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Several donor-specific factors influence the functional recovery and long-term outcomes of liver grafts. This study investigated the association between donor fasting glucose (DFG) and recipient outcomes after living donor liver transplantation (LDLT) in 950 cases at a single center. Patients were divided into two groups: low-DFG (< 85 mg/dL, n = 120) and control (≥ 85 mg/dL, n = 830). The five-year graft survival rate was significantly lower in the low-DFG group (71.5%) compared to the control group (80.0%) (P = 0.02). Multivariable Cox regression analysis showed that low DFG was independently associated with graft loss (hazard ratio 1.72, 95% CI 1.15-2.56, P = 0.008). In propensity score-matched groups, the low-DFG group also had lower survival rates (71% vs. 83.1%, P = 0.004). The presence of additional risk factors, such as low graft-to-recipient weight ratio, older donor age, and longer cold ischemic time, further reduced graft survival in the low-DFG group. A DFG level < 85 mg/dL is associated with higher risk of graft failure after LDLT, especially when combined with other risk factors. Low DFG should be considered a prognostic marker in LDLT planning, with potential to improve patient outcomes as further research clarifies the underlying pathophysiological mechanisms., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Metabolic syndrome is a significant risk factor for poor graft outcomes in kidney transplant (KT) patients. However, the effects of variability in metabolic parameters on graft outcomes in KT patients have not been completely elucidated. A total of 852 KT patients were included from the Korean Organ Transplantation Registry. The study exposure was variability in body mass index (BMI) or other metabolic parameters measured at 6 months, 1 year, and 2 years after KT. Patients were classified into tertiles according to the degree of variability. The primary outcome was a composite of adverse kidney outcomes, such as death-censored graft loss or ≥ 30% decline in estimated glomerular filtration rate. The adverse kidney outcomes occurred in 73 (8.6%) participants. The high-BMI variability group had a higher risk for adverse kidney outcomes compared to the low-variability group. High variabilities in triglyceride, fasting blood glucose, and systolic blood pressure were also associated with adverse kidney outcomes. Furthermore, high variability in metabolic syndrome-related composite indices, such as the triglyceride and glucose index and metabolic variability scores, showed a higher risk for adverse kidney outcomes. In conclusion, high variability in metabolic parameters could be associated with an increased risk of adverse kidney outcome in KT patients., (© 2024. The Author(s).)

Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells., (© 2024. The Author(s).)

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes 1-6 ; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network., (© 2024. The Author(s).)

Cardiovascular disease remains a leading cause of morbidity and mortality after kidney transplantation (KT). Although statins reduce cardiovascular risk and have renal benefits in the general population, their effects on KT recipients are not well-established. We studied the effects of early statin use (within 1-year post-transplantation) on long-term outcomes in 714 KT recipients from the Korean cohort study for outcome in patients with KT. Compared with the control group, statin group recipients were significantly older, had a higher body mass index, and had a higher prevalence of diabetes mellitus. During a median follow-up of 85 months, 74 graft losses occurred (54 death-censored graft losses and 20 deaths). Early statin use was independently associated with lower mortality (hazard ratio, 0.280; 95% confidence interval 0.111-0.703) and lower death-censored graft loss (hazard ratio, 0.350; 95% confidence interval 0.198-0.616). Statin therapy significantly reduced low-density lipoprotein cholesterol levels but did not decrease the risk of major adverse cardiovascular events. Biopsy-proven rejection and graft renal function were not significantly different between statin and control groups. Our findings suggest that early statin use is an effective strategy for reducing low-density lipoprotein cholesterol and improving patient and graft survival after KT., (© 2024. The Author(s).)

Death with a functioning graft is important cause of graft loss after kidney transplantation. However, little is known about factors predicting death with a functioning graft among kidney transplant recipients. In this study, we evaluated the association between post-transplant creatinine-cystatin C ratio and death with a functioning graft in 1592 kidney transplant recipients. We divided the patients into tertiles based on sex-specific creatinine-cystatin C ratio. Among the 1592 recipients, 39.5% were female, and 86.1% underwent living-donor kidney transplantation. The cut-off value for the lowest creatinine-cystatin C ratio tertile was 0.86 in males and 0.73 in females. The lowest tertile had a significantly lower 5-year patient survival rate and was independently associated with death with a functioning graft (adjusted hazard ratio 2.574, 95% confidence interval 1.339-4.950, P < 0.001). Infection was the most common cause of death in the lowest tertile group, accounting for 62% of deaths. A low creatinine-cystatin C ratio was significantly associated with an increased risk of death with a functioning graft after kidney transplantation., (© 2024. The Author(s).)

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed., (© 2024. The Author(s).)

Barium sulfate and iohexol are commonly used as contrast agents for videofluoroscopic swallowing study (VFSS). This study compared their usefulness as contrast agents in visualizing components of swallowing predictable of subsequent pneumonia and unintentional weight loss after VFSS. This was a randomized, controlled, crossover trial. The two contrast agents were alternately used in the same participants, and the order in which the contrast agent was tested first was randomly assigned. After VFSS, we followed the participants for 3 months and the association between VFSS findings of each contrast agent and the subsequent pneumonia and unintentional weight loss were analyzed. A total of 30 participants were included in the analysis. We recorded 11 cases of subsequent pneumonia and 13 of unintentional weight loss. Regarding the risk of subsequent pneumonia after VFSS, only the oral transit time and number of swallows tested with barium sulfate indicated significant differences between participants with and without subsequent pneumonia. For unintentional weight loss, oral transit time and pharyngeal wall coating after swallowing tested with barium sulfate, as well as oral transit time, nasal penetration, residue in the valleculae, PAS scores, and number of swallows when testing with iohexol demonstrated significant differences between those with and without unintentional weight loss., (© 2023. The Author(s).)

The clinical effects of tacrolimus (TAC) exposure on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) remain unclear. In this retrospective single centric study, 512 patients who underwent LT for HCC were divided into four groups according to cumulative exposure to tacrolimus (CET) during 3 months after LT: conventional (n = 218), aggressive minimization (n = 32), minimization (n = 161), and high exposure (n = 101). Impact of CET on HCC recurrence and death were analyzed. Compared with the conventional group, the other three CET groups showed a similar risk of HCC recurrence. The aggressive minimization group showed a higher risk [hazard ratio (HR) 5.64, P < 0.001] and the high exposure group showed a marginal risk (HR 1.67, P = 0.081) of overall death compared to the conventional group. CET during 3 months was not associated with HCC recurrence in the matched cohort and various subgroups. TAC minimization is not effective to prevent HCC recurrence but could result in higher mortality in LT recipients., (© 2023. The Author(s).)

Ticagrelor-based dual antiplatelet therapy (DAPT) provides potent antiplatelet inhibition but may increase the bleeding risk in Asian populations. We investigated the influence of early ticagrelor dose reduction (120 mg) on clinical outcomes in Korean patients undergoing percutaneous coronary intervention (PCI). A multicenter prospective clinical cohort study was conducted with patients who received standard-dose ticagrelor-based DAPT (180 mg) after PCI for complex lesions. Major adverse cardiovascular event (MACE: a composite of cardiovascular death, myocardial infarction, stroke, and repeat revascularization), bleeding, and net adverse clinical events (NACE: a composite of MACE and bleeding) were assessed. Among the 772 patients on standard-dose ticagrelor-based DAPT, 115 (14.8%) switched to low-dose ticagrelor-based DAPT (120 mg) within 6 months. Common reasons for the regimen changes were switching as planned (38.8%), dyspnea (25.5%), and bleeding (23.6%). A multivariable Cox proportional hazard model (CPH) showed that the risks of MACE, bleeding, and NACE were not different between the low-dose and standard-dose groups throughout the entire follow-up period and the period beyond 6 months post-PCI. Time-varying multivariable CPH models of the ticagrelor dose reduction yielded similar results. A reduction of the ticagrelor dose within 6 months after PCI is feasible and safe even in patients with complex lesions harboring a high ischemic event risk., (© 2023. Springer Nature Limited.)

The aim of this study was to evaluate the association between obstructive sleep apnea and morning headache and to assess the improvement of morning headache following positive airway pressure therapy. One hundred and sixteen participants were enrolled in this study; all of them received positive airway pressure therapy for at least 3 months. We checked the differences in various sleep apnea-related parameters according to the presence of morning headache and evaluated the improvement of morning headache following positive airway pressure therapy. Among the 116 study participants, 103 were men, with a mean age and body mass index of 50.34 ± 10.23 years and 28.00 ± 4.21 kg/m 2 , respectively. The severity of morning headache was higher in the severe obstructive sleep apnea group than in the mild to moderate group (2.16 ± 1.70 vs. 1.50 ± 1.57, P = 0.027). However, the various polysomnographic parameters did not significantly differ according to the presence of headache. The Epworth sleepiness scale score was significantly higher in the morning headache presence group than in the absence group (10.90 ± 5.45 vs. 8.13 ± 4.27, P = 0.003). Furthermore, a notable correlation was observed between the reduction in daytime sleepiness and the improvement in morning headache following PAP treatment (r = 0.503, P < 0.001). Morning headache significantly improved following positive airway pressure therapy (prevalence: 53.4-16.4%; severity: 1.92 ± 1.67 vs. 0.86 ± 0.80, all P < 0.001), especially in the patients with morning headache before positive airway pressure therapy. Morning headache is significantly associated with daytime sleepiness and positive airway pressure therapy improves morning headache., (© 2023. Springer Nature Limited.)

Anti-thymocyte globulin (ATG) is currently the most widely prescribed induction regimen for preventing acute rejection after solid organ transplantation. However, the optimal dose of ATG induction regimen in Asian kidney recipients is unclear. Using the Korean Organ Transplantation Registry, we performed a retrospective cohort study of 4579 adult patients who received renal transplantation in South Korea and divided them into three groups according to the induction regimen: basiliximab group (n = 3655), low-dose ATG group (≤ 4.5 mg/kg; n = 467), and high-dose ATG group (> 4.5 mg/kg; n = 457). We applied the Toolkit for Weighting and Analysis of Nonequivalent Groups (TWANG) package to generate high-quality propensity score weights for intergroup comparisons. During four-year follow-ups, the high-dose ATG group had the highest biopsy-proven acute rejection rate (basiliximab 20.8% vs. low-dose ATG 22.4% vs. high-dose ATG 25.6%; P < 0.001). However, the rates of overall graft failure (4.0% vs. 5.0% vs. 2.6%; P < 0.001) and mortality (1.7% vs. 2.8% vs. 1.0%; P < 0.001) were the lowest in the high-dose ATG group. Our results show that high-dose ATG induction (> 4.5 mg/kg) was superior to basiliximab and low-dose ATG induction in terms of graft and patient survival in Asian patients undergoing kidney transplant., (© 2023. The Author(s).)

A simple sidewall patterning process for organic-inorganic multilayer thin-film encapsulation (TFE) has been proposed and demonstrated. An Al 2 O 3 thin film grown by atomic layer deposition (ALD) was patterned by adhesion lithography using the difference in interfacial adhesion strength. The difference in interfacial adhesion strength was provided by the vapor-deposited fluoro-octyl-trichloro-silane self-assembled monolayer (SAM) patterns formed by a shadow mask. The sidewall patterning of multilayer TFE was shown possible by repeating the adhesion lithography and the vapor deposition of organic polymer and SAM patterns using shadow masks. The proposed process has the advantage of being able to pattern the blanket ALD-grown Al 2 O 3 thin films by adhesion lithography using a SAM pattern that can be more accurately predefined with a shadow mask., (© 2023. The Author(s).)

Neurodegenerative diseases are explained by progressive defects of cognitive function and memory. These defects of cognition and memory dysfunction can be induced by the loss of brain-derived neurotrophic factors (BDNF) signaling. Paeonia lactiflora is a traditionally used medicinal herb in Asian countries and some beneficial effects have been reported, including anti-oxidative, anti-inflammatory, anti-cancer activity, and potential neuroprotective effects recently. In this study, we found that suffruticosol A is a major compound in seeds of Paeonia lactiflora. When treated in a SH-SY5 cell line for measuring cell viability and cell survival, suffruticosol A increased cell viability (at 20 µM) and recovered scopolamine-induced neurodegenerative characteristics in the cells. To further confirm its neural amelioration effects in the animals, suffruticosol A (4 or 15 ng, twice a week) was administered into the third ventricle beside the brain of C57BL/6 mice for one month then the scopolamine was intraperitoneally injected into these mice to induce impairments of cognition and memory before conducting behavioral experiments. Central administration of suffruticosol A into the brain restored the memory and cognition behaviors in mice that received the scopolamine. Consistently, the central treatments of suffruticosol A showed rescued cholinergic deficits and BDNF signaling in the hippocampus of mice. Finally, we measured the long-term potentiation (LTP) in the hippocampal CA3-CA1 synapse to figure out the restoration of the synaptic mechanism of learning and memory. Bath application of suffruticosol A (40 µM) improved LTP impairment induced by scopolamine in hippocampal slices. In conclusion, the central administration of suffruticosol A ameliorated neuronal effects partly through elevated BDNF signaling., (© 2023. The Author(s).)

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients., (© 2023. The Author(s).)

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD., (© 2023. The Author(s).)

Surgical outcomes of degenerative cervical spinal disease are dependent on the selection of surgical techniques. Although a standardized decision cannot be made in an actual clinical setting, continued education is provided to standardize the medical practice among surgeons. Therefore, it is necessary to supervise and regularly update overall surgical outcomes. This study aimed to compare the rate of additional surgery between anterior and posterior surgeries for degenerative cervical spinal disease using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) nationwide patient database. The NHIS-NSC is a population-based cohort with about a million participants. This retrospective cohort study included 741 adult patients (> 18 years) who underwent their first cervical spinal surgery for degenerative cervical spinal disease. The median follow-up period was 7.3 years. An event was defined as the registration of any type of cervical spinal surgery during the follow-up period. Event-free survival analysis was used for outcome analysis, and the following factors were used as covariates for adjustment: location of disease, sex, age, type of insurance, disability, type of hospital, Charles comorbidity Index, and osteoporosis. Anterior cervical surgery was selected for 75.0% of the patients, and posterior cervical surgery for the remaining 25.0%. Cervical radiculopathy due to foraminal stenosis, hard disc, or soft disc was the primary diagnosis in 78.0% of the patients, and central spinal stenosis was the primary diagnosis in 22.0% of them. Additional surgery was performed for 5.0% of the patients after anterior cervical surgery and 6.5% of the patients after posterior cervical surgery (adjusted subhazard ratio, 0.83; 95% confidence interval, 0.40-1.74). The rates of additional surgery were not different between anterior and posterior cervical surgeries. The results would be helpful in evaluating current practice as a whole and adjusting the health insurance policy., (© 2023. The Author(s).)

Malate dehydrogenase (MDH) plays an important role in the conversion of malate to oxaloacetate during the tricarboxylic acid cycle. In this study, we examined the role of cytoplasmic MDH (MDH1) in hydrogen peroxide (H 2 O 2 )-induced oxidative stress in HT22 cells and ischemia-induced neuronal damage in the gerbil hippocampus. The Tat-MDH1 fusion protein was constructed to enable the delivery of MDH1 into the intracellular space and penetration of the blood-brain barrier. Tat-MDH1, but not MDH1 control protein, showed significant cellular delivery in HT22 cells in a concentration- and time-dependent manner and gradual intracellular degradation in HT22 cells. Treatment with 4 μM Tat-MDH1 significantly ameliorated 200 μM H 2 O 2 -induced cell death, DNA fragmentation, and reactive oxygen species formation in HT22 cells. Transient increases in MDH1 immunoreactivity were detected in the hippocampal CA1 region 6-12 h after ischemia, but MDH1 activity significantly decreased 2 days after ischemia. Supplementation of Tat-MDH1 immediately after ischemia alleviated ischemia-induced hyperlocomotion and neuronal damage 1 and 4 days after ischemia. In addition, treatment with Tat-MDH1 significantly ameliorated the increases in hydroperoxides, lipid peroxidation, and reactive oxygen species 2 days after ischemia. Tat-MDH1 treatment maintained the redox status of the glutathione system in the hippocampus 2 days after ischemia. These results suggest that Tat-MDH1 exerts neuroprotective effects by reducing oxidative stress and maintaining glutathione redox system in the hippocampus., (© 2023. The Author(s).)

Pilot balloon palpation is still a commonly used method to evaluate cuff pressure of the endotracheal tube after intubation. This study determined whether the size of the tracheal tube influenced the accuracy of pilot balloon palpation. A prospective observational analysis of 208 patients intubated with an endotracheal tube of internal diameter (ID) 6.0 or 8.0 was conducted. An anesthesiologist judged the cuff pressure by manual pilot balloon palpation, and then measured the cuff pressure with a pressure gauge. Cuff pressure exceeding 20-30 cmH 2 O was defined as false recognition. The intracuff pressure was significantly higher in ID 6.0 tube than in the ID 8.0 tube (41.9 ± 18.8 cmH 2 O vs. 30.3 ± 11.9 cmH 2 O, p < 0.001). The number of patients that were mistakenly perceived to have appropriate cuff pressure by pilot balloon palpation was significantly higher in the ID 6.0 group compared to the ID 8.0 group (85 (81.7%) vs. 64 (61.5%), p = 0.001). Therefore, a smaller tube size may further increase risk of inaccurate measurement by pilot balloon palpation and although pressure gauge is recommended for all sizes to maximize accuracy, groups with increased risk factors should be targeted for standardized use of the pressure gauge., (© 2023. The Author(s).)

This study assessed the trends in methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine-cisplatin (GC) regimens in Korean patients with metastatic urothelial carcinoma (UC) and compared the side effects and overall survival (OS) rates of the two regimens using nationwide population-based data. The data of patients diagnosed with UC between 2004 and 2016 were collected using the National Health Insurance Service database. The overall treatment trends were assessed according to the chemotherapy regimens. The MVAC and GC groups were matched by propensity scores. Cox proportional hazard analysis and Kaplan-Meier analysis were performed to assess survival. Of 3108 patients with UC, 2,880 patients were treated with GC and 228 (7.3%) were treated with MVAC. The transfusion rate and volume were similar in both the groups, but the granulocyte colony-stimulating factor (G-CSF) usage rate and number were higher in the MVAC group than in the GC group. Both groups had similar OS. Multivariate analysis revealed that the chemotherapy regimen was not a significant factor for OS. Subgroup analysis revealed that a period of ≥ 3 months from diagnosis to systemic therapy enhanced the prognostic effects of the GC regimen. The GC regimen was widely used as the first-line chemotherapy in more than 90% of our study population with metastatic UC. The MVAC regimen showed similar OS to the GC regimen but needed greater use of G-CSF. The GC regimen could be a suitable treatment option for metastatic UC after ≥ 3 months from diagnosis., (© 2023. The Author(s).)

We attempted to assess the performance of an ethnic-specific polygenic risk score (PRS) designed from a Korean population to predict aggressive prostate cancer (PCa) and early-onset (age < 60). A PRS score comprised of 22 SNPs was computed in 3695 patients gathered from one of 4 tertiary centers in Korea. Males with biopsy or radical prostatectomy-proven PCa were included for analysis, collecting additional clinical parameters such as age, BMI, PSA, Gleason Group (GG), and staging. Patients were divided into 4 groups of PRS quartiles. Intergroup differences were assessed, as well as risk ratio and predictive performance based on GG using logistic regression analysis and AUC. No significant intergroup differences were observed for BMI, PSA, and rate of ≥ T3a tumors on pathology. Rate of GG ≥ 2, GG ≥ 3, and GG ≥ 4 showed a significant pattern of increase by PRS quartile (p < 0.001, < 0.001, and 0.039, respectively). With the lowest PRS quartile as reference, higher PRS groups showed sequentially escalating risk for GG ≥ 2 and GG ≥ 3 pathology, with a 4.6-fold rise in GG ≥ 2 (p < 0.001) and 2.0-fold rise in GG ≥ 3 (p < 0.001) for the highest PRS quartiles. Combining PRS with PSA improved prediction of early onset csPCa (AUC 0.759) compared to PRS (AUC 0.627) and PSA alone (AUC 0.736). To conclude, an ethnic-specific PRS was found to predict susceptibility of aggressive PCa in addition to improving detection of csPCa when combined with PSA in early onset populations. PRS may have a role as a risk-stratification model in actual practice. Large scale, multi-ethnic trials are required to validate our results., (© 2023. The Author(s).)

Epidermal growth factor receptor (EGFR) is an effective target for those patients with metastatic colorectal cancers that retain the wild-type RAS gene. However, its efficacy in many cancers, including bladder cancer, is unclear. Here, we studied the in vitro effects of cetuximab monoclonal antibodies (mAbs) targeting EGFR on the bladder cancer cells and role of CD46. Cetuximab was found to inhibit the growth of both colon and bladder cancer cell lines. Furthermore, cetuximab treatment inhibited AKT and ERK phosphorylation in the bladder cancer cells and reduced the expression of CD46 membrane-bound proteins. Restoration of CD46 expression protected the bladder cancer cells from cetuximab-mediated inhibition of AKT and ERK phosphorylation. We hypothesized that CD46 provides protection to the bladder cancer cells against mAb therapies. Bladder cancer cells were also susceptible to cetuximab-mediated immunologic anti-tumor effects. Further, cetuximab enhanced the cell killing by activating both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in bladder cancer cells. Restoration of CD46 expression protected the cells from both CDC and ADCC induced by cetuximab. Together, CD46 exhibited a cancer-protective effect against both direct (by involvement of PBMC or complement) and indirect cytotoxic activity by cetuximab in bladder cancer cells. Considering its clinical importance, CD46 could be an important link in the action mechanism of ADCC and CDC intercommunication and may be used for the development of novel therapeutic strategies., (© 2022. The Author(s).)

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged < 12 years at the Severance Hospital between January 2010 and September 2020 were included as data samples. Preoperative conditions of recipients and donors, intraoperative care, postoperative serial laboratory parameters, and events observed within seven days of surgery were collected as features. A least absolute shrinkage and selection operator (LASSO) -based method was used for feature selection to overcome the high dimensionality and collinearity of variables. Among 146 features, four variables were selected as the resultant features, namely, preoperative hepatic encephalopathy, sodium level at the end of surgery, hepatic artery thrombosis, and total bilirubin level on postoperative day 7. These features were selected from different times and represent distinct clinical aspects. The model with logistic regression demonstrated the best prediction performance among various machine learning methods tested (area under the receiver operating characteristic curve (AUROC) = 0.898 and area under the precision-recall curve (AUPR) = 0.882). The risk scoring system developed based on the logistic regression model showed an AUROC of 0.910 and an AUPR of 0.830. Together, the prediction of graft failure in pediatric liver transplantation using the proposed machine learning model exhibited superior discrimination power and, therefore, can provide valuable information to clinicians for their decision making during the postoperative management of the patients., (© 2022. The Author(s).)

Worldwide, catastrophic landslides are occurring as a result of abnormal climatic conditions. Since a landslide is caused by a combination of the triggers of rainfall and the vulnerability of spatial information, a study that can suggest a method to analyze the complex relationship between the two factors is required. In this study, the relationship between complex factors (rainfall period, accumulated rainfall, and spatial information characteristics) was designed as a system dynamics model as variables to check the possibility of occurrence of vulnerable areas according to the rainfall characteristics that change in real-time. In contrast to the current way of predicting the collapse time by analysing rainfall data, the developed model can set the precipitation period during rainfall. By setting the induced rainfall period, the researcher can then assess the susceptibility of the landslide-vulnerable area. Further, because the geospatial information features and rainfall data for the 672 h before the landslide's occurrence were combined, the results of the susceptibility analysis could be determined for each topographical characteristic according to the rainfall period and cumulative rainfall change. Third, by adjusting the General cumulative rainfall period (D G ) and Inter-event time definition (IETD), the preceding rainfall period can be adjusted, and desired results can be obtained. An analysis method that can solve complex relationships can contribute to the prediction of landslide warning times and expected occurrence locations., (© 2022. The Author(s).)

The waiting time for deceased donor kidney transplants (DDKT) is increasing. We evaluated DDKT prognosis according to the pretransplant dialysis vintage. A total of 4117 first-time kidney transplant recipients were enrolled from a prospective nationwide cohort in Korea. DDKT recipients were divided into tertiles according to pretransplant dialysis duration. Graft failure, mortality, and composite were compared between DDKT and living donor kidney transplant (LDKT) recipients. Pretransplant dialysis vintage was longer annually in DDKT recipients. In the subdistribution of the hazard model for the competing risk, the first tertile did not show an increased risk of graft failure compared with LDKT recipients; however, the second and third tertile groups had an increased risk of graft failure compared to LDKT recipients (adjusted hazard ratio [aHR] 3.59; 95% confidence interval [CI] 1.69-7.63; P < 0.001; aHR 2.37; 95% CI 1.06-5.33; P = 0.037). All DDKT groups showed a significantly higher risk of patient death than LDKT, with the highest risk in the third tertile group (aHR 11.12; 95% CI 4.94-25.00; P < 0.001). A longer pretransplant dialysis period was associated with a higher risk of the composite of patient death and graft failure in DDKT recipients. DDKT after a short period of dialysis had non-inferior results on graft survival compared with LDKT., (© 2022. The Author(s).)

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084-4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272-3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC., (© 2022. The Author(s).)

We aimed to determine whether vitamin D levels before prostate biopsy have diagnostic value for clinically significant prostate cancer. The study cohort included patients who underwent prostate biopsy. A total of 224 patients were enrolled in our study and serum vitamin D levels were measured from February 2016 to December 2019 in routine laboratory tests. To determine the relationship between vitamin D levels and aggressiveness of prostate cancer, we used logistic multivariate analysis. Based on the histopathological results of patients who underwent radical prostatectomy, the serum vitamin D level was significantly lower with the large tumor volume group. In the univariate analysis, the prostate cancer diagnosis rate was associated with low vitamin D levels. Low vitamin D level is negatively correlated with clinically significant prostate cancer (biopsy Gleason score of 7 or higher) in the univariate (Odds ratio [OR], 0.955; P < 0.001) and multivariate (OR, 0.944; P = 0.027) analyses. In conclusion, we found that the incidence of clinically significant prostate cancer might related to low vitamin D level in the Asian population. In the future, a larger population and prospective study are needed., (© 2022. The Author(s).)

The contaminated healthcare environment plays an important role in the spread of multidrug-resistant organisms (MDROs) and Clostridioides difficile. This study aimed to evaluate the antimicrobial effects of ozone generated by a dielectric barrier discharge (DBD) plasma reactor on various materials that were contaminated by vancomycin-resistant Enterococcus faecium (VRE), carbapenem-resistant Klebsiella pneumoniae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Acinetobacter baumannii (CRAB) and C. difficile spores. Various materials contaminated by VRE, CRE, CRPA, CRAB and C. difficile spores were treated with different ozone concentrations and exposure times. Atomic force microscopy (AFM) demonstrated bacterial surface modifications following ozone treatment. When an ozone dosage of 500 ppm for 15 min was applied to VRE and CRAB, about 2 or more log 10 reduction was observed in stainless steel, fabric and wood, and a 1-2 log 10 reduction in glass and plastic. Spores of C. difficile were more resistant to ozone than were all other tested organisms. On AFM, the bacterial cells, following ozone treatment, were swollen and distorted. The ozone generated by the DBD plasma reactor provided a simple and valuable decontamination tool for the MDROs and C. difficile spores, which are known as common pathogens in healthcare-associated infections., (© 2022. The Author(s).)

Oxygen supplementation is crucial for awake tracheal intubation (ATI) using a flexible bronchoscope in patients with an anticipated difficult airway. However, the modality of optimal oxygen delivery remains unclear. This retrospective study compared high-flow nasal oxygen (HFNO) and conventional low-flow oxygen supply during ATI. We applied inverse probability of treatment weighting (IPTW) to account for biases due to clinical characteristic differences between the groups. The primary endpoint was the lowest oxygen saturation during ATI. The secondary endpoints were incidence of desaturation, multiple attempts, failure rate, and procedural duration. After IPTW adjustment, the lowest oxygen saturation in the HFNO group during ATI was significantly higher than that in the conventional oxygenation group (99.3 ± 0.2 vs. 97.5 ± 0.5, P < 0.001). Moreover, the HFNO group had fewer cases with multiple attempts than the conventional oxygenation group (3% vs. 16%, P = 0.007). There were no significant differences between the two groups in the incidence of desaturation, failure and procedural duration. Our findings suggest that HFNO was associated with improved lowest oxygen saturation and a lower rate of multiple attempts during ATI. Therefore, we recommend using HFNO for safer oxygen delivery and improved quality of procedure during ATI., (© 2022. The Author(s).)

Quantum state tomography is the experimental procedure of determining an unknown state. It is not only essential for the verification of resources and processors of quantum information but is also important in its own right with regard to the foundation of quantum mechanics. Standard methods have been elusive for large systems because of the enormous number of observables to be measured and the exponential complexity of data post-processing. Here, we propose a new scheme of quantum state tomography that requires the measurement of only three observables (acting jointly on the system and pointer) regardless of the size of the system. The system is coupled to a "pointer" of single qubit, and the wavefunction of the system is "reaped" onto the pointer upon the measurement of the system. Subsequently, standard two-state tomography on the pointer and classical post-processing are used to reconstruct the quantum state of the system. We also developed an efficient and scalable iterative maximum likelihood algorithm to estimate states from statistically incomplete data., (© 2022. The Author(s).)

Late Pneumocystis jirovecii pneumonia (PJP) is not rare in the era of universal prophylaxis after kidney transplantation. We aimed to determine the nationwide status of PJP prophylaxis in Korea and compare the incidence, risk factors, and outcomes of early and late PJP using data from the Korean Organ Transplantation Registry (KOTRY), a nationwide Korean transplant cohort. We conducted a retrospective analysis using data of 4,839 kidney transplant patients from KOTRY between 2014 and 2018, excluding patients who received multi-organ transplantation or were under 18 years old. Cox regression analysis was performed to determine risk factors for early and late PJP. A total of 50 patients developed PJP. The number of patients who developed PJP was same between onset before 6 months and onsets after 6 months. There were no differences in the rate, duration, or dose of PJP prophylaxis between early and late PJP. Desensitization, higher tacrolimus dose at discharge, and acute rejection were associated with early PJP. In late PJP, old age as well as acute rejection were significant risk factors. In conclusion late PJP is as common and risky as early PJP and requires individualized risk-based prophylaxis, such as prolonged prophylaxis for old patients with a history of rejection., (© 2022. The Author(s).)

Clustering stroke patients with similar characteristics to predict subsequent vascular outcome events is critical. This study aimed to compare several clustering methods, particularly a deep neural network-based model, and identify the best clustering method with a maximally distinct 1-year outcome in patients with ischemic stroke. Prospective stroke registry data from a comprehensive stroke center from January 2011 to July 2018 were retrospectively analyzed. Patients with acute ischemic stroke within 7 days of onset were included. The primary outcomes were the composite of all strokes (either hemorrhagic or ischemic), myocardial infarction, and all-cause mortality within one year. Neural network-based clustering models (deep lifetime clustering) were compared with other clustering models (k-prototype and semi-supervised clustering, SSC) and a conventional risk score (Stroke Prognostic Instrument-II, SPI-II) to obtain a distinct distribution of 1-year vascular events. Ultimately, 7,650 patients were included, and the 1-year primary outcome event occurred in 13.1%. The DLC-Kuiper UB model had a significantly higher C-index (0.674), log-rank score (153.1), and Brier score (0.08) than the other cluster models (SSC and DLC-MMD) and the SPI-II score. There were significant differences in primary outcome events among the 3 clusters (41.7%, 13.4%, and 6.5% in clusters 0, 1, and 2, respectively) when the DLC-Kuiper UB model was used. A neural network-based clustering model, the DLC-Kuiper UB model, can improve the clustering of stroke patients with a maximally distinct distribution of 1-year vascular outcomes among each cluster. Further studies are warranted to validate this deep neural network-based clustering model in ischemic stroke., (© 2022. The Author(s).)

Data for Asian kidney transplants are very limited. We investigated the relative importance of prognostic markers in Asian kidney transplants by using Korean Organ Transplantation Registry (KOTRY) cohort. Prediction models were developed by data-driven variable selection approach. The relative importance of the selected predictors was measured by dominance analysis. A total of 4854 kidney transplant donor-recipient pairs were analyzed. Overall patient survival rates were 99.8%, 98.8%, and 91.8% at 1, 3, and 5 years, respectively. Death-censored graft survival rates were 98.4%, 97.0%, and 95.8% at 1, 3, and 5 years. Biopsy-proven acute rejection free survival rates were 90.1%, 87.4%, and 87.03% at 1, 3, and 5 years. The top 3 dominant predictors for recipient mortality within 1 year were recipient cardiovascular disease history, deceased donor, and recipient age. The dominant predictors for death-censored graft loss within 1 year were acute rejection, deceased donor, and desensitization. The dominant predictors to acute rejection within 1 year were donor age, HLA mismatched numbers, and desensitization. We presented clinical characteristics of patients enrolled in KOTRY during the last 5 years and investigated dominant predictors for early post-transplant outcomes, which would be useful for clinical decision-making based on quantitative measures., (© 2022. The Author(s).)

Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers., (© 2022. The Author(s).)

We aimed to assess the relationship between lifestyle-related variables, metabolic syndrome, and lower urinary tract symptoms (LUTS) in men ≥ 40 years. We also assessed the impact of these variables on quality of life. From 2014 to 2020, 5355 men who underwent health check-ups with I-PSS questionnaires at our institute were included in the analysis. The impact of LUTS on sleep disorders and moderate to severe degrees of stress were assessed. Multivariate analysis was performed to determine the variables associated with LUTS and prostate volume. Moderate and severe LUTS were present in 1317 (24.6%) and 211 (3.9%) men, respectively. Moderate and severe LUTS were significantly associated with the presence of sleep disorders and stress. On multivariable analysis, age, amount of life-long smoking, marital status, income, job, and decreased HDL-cholesterol were associated with the presence of moderate to severe LUTS. Although older age and the amount of life-long smoking was associated with both voiding and storage sub-score, socioeconomic status, including marital status and income were only associated with storage sub-score. In men ≥ 40 years, stable socioeconomic status, in addition to older age, and life-long smoking amount are associated with the presence of moderate to severe LUTS, which worsens sleep quality and stress level, by worsen storage sub-score., (© 2022. The Author(s).)

To investigate the significance of detrusor muscle thickness (DMT) to bladder wall thickness (BWT) ratio as a detrusor-sarcopenia and a consistently applicable factor for noninvasive diagnosis of detrusor underactivity (DU). We prospectively performed a urodynamic study of 100 male with medical refractory lower-urinary-tract-symptoms during 2017-2019. The DMT, BWT and DMT/BWT ratio were measured by ultrasonography every 50 mL during bladder filling, and were analyzed for non-invasive diagnosis of DU and prediction of prostate surgery outcome with questionnaire and the maximum-flow-rate. Of the 94 patients, DU was urodynamically diagnosed in 24 (25.5%). The DMT/BWT ratio was maintained in all patients until the 50% of the maximum cystometric capacity (MCC), and then rapidly decreased. At 20% of the MCC, the DMT/BWT ratio was significantly lower in the DU group (44.0 ± 4.9% vs. 49.4 ± 6.7%, p = 0.008). The DMT/BWT ratio of less than 47.5% at 20% of the MCC showed the ideal accuracy for diagnosing DU (AUC = 0.763), and was a predictor of failure at 12 months after prostate surgery (OR 8.78, p = 0.024). A DMT/BWT ratio of less than 47.5% at 20% of the MCC is a consistently applicable factor for non-invasive diagnosis of DU and could also be considered detrusor-sarcopenia., (© 2022. The Author(s).)

Bacterial vaginosis (BV) is the most common vaginal infection in reproductive women, which is characterized by depleted level of lactic acid bacteria and overgrowth of anaerobes such as Gardnerella vaginalis spp. Lactic acid bacteria have been known to be beneficial for amelioration of BV, since they produce antimicrobial substances against G. vaginalis spp. The objectives of this study were to characterize different fractions of cell-free supernatant of Lactobacillus paracasei CH88 (LCFS) and investigate antibacterial activity of the LCFS fractions against G. vaginalis in-vitro and in-vivo. Antibacterial activity of the LCFS was stable during thermal treatment up to 120 °C for 30 min and maintained at pH ranging from 3.0 to 13.0 except pH 5.0. Fraction below 3 kDa of the LCFS partially lost its antibacterial activity after treatment with proteolytic enzymes. Precipitated protein fraction below 3 kDa of the LCFS (< 3 kDa LCFSP) inhibited the growth and biofilm formation of G. vaginalis. Treatment of L. paracasei CH88 or the < 3 kDa LCFSP attenuated G. vaginalis-induced BV in mice by inhibiting the growth of G. vaginalis, reducing exfoliation of vaginal epithelial cells, and regulating immune response. These results suggest that L. paracasei CH88 may have potential in ameliorating G. vaginalis-induced BV., (© 2022. The Author(s).)

To compare the postoperative estimated-glomerular-filtration-rate (eGFR) and parenchymal changes between cold ischemia and zero/selective ischemia for a T1a mass. We analyzed 104 patients who underwent open partial nephrectomy with cold ischemia (53) or zero/selective ischemia (51) for T1a between 2008 and 2018 to determine postoperative renal function changes and associated factors. Postoperative renal function was expressed as (postoperative-eGFR - preoperative-eGFR)/preoperative-eGFR × 100%. Parenchymal enhancement and thicknesses of the ipsilateral kidney as tissue changes were measured on postoperative CT to identify the correlation with the renal function change. Patients with 10% or 25% decrease in eGFR were significantly more in the cold ischemia group (p = 0.032, p = 0.006). On multivariable analysis, preoperative eGFR, ischemic type, and percent change of parenchymal thickness were identified to be significantly associated with postoperative 12 months renal function (B = - 0.367, p = 0.020; B = 6.788, p = 0.042; B = 0.797, p = 0.029). Change in parenchymal thickness was negatively correlated with changes in postoperative renal function (r = - 0.277, p = 0.012). Changes in eGFR were associated with a decrease in parenchymal thickness and the type of ischemic technique. Zero/selective ischemia during partial nephrectomy may have an advantage in preserving postoperative renal function compared to cold ischemia., (© 2022. The Author(s).)

We evaluated the surgical margin status after radical prostatectomy according to sites positive for prostate cancer on standard 12-core transrectal ultrasound-guided prostate biopsy. Among patients who underwent radical prostatectomy at Boramae Medical Center, 520 patients with preoperative prostate-specific antigen (PSA) level < 20 ng/mL and locally confined prostate cancer on preoperative magnetic resonance imaging, treated with nerve-sparing radical prostatectomy, were included in the analysis. The surgical margin was positive for cancer in 166 (31.9% of the total) patients. The preoperative PSA level (9.3 vs. 8.0, ng/mL p = 0.001) and number of positive cores on 12-core prostate biopsy (4.1 vs. 3.4, p = 0.003) were significantly higher in patients with positive surgical margins. Moreover, the biopsy Gleason grade was higher in patients with positive surgical margins (p = 0.001). However, the pathologic Gleason grade and tumor volume were equivalent between the 2 groups. On multivariate analysis, the detection of prostate cancer on anterior lateral biopsy was associated with an increased rate of positive surgical margins (hazard ratio [HR]: 1.781, p = 0.008) after adjusting for other variables. Anterior lateral (HR: 1.919, p = 0.020), basal lateral (HR: 9.176, p < 0.001), basal medial (HR: 3.302, p = 0.031), and mid lateral (HR: 2.501, p = 0.044) biopsies were associated with positive apical, posterior, basal, and lateral surgical margins, respectively, after adjusting for other variables. The sites of prostate cancer on standard 12-core prostate biopsy could be useful for predicting surgical margin positivity after radical prostatectomy. In other words, clinicians should consider the sites of prostate cancer on prostate biopsy to reduce margin positivity after radical prostatectomy., (© 2022. The Author(s).)

The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer's disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEX TM Alz plus assay kit for the prescreening of Aβ accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aβ accumulation. We included a total of 221 CN participants with or without brain Aβ. The QPLEX TM biomarkers were characterized based on age groups (1 st -3 rd tertile) and across various brain regions with cerebral amyloid deposition. The 3 rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3 rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aβ1-42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEX TM Alz plus assay is useful for prescreening brain Aβ levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation., (© 2022. The Author(s).)

We sought to evaluate the clinical implication of LAE based on left atrial anterior-posterior (LA AP) dimension or LA volume index (LAVI) in Korean patients with atrial fibrillation (AF). We enrolled 8159 AF patients from the CODE-AF registry. The primary outcome was rate of stroke or systemic embolism (SSE). The prevalence of mild, moderate, and severe LAE by LA AP dimension was 30.6%, 18.5%, and 21.4%, and by LAVI (available in 5808 patients) was 15.7%, 12.5% and 37.8%, respectively. Compared with no or mild LAE, patients with significant LAE (moderate to severe LAE, n = 3258, 39.9%) were associated with a higher rate of SSE (2.5% vs. 1.4%, P = 0.001). Multivariable analysis suggested presence of significant LAE by LA AP dimension was associated with a higher risk of SSE in the overall population (HR 1.57, 95% CI: 1.14-2.17, P = 0.005) and in patients using anticoagulants (n = 5836, HR 1.79, 95% CI: 1.23-2.63, P = 0.002). Patients with significant LAE by LAVI were also at higher risk of SSE (HR 1.58, 95% CI: 1.09-2.29, P = 0.017). In conclusion, significant LAE by LA dimension or LAVI was present in 39.9% and 50.2% of AF patients, respectively, and was associated with a higher rate of SSE., (© 2021. The Author(s).)

Parkinson's disease (PD) is a movement disorder caused by progressive degeneration of the midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNc). Despite intense research efforts over the past decades, the etiology of PD remains largely unknown. Here, we discovered the involvement of trophoblast glycoprotein (Tpbg) in the development of PD-like phenotypes in mice. Tpbg expression was detected in the ventral midbrain during embryonic development and in mDA neurons in adulthood. Genetic ablation of Tpbg resulted in mild degeneration of mDA neurons in aged mice (12-14 months) with behavioral deficits reminiscent of PD symptoms. Through in silico analysis, we predicted potential TPBG-interacting partners whose functions were relevant to PD pathogenesis; this result was substantiated by transcriptomic analysis of the SNc of aged Tpbg knockout mice. These findings suggest that Tpbg is a new candidate gene associated with PD and provide a new insight into PD pathogenesis., (© 2021. The Author(s).)

An understanding of the anatomy of the Denonvilliers' fascia is essential for successful surgical outcomes for patients with rectal cancer in the mid- to lower regions, especially near the seminal vesicles and prostate in males. Whether the correct surgical plane during a total mesorectal excision should be anterior or posterior to the Denonvilliers' fascia is currently under debate. This study aimed to investigate the Denonvilliers' fascia using micro-computed tomography (micro-CT) to acquire three-dimensional images nondestructively for assessments of the relationship between the Denonvilliers' fascia, the mesorectal fascia, and neurovascular bundles to elucidate the correct anterior total mesorectal excision plane. Eight specimens were obtained bilaterally from four fresh human cadavers. Four specimens were stained with phosphotungstic acid to visualize the soft tissue, and micro-CT images were obtained; the other four specimens were stained with Masson's trichrome to visualize connective tissue. Micro-CT images corroborate that the Denonvilliers' fascia consists of a multilayered structure that separates the rectum from the seminal vesicles and the prostate. Specimens stained with Masson's trichrome showed that the urogenital neurovascular bundle located at the posterolateral corner of the prostate is separated from the mesorectum by the Denonvilliers' fascia. For the preservation of autonomic nerves necessary for urogenital function and optimal oncologic outcomes in patients with rectal cancer, a successful mesorectal excision requires a dissection plane posterior to the Denonvilliers' fascia., (© 2021. The Author(s).)

Sargassum serratifolium (C. Agardh) C.Agardh, a marine brown alga, has been consumed as a food and traditional medicine in Asia. A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of S. serratifolium (MES) induced adipose tissue browning and suppressed diet-induced obesity and metabolic syndrome when orally supplemented. Sargahydroquinoic acid (SHQA) is a major component of MES. However, it is unclear whether SHQA regulates energy homeostasis through the central nervous system. To examine this, SHQA was administrated through the third ventricle in the hypothalamus in high-fat diet-fed C57BL/6 mice and investigated its effects on energy homeostasis. Chronic administration of SHQA into the brain reduced body weight without a change in food intake and improved metabolic syndrome-related phenotypes. Cold experiments and biochemical analyses indicated that SHQA elevated thermogenic signaling pathways, as evidenced by an increase in body temperature and UCP1 signaling in white and brown adipose tissues. Peripheral denervation experiments using 6-OHDA indicated that the SHQA-induced anti-obesity effect is mediated by the activation of the sympathetic nervous system, possibly by regulating genes associated with sympathetic outflow and GABA signaling pathways. In conclusion, hypothalamic injection of SHQA elevates peripheral thermogenic signaling and ameliorates diet-induced obesity., (© 2021. The Author(s).)

Smoking cessation aids in restoring lung function. However, whether long-term cessation can fully restore lung function has not been studied thoroughly, especially in Asian countries. This study aimed to evaluate the association between smoking cessation status and obstructive spirometry pattern among Koreans aged 40-79 years. In total, 6298 men and 8088 women aged 40-79 years from the Korea National Health and Nutrition Examination Survey (2015-2019) were analyzed for smoking cessation status, including the duration after quitting. Current-smokers showed a higher likelihood of having an obstructive spirometry pattern than never-smokers among both men (odds ratio [OR]: 3.15, 95% confidence interval [CI]: 2.32-4.29) and women (OR: 2.60, 95% CI: 1.59-4.23). In men, the effect tended to decrease with longer duration after cessation, but male ex-smokers who had quit smoking ≥ 20 years ago still showed a higher likelihood of having an obstructive spirometry pattern than male never-smokers (OR: 1.40, 95% CI: 1.05-1.89). In female ex-smokers, there was no significant association with the obstructive spirometry pattern, compared to that in female never-smokers. This study emphasizes the benefits of smoking cessation, possibility of long-lasting harm to lung function due to tobacco smoking, and importance of smoking prevention., (© 2021. The Author(s).)

The biodiesel containing fatty acid methyl esters (FAMEs) are blended with refined diesel products. Here, we evaluate relative FAME composition ratio as a potential index to discriminate the pollution origin in diesel-contaminated soil. Artificially contaminated soil was prepared to mimic the release of petroleum products using four different refined diesels; in addition, the contaminated soil was put under natural weathering conditions. The variations in the relative FAME composition ratio was compared with those of the corresponding diesel origin using principal component analysis (PCA) for 60 days. All soil samples could be classified into four groups according to diesel origin using two principal components. The proposed method can be used to discriminate the specific diesel pollution origin in contaminated soils., (© 2021. The Author(s).)

Successful cell therapy for Parkinson's disease (PD) requires large numbers of homogeneous ventral mesencephalic dopaminergic (vmDA) precursors. Enrichment of vmDA precursors via cell sorting is required to ensure high safety and efficacy of the cell therapy. Here, using LMX1A-eGFP knock-in reporter human embryonic stem cells, we discovered a novel surface antigen, trophoblast glycoprotein (TPBG), which was preferentially expressed in vmDA precursors. TPBG-targeted cell sorting enriched FOXA2 + LMX1A + vmDA precursors and helped attain efficient behavioral recovery of rodent PD models with increased numbers of TH + , NURR1 + , and PITX3 + vmDA neurons in the grafts. Additionally, fewer proliferating cells were detected in TPBG + cell-derived grafts than in TPBG - cell-derived grafts. Our approach is an efficient way to obtain enriched bona fide vmDA precursors, which could open a new avenue for effective PD treatment., (© 2021. The Author(s).)

High intra-patient variability (IPV) of tacrolimus trough concentrations is increasingly recognized as a predictor of poor long-term outcomes in kidney transplant. However, there is a lack of information regarding the association between tacrolimus IPV and graft outcomes according to immunological risk. We analyzed tacrolimus IPV using the coefficient of variability from months 6-12 after transplantation in 1080 kidney transplant recipients. Patients were divided into two immunological risk groups based on pre-transplant panel reactive antibodies and donor-specific antibodies. High immunological risk was defined as panel reactive antibodies ≥ 20% or the presence of donor-specific antibodies. The effects of tacrolimus IPV on graft outcomes were significantly different between low and high immunological risk patients. A multivariable Cox regression model confirmed that high tacrolimus IPV was an independent risk factor for graft failure in the high risk group (HR, 2.90; 95% CI, 1.42-5.95, P = 0.004). In the high risk group, high tacrolimus IPV was also significantly associated with increased risk of antibody-mediated rejection (P = 0.006). In contrast, death-censored graft survival and antibody-mediated rejection in the low immunological risk group was not significantly different by tacrolimus IPV. High tacrolimus IPV significantly increases the risk of graft failure and antibody-mediated rejection in patients with high immunological risk.

Alzheimer's disease (AD) is the leading cause of dementia, and many studies have focused on finding effective blood biomarkers for the accurate diagnosis of this disease. Predicting cerebral amyloid deposition is considered the key for AD diagnosis because a cerebral amyloid deposition is the hallmark of AD pathogenesis. Previously, blood biomarkers were discovered to predict cerebral amyloid deposition, and further efforts have been made to increase their sensitivity and specificity. In this study, we analyzed blood-test factors (BTFs) that can be commonly measured in medical health check-ups from 149 participants with cognitively normal, 87 patients with mild cognitive impairment, and 64 patients with clinically diagnosed AD dementia with brain amyloid imaging data available. We demonstrated that four factors among regular health check-up blood tests, cortisol, triglyceride/high-density lipoprotein cholesterol ratio, alanine aminotransferase, and free triiodothyronine, showed either a significant difference by or correlation with cerebral amyloid deposition. Furthermore, we made a prediction model for Pittsburgh compound B-positron emission tomography positivity, using BTFs and the previously discovered blood biomarkers, the QPLEX TM Alz plus assay kit biomarker panel, and the area under the curve was significantly increased up to 0.845% with 69.4% sensitivity and 90.6% specificity. These results show that BTFs could be used as co-biomarkers and that a highly advanced prediction model for amyloid plaque deposition could be achieved by the combinational use of diverse biomarkers.