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Preoperative neutrophil–lymphocyte ratio (NLR), has shown a predictive value in living donor liver transplantation (LDLT). However, the change in the NLR during LDLT has not been fully investigated. We aimed to compare graft survival between the NLR increase and decrease during LDLT. From June 1997 to April 2019, we identified 1292 adult LDLT recipients with intraoperative NLR change. The recipients were divided according to NLR change: 103 (8.0%) in the decrease group and 1189 (92.0%) in the increase group. The primary outcome was graft failure in the first year. In addition, variables associated with NLR change during LDLT were evaluated. During 1-year follow-up, graft failure was significantly higher in the decrease group (22.3% vs. 9.1%; hazard ratio 1.87; 95% confidence interval 1.10–3.18; p  = 0.02), but postoperative complications did not differ between two groups. This finding was consistent for the overall follow-up. Variables associated with NLR decrease included preoperative NLR > 4, model for end-stage liver disease score, intraoperative inotropic infusion and red blood cell transfusion, and operative duration. The least absolute shrinkage and selection operator model yielded similar results. NLR decrease during LDLT appeared to be independently associated with graft survival. Further studies are needed to confirm our findings.

Despite various intraoperative thermal strategies, core heat loss is considerable during liver transplantation and hypothermia is common. We tested whether forced-air prewarming prevents hypothermia during liver transplantation. Adult patients undergoing living donor liver transplantation were randomly assigned to non-prewarming group ( n  = 20) or prewarming group ( n  = 20). Patients in prewarming group underwent 30-min forced-air warming before anesthetic induction. During surgery, core temperature was measured in the pulmonary artery. The primary outcome was intraoperative hypothermia (< 36.0 °C). The secondary outcomes included plasma lactate concentration. Intraoperative hypothermia risk was significantly lower in prewarming group than in non-prewarming group (60.0% vs. 95.0%, P  = 0.020). The difference in hypothermia incidence between groups was greater in the post-induction phase (20.0% vs. 85.0%, P  < 0.001) than in the anhepatic or post-reperfusion phase, suggesting that prewarming mainly acts on preventing post-induction core-to-peripheral heat redistribution. Hypothermia duration was significantly shorter in prewarming group (60 [0–221] min vs. 383 [108–426] min, P  = 0.001). Lactate concentration decreased during 3 h after graft reperfusion in prewarming group, whereas it continuously increased in non-prewarming group (− 0.19 [− 0.48 to 0.13] mmol/L vs. 1.17 [3.31–0.77] mmol/L, P  = 0.034). In conclusion, forced-air prewarming decreases the incidence and duration of intraoperative hypothermia with potential clinical benefit while mainly acting by preventing the core-to-peripheral heat redistribution. Clinical trial registration : Registered at the Clinical Research Information Service ( https://cris.nih.go.kr , [KCT0003230]) on 01/10/2018.

Pure laparoscopic donor right hepatectomy (PLDRH) is not a standard procedure for living donor liver transplantation but is safe and reproducible in the hands of experienced surgeons. However, the perioperative outcomes of PLDRH have not been fully evaluated yet. We used propensity score matching to compare the perioperative complications and postoperative short-term outcomes of donors undergoing PLDRH and open donor right hepatectomy (ODRH). A total of 325 consecutive donors who underwent elective, adult-to-adult right hepatectomy were initially screened. After propensity score matching, all patients were divided into two groups: PLDRH (n = 123) and ODRH (n = 123) groups. Perioperative complications and postoperative outcomes were compared between the two groups. Postoperative pulmonary complications were significantly more common in the ODRH than in the PLDRH group (54.5 vs. 31.7%, P  < 0.001). The biliary complications (leak and stricture) were higher in PLDRH group than in the ODRH group (8% vs. 3%), but it failed to reach statistical significance ( P  = 0.167). Overall, surgical complication rates were similar between the two groups ( P  = 0.730). The opioid requirement during the first 7 postoperative days was higher in the ODRH group (686 vs. 568 mg, P  < 0.001). The hospital stay and time to the first meal were shorter in the PLDRH than in the ODRH group ( P  = 0.003 and P  < 0.001, respectively). PLDRH reduced the incidence of postoperative pulmonary complications and afforded better short-term postoperative outcomes compared to ODRH. However, surgical complication rates were similar in both groups.

Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage. Osteoarthritis results from the progressive destruction of cartilage matrix. Here, Kim et al. identify tankyrase as a regulator of cartilage matrix anabolism, and find that tankyrase inhibition, by preventing SOX9 PARylation, protects from cartilage destruction in a mouse model of osteoarthritis.

This study sought to evaluate the association between newly-developed significant hypercholesterolemia within one year following living donor liver transplantation (LDLT) and long term outcomes in light of cardiovascular events and graft failure. From October 2003 to July 2017, 877 LDLT recipients were stratified according to development of significant hypercholesterolemia within one year following LDLT. The primary outcome was occurrence of a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and coronary revascularization after LDLT. The incidence of graft failure, defined as all-cause death or retransplantation, was also compared. A total of 113 (12.9%) recipients developed significant hypercholesterolemia within one year. The differences in incidences of cardiac related events and graft related events began emerging significantly higher in the hypercholesterolemia group after 24 months and 60 months since the LDLT, respectively. After adjustment using the inverse probability of weighting, the hazard ratio (HR) for MACE was 2.77 (95% confidence interval (CI) 1.16–6.61; p  = 0.02), while that for graft failure was 3.76 (95% CI 1.97–7.17, p  < 0.001). A significant hypercholesterolemia after LDLT may be associated with cardiac and graft-related outcome; therefore, a further study and close monitoring of cholesterol level after LDLT is needed.

Decompensated cirrhotic patients experience severely increased intestinal permeability and bacterial translocation. Thus, autologous blood salvaged during deceased donor liver transplantation (DDLT) may be contaminated with enteric bacteria. We aimed to evaluate bacterial contamination of autologous blood salvaged during DDLT and its association with post-transplant bacteremia. In 30 patients undergoing DDLT, bacterial culture was performed in salvaged autologous blood samples: one before graft reperfusion (non-leukoreduced) and two after graft reperfusion (non-leukoreduced and leukoreduced). The primary outcome was bacterial contamination of salvaged autologous blood. Seven of 30 patients (23.3%) were positive for bacteria (3 enteric/4 non-enteric) before graft reperfusion while 11 patients (36.7%) were positive (5 enteric/6 non-enteric) after graft reperfusion. Six of 7 patients who were positive for bacteria before graft reperfusion were positive after graft reperfusion with the same bacteria. Only 4 of 11 contaminated blood samples were converted to negative after leukoreduction. Post-transplant bacteremia risk was insignificantly greater in patients who received autologous blood with bacteria than in patients without bacteria (30.0% vs. 5.0%, P  = 0.06). We found contamination of salvaged autologous blood with enteric bacteria throughout DDLT and incomplete performance of leukoreduction, indicating high bacterial load. The potential association between contaminated autotransfusion and post-transplant bacteremia warrants further validation in a larger prospective study. Clinical trial notation : This study was registered at the Clinical Research Information Service (CRiS; https://cris.nih.go.kr ; No. KCT0007223; principal registration investigator: Sangbin Han, date of registration: April 25, 2022).

Greater graft-failure-risk of female-to-male liver transplantation (LT) is thought to be due to acute decrease in hepatic-estrogen-signaling. Our previous research found evidence that female hepatic-estrogen-signaling decreases after 40 years or with macrosteatosis. Thus, we hypothesized that inferiority of female-to-male LT changes according to donor-age and macrosteatosis. We stratified 780 recipients of grafts from living-donors into four subgroups by donor-age and macrosteatosis and compared graft-failure-risk between female-to-male LT and other LTs within each subgroup using Cox model. In recipients with ≤ 40 years non-macrosteatotic donors, graft-failure-risk was significantly greater in female-to-male LT than others (HR 2.03 [1.18–3.49], P  = 0.011). Within the subgroup of recipients without hepatocellular carcinoma, the inferiority of female-to-male LT became greater (HR 4.75 [2.02–11.21], P  < 0.001). Despite good graft quality, 1y-graft-failure-probability was 37.9% (23.1%–57.9%) in female-to-male LT within this subgroup while such exceptionally high probability was not shown in any other subgroups even with worse graft quality. When donor was > 40 years or macrosteatotic, graft-failure-risk was not significantly different between female-to-male LT and others ( P  > 0.60). These results were in agreement with the estrogen receptor immunohistochemistry evaluation of donor liver. In conclusion, we found that the inferiority of female-to-male LT was only found when donor was ≤ 40 years and non-macrosteatotic. Abrogation of the inferiority when donor was > 40 years or macrosteatotic suggests the presence of dominant contributors for post-transplant graft-failure other than graft quality/quantity and supports the role of hepatic-estrogen-signaling mismatch on graft-failure after female-to-male LT.

Transfusion-associated graft-versus-host disease (TA-GvHD) is caused by leukocytes, specifically T cells within a transfused blood product. Currently, the prevention of transfusion-associated graft-versus-host disease is performed by irradiation of blood products. With a sufficient reduction of leukocytes, the risk for TA-GvHD can be decreased. With consistent advances in current state-of-the-art blood filters, we herein propose that double filtration can sufficiently reduce leukocytes to reduce the risk for TA-GvHD. Thirty RBC concentrates were filtered with leukocyte filters, followed by storage at 1-6 oC for 72 hours, and then a second filtration was performed. Residual leukocytes in the double-filtered RBC units (n = 30) were assessed with flow cytometric methods, and an additional assay with isolated peripheral blood mononuclear cells (PBMCs) (n = 6) was done by both flow cytometric methods and an automated hematology analyzer. Quality of the RBCs after filtration was evaluated by hematological and biochemical tests. In vitro T cell expansion was performed using anti-CD3/CD28-coated Dynabeads or anti-CD3 (OKT3). In vivo experiment for GvHD was performed by using NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Double-filtered blood products showed residual leukocyte levels below detection limits, which calculated to be below 1200-2500 cells per blood unit. In vitro expansion rate of T cells showed that 6x103 and 1x103 cell-seeded specimens showed 60.8±10.6 fold and 10.2±9.7-fold expansion, respectively. Cell expansion was not sufficiently observed in wells planted with 1x102 or 10 cells. In vivo experiments showed that mice injected with 1x105 or more cells cause fatal GvHD. GvHD induced inflammation was observed in mice injected with 1x104 or more cells. No evidence of GvHD was found in mice injected with 103 cells. Our study suggests that additional removal of contaminating lymphocytes by a second leukodepletion step may further reduce the risk for TA-GvHD.

Measurement of natural killer (NK) cell function has important clinical utility in several diseases. Although the flow cytometry (FC)-based 4-h NK cytotoxicity assay using peripheral blood mononuclear cells (PBMCs) in the clinical laboratory has been used for this purpose, this assay requires large amounts of blood and a rapid PBMC isolation step. Here, we developed an FC-based overnight NK cytotoxicity assay using whole blood (WB), and applied it to patients with liver diseases. Peripheral blood of healthy volunteers ( = 28) and patients with liver diseases, including hepatocellular carcinoma ( = 19) and liver cirrhosis ( = 7), was analyzed for complete blood count, absolute NK cell count, and NK cell activity (NKA). NKA was evaluated in three assay types: an FC-based overnight WB NK cytotoxicity assay using carboxyfluorescein diacetate succinimidyl ester-labeled K562 cells in the presence of various cytokine combinations [including interleukin (IL)-2, IL-18, and IL-21], an FC-based 4-h PBMC NK cytotoxicity assay, and an FC-based CD107a degranulation assay using WB and PBMCs. Optimal cytokine combinations for NK cell activation in WB were determined (IL-2/IL-18, IL-2/IL-21, and IL-2/IL-18/IL-21). A good correlation was observed between WB and PBMC NK cytotoxicity assays; absolute NK cell counts were better correlated with the WB NK cytotoxicity assay than with the PBMC NK cytotoxicity assay. This WB NK cytotoxicity assay showed that patients with liver diseases had significantly lower NK cytotoxicity than healthy volunteers, under stimulation with various cytokines ( < 0.001). The proposed FC-based overnight WB NK cytotoxicity assay correlates well with the conventional 4-h PBMC NK cytotoxicity assay, demonstrating future potential as a supportive assay for clinical laboratory research and observational studies.

Risk factors for postoperative pulmonary complication (PPC) have not been determined according to preoperative respiratory spirometry. Thus, we aimed to find contributors for PPC in patients with restrictive or normal spirometric pattern. We analyzed 654 patients (379 with normal and 275 with restrictive spirometric pattern). PPCs comprised respiratory failure, pleural effusion, atelectasis, respiratory infection, and bronchospasm. We analyzed the association between perioperative factors and PPC using binary logistic regression. In particular, we conducted subgroup analysis on the patients stratified according to preoperative spirometry. Of 654 patients, 27/379 patients (7.1%) with normal spirometric pattern and 33/275 patients (12.0%) with restrictive spirometric pattern developed PPCs. Multivariable analysis demonstrated that high driving pressure was the only intraoperative modifiable factor increasing PPC risk (OR = 1.13 [1.02–1.25], p = 0.025). In the subgroup of patients with restrictive spirometric pattern, intraoperative driving pressure was significantly associated with PPC (OR = 1.21 [1.05–1.39], p = 0.009), whereas driving pressure was not associated with PPC in patients with normal spirometric pattern (OR = 1.04 [0.89–1.21], p = 0.639). In patients with restrictive spirometric pattern, greater intraoperative driving pressure is significantly associated with increased PPC risk. In contrast, intraoperative driving pressure is not associated with PPC in patients with normal spirometric pattern.