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The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC. [ABSTRACT FROM AUTHOR]

As the size of a model increases, making predictions using deep neural networks (DNNs) is becoming more computationally expensive. Multi-exit neural network is one promising solution that can flexibly make anytime predictions via early exits, depending on the current test-time budget which may vary over time in practice (e.g., self-driving cars with dynamically changing speeds). However, the prediction performance at the earlier exits is generally much lower than the final exit, which becomes a critical issue in low-latency applications having a tight test-time budget. Compared to the previous works where each block is optimized to minimize the losses of all exits simultaneously, in this work, we propose a new method for training multi-exit neural networks by strategically imposing different objectives on individual blocks. The proposed idea based on grouping and overlapping strategies improves the prediction performance at the earlier exits while not degrading the performance of later ones, making our scheme to be more suitable for low-latency applications. Extensive experimental results on both image classification and semantic segmentation confirm the advantage of our approach. The proposed idea does not require any modifications in the model architecture and can be easily combined with existing strategies aiming to improve the performance of multi-exit neural networks.

Background: Torsion of the right middle lobe following right upper lobectomy is a rare but potentially fatal complication. To prevent this, fixation of the right middle lobe has been suggested. This study was performed to examine the impact of right middle lobe fixation on postoperative outcomes and bronchial changes., Methods: We enrolled patients who underwent curative-intent video-assisted thoracic surgery (VATS) right upper lobectomy for lung cancer from 2019 to 2022. Participants were grouped based on whether they did or did not receive right middle lobe fixation. Bronchial angles were measured using preoperative and postoperative chest computed tomography images, and postoperative outcomes and bronchial changes were compared between the 2 groups., Results: The study included a total of 50 patients, with 17 (34%) undergoing right middle lobe fixation. All procedures were performed using VATS. No significant differences between groups were observed in preoperative characteristics or postoperative outcomes. After surgery, both groups exhibited a significant increase in the right bronchus intermedius angle and a significant decrease in the branch angle. The postoperative right bronchus intermedius angle was significantly larger in the group without right middle lobe fixation compared to the group with fixation (47.38°±10.98° vs. 39.41°±9.21°, p=0.014). Three cases of atelectasis occurred in the group that did not undergo fixation while no cases were observed in the fixation group; however, this difference was not statistically significant., Conclusion: Fixation of the right middle lobe reduced postoperative angulation of the right bronchus intermedius, which may help prevent postoperative atelectasis.

Background: Determining the impact of somatic mutations requires understanding the functional relationship of genes acquiring mutations; however, it is largely unknown how mutations in functionally related genes influence each other., Methods: We employed non-synonymous-to-synonymous or dNdS ratios to evaluate the evolutionary dependency (ED) of gene pairs, assuming a mutation in one gene of a gene pair can affect the evolutionary fitness of mutations in its partner genes as mutation context. We employed PanCancer- and tumor type-specific mutational profiles to infer the ED of gene pairs and evaluated their biological relevance with respect to gene dependency and drug sensitivity., Results: We propose that dNdS ratios of gene pairs and their derived cdNS (context-dependent dNdS) scores as measure of ED distinguishing gene pairs either as synergistic (SYN) or antagonistic (ANT). Mutation contexts can induce substantial changes in the evolutionary fitness of mutations in the paired genes, e.g., IDH1 and IDH2 mutation contexts lead to substantial increase and decrease of dNdS ratios of ATRX indels and IDH1 missense mutations corresponding to SYN and ANT relationship with positive and negative cdNS scores, respectively. The impact of gene silencing or knock-outs on cell viability (genetic dependencies) often depends on ED, suggesting that ED can guide the selection of candidates for synthetic lethality such as TCF7L2-KRAS mutations. Using cell line-based drug sensitivity data, the effects of targeted agents on cell lines are often associated with mutations of genes exhibiting ED with the target genes, informing drug sensitizing or resistant mutations for targeted inhibitors, e.g., PRSS1 and CTCF mutations as resistant mutations to EGFR and BRAF inhibitors for lung adenocarcinomas and melanomas, respectively., Conclusions: We propose that the ED of gene pairs evaluated by dNdS ratios can advance our understanding of the functional relationship of genes with potential biological and clinical implications., (© 2024. The Author(s).)

Deficiencies in DNA mismatch repair (MMRd) leave characteristic footprints of microsatellite instability (MSI) in cancer genomes. We used data from the Cancer Genome Atlas and International Cancer Genome Consortium to conduct a comprehensive analysis of MSI-associated cancers, focusing on indel mutational signatures. We classified MSI-high genomes into two subtypes based on their indel profiles: deletion-dominant (MMRd-del) and insertion-dominant (MMRd-ins). Compared with MMRd-del genomes, MMRd-ins genomes exhibit distinct mutational and transcriptomic features, including a higher prevalence of T>C substitutions and related mutation signatures. Short insertions and deletions in MMRd-ins and MMRd-del genomes target different sets of genes, resulting in distinct indel profiles between the two subtypes. In addition, indels in the MMRd-ins genomes are enriched with subclonal alterations that provide clues about a distinct evolutionary relationship between the MMRd-ins and MMRd-del genomes. Notably, the transcriptome analysis indicated that MMRd-ins cancers upregulate immune-related genes, show a high level of immune cell infiltration, and display an elevated neoantigen burden. The genomic and transcriptomic distinctions between the two types of MMRd genomes highlight the heterogeneity of genetic mechanisms and resulting genomic footprints and transcriptomic changes in cancers, which has potential clinical implications.

Verifying habitats, including the foraging and nesting areas for sea turtles, enables an understanding of their spatial ecology and successful planning of their conservation and management strategies. Recently, the observation frequency and bycatch of loggerhead (Caretta caretta) and green (Chelonia mydas) turtles have increased in the northern limit of their distribution range, in the northern part of the East China Sea and East (Japan) Sea. We conducted satellite tracking to investigate the habitat use of seven loggerhead and eight green turtles from June 2016 to August 2022 in this area, where little is known about their spatial ecology. We applied a 50 percent volume contour method to determine their main foraging areas and analyzed 6 environmental variables to characterize their habitats. Loggerhead turtles mainly stayed in and used the East China Sea as a foraging area during the tracking period, while two individuals among them also used the East Sea as a seasonal foraging area. Most green turtles also used the East China Sea as a foraging area, near South Korea and Japan, with one individual among them using the lower area of the East Sea as a seasonal foraging area. Notably, one green turtle traveled to Hainan Island in the South China Sea, a historical nesting area. Our results showed that the two sea turtle species included the East Sea as a seasonal foraging area, possibly owing to the abundance of food sources available, despite its relatively lower sea temperature. Considering that loggerhead and green sea turtles were observed using the northern part of the East China Sea and East Sea more frequently than previously known and that the sea temperature gradually increases due to climate change, conservation and management activities are required for sea turtles in these areas., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Previous studies have reported that genes highly expressed in leukemic stem cells (LSC) may dictate the survival probability of patients and expression-based cellular deconvolution may be informative in forecasting prognosis. However, whether the prognosis of acute myeloid leukemia (AML) can be predicted using gene expression and deconvoluted cellular abundances is debatable. Methods: Nine different cell-type abundances of a training set composed of the AML samples of 422 patients, were used to build a model for predicting prognosis by least absolute shrinkage and selection operator Cox regression. This model was validated in two different validation sets, TCGA-LAML and Beat AML ( n = 179 and 451, respectively). Results: We introduce a new prognosis predicting model for AML called the LSC activity (LSCA) score, which incorporates the abundance of 5 cell types, granulocyte-monocyte progenitors, common myeloid progenitors, CD45RA + cells, megakaryocyte-erythrocyte progenitors, and multipotent progenitors. Overall survival probabilities between the high and low LSCA score groups were significantly different in TCGA-LAML and Beat AML cohorts (log-rank p -value = 3.3 × 10 - 4 and 4.3 × 10 - 3 , respectively). Also, multivariate Cox regression analysis on these two validation sets shows that LSCA score is independent prognostic factor when considering age, sex, and cytogenetic risk (hazard ratio, HR = 2.17; 95% CI 1.40-3.34; p < 0.001 and HR = 1.20; 95% CI 1.02-1.43; p < 0.03, respectively). The performance of the LSCA score was comparable to other prognostic models, LSC17, APS, and CTC scores, as indicated by the area under the curve. Gene set variation analysis with six LSC-related functional gene sets indicated that high and low LSCA scores are associated with upregulated and downregulated genes in LSCs. Conclusion: We have developed a new prognosis prediction scoring system for AML patients, the LSCA score, which uses deconvoluted cell-type abundance only., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Han, Kim, Lee, Kang, Moon, Kim, Kim and Kim.)

Regulation of host miRNA expression is a contested node that controls the host immune response to mycobacterial infection. The host must counter subversive efforts of pathogenic mycobacteria to launch a protective immune response. Here, we examine the role of miR-126 in the zebrafish- Mycobacterium marinum infection model and identify a protective role for infection-induced miR-126 through multiple effector pathways. We identified a putative link between miR-126 and the tsc1a and cxcl12a/ccl2/ccr2 signalling axes resulting in the suppression of non- tnfa expressing macrophage accumulation at early M. marinum granulomas. Mechanistically, we found a detrimental effect of tsc1a expression that renders zebrafish embryos susceptible to higher bacterial burden and increased cell death via mTOR inhibition. We found that macrophage recruitment driven by the cxcl12a/ccl2/ccr2 signalling axis was at the expense of the recruitment of classically activated tnfa -expressing macrophages and increased cell death around granulomas. Together, our results delineate putative pathways by which infection-induced miR-126 may shape an effective immune response to M. marinum infection in zebrafish embryos., (© 2024 Wright et al.)

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance. Treatment of 3T3-L1 adipocytes with caspase 8 inhibitor Z-IETD-FMK decreased both death receptor-mediated signaling and targets of nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling. We generated novel adipose tissue and adipocyte-specific caspase 8 knockout mice (aP2Casp8-/- and adipoqCasp8-/-). Both males and females had improved glucose tolerance in the setting of high-fat diet (HFD) feeding. Knockout mice also gained less weight on HFD, with decreased adiposity, adipocyte size, and hepatic steatosis. These mice had decreased adipose tissue inflammation and decreased activation of canonical and noncanonical NF-κB signaling. Furthermore, they demonstrated increased energy expenditure, core body temperature, and UCP1 expression. Adipocyte-specific activation of Ikbkb or housing mice at thermoneutrality attenuated improvements in glucose tolerance. These data demonstrate an important role for caspase 8 in mediating adipocyte cell death and inflammation to regulate glucose and energy homeostasis., Article Highlights: Caspase 8 is increased in adipocytes from mice and humans with obesity and insulin resistance. Knockdown of caspase 8 in adipocytes protects mice from glucose intolerance and weight gain on a high-fat diet. Knockdown of caspase 8 decreases Fas signaling, as well as canonical and noncanonical nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling in adipose tissue. Improved glucose tolerance occurs via reduced activation of NF-κB signaling and via induction of UCP1 in adipocytes., (© 2023 by the American Diabetes Association.)

The success of mRNA vaccines has been realised, in part, by advances in manufacturing that enabled billions of doses to be produced at sufficient quality and safety. However, mRNA vaccines must be rigorously analysed to measure their integrity and detect contaminants that reduce their effectiveness and induce side-effects. Currently, mRNA vaccines and therapies are analysed using a range of time-consuming and costly methods. Here we describe a streamlined method to analyse mRNA vaccines and therapies using long-read nanopore sequencing. Compared to other industry-standard techniques, VAX-seq can comprehensively measure key mRNA vaccine quality attributes, including sequence, length, integrity, and purity. We also show how direct RNA sequencing can analyse mRNA chemistry, including the detection of nucleoside modifications. To support this approach, we provide supporting software to automatically report on mRNA and plasmid template quality and integrity. Given these advantages, we anticipate that RNA sequencing methods, such as VAX-seq, will become central to the development and manufacture of mRNA drugs., (© 2023. Springer Nature Limited.)

Background: The optimal dose of anti-thymocyte globulin (ATG) as an induction regimen in Asian living-donor kidney recipients is unclear., Methods: This is a pilot study in which 36 consecutive patients undergoing living-donor kidney transplantation were randomly assigned to receive either 4.5 mg/kg (n = 19) or 6.0 mg/kg (n = 17) of ATG; all patients had corticosteroid withdrawal within 7 days. The primary end point was a composite of biopsy-proven acute rejection, de novo donor-specific antibody formation, and graft failure., Results: At 12 months post-transplant, biopsy-proven acute rejection was more common in the ATG4.5 group (21.1%) than in the ATG6.0 group (0%)(P = .048). Importantly, the rate of the composite end point was significantly higher in the ATG4.5 group (36.8% vs 0%)(P = .006). There were significant differences in neither the renal function nor adverse events between the two groups. One case of death-censored graft failure occurred in the ATG4.5 group and no mortality was observed overall. Compared with pre-transplantation, T cells, natural killer (NK) cells, and natural killer T (NKT) cells were significantly decreased in the first week post-transplantation except for B cells. Although T and NKT cells in both groups and NK cells in the ATG4.5 group had recovered to the pre-transplant levels, NK cells in the ATG6.0 group remained suppressed until six months post-transplant., Conclusions: Compared with ATG 6.0 mg/kg, ATG 4.5 mg/kg with early corticosteroid withdrawal and low dose maintenance regimen was associated with higher rates of acute rejection in non-sensitized Asian living-donor kidney recipients., Trial Registration: ClinicalTrials.gov: NCT02447822., Competing Interests: DJ Han received the fund from Sanofi-Aventis Korea Company (Grant number: THYMOL07047) for this study. Related to this grant, he is not related to ownership of stocks or shares, paid employment or consultancy, board membership, patent applications, travel grants, and gifts. The funder did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing of data and materials., (Copyright: © 2023 Ko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic alterations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naïve spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was identified along with predisposing germline variants in the DNA-damage-repair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Adipose tissue is a very dynamic metabolic organ that plays an essential role in regulating whole-body glucose homeostasis. Dysfunctional adipose tissue hypertrophy with obesity is associated with fibrosis and type 2 diabetes. Yes-associated protein 1 (YAP) is a transcription cofactor important in the Hippo signaling pathway. However, the role of YAP in adipose tissue and glucose homeostasis is unknown., Methods: To study the role of YAP with metabolic stress, we assessed how increased weight and insulin resistance impact YAP in humans and mouse models. To further investigate the in vivo role of YAP specifically in adipose tissue and glucose homeostasis, we developed adipose tissue-specific YAP knockout mice and placed them on either chow or high fat diet (HFD) for 12-14 weeks. To further study the direct role of YAP in adipocytes we used 3T3-L1 cells., Results: We found that YAP protein levels increase in adipose tissue from humans with type 2 diabetes and mouse models of diet-induced obesity and insulin resistance. This suggests that YAP signaling may contribute to adipocyte dysfunction and insulin resistance under metabolic stress conditions. On an HFD, adipose tissue YAP knockout mice had improved glucose tolerance compared to littermate controls. Perigonadal fat pad weight was also decreased in knockout animals, with smaller adipocyte size. Adipose tissue fibrosis and gene expression associated with fibrosis was decreased in vivo and in vitro in 3T3-L1 cells treated with a YAP inhibitor or siRNA., Conclusions: We show that YAP is increased in adipose tissue with weight gain and insulin resistance. Disruption of YAP in adipocytes prevents glucose intolerance and adipose tissue fibrosis, suggesting that YAP plays an important role in regulating adipose tissue and glucose homeostasis with metabolic stress., Competing Interests: CONFLICT OF INTEREST None declared., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

With most sea turtle populations declining, activities to conserve their habitat and nesting grounds and restore their populations are being implemented worldwide. To preserve the Northwestern Pacific populations, the National Marine Biodiversity Institute of Korea has been releasing artificially propagated sea turtles, but whether these individuals join the wild population remains unknown. The present study aimed to determine the movement patterns of artificially propagated juvenile loggerhead (Caretta caretta) and green (Chelonia mydas) turtles fitted with satellite transmitters on their carapaces and released in the waters of Jeju or Yeosu, Republic of Korea, between August 2018 and April 2022. Loggerheads traveled northward to the East Sea, whereas green turtles moved west or southwest. Two 36-month-old and two 48-month-old loggerheads moved toward their potential nursery grounds and toward their feeding grounds, respectively. Three green turtles with a curved carapace length (CCL) of <40 cm moved toward their nursery or feeding grounds, while three individuals (CCL > 45 cm) moved toward their inshore foraging areas. The travel paths were closely related to the direction of local sea currents. Our results implied that releasing artificially propagated sea turtles, considering their age and CCL, can positively contribute to the conservation of Northwestern Pacific populations.

Objective: We compared the clinical outcomes of recipients of ABO-incompatible (ABOi) kidney transplantation (KT) according to the blood group of the plasma transfused., Materials and Methods: We retrospectively analyzed the data of 60 recipients of ABOi-KT with blood type O and A or B donors. Demographic and clinical characteristics were compared between 2 groups of recipients: 1 group received AB plasma regardless of the donor's blood type (n = 30), and the other group received donor-type plasma (n = 30)., Results: There were no significant differences between the groups in terms of demographic characteristics. Transfusion of donor-type plasma was noninferior to transfusion of type AB plasma in terms of both rejection-free survival and rejection rate (P = .455, P = .335)., Conclusion: There was no significant prognostic difference between the 2 groups. In terms of blood supply and inventory management, we suggest that the blood group of the plasma should match the donor's type., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The lyophilization process is the most convenient and successful method to preserve probiotics, although microorganisms are exposed to conditions of extremely low freezing temperatures as well as dehydration. In this study, we evaluated the cryoprotective effect of turanose on Lactobacillus paracasei subsp. paracasei , L. casei 431 ( L. casei 431) as a method to increase survival rate by improving cell viability. The results indicated that the viability of L. casei 431 was 9.6% without the cryoprotective agent, whereas bacterial cell viability was increased to 67.1% with the addition of 12% turanose. When turanose-treated freeze-dried cells were stored at 4 °C for 30 days, the survival rate decreased from 67.1 to 53.4%. Furthermore, cell viability significantly decreased by 50% after 30 days when stored at 25 °C with the same amount of turanose. Overall, turanose may be used as an effective cryoprotectant to preserve probiotics against the freeze-drying process and for extended storage at 4 °C., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© The Korean Society of Food Science and Technology 2022.)

Objective: We analyzed the efficacy and safety of an everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard-exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study., Methods: In this 24-month, open-label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids., Results: Of the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m 2 or treated biopsy-proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m 2 , P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m 2 , P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm., Conclusion: This subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819)., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The purpose of this study was to evaluate the characteristics and prognosis of de novo CRC patients who underwent liver or kidney transplantation., Methods: We retrospectively reviewed the medical records of 66 de novo CRC patients selected from 8,734 liver transplant (LT) or kidney transplant (KT) recipients. We analyzed characteristics and survival outcomes of de novo CRC patients and sporadic CRC patients who underwent radical surgery with stage I-III in Asan Medical Center between 2005 and 2016. Survival outcomes were analyzed via the 1:4 matching method., Results: The standard incidence ratio (SIR) of de novo CRC in KT recipients is 1.67 in men and 2.54 in women. That in LT recipients is 3.10 in men and 2.25 in women. Compared with sporadic CRC patients, de novo CRC patients had more colon cancer than rectal cancer (p=0.041). In 9 patients (13.6%), CRC was diagnosed within one year after transplantation, 21 patients (31.8%) were diagnosed between 1-5 years, and the remaining 36 patients (54.6%) were diagnosed thereafter. There were no significant differences in recurrence-free survival and overall survival between the two groups (p=0.211 and p=0.324, respectively)., Conclusions: The risk of developing de novo CRC in transplant recipients was higher than in the general population. The survival outcome of de novo CRC was no different compared with the sporadic CRC. Therefore, regular surveillance is essential for timely diagnosis and treatment for transplantation patients. A large prospective study for an intense CRC surveillance program in transplantation patients is needed., (© 2021. Société Internationale de Chirurgie.)

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of β-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m 2 ) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3' end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.

Mitotic catastrophe, a cell death mechanism characterized by abnormal mitosis, has been regarded as a therapeutic approach for the development of anti‑cancer drug candidates. The aim of the present study was to investigate the potential effect of the ethanolic extract of Juniperus squamata  (EEJS) on the occurrence of mitotic catastrophe in human oral cancer cell lines. The effect of EEJS on the occurrence of mitotic catastrophe was evaluated by measuring cytotoxicity, observing phase‑contrast or transmission electron microscope findings, evaluating the appearance of microtubule or chromosome abnormalities, and detecting the phosphorylation of histone H3 (Ser 10 ). The apoptotic effect of EEJS was assessed by detecting cleaved PARP, analyzing the sub‑G 1 population, Annexin V‑FITC/PI double staining, western blot analysis, and the transient transfection of myeloid cell leukemia‑1 (Mcl‑1) overexpression vectors. EEJS treatment was effective in inhibiting cell proliferation in human oral cancer cell lines. EEJS resulted in the enrichment of enlarged multinucleated cells, the disturbance of microtubule formation, and increased phosphorylation of histone H3 (Ser 10 ), which demonstrates the occurrence of mitotic catastrophe. Additionally, the multinucleated cells underwent apoptotic cell death in a cell context‑dependent manner, which was associated with the reduction of Mcl‑1 protein levels. Findings of the present study indicate that EEJS could be effective for treating human oral cancer by promoting mitotic catastrophe linked to apoptotic cell death.

Purpose: Type 2 diabetes develops in the presence of chronic overnutrition and genetic susceptibility, and causes insulin resistance and relative insulin deficiency. We hypothesized that islet transplantation can improve insulin sensitivity by modifying the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues., Methods: Eight-week-old male mice were used as both recipients and donors in this study. To induce type 2 diabetes with partial β-cell failure, the mice were fed a high-fat diet for 4 weeks and then injected with low-dose streptozotocin. Approximately 400 islet cells from a donor mouse were injected into the renal capsule of a recipient mouse for islet transplantation. After 6 weeks following transplantation, the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues were quantitatively compared between islet-transplanted and non-transplanted groups., Results: Intravenous glucose tolerance test showed that whereas the non-transplanted mice failed to show notable reductions in the glucose level, the islet-transplanted mice showed significant reductions in the serum glucose level to ~200 mg/dL at 6 weeks after islet transplantation. The islet-transplanted mice showed significantly higher Matsuda index and significantly lower HOMA-IR than did the non-transplanted mice, thus signifying improved insulin sensitivity., Conclusions: Islet transplantation resulted in improvements in multiple indices of insulin sensitivity in a murine model of type 2 diabetes. Islet transplantation may be utilized to improve insulin sensitivity in patients with type 2 diabetes.

Objectives: This study aimed to assess posttransplant changes in insulin sensitivity and β-cell function of pancreas transplant recipients according to the type of diabetes mellitus (DM) and the pretransplant insulin sensitivity measured by the Matsuda Index (MI)., Methods: We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant., Results: At 1 month posttransplant, insulin sensitivity did not show significant improvement; particularly, the MI was significantly lower after transplant in recipients with type 1 DM (T1DM) and those with pretransplant MI of 5 or greater. β-cell function was significantly improved after transplant in all recipients regardless of the type of DM and pretransplant MI values. Glucose control was significantly improved in recipients with T1DM and in all recipients regardless of the pretransplant MI values. Additional oral glucose tolerance test at 1 year posttransplant revealed that insulin sensitivity remained unimproved and β-cell function was higher compared with pretransplant. Glucose control had partially reverted to pretransplant levels in recipients with T1DM and those with pretransplant MI of 5 or greater., Conclusions: Unlike β-cell function and glucose control, insulin sensitivity did not significantly improve until posttransplant 1 year after pancreas transplantation regardless of the type of DM or the degree of pretransplant insulin sensitivity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Laboratory biomarkers that can differentiate non-infectious fever from infectious fever after pancreas transplantation have yet to be discovered. Non-infectious fever was defined as the presence of fever (>38.3°C) in the absence of a documented clinical diagnosis of infection or a positive culture. Among 184 consecutive recipients, a total of 91 recipients developed fever within 1-month post-transplant, of whom 46 had infectious fever and 45 had non-infectious fever at our center between August 2014 and July 2019. The onset of fever was earlier in the non-infectious fever group (14.4 ± 3.7 post-transplant days) compared with the infectious fever group (16.5 ± 5.8 post-transplant days; p = .033). Multivariate analysis showed that serum procalcitonin at the peak of fever could significantly differentiate infectious fever from non-infectious fever (OR 53.378, 95% CI: 6.819-417.802, p < .001). The area under the curve for differentiating between the two groups was 0.853 (95% CI, 0.780-0.926) for procalcitonin and 0.667 (95% CI, 0.549-0.785) for CRP. The best cutoff values of serum procalcitonin and CRP were 0.405 ng/ml (sensitivity, 77.1%; specificity, 80.8%) and 7.355 mg/dl (sensitivity, 66.7%; specificity, 67.3%), respectively. Serum procalcitonin may be useful for differentiating non-infectious fever from infectious fever after pancreas transplantation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Among the structural isomers of sucrose, turanose has been considered as one of good candidates as novel sweetener due to its mild taste, low calorie, and anti-cariogenicity. Here, various physicochemical properties of turanose, such as solubility, temperature and pH stabilities, viscosity, non-enzymatic browning reaction, and dynamic vapor sorption, were investigated by comparing them to those of other commercial sugars. Turanose did not significantly hydrolyze through the simulated digestion tract overall but in the artificial small intestinal environment specifically, turanose degraded by only 18% when sucrose was hydrolyzed by 36% after 4 h. In addition, physicochemical properties of turanose confirmed that it had a potential to replace sucrose due to similar or better product qualities as a food ingredient than other types of sugars with similar chemical structure. Thus, our study suggests that turanose can be applied as a functional sweetener or bulking agent in food processing., Competing Interests: Conflict of interestThere are no conflicts of interest to declare., (© The Korean Society of Food Science and Technology 2021.)

Backgrounds/aims: Simultaneous liver and kidney transplantation (SLKT) has been established as the treatment of choice for patients with concurrent end-stage liver and end-stage kidney diseases. The objective of this study was to analyze the nationwide incidence of SLKT in Korea and the outcomes of SLKT in a high-volume transplant center., Methods: Databases of the Korean Network for Organ Sharing (KONOS) and Asan Medical Center from 2000 to 2019 were retrospectively reviewed to determine the incidence of SLKT., Results: During 20 years from 2000 to 2019, deceased donor SLKT was performed for 38 cases in the KONOS database. The proportion of deceased donor SLKT was 0.6% (20 of 3333) before adoption of MELD score, which was significantly increased to 1.2% (18 of 1524) after the adoption of MELD score ( p =0.034). In our institution, there were 11 cases of SLKT (2 cases with deceased donors and 9 cases with living donors). SLKT accounted for 0.2% (11 of 6468) of total liver transplantation volume. During follow-up, five patients died due to hepatocellular carcinoma recurrence (n=2), infection (n=2), or unknown cause (n=1). The 1-year and 10-year overall patient survival rates were 90.9% and 81.8%, respectively., Conclusions: Results of this study revealed that the incidence of deceased donor SLKT was very low. An increase of such incidence is not anticipated unless the number of deceased donors is markedly increased. Currently, sequential living donor liver transplantation and kidney transplantation with deceased or living donors are mainstays of transplantation rather than SLKT in our institution.

Supercapacitors are strong future candidates for energy storage devices owing to their high power density, fast charge-discharge rate, and long cycle stability. Here, a flexible supercapacitor with a large specific capacitance of 443 F g -1 at a scan rate of 2 mV s -1 is demonstrated using nanotube-reinforced polypyrrole nanowires with hollowed cavities grown vertically on a nanotube/graphene based film. Using these electrodes, we obtain improved capacitance, rate capability, and cycle stability for over 3000 cycles. The assembled all-solid-state supercapacitor exhibits excellent mechanical flexibility, with the capacity to endure a 180° bending angle along with a maximum specific and volumetric energy density of 7 W h kg -1 (8.2 mW h cm -3 ) at a power density of 75 W kg -1 (0.087 W cm -3 ), and it showed an energy density of 4.13 W h kg -1 (4.82 mW h cm -3 ) even at a high power density of 3.8 kW kg -1 (4.4 W cm -3 ). Also, it demonstrates a high cycling stability of 94.3% after 10 000 charge/discharge cycles at a current density of 10 A g -1 . Finally, a foldable all-solid-state supercapacitor is demonstrated, which confirms the applicability of the reported supercapacitor for use in energy storage devices for future portable, foldable, or wearable electronics., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

BACKGROUND Given that pregnancy is an immune-sensitizing event, female kidney transplant recipients who receive allografts from their offspring or husbands may have a higher risk of rejection and graft failure due to pre-sensitization acquired during pregnancy or childbirth. We investigated the association between donor relatedness (i.e., offspring, husband, unrelated) and graft survival among female living-donor kidney transplant (LDKT) recipients with pregnancy histories. MATERIAL AND METHODS From January 2009 to January 2018, a total of 2060 LDKTs were performed at Asan Medical Center, Seoul, Korea. After excluding HLA-incompatible transplantation, re-transplantation, and those without a clear history of childbirth, 390 female recipients were included and categorized into group I (offspring-to-mother, n=175), group II (husband-to-wife, n=159), and group III (unrelated, n=56). The primary endpoint was biopsy-proven acute rejection (BPAR) and graft survival. We also evaluated delayed graft function (DGF), death-censored graft failure, and mortality. RESULTS Group I had the lowest number of HLA mismatches (p<0.001), and group II had the highest number of ABO-incompatible transplantations (p=0.005). At 5 years after transplant, graft survival and death-censored graft survival did not significantly differ among the 3 groups (graft survival: 96.0% vs. 95.5% vs. 93.3%, p=0.685; death-censored graft survival: 98.3% vs. 97.5% vs. 100%, p=0.732). Five-year BPAR-free survival showed no significant differences among the 3 groups (88.6 vs. 88.7 vs. 88.6%, p=0.842). Group II had the highest rate of clinical rejection (p=0.103) and DGF (p=0.174), but the difference was not statistically significant. CONCLUSIONS Female LDKT recipients with possible pregnancy-related pre-sensitization who received grafts from offspring or husbands did not show significantly worse clinical outcomes than those who received grafts from unrelated donors.

BACKGROUND Patients receiving ABO-incompatible (ABOi) or human leukocyte antigen (HLA)-incompatible (HLAi) kidney transplantation (KT) require potent immunosuppression and are thus at a higher risk of infectious complications. We evaluated the clinical outcomes of KT stratified by ABO and HLA incompatibilities and identified the factors associated with the clinical outcomes. MATERIAL AND METHODS Recipients who underwent living-related KT between 2012 and 2017 were included and classified into 4 groups: ABO-compatible and HLA-compatible (ABOc/HLAc), HLA-incompatible (ABOc/HLAi), ABO-incompatible (ABOi/HLAc), and ABO-incompatible and HLA-incompatible (ABOi/HLAi). Cox proportional hazards regression analyses were carried out to evaluate the risk factors of acute rejection. Out of the 1732 patients who underwent KT, 1190, 131, 358, and 53 were in the ABOc/HLAc, ABOi/HLAc, ABOc/HLAi, and ABOi/HLAi groups, respectively. RESULTS The ABO/HLAi group showed the lowest 5-year graft survival rate (91.7%). Death-censored graft survival was not significantly different among the groups. The mortality rate from infections was significantly higher in the ABOi/HLAi group (7.5%) than the other groups. Antibody-mediated rejection-free graft survival was the lowest in the ABOi/HLAi group, with significant differences compared with the ABOi/HLAc group (P=0.02) and the ABOc/HLAi group (P=0.03). ABOi/HLAi (hazard ratio [HR], 2.63; 95% confidence interval [CI], 1.04-6.65; P<0.01) and combined infection (HR, 1.91; 95% CI, 1.45-2.51; P<0.01) were significant risk factors for acute rejection. CONCLUSIONS Patients with both ABO and HLA incompatibilities showed inferior rates of overall patient and graft survival due to infectious complications. Infection was a prominent risk factor of acute rejection following KT after adjusting for possible confounders including ABO and HLA incompatibility.

Objectives: In TRANSFORM, de novo kidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3-8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15., Methods: Patients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19., Results: The safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20., Conclusion: The immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21., Ct.gov Identifier: NCT01950819.

Objectives: We evaluated the effectiveness of IGRA-based isoniazid (INH) treatment with the diagnostic value of quantitative IGRA titer for post-transplant tuberculosis (TB) in kidney transplant (KT) recipients., Methods: All adult KT recipients were enrolled from January 2014 to December 2017. The development of TB after KT was observed, stratified by quantitative IGRA results as well as by IGRA results with/without INH treatment., Results: Of 1150 KT recipients, 322 (28%) revealed positive IGRA results (≥0.35 IU/mL) and 12 (1.0%) developed TB. Seven (3.2%) of 217 patients with positive IGRA without INH developed TB, whereas none of 105 patients with positive IGRA with INH developed TB (rate difference -1616 per 100,000 person-years, P = 0.016) and 5 (0.6%) of 828 patients with negative or indeterminate IGRA developed TB (rate difference -1388 per 100,000 person-years, P<0.001). Among the 217 positive IGRA patients without INH, 6 (6.4%) of 94 patients who had positive IGRA titer>2.96 IU/mL developed TB, whereas one (0.8%) of 123 patients who had positive IGRA titer≤2.96 IU/mL developed TB (rate difference 2964 per 100,000 person-years, P = 0.017)., Conclusions: IGRA-based INH treatment with risk stratification by quantitative IGRA results appears to be effective to prevent the development of TB in KT recipients., Competing Interests: Declaration of Competing Interest The authors of this manuscript have no conflicts of interest to disclose as described by the Journal of Infection., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

BACKGROUND Kidney donors may be at increased risk for end-stage renal disease (ESRD) as well as cardiovascular and all-cause mortality. In particular, data on long-term safety after kidney donation in Asian populations are lacking. We aimed to assess the safety of live kidney donation in Korean donors by using a matched control group. MATERIAL AND METHODS We conducted a retrospective cohort study using a hospital-based database (Asan Medical Center, Seoul, Korea) and a control group from the national health insurance claims database in South Korea. We analyzed the health status of 1608 kidney donors who underwent donation between September 1990 and December 2015, and we compared their characteristics with those of matched 6426 non-donors (1: 4 ratio). We also measured the glomerular filtration rate (GFR) with ⁵¹Cr EDTA and urinary albumin excretion and assessed the prevalence of hypertension, diabetes, and general health status in 200 volunteer donors. RESULTS Mortality was significantly lower in kidney donors compared with the matched controls (130.2 vs. 185.4 per 100,000 person-years, P=0.02). There was no significant difference in mortality if a donor had hypertension or was a current smoker at the time of donation. There was also no significant difference in ESRD (43.1 vs. 35.2 per 100,000 person-years, P=0.07) between the 2 groups regardless of hypertension and smoking status. Among the 200 donors with measured GFR, 11.5% had GFR values <60 ml/min/1.73 m² at 9.4±5.3 years after donation. Older age (P=0.001) and female sex (P=0.021) were significantly associated with GFR values <60 mL/min/1.73 m². CONCLUSIONS Mortality and ESRD were uncommon in carefully selected kidney donors. However, donors with pre-existing risk factors should be followed up more closely to ensure long-term safety.

Reactive oxygen species (ROS) homeostasis is critical for both physiological processes and stress responses of plants. NADPH oxidases (NOXs) are the key producers of ROS in plants. However, their functions in ROS homeostasis and plant growth regulation in wheat ( Triticum aestivum ) are little investigated. Here, we cloned and characterized a NOX isoform TaNOX7 in wheat. Overexpression of TaNOX7 in rice led to enhanced root length, ROS production, drought tolerance as well as bigger panicles and higher yield but shorter growth period duration. Further results indicate that TaCDPK13, a member of calcium-dependent protein kinases (CDPKs), can directly interact with TaNOX7 and enhance ROS production in plants. These results demonstrate that TaNOX7 plays crucial roles in wheat development, fertility, and drought tolerance via interaction with TaCDPK13, which may act as an upstream regulator of TaNOX7 to regulate ROS production in wheat.

Purpose: To investigate the tomographic structural changes in the retinal layers after internal limiting membrane (ILM) peeling for idiopathic epiretinal membrane (ERM)., Methods: Sixty-nine eyes treated with vitrectomy and ILM peeling for idiopathic ERM were analyzed. Parafoveal retinal thickness was measured at baseline and 6 months after surgery., Results: Total retinal thickness decreased significantly in the nasal and temporal subfields after surgery ( p < 0.001), whereas the inner nuclear layer and outer nuclear layer showed nasal thickening (all, p < 0.001). The postoperative temporal/nasal subfield thickness ratio of each layer was significantly lower than that of fellow eyes. Eyes with larger ILM peeling showed a significantly lower temporal/nasal subfield thickness ratio ( p = 0.033) than those with smaller sizes., Conclusions: The retinal thickness of each layer showed anatomical changes from ILM peeling and ERM removal. Nasal parafoveal thickening and temporal thinning occurred in the inner retinal architecture, which might be affected by ILM peeling size., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2020 The Korean Ophthalmological Society.)

Background: Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in kidney transplant recipients (KTRs), and prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is recommended. The aim of this study was to investigate incidence and risk factors for PCP in KTRs after 6-month TMP-SMX prophylaxis., Methods: We conducted a case-control study of patients with PCP who received 6-month PCP prophylaxis with TMP-SMX after kidney transplantation (KT). In cases of rejection, PCP prophylaxis was provided for six additional months after anti-rejection therapy. Cytomegalovirus (CMV) infection was not considered an indication for PCP prophylaxis due to concerns of nephrotoxicity associated with TMP-SMX., Results: Among 3941 kidney or pancreas-kidney transplant recipients, 67 (1.7%) developed PCP after discontinuing TMP-SMX. A total of 47 patients with KT PCP and 94 controls were included. Duration of PCP prophylaxis was similar between cases and controls (median 6 months, P = .53). In multivariate analysis, rejection (OR 3.9; 95% CI 1.4-11.1) and CMV infection (OR 2.4; 95% CI 1.0-5.8) were independently associated with PCP development after TMP-SMX. Rejection or CMV infection was observed in 70% of patients with PCP. Time to PCP development after rejection (median [IQR] 6 [5-19] months) was slightly shorter than after CMV infection (median [IQR] 9 [5-12] months; P = .18)., Conclusion: Post-prophylaxis PCP occurred in <2% of KTRs, and about two-thirds of these experienced rejection or CMV infection. These data suggest that at least 6 to 9-month additional chemoprophylaxis may be needed to prevent PCP in KTRs with transplant rejection or CMV infection., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pneumocystis pneumonia (PCP) is a life-threatening fungal infection that can occur in kidney transplantation (KT) recipients. A growing number of KT recipients are receiving perioperative treatment with rituximab, which is associated with prolonged B-cell depletion and possible risk of PCP occurrence; however, the optimal prophylaxis duration according to rituximab treatment is yet unknown. We compared the occurrence of PCP and the duration of prophylaxis in KT recipients according to rituximab treatment., Methods: We retrospectively analyzed 2110 patients who underwent KT between January 2009 and December 2016, who were divided into non-Rituximab group (n = 1588, 75.3%) and rituximab group (n = 522, 24.7%)., Results: In the rituximab group, the estimated number needed to treat (NNT) for prophylaxis prolongation from 6 to 12 months was 29.0 with a relative risk reduction of 90.0%. In the non-rituximab group, the estimated NNT value was 133.3 and the relative risk reduction was 66.4%. Rituximab treatment (hazard ratio (HR) = 3.09; P <  0.01) and acute rejection (HR = 2.19; P = 0.03) were significant risk factors for PCP in multivariate analysis., Conclusions: Our results suggest that maintaining PCP prophylaxis for 12 months may be beneficial in KT recipients treated with rituximab for desensitization or acute rejection treatment.

Background/aims: We evaluated the usefulness in kidney transplant (KT) candidates of cytomegalovirus (CMV)-specific enzyme-linked immunospot (ELISPOT) assays for predicting the development of post-transplant CMV infections., Methods: All adult recipients admitted for living-donor KT between March 2014 and March 2015 were prospectively enrolled except donor CMV-seropositive and recipient seronegative (D+/R-) recipients. All the enrolled patients underwent CMV-specific ELISPOT assays before transplant, and a researcher blinded to the results of these assays examined the patients for CMV infection at least 6 months post-transplant., Results: Of 133 KT recipients, 44 (33%) developed CMV infections. When we used the cut-off determined by receiver operator characteristic curve, 16 of the 34 patients (47%) with negative pp65-specific ELISPOT results (< 11 spots/200,000 cells) developed CMV infections, whereas 28 of the 99 patients (39%) with positive pp65-specific ELISPOT results at baseline (≥ 11 spots/200,000 cells) developed CMV infections after KT (p = 0.02). Based on the multivariable Cox regression model, negative pp65-specific ELISPOT assay results was an independent risk factor for CMV infection (adjusted hazard ratio [AHR], 1.87; 95% confidence interval [CI], 1.01 to 3.46; p = 0.047) as well as age (AHR, 1.05; 95% CI, 1.01 to 1.08; p = 0.007)., Conclusion: Pre-transplant CMV-specific ELISPOT assay appears to predict the development of CMV infections after KT in recipients at moderate risk such as CMV-seropositive recipients (Clinical Trial Registration Number NCT02025335).

Background: Recent advances in desensitization techniques and immunosuppressive therapy have led to improved outcomes after ABO-incompatible (ABO-i) kidney transplantation (KT). However, questions remain unanswered, particularly regarding which type of ABO isoagglutinin-immunoglobulin M (IgM) or immunoglobulin M (IgG)-is significantly involved in antibody-mediated rejection (AMR)., Study Design and Methods: We retrospectively analyzed data from 120 patients who underwent ABO-i KT between 2012 and 2014. Preoperative plasma exchange was performed until the IgM isoagglutinin titer was 4 or less, regardless of the IgG titer. Clinical data were compared between patient groups with pre-KT IgG isoagglutinin titer 16 or greater (high IgG; titer range, 16-256; n = 39) and 8 or less (low IgG; titer range, -8; n = 81)., Results: The median follow-up periods were 59 (high IgG) and 55 (low IgG) months. Patient survival at 5 years (p = 0.314) was 100% (high IgG) and 97.4% (low IgG). Graft survival at 5 years (p = 0.480) was 100% (high IgG) and 98.7% (low IgG). AMR by anti-ABO antibody occurred in only one patient in the low-IgG group., Conclusion: Patients with high pre-KT IgG isoagglutinin titers had equally successful outcomes as those with low IgG titers. ABO-i KT can be successfully performed by reducing the pre-KT IgM isoagglutinin titer to 4 or less, as determined by the immediate spin tube method., (© 2020 AABB.)

This study aimed to determine whether the closure of a functioning arteriovenous (AV) access affects the estimated glomerular filtration rate (eGFR) and to compare outcomes according to the timing of AV access closure after kidney transplantation (KT). From 2009 to 2015, medical records were retrospectively reviewed for 142 kidney transplant recipients (KTRs) who underwent AV access closure. The 142 KTRs were categorized into three groups: AV access closure was performed within 6 months after KT in Group 1 (n = 45), at 6-12 months after KT in Group 2 (n = 49), and at 12-24 months after KT in Group 3 (n = 48). The baseline (at the time of AV access closure) and follow-up eGFR values during the 3-year follow-up period were compared. Linear mixed model analysis revealed no significant association between longitudinally observed eGFR values and the amount of time elapsed after AV access closure in the study population (P = 0.36). There was no significant association between 3-year eGFR values and the timing of AV access closure (P = 0.58). In conclusion, after successful KT, AV access closure did not affect the eGFR significantly, and the timing of AV access closure was not significantly associated with outcomes., Competing Interests: The authors have declared that no competing interests exist.

ABO-incompatible (ABOi) and positive crossmatch (XM) kidney transplantation (KT) have been considered immunologically challenging. The present study analyzed the clinical outcomes in XM positive KT based on ABO incompatibility. We used data from the Korea Organ Transplantation Registry, a nationwide database, and a single-center registry. A total of 263 patients with positive XM were divided into an ABO compatible (ABOc) & XM positive (ABOc/XM+, n = 176) group and an ABOi & XM positive (ABOi/XM+, n = 87) group. The overall rejection rate one year after KT was significantly higher in the ABOi/XM+ group than in the ABOc/XM+ group (P < 0.01). A total of four mortalities occurred, all in the ABOi/XM+ patients (P < 0.01). There were no differences in surgical complications or the occurrence of infection-related complications, including BK virus nephropathy. Multivariate analysis indicated that female vs. male (odds ratio (OR), 2.27; P = 0.03), DSA class I (MFI/1000) (OR, 1.10; P = 0.03), DSA class II (MFI/1000) (OR, 1.10; P < 0.01), and ABOi & XM+ status (OR, 2.38; P < 0.01) were significant risk factors for acute rejection during the year after transplantation. Overall graft survival was inferior in ABOi/XM+ patients than in ABOc/XM+ patients (P = 0.02). ABO incompatibility in XM-positive KT patients was found to be a significant risk factor for the development of rejection within one year after transplantation as well as for long-term graft survival. The anti-blood group A, B and anti-HLA antibodies may show synergistic activity.

Little is known about the characteristics and clinical implications of specific subsets of intragraft natural killer (NK) cells in kidney transplant recipients. We analyzed 39 for-cause renal transplant biopsies performed at our center from May 2015 to July 2017. According to histopathologic reports, 8 patients (20.5%) had no rejection (NR), 11 (28.2%) had T cell-mediated rejections (TCMR) only, and 20 (51.3%) had antibody-mediated rejection (ABMR). NK cells were defined as CD3 - CD56 + lymphocytes that are positive for CD57, CD49b, NKG2A, or KIR. The density of NK cells was significantly higher in the ABMR group (2.57 ± 2.58/mm 2 ) than in the NR (0.12 ± 0.22/mm 2 ) or the TCMR (0.25 ± 0.34/mm 2 ) group (P = 0.002). Notably, CD56 + CD57 + infiltrates (2.16 ± 1.89) were the most frequently observed compared with CD56 + CD49b + (0.05 ± 0.13), CD56 + NKG2A + (0.21 ± 0.69), and CD56 + KIR + (0.15 ± 0.42) cells in the ABMR group (P < 0.001). Death-censored graft failure was significantly higher in patients with NK cell infiltration than those without (Log-rank test, P = 0.025). In conclusion, CD56 + CD57 + infiltrates are a major subset of NK cells in kidney transplant recipients with ABMR and NK cell infiltration is significantly associated with graft failure post-transplant.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure. One of the most serious extrarenal complications of ADPKD is comorbid intracranial aneurysms. The aim of this study is to evaluate the prevalence, rupture rate, and treatment outcomes of intracranial aneurysms in ADPKD., Methods: Adult patients with a documented diagnosis of ADPKD who received kidney transplantation at our center from January 1994 to December 2018 were included in the study. Medical history, physical examination, laboratory findings, imaging studies, and operation records were collected and analyzed from our database., Results: Among 154 kidney transplant recipients with ADPKD, 113 (73.4%) patients were screened for intracranial aneurysms preoperatively. Twenty three patients (14.9%) had intracranial aneurysms with mean diameter size of 4.5 ± 2.7 mm. Nine patients (5.8%) experienced aneurysm rupture and the mean age at time of rupture was 34.9 ± 9.3 years. Twelve patients (52.2%) presented with multiple aneurysms. The most common aneurysm location was the bifurcation of the middle cerebral artery (34.9%). Clipping was the most common treatment in both ruptured and unruptured aneurysms., Conclusions: Intracranial aneurysms are more frequent in patients with ADPKD, and the average age of intracranial artery rupture in patients with ADPKD is earlier than in the general population. It is necessary to consider proper evaluation and management of intracranial aneurysms when counseling ADPKD patients who will undergo kidney transplantation.

Immunosuppressants are crucial in organ transplantation but their side effects are a trade-off for long-term use. Colchicine has been shown to be effective in various diseases, albeit with many side effects. To enhance the immunosuppressive effects of colchicine, in addition to minimizing its side effects, we attempted to synthesize new colchicine derivatives (KR compounds). In rat cardiac and pancreatic islet allograft, long-term graft survival was identified in KR compound-treated groups. The use of cyclosporine A (CsA) or colchicine inhibited the CD3 + and CD4 + T-cell proliferation, whereas KR compounds inhibited the CD8 + T cells as well as CD4 + T cells. KR compounds reduced the apoptosis, interleukin-2 receptor expression, and signal transducer and activator of transcription 3 phosphorylation more than CsA. These results indicate that KR compounds have a potential therapeutic value as novel agents for prevention of graft deterioration by allograft of rejection., (© 2019 Wiley Periodicals, Inc.)

Purpose: Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. We tested whether quantification of urinary TG2 may represent a noninvasive method to estimate the severity of kidney allograft fibrosis., Methods: We prospectively collected urine specimens from 18 deceased donor kidney transplant recipients at 1-day, 7-day, 1-month, 3-month, and 6-month posttransplant. In addition, kidney allograft tissue specimens at 0-day and 6-month posttransplant were sampled to analyze the correlation of urinary TG2 and kidney allograft fibrosis., Results: Thirteen recipients had increased interstitial fibrosis and tubular atrophy (IFTA) scores at the 6-month protocol biopsy (IFTA group). The mean level of urinary TG2 in the IFTA group was higher compared to that of 5 other recipients without IFTA (no IFTA group). Conversely, the mean level of urinary syndecan-4 in the IFTA group was lower than levels in patients without IFTA. In the IFTA group, double immunofluorescent staining revealed that TG2 intensity was significantly upregulated and colocalizations of TG2/heparin sulfate proteoglycan and nuclear syndecan-4 were prominent, usually around tubular structures., Conclusion: Urinary TG2 in early posttransplant periods is a potent biomarker for kidney allograft inflammation or fibrosis., Competing Interests: CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.