the same period. There was a huge increase in the total number of FFP units used, from 2,255 units in 2002-2005 to 51,531 units in 2014-2017. The number of TPE procedures performed also increased from 296 to 6,479 during the same period. Patients with acute rejection accounted for 8.8% of all KT patients, and more RBC and FFP were used for these patients and a greater number of TPE procedures were performed compared to those who did not experience rejection. DISCUSSION: Blood usage and TPE have increased steadily with the increasing numbers of KTs. Therefore, continuous efforts are needed to ensure appropriate perioperative blood preparation and usage for KT patients.

De Novo Cancer Incidence after Kidney Transplantation in South Korea from 2002 to 2017.

Advances in patient care and immunosuppressive drugs have improved graft survival, resulting in an increase in kidney transplantation (KT); however, persistent immunosuppression is thought to cause late occurrence of cancer. This population-based study consisted of a total of 14,842 patients whose data from the years 2002 to 2017 were collected from the National Health Information Database in South Korea. Malignancies occurred in 7.6% of the total KT patients. Prostate and thyroid cancers were the most common in males and females, respectively. From the age-adjusted incidence analysis, Kaposi's sarcoma showed the highest standardized incidence ratio in both male and female patients. According to the linear regression model, cancer incidence in KT recipients under immunosuppressive conditions increased by approximately 0.1% each month. Patients' age over 39 and the use of prednisolone as an initial steroid regimen were associated with increased risk of cancer development after KT. Our regression and proportional hazards models will help clinicians to predict the approximate cancer incidence risk when monitoring KT recipients. Based on the largest available national database, screening or monitoring methods for cancer detection and prevention can be established for KT patients by considering the factors involved in cancer development.

LCCL peptide cleavage after noise exposure exacerbates hearing loss and is associated with the monocyte infiltration in the cochlea.

Acoustic trauma induces an inflammatory response in the cochlea, resulting in debilitating hearing function. Clinically, amelioration of inflammation substantially prevents noise-induced hearing loss. The Limulus factor C, Cochlin, and Lgl1 (LCCL) peptide plays an important role in innate immunity during bacteria-induced inflammation in the cochlea. We aimed to investigate the LCCL-induced innate immune response to noise exposure and its impact on hearing function. METHODS: We used Coch (encodes cochlin harboring LCCL peptide) knock-out and p.G88E knock-in mice to compare the immune responses before and after noise exposure. We explored their hearing function and hair cell degeneration. Moreover, we investigated distinct characteristics of immune responses upon noise exposure using flow cytometry and RNA sequencing. RESULTS: One day after noise exposure, the LCCL peptide cleaved from cochlin increased over time in the perilymph space. Both Coch-/- and CochG88E/G88E mutant mice revealed more preserved hearing following acoustic trauma compared to wild-type mice. The outer hair cells were more preserved in Coch-/- than in wild-type mice upon noise exposure. The RNA sequencing data demonstrated significantly upregulated cell migration gene ontology in wild-type mice than in Coch-/- mice following noise exposure, indicating that the infiltration of immune cells was dependent on cochlin. Notably, infiltrated monocytes from blood (C11b+/Ly6G-/Ly6C+) were remarkably higher in wild-type mice than in Coch-/- mice at 1 day after noise exposure. CONCLUSIONS: Noise-induced hearing loss was attributed to over-stimulated cochlin, and led to the cleavage and secretion of LCCL peptide in the cochlea. The LCCL peptide recruited more monocytes from the blood vessels upon noise stimulation, thus highlighting a novel therapeutic target for noise-induced hearing loss.

A population-based epidemiology of Wilson's disease in South Korea between 2010 and 2016.

Very few population-based studies have examined the epidemiology of Wilson's disease (WD). We investigated the epidemiology of WD using the National Health Insurance Service (NHIS) database in South Korea. We analyzed not only the statistical variables of WD, but also those of WD-related diseases. WD patients were identified with the relevant International Classification of Diseases-10 code out of 50.5 million people. We used the NHIS database from 2009 to 2016 and analyzed the incidence rate, prevalence, and clinical symptoms of WD. A total of 1,333 patients were identified. The average annual incidence rate was 3.8 per million person-years. The prevalence was 38.7 per million people. The mean diagnostic age was 26.1 ± 17.2 with earlier diagnosis in men (P = 0.0003). Among the patients, 988 (74.1%) had hepatic symptoms, 510 (38.3%) had neurologic symptoms, and 601 (45.1%) had psychiatric symptoms. Before the diagnosis of WD, 350 (26.3%) had neurologic symptoms, and 427 (32%) had psychiatric symptoms. The annual mortality rate was 0.7%. Age, liver cirrhosis, and liver failure correlated with a fatal prognosis (P < 0.05). Many patients showed neurologic and psychiatric symptoms before they were diagnosed with WD. Prognosis correlated with age, liver cirrhosis, and liver failure.