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Study Objective: This study aimed to analyze the effects of two volatile anesthetic agents, desflurane and sevoflurane, on graft outcomes in patients undergoing deceased donor liver transplantation (DDLT) for cirrhosis, with a specific focus on fatty grafts., Design: A retrospective observational study., Setting: A tertiary hospital (Severance Hospital, Korea)., Patients: This study included 151 patients with liver cirrhosis who underwent DDLT for cirrhosis between January 2006 and December 2022., Interventions: Patients were grouped according to maintenance anesthesia received (desflurane or sevoflurane), the model for end-stage liver disease (MELD) score, and macrovesicular steatosis (MVS) of the liver graft., Measurements: Survival curves were constructed from the date of surgery to graft failure or death. After propensity score matching (PSM), Cox regression analysis was used to compare hazards ratios (HR) for 5-year graft and overall survival. Subgroup analyses were performed for the MELD score and MVS of the liver graft. Incidences of 1-month acute rejection and early allograft dysfunction (EAD) were also compared between the two groups., Main Results: Among 151 eligible patients, 49 patients remained in each group after PSM, with 14 (28.6 %) graft failures and deaths occurring in each group. In matched analysis, sevoflurane showed poorer 5-year graft and overall survival compared to desflurane in recipients of graft with ≥10 % MVS, and this trend was significant in patients with MELD score of ≥35. In Cox regression model, compared to desflurane sevoflurane showed a propensity score-matched HR of 5.8 (95 % CI, 1.13-30.50 for both 5-year graft and overall survival. Additionally, sevoflurane showed an increased risk of 1-month acute rejection; however, no difference was observed for EAD., Conclusions: Sevoflurane as a maintenance agent during DDLT in recipients with high MELD scores and fatty grafts may be associated with poorer outcomes compared to desflurane., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The aim of this systematic review and meta-analysis was to evaluate the effects of volatile anesthesia (VA) on early clinical outcomes in liver transplantation., Methods: We searched electronic databases to identify relevant studies comparing VA to non-VA in liver transplant recipients. The primary outcome assessed was early allograft dysfunction (EAD), and secondary outcomes were postoperative peak liver function tests (LFT) including aspartate transaminase (AST) and alanine transaminase (ALT) levels, and hospitalization time., Results: Six relevant studies involving 919 patients were analyzed. In meta-analysis of prospective studies, VA was associated with fewer incidence of EAD than non-VA (RR: 0.45; 95% CI: 0.25, 0.84; P = .012; I 2 = 0%; P h = 0.334) but this association was not significant in meta-analysis of retrospective studies (OR: 0.83; 95% CI: 0.58, 1.19; P = .310; I 2 = 0%; P h = 0.624). No significant difference in peak AST (SMD: -0.14 U/L; 95% CI: -0.65, 0.37 U/L; P = .594; I 2 = 69.9%; P h = 0.036) and ALT (SMD: -0.16 U/L; 95% CI: -0.65, 0.33 U/L; P = .529; I 2 = 67.0%; P h = 0.048) were found between VA and non-VA. The hospitalization time also did not differ between the two groups (SMD: -0.09 days; 95% CI: -0.29, 0.10 days; P = .350; I 2 = 0%; P h = 0.864)., Conclusions: While there is potential protective effect of VA against EAD in liver transplant recipients, certainty remains low, whereas VA was not associated with postoperative LFT or hospitalization time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Although ABO-incompatible liver transplantation (ABOi LT) has undergone remarkable progress, the prognostic factors are poorly understood. This study aimed to elucidate the preoperative factors affecting graft survival after ABOi LT., Methods: Patients who underwent ABOi LT between January 2012 and December 2020 at a single institution in South Korea were retrospectively reviewed. A total of 146 recipients, including 34 patients with graft loss, were analyzed., Results: In the multivariate Cox proportional hazard model, recipient age (≥55 y; hazard ratio, 2.47; 95% confidence interval, 1.18-5.19; P = 0.017) and donor ABO type (donor A, hazard ratio, 3.12; 95% confidence interval, 1.33-7.33; P = 0.009) were significantly associated with an increased risk of graft loss. The most common cause of graft loss was recipient death due to bacterial infection (15/34, 44.1%). Both recipient age and donor ABO type were associated with an increased risk of recipient death due to bacterial infections. The incidence of complications after ABOi LT, including antibody-mediated rejection and diffuse intrahepatic biliary stricture, did not differ according to recipient age or donor ABO type., Conclusions: These findings suggest that recipient age and donor ABO type should be considered when preparing for ABOi LT. Careful monitoring and care after transplantation are required for recipients with preoperative risk factors., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Although polyethylene terephthalate (PET) fibers are a representative form of plastic pollutants, studies on their toxicity are currently limited compared to other plastic types. Moreover, the effect of natural organic matter (NOM) on their toxicity has not been investigated. In this study, female and male adult zebrafish were exposed to synthesized PET fibers at concentrations of 0.1, 1, 10, and 100 mg/L in the presence and absence of 10 mg/L of NOM for 10 d. Bioaccumulation of PET fibers in zebrafish intestine, liver, and gills was identified and expression levels of reactive oxygen species (ROS) generation, sex hormones, and oxidative stress and sex hormone-related genes were measured. In addition, the developmental stages of gonadal cells were examined through histological analysis. We found that PET fibers bioaccumulated in the intestine and liver of zebrafish. ROS generation significantly increased at 100 mg/L of PET fibers, the expression of oxidative stress-related genes decreased in female and increased in male zebrafish. Exposure to 100 mg/L of PET fibers did not affect 17-beta estradiol, but significantly decreased the testosterone levels in male zebrafish. Sex hormone-related genes significantly decreased in both female and male zebrafish, except for androgen receptor in female zebrafish. However, these changes were exacerbated by the removal of NOM, suggesting a protective effect of NOM against PET fibers toxicity. We demonstrated that the accumulated PET fibers may lead to oxidative stress and sex hormone alteration, and disrupt the development of gonadal cells. Additionally, the NOM coating did not alter bioaccumulation considerably, but mitigated the adverse effects at the hormone level in PET fiber-exposed zebrafish. Thus, this study provides a basis for further research on the toxicity assessment of PET fibers and interactions between NOM and PET fiber-related toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Bacterial infections are major complications that cause significant mortality and morbidity in living donor liver transplantation (LDLT). The risk of bacterial infection has not been studied in ABO-incompatible (ABOi) recipients with a desensitization protocol in relation to the number of plasma exchanges (PEs). Therefore, we aimed to analyze the risk of bacterial infection in ABOi LDLT recipients with a high number of PEs compared with recipients with a low number of PEs., Methods: A retrospective study was performed with 681 adult LDLT recipients, of whom 171 ABOi LDLT recipients were categorized into the high (n = 52) or low (n = 119) PE groups based on a cutoff value of 6 PE sessions. We compared bacterial infections and postoperative bacteremia within 6 mo after liver transplantation with the ABO-compatible (ABOc) LDLT group (n = 510) as a control group., Results: The high PE group showed a bacterial infection rate of 49.9% and a postoperative bacteremia rate of 28.8%, which were significantly higher than those of the low PE group (31.1%, 17.8%) and the ABOc group (26.7%, 18.0%). In multivariate analysis, the high PE group was found to have a 2.4-fold higher risk of bacterial infection ( P  = 0.008). This group presented a lower 5-y survival rate of 58.6% compared with the other 2 groups (81.5% and 78.5%; P  = 0.030 and 0.001)., Conclusions: A high number of preoperative PEs increases bacterial infection rate and postoperative bacteremia in ABOi LDLT., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adapted immune cells are known to develop memory functions that increase resistance to subsequent infections after initial pathogen exposure, however, it is unclear whether non-immune cells, like tissue-resident stem cells, have similar memory functions. Here, it is found that tissue-resident stem cells crucial for tissue regeneration show diminished adverse effects on diverse stem cell functions against successive exposure to foreign antigen (β-glucan) to maintain tissue homeostasis and stability both in vitro and in vivo. These data suggest that endometrial stem cells may possess a robust memory function, in contrast, fully differentiated cells like fibroblasts and vesicular cells do not show these memory mechanisms upon consecutive antigen exposure. Moreover, the pivotal role of Angiopoietin-like 4 (ANGPTL4) in regulating the memory functions of endometrial stem cells is identified through specific shRNA knockdown in vitro and knockout mice in vivo experiments. ANGPTL4 is associated with the alteration of diverse stem cell functions and epigenetic modifications, notably through histone H3 methylation changes and two pathways (i.e., PI3K/Akt and FAK/ERK1/2 signaling) upon consecutive antigen exposure. These findings imply the existence of inherent self-defense mechanisms through which local stem cells can adapt and protect themselves from recurrent antigenic challenges, ultimately mitigating adverse consequences., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Seizures are a frequent neurological consequence following liver transplantation (LT), however, research on their clinical impact and risk factors is lacking. Using a nested case-control design, patients diagnosed with seizures (seizure group) within 1-year post-transplantation were matched to controls who had not experienced seizures until the corresponding time points at a 1:5 ratio to perform survival and risk factor analyses. Seizures developed in 61 of 1,243 patients (4.9%) at median of 11 days after LT. Five-year graft survival was significantly lower in the seizure group than in the controls (50.6% vs. 78.2%, respectively, p < 0.001) and seizure was a significant risk factor for graft loss after adjusting for variables (HR 2.04, 95% CI 1.24-3.33). In multivariable logistic regression, body mass index <23 kg/m 2 , donor age ≥45 years, intraoperative continuous renal replacement therapy and delta sodium level ≥4 mmol/L emerged as independent risk factors for post-LT seizure. Delta sodium level ≥4 mmol/L was associated with seizures, regardless of the severity of preoperative hyponatremia. Identifying and controlling those risk factors are required to prevent post-LT seizures which could result in worse graft outcome., 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 Kang, Koh, Kim, Yim, Choi, Min, Lee, Kim and Joo.)

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease processes. However, it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical outcomes. Here, we conducted a time-dependent multi-omics integration (TDMI) in a sepsis-associated liver dysfunction (SALD) model. We successfully deduced the relation of the Toll-like receptor 4 (TLR4) pathway with SALD. Although TLR4 is a critical factor in sepsis progression, it is not specified in single-omics analyses but only in the TDMI analysis. This finding indicates that the TDMI-based approach is more advantageous than single-omics analyses in terms of exploring the underlying pathophysiological mechanism of SALD. Furthermore, TDMI-based approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology, health, and diseases, thus allowing the identification of promising candidates for therapeutic strategies., (Copyright © 2023 The Authors. Published by Elsevier B.V. and Science Press on behalf of Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation and Genetics Society of China. Published by Elsevier B.V. All rights reserved.)

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).)

Background: Although acetylsalicylic acid has been widely used for decades to treat and prevent various diseases, its potential effects on endometrial receptivity and subsequent pregnancy rates are still controversial due to conflicting data: many reports have shown positive effects of acetylsalicylic acid, whereas others have found that it has no effect. Furthermore, the direct effects of acetylsalicylic acid on various functions of normal endometrial cells, especially endometrial stem cells, and their underlying molecular mechanisms have not yet been proven. Recently, studies have revealed that a reduced number of active stem/progenitor cells within endometrial tissue limits cyclic endometrial regeneration and subsequently decreases pregnancy success rates, suggesting that endometrial stem cells play a critical role in endometrial regeneration and subsequent endometrial receptivity., Methods: We assessed whether aspirin treatment can inhibit various endometrial stem cell functions related to regenerative capacity, such as self-renewal, migration, pluripotency/stemness, and differentiation capacity, in vitro. Next, we evaluated whether SERPINB2 regulates the effects of aspirin on endometrial stem cell functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. To further investigate whether aspirin also inhibits various endometrial stem cell functions in vivo, aspirin was administered daily to mice through intraperitoneal (i.p.) injection for 7 days., Results: In addition to its previously identified roles, to the best of our knowledge, we found for the first time that acetylsalicylic acid directly inhibits various human endometrial stem cell functions related to regenerative capacity (i.e., self-renewal, migration, differentiation, and capacity) through its novel target gene SERPINB2 in vitro. Acetylsalicylic acid exerts its function by suppressing well-known prosurvival pathways, such as Akt and/or ERK1/2 signaling, through a SERPINB2 signaling cascade. Moreover, we also found that acetylsalicylic acid markedly inhibits regenerative capacity-related functions in endometrial stem cells within tissue., Conclusions: We have found that acetylsalicylic acid has diverse effects on various endometrial stem cell functions related to regenerative capacity. Our findings are a critical step toward the development of more effective therapeutic strategies to increase the chances of successful pregnancy. Video Abstract., (© 2023. The Author(s).)

Background: The benefits of living-donor liver transplantation (LDLT) in patients with a high Model for End-stage Liver Disease (MELD) score (who have high waitlist mortality) are unclear. Regional availability of deceased-donor organs must be considered when evaluating LDLT benefits. The authors aimed to compare the survival benefit of intended-LDLT to awaiting deceased-donor liver transplantation (DDLT) in patients with a MELD score greater than or equal to 30 in a region with severe organ shortage., Materials and Methods: This retrospective review included 649 patients with a MELD score greater than or equal to 30 placed on the liver transplantation waitlist. They were divided into intended-LDLT ( n =205) or waiting-DDLT ( n =444) groups based on living-donor eligibility and compared for patient survival from the time of waitlisting. Post-transplantation outcomes of transplant recipients and living donors were analyzed., Results: Intended-LDLT patients had higher 1-year survival than waiting-DDLT patients (53.7 vs. 28.8%, P <0.001). LDLT was independently associated with lower mortality [hazard ratio (HR), 0.62; 95% CI, 0.48-0.79; P <0.001]. During follow-up, 25 patients were de-listed, 120 underwent LDLT, 170 underwent DDLT, and 334 remained on the waitlist. Among patients undergoing transplantation, the risk of post-transplantation mortality was similar for LDLT and DDLT after adjusting for pretransplantation MELD score (HR, 1.86; 95% CI, 0.73-4.75; P =0.193), despite increased surgical complications after LDLT (33.1 vs. 19.4%, P =0.013). There was no mortality among living-donors, but 4.2% experienced complications of grade 3 or higher., Conclusions: Compared to awaiting DDLT, LDLT offers survival benefits for patients with a MELD score greater than or equal to 30, while maintaining acceptable donor outcomes. LDLT is a feasible treatment for patients with a MELD score greater than or equal to 30 in regions with severe organ shortages., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Unusual grafts, including extended left liver plus caudate lobe, right anterior section, and right posterior section grafts, are alternatives to left and right lobe grafts for living-donor liver transplantation. This study aimed to investigate unusual grafts from the perspectives of recipients and donors., Methods: From 2016 to 2021, 497 patients received living-donor liver transplantation at Severance Hospital. Among them, 10 patients received unusual grafts. Three patients received extended left liver plus caudate lobe grafts, two patients received right anterior section grafts, and five patients received right posterior section grafts. Liver volumetrics and anatomy were analyzed for all recipients and donors. We collected data on laboratory examinations (alanine aminotransferase, total bilirubin, international normalized ratio), imaging studies, graft survival, and complications. A 1:2 ratio propensity-score matching method was used to reduce selection bias and balance variables between the unusual and conventional graft groups., Results: The median of Model for End-stage Liver Disease score of unusual graft recipients was 13.5 (interquartile range 11.5-19.3) and that of graft-recipient weight ratio was 0.767 (0.7-0.9). ABO incompatibility was observed in four cases. The alanine aminotransferase level, total bilirubin level, and international normalized ratio decreased in both recipients and donors. Unusual and conventional grafts had similar survival rates (p = 0.492). The right and left subgroups did not differ from each counter-conventional subgroup (p = 0.339 and p = 0.695, respectively). The incidence of major complications was not significantly different between unusual and conventional graft recipients (p = 0.513). Wound seromas were reported by unusual graft donors; the complication ratio was similar to that in conventional graft donors (p = 0.169)., Conclusion: Although unusual grafts require a complex indication, they may show feasible surgical outcomes for recipients with an acceptable donor complication., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The molecular mechanism of perfluorobutanesulfonic acid (PFBS), an alternative to legacy perfluorooctanesulfonic acid (PFOS), is not fully understood yet. Therefore, we conducted a developmental toxicity evaluation on zebrafish embryos exposed to PFBS and PFOS and assessed neurobehavioral changes at concentrations below each point of departure (POD) determined by embryonic mortality. Using transcriptomics, proteomics, and metabolomics, biomolecular perturbations in response to PFBS were profiled and then integrated for comparison with those for PFOS. Although PFBS (7525.47 μM POD) was approximately 700 times less toxic than PFOS (11.42 μM POD), altered neurobehavior patterns and affected kinds of endogenous neurochemicals were similar between PFBS and PFOS at the corresponding POD-based concentrations. Multi-omics analysis revealed that the PFBS neurotoxicity mechanism was associated with oxidative stress, lipid metabolism, and glycolysis/glucogenesis. The commonalities in developmental neurotoxicity-related mechanisms between PFBS and PFOS interconnected by knowledge-based integration of multi-omics included the calcium signaling pathway, lipid homeostasis, and primary bile acid biosynthesis. Despite being less toxic than PFOS, PFBS exhibited similar dysregulated molecular mechanisms, suggesting that chain length differences do not affect the intrinsic toxicity mechanism. Overall, carefully managing potential toxicity of PFBS can secure its status as an alternative to PFOS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The model for end-stage liver disease 3.0 (MELD3.0) is expected to address the flaws of the current allocation system for deceased donor liver transplantation (DDLT). We aimed to validate MELD3.0 in the Korean population where living donor liver transplantation is predominant due to organ shortages., Methods: Korean large-volume single-centric waitlist data were merged with the Korean Network for Organ Sharing (KONOS) data. The 90-day mortality was compared between MELD and MELD3.0 using the C-index in 2,353 eligible patients registered for liver transplantation. Patient numbers and outcomes were compared based on changes in KONOS-MELD categorization using MELD3.0. Possible gains in MELD points and reduced waitlist mortality were analyzed., Results: MELD3.0 performed better than MELD (C-index 0.893 for MELD3.0 vs. 0.889 for MELD). When stratified according to the KONOS-MELD categories, 15.9% of the total patients and 35.2% of the deceased patients were up-categorized using MELD3.0 versus MELD categories. The mean gain of MELD points was higher in women (2.6 ± 2.1) than men (2.1 ± 1.9, P < 0.001), and higher in patients with severe ascites (3.3 ± 1.8) than in controls (1.9 ± 1.8, P < 0.001); however, this trend was not significant when the MELD score was higher than 30. When the possible increase in DDLT chance was calculated via up-categorizing using MELD3.0, reducible waitlist mortality was 2.7%., Conclusion: MELD3.0 could predict better waitlist mortality than MELD; however, the merit for women and patients with severe ascites is uncertain, and reduced waitlist mortality from implementing MELD3.0 is limited in regions suffering from organ shortage, as in Korea., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias., Methods: Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling., Results: Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not., Conclusion: Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The risk factors for late-onset Pneumocystis jirovecii pneumonia (PCP) after liver transplantation (LT) have not been well studied. We aimed to analyze the clinical features preceding PCP in LT recipients that would guide individualized prophylaxis., Methods: Among 742 patients who underwent LT and routine PCP prophylaxis from January 2009 through December 2019 at Severance Hospital, 27 patients developed PCP. We conducted a retrospective case-control study matching each patient with four controls and analyzed the risk factors for late-onset PCP., Results: After 6 months, post-transplant PCP cases increased steadily with an overall incidence of 6.36 cases per 1000 patient-year. The PCP-related mortality was 37.0%. In the multivariate analyses, age at LT ≥65 years (odds ratio [OR], 13.305; 95% confidence interval [CI], 2.507-70.618; P = 0.002), cytomegalovirus infection (OR, 5.390; 95% CI, 1.602-18.132; P = 0.006), steroid pulse therapy (OR, 6.564; 95% CI, 1.984-21.719; P = 0.002), hepatocellular carcinoma recurrence (OR, 18.180; 95% CI, 3.420-96.636; P = 0.001), and lymphocytopenia (OR, 3.758; 95% CI, 1.176-12.013; P = 0.026) were independently associated with PCP., Conclusion: Late-onset PCP after routine prophylaxis after LT remains a lethal infection and is associated with age ≥65 years at LT, cytomegalovirus infection, steroid pulse therapy, hepatocellular carcinoma recurrence, and lymphocytopenia. Targeted prophylaxis considering these risk factors could improve the prevention of this potentially lethal complication., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Carbapenem-resistant Acinetobacter baumannii bacteremia (CRAB-B) is a fatal infectious complication of liver transplantation (LT). This study investigated the incidence, effects, and risk factors associated with CRAB-B during the early post-LT period. Among 1051 eligible LT recipients, 29 patients experienced CRAB-B within 30 days of LT with a cumulative incidence of 2.7%. In the patients with CRAB-B (n = 29) and matched controls (n = 145) by nested-case control design, the cumulative incidence of death on days 5, 10, and 30 from the index date was 58.6%, 65.5%, and 65.5%, and 2.1%, 2.8%, and 4.2%, respectively (p < .001). Pre-transplant MELD (OR 1.11, 95% confidence interval [CI] 1.04-1.19, p = .002), severe encephalopathy (OR 4.62, 95% CI 1.24-18.61, p = .025), donor body mass index (OR .57, 95% CI .41-.75, p < .001), and reoperation (OR 6.40, 95% CI 1.19-36.82, p = .032) were independent risk factors for 30-day CRAB-B. CRAB-B showed extremely high mortality within 30 days after LT, especially within 5 days after its occurrence. Therefore, assessment of risk factors and early detection of CRAB, followed by proper treatment, are necessary to control CRAB-B after LT., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Extracorporeal membrane oxygenation (ECMO) has emerged as an alternative treatment to conventional ventilation maneuvers in the nontransplantation literature to support acute respiratory distress syndrome. However, the role of ECMO in transplant is unclear, and few case reports have described using ECMO pretransplant. We discuss the successful use of veno-arteriovenous ECMO as a bridge therapy to deceased donor liver transplant (LT) in acute respiratory distress syndrome. Because the incidence of severe pulmonary complications resulting in acute respiratory distress syndrome with multiorgan failure is rare before LT, determining the usefulness of ECMO is challenging. However, in acute but reversible respiratory failure and cardiovascular failure, veno-arteriovenous ECMO provides a useful therapeutic option as a bridge for patients awaiting LT and should be considered if available even in multiorgan failure., Competing Interests: DISCLOSURE All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cytomegalovirus (CMV), a common pathogen, causes infectious complications and affects long-term survival after transplantation. Studies examining living donor liver transplantation (LDLT) are limited. This study analyzed the risk factors for CMV infection and its impact on the survival of LDLT patients. A nested case-control design retrospectively analyzed data from 952 patients who underwent LDLT from 2005-2021. The incidence of CMV infection for the study cohort was 15.2% at 3 months for LDLT patients managed preemptively. Patients with CMV infections were matched with those without the infection at corresponding time points (index postoperative day) in a 1:2 ratio. Graft survival was significantly lower in the CMV infection group than in the control group. CMV infection was an independent risk factor for graft survival in the matched cohort (HR 1.93, p = 0.012). Independent risk factors for CMV infection were female sex (HR 2.4, p = 0.003), pretransplant MELD (HR 1.06, p = 0.004), pretransplant in-hospital stay (HR 1.83, p = 0.030), ABO incompatibility (HR 2.10, p = 0.009), donor macrovesicular steatosis ≥10% (HR 2.01, p = 0.030), and re-operation before index POD (HR 2.51, p = 0.035). CMV infection is an independent survival risk factor, and its risk factors should be included in the surveillance and treatment of CMV infections after LDLT.

Previous studies reported suppressive effects of antiplatelet agents on hepatocellular carcinoma (HCC); however, this has never been assessed in patients who underwent liver transplantation (LT). This retrospective observational study used data from LT recipients with pre-transplant HCC in a single tertiary hospital. The study population was divided into two groups according to the use of antiplatelet agents for >90 days within the study period (377 antiplatelet groups versus 91 non-antiplatelet groups). Matched groups containing 79 patients in each group were also compared regarding HCC-recurrence and HCC-related mortality, which were analyzed by treating non-HCC death as a competing risk. In Kaplan−Meier analyses of the matched cohort, the 5-year cumulative incidences of HCC recurrence and HCC-specific death were similar between the antiplatelet (p = 0.876) and non-antiplatelet groups (p = 0.701). All-cause and non-HCC deaths were also similar between the two groups (p = 0.867 and p = 0.413, respectively). In multivariable analyses of the entire cohort, antiplatelet use was not associated with HCC recurrence (hazard ratio [HR] 1.37, p = 0.300) or HCC-specific death (HR 1.54, p = 0.310). Therefore, unlike the usual setting with liver disease, antiplatelet therapy did not affect HCC recurrence or HCC-specific mortality when used after LT.

Background: Transduodenal ampullectomy (TDA) is performed for adenoma or early cancer of the ampulla of Vater (AoV). This study aimed to analyze the short- and long-term outcomes of TDA (TDA group) when compared with conventional pancreaticoduodenectomy (PD) or pylorus-preserving pancreaticoduodenectomy (PD group)., Methods: Patients who underwent TDA between January 2006 and December 2019, and PD cases performed for AoV malignancy with carcinoma in-situ (Tis) (high-grade dysplasia, HGD) and T1 and T2 stage from January 2010 to December 2019 were reviewed., Results: Forty-six patients underwent TDA; 21 had a benign tumor, and 25 cases with malignant tumors were compared with PD cases (n = 133). Operation time (p < 0.001), estimated blood loss (p < 0.001), length of hospital stays (p = 0.003), and overall complication rate (p < 0.001) were lower in the TDA group than in the PD group. Lymph node metastasis rates were 14.6% in pT1 and 28.9% in pT2 patients. The 5-year disease-free survival and 5-year overall survival rates for HGD/Tis and T1 tumor between the two groups were similar (TDA group vs PD group, 72.2% vs 77.7%, p = 0.550; 85.6% vs 79.2%, p = 0.816, respectively)., Conclusion: TDA accompanied with lymph node dissection is advisable in HGD/Tis and T1 AoV cancers in view of superior perioperative outcomes and similar long-term survival rates compared with PD., (© 2021. The Author(s).)

Limited studies on multi-omics have been conducted to comprehensively investigate the molecular mechanism underlying the developmental neurotoxicity of perfluorooctanesulfonic acid (PFOS). In this study, the locomotor behavior of zebrafish larvae was assessed under the exposure to 0.1-20 μM PFOS based on its reported neurobehavioral effect. After the number of zebrafish larvae was optimized for proteomics and metabolomics studies, three kinds of omics (i.e., transcriptomics, proteomics, and metabolomics) were carried out with zebrafish larvae exposed to 0.1, 1, 5, and 10 μM PFOS. More importantly, a data-driven integration of multi-omics was performed to elucidate the toxicity mechanism involved in developmental neurotoxicity. In a concentration-dependent manner, exposure to PFOS provoked hyperactivity and hypoactivity under light and dark conditions, respectively. Individual omics revealed that PFOS exposure caused perturbations in the pathways of neurological function, oxidative stress, and energy metabolism. Integrated omics implied that there were decisive pathways for axonal deformation, neuroinflammatory stimulation, and dysregulation of calcium ion signaling, which are more clearly specified for neurotoxicity. Overall, our findings broaden the molecular understanding of the developmental neurotoxicity of PFOS, for which multi-omics and integrated omics analyses are efficient for discovering the significant molecular pathways related to developmental neurotoxicity in zebrafish., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Burns are painful injuries associated with a long recovery. Patients may not be receiving sufficient pain management education to optimize their experience and recovery after burn injury. Therefore, we aimed to obtain patients' perspectives about the effectiveness of current burn pain education to inform future efforts., Methods: We used a mixed-methods research design that included both inpatients and outpatients cared for at a single, American Burn Association-verified burn center. Participants were at least 14 years of age with an acute burn who received a minimum of two wound interventions. The interview was designed by clinician stakeholders using a modified Delphi technique and focused on patient respondent's pain experience, understanding and desire to gain knowledge concerning burn pain and its management. Descriptive quantitative analysis was performed on categorical data. Recorded interview segments were transcribed for content analysis., Results: Twenty-one adult burn patients were interviewed. Participants reported experiencing variable levels of pain and pain management effectiveness. Inpatients reported more severe pain than outpatients. Only 11% of inpatients reported having received enough pain information, compared to 50% of outpatients. Content analysis yielded 3 themes: patient's pain experience, range of expectations, and clinical information/services desired. Mental and physical effects were key factors in respondents' pain experiences, with many participants reporting mental anguish in addition to pain. Of participants who had pain expectations, most were matched by their experience (56%), although many individuals (44%) described higher pain levels than they anticipated. Positive experiences with the burn care team primarily revolved around receiving pain education from a provider, whereas negative experiences focused on wound care events. Participants desired more information on sleep and pain medications, alternative treatments, weaning and addiction risk, realistic expectations of recovery timelines, and available mental health services. Written (pamphlet) education ranked as the most desirable delivery method, followed by in-person and video education., Conclusions: Burn patients reported variable pain experiences and a strong desire to receive additional pain education. This project informs key strategies to educate burn patients on pain: leverage the high-level of interest in pain to foster education, describe pharmacologic and alternative therapies, offer weaning plans and explanation of addiction risks., Applicability to Practice: Burn patients' perspectives help inform strategies and content creation for pain-related education materials that burn centers can provide to improve patients' experiences., External Funding: Project was supported in part by the NIH grant for Insight Student Research Program at the Harborview Injury Prevention and Research Center (R25 HD094336)., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Evidence suggests that tumor cells and tumor-infiltrating lymphocytes (TILs) compete for glucose in the tumor microenvironment and that tumor metabolic parameters correlate with localized immune markers in several solid tumors. We investigated the relationship of the standardized uptake value (SUV) of 18 F-fluorodeoxyglucose positron emission tomography computed tomography ( 18 F-FDG-PET-CT) with stromal TIL levels in breast cancer. We included 202 patients who underwent preoperative 18 F-FDG-PET-CT and had a tumor measuring ≥ 1 cm. Maximum SUV (SUVmax) was determined using 18 F-FDG-PET-CT. Multiple logistic regression was used to identify factors related to high TIL levels (≥ 40%). All tumors were treatment naïve. A significant and weak correlation existed between continuous SUVmax and continuous TIL levels (p = 0.002, R = 0.215). Tumors with high SUVmax (≥ 4) had higher mean TIL levels than those with low SUVmax (< 4). In multivariable analysis, continuous SUVmax was an independent factor associated with high TIL levels; each 1-unit increment in SUVmax corresponded to an odds ratio of 1.14 (95% confidence interval: 1.01-1.29) for high TIL levels. Our study implies that SUV is associated with TILs in breast cancer and provides clinical evidence that elevated glucose uptake by breast tumors can predict the immune system-activated tumor micromilieu.

In the last decade, several advancements have been made in omics technologies and they have been applied extensively in diverse research areas. Especially in toxicological research, omics technology can efficiently and accurately generate relevant data on the molecular dynamics associated with adverse outcomes. Toxicomics is defined as the combination of toxicology and omics technologies and encompasses toxicogenomics, toxicoproteomics, and toxicometabolomics. This paper reviews the trend of applying omics technologies to evaluate cadmium (Cd) toxicity in zebrafish ( D. rerio ). Cd is a toxic heavy metal posing several environmental concerns; however, it is being used widely in everyday life. Zebrafish embryos and larvae are employed as standard models for many toxicity tests because they share 71.4% genetic homology with humans. This study summarizes the toxicity of Cd on the nerves, liver, heart, skeleton, etc. of zebrafish and introduces detailed omics techniques to understand the results of the toxicomic studies. Finally, the trend of toxicity evaluation in the zebrafish model of Cd based on omics technology is presented., Competing Interests: Conflict of interestThe authors have no conflict of interest to disclose., (© Korean Society of Toxicology 2021.)

For accurately predicting prognosis and for effectively describing cancer states at a certain point during treatment to other care providers and patients, various staging systems have been utilized in gastric cancer. Among these, the UICC/AJCC tumor-node-metastasis (TNM) staging system is most widely used. However, even within the same substage, gastric cancers can vary substantially in regards to prognosis after treatment. For more accurate and individualized prognostication, staging systems have been found to benefit from including molecular markers and genomic subtypes, in addition to clinicopathological parameters, such as age, sex, tumor size, tumor location, Lauren classification, number of lymph nodes resected, extent of surgical resection, lymphovascular invasion, and adjuvant chemotherapy. In this review article, we review and summarize relevant biomarkers for gastric cancer that can be incorporated into the current anatomy-based TNM staging system, as well as results from validation studies thereof., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Aim: To investigate the association between postoperative pain control and oncologic outcomes in resected pancreatic ductal adenocarcinoma (PDAC)., Methods: From January 2009 to December 2014, 221 patients were diagnosed with PDAC and underwent resection with curative intent. Retrospective review of the patients was performed based on electronic medical records system. One patient without records of numerical rating scale (NRS) pain intensity scores was excluded and eight patients who underwent total pancreatectomy were also excluded. NRS scores during 7 postoperative days following resection of PDAC were reviewed along with clinicopathologic characteristics. Patients were stratified into a good pain control group and a poor pain control group according to the difference in average pain intensity between the early (POD 1, 2, 3) and late (POD 5, 7) postoperative periods. Cox-proportional hazards multivariate analysis was performed to determine association between postoperative pain control and oncologic outcomes., Results: A total of 212 patients were dichotomized into good pain control group ( n = 162) and poor pain control group ( n = 66). Median follow-up period was 17 mo. A negative impact of poor postoperative pain control on overall survival (OS) was observed in the group of patients receiving distal pancreatectomy (DP group; 42.0 mo vs 5.0 mo, P = 0.001). Poor postoperative pain control was also associated with poor disease-free survival (DFS) in the DP group (18.0 mo vs 8.0 mo, P = 0.001). Patients undergoing pancreaticoduodenectomy or pylorus-preserving pancreaticoduodenectomy (PD group) did not show associations between postoperative pain control and oncologic outcomes. Poor patients' perceived pain control was revealed as an independent risk factor of both DFS (HR = 4.157; 95%CI: 1.938-8.915; P < 0.001) and OS (HR = 4.741; 95%CI: 2.214-10.153; P < 0.001) in resected left-sided pancreatic cancer., Conclusion: Adequate postoperative pain relief during the early postoperative period has important clinical implications for oncologic outcomes after resection of left-sided pancreatic cancer., Competing Interests: Conflict-of-interest statement: All authors have no financial relationships to disclose.

Although both glucose deprivation and hypoxia have been reported to promote cascades of biological alterations that lead to induction of inflammatory mediators, we hypothesized that glucose deprivation and hypoxia might show neutral, synergistic or antagonistic effects to each other on gene expression of inflammatory mediators depending on the regulatory components in their promoters. Gene expression of interleukin 6 (IL-6) was analyzed by real-time PCR, ELISA, or Western blot. Effects of glucose deprivation and/or hypoxia on activation of signaling pathways were analyzed by time-dependent phosphorylation patterns of signaling molecules. We demonstrate that hypoxia antagonized the effects of glucose deprivation on induction of IL-6 gene expression in microglia, macrophages, and monocytes. Hypoxia also antagonized thapsigargin-induced IL-6 gene expression. Hypoxia enhanced phosphorylation of Akt, and inhibition of Akt was able to reverse the effects of hypoxia on IL-6 gene expression. However, inhibition of HIF-1/2α did not reverse the effects of hypoxia on IL-6 gene expression. In addition, phosphorylation of p38, but not JNK, was responsible for the effects of glucose deprivation on IL-6 gene expression.