A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Increased number and function of endothelial progenitor cells in breast cancer patients and the linear correlation with VEGF level.

The number of circulating endothelial progenitor cells (EPCs) was found to increase in patients with breast cancer, but the alteration in EPC function remains to be elusive. We conducted this study to evaluate the number and function of peripheral EPCs of breast cancer patients and its possible underlying mechanism. Besides, the vascular endothelial growth factor (VEGF), VCAM-1, IL-6, and IL-34 levels were measured in blood samples and also in vitro in a medium of EPCs. We found that the number of circulating EPCs in breast cancer patients was significantly higher than that in normal control and remarkably augmented in a stage-dependent manner. Meanwhile, a similar enhancement was observed in the migratory, proliferative, and adhesive activity of circulating EPCs originating from breast cancer patients. More importantly, the VEGF level in blood samples was dramatically elevated in comparison to the control, which was correlated positively with the number and activity of circulating EPCs from breast cancer patients. Moreover, in vitro medium of EPCs from breast cancer patients highly expressed VEGF compared with that from the control, which also had a positive correlation with the number and activity of circulating EPCs from breast cancer patients. This is the first time to demonstrate that the number and function of circulating EPCs are promoted in breast cancer patients, which are positively related to an enhanced VEGF production. These may provide a novel target for improving the outcome of breast cancer.

Clinical Impacts and Outcomes With Possible Donor-Derived Infection in Infected Donor Liver Transplantation: A Single-Center Retrospective Study in China.

BACKGROUND: Information on possible donor-derived transmission events in China is limited. We evaluated the impacts of liver transplantation from infected deceased-donors, analyzed possible donor-derived bacterial or fungal infection events in recipients, and evaluated the etiologic agents' characteristics and cases outcomes. METHODS: A single-center observational study was performed from January 2015 to March 2017 to retrospectively collect data from deceased-donors diagnosed with infection. Clinical data were recorded for each culture-positive donor and the matched liver recipient. The microorganisms were isolated and identified, and antibiotic sensitivity testing was performed. The pathogens distribution and incidence of possible donor-derived infection (P-DDI) events were analyzed and evaluated. RESULTS: Information from 211 donors was collected. Of these, 82 donors were infected and classified as the donation after brain death category. Overall, 149 and 138 pathogens were isolated from 82 infected donors and 82 matched liver recipients, respectively. Gram-positive bacteria, Gram-negative bacteria, and fungi accounted for 42.3% (63 of 149), 46.3% (69 of 149), and 11.4% (17 of 149) of pathogens in infected donors. The incidence of multidrug-resistant bacteria was high and Acinetobacter baumannii was the most concerning species. Infections occurred within the first 2 weeks after liver transplantation with an organ from an infected donor. Compared with the noninfection recipient group, the infection recipient group experienced a longer mechanical ventilation time (P = .004) and intensive care unit stay (P = .003), a higher incidence of renal dysfunction (P = .026) and renal replacement therapy (P = .001), and higher hospital mortality (P = .015). Possible donor-derived infection was observed in 14.6% of cases. Recipients with acute-on-chronic liver failure were more prone to have P-DDI than recipients with other diseases (P = .007; odds ratio = 0.114; 95% confidence interval, .025-.529). CONCLUSIONS: When a liver recipient receives a graft from an infected deceased-donor, the postoperative incidence of infection is high and the infection interval is short. In addition, when a possible donor-derived, drug-resistant bacterial infection occurs, recipients may have serious complications and poor outcomes.

Improving Intestinal Barrier Function in Sepsis by Partially Hydrolysed Guar Gum via the Suppression of the NF-κB/MLCK Pathway.

Partially hydrolyzed guar gum (PHGG) protects against intestinal barrier dysfunction and can ameliorate some intestinal diseases. However, whether PHGG has a role in protecting intestinal barrier function (IBF) during sepsis remains unclear. This study aimed to investigate the role and probable mechanism of PHGG in the intestinal mucosa in sepsis. A rat sepsis model was constructed using cecal ligation and puncture (CLP). FITC-dextran 4 (FD-4) flux, serum inflammatory mediator levels, tight junction (TJ) levels, jejunum mucosa pathology, and epithelial intercellular junction ultrastructure were monitored to evaluate the effect of PHGG on IBF. Caco-2 monolayers were used to study the impact and mechanism of PHGG on lipopolysaccharide (LPS)-induced barrier dysfunction in vitro. The expression of zonula occludens protein-1 and occludin and the location of P65 were studied by immunofluorescence. Nuclear factor kappa B (NF-κB) and myosin light chain kinase 3 (MLCK) pathway-related protein expression was verified by quantitative reverse transcriptase polymerase chain reaction or western blotting. The results indicated that the jejunal mucosa structure was destroyed, the villi were disrupted and shortened, and neutrophil infiltration was evident in the septic rats. Compared to Sham group, spetic rats had increased Chiu's score, serum inflammatory mediator levels, and FD-4 flux but decreased TJ and gap junction density. In addition, the expression of MLCK, p-MLC, and TJ proteins and the expression of P65 in the nucleus were increased in septic rats. Furthermore, compared to those in the Control group, LPS-treated Caco-2 cells showed lower cell viability and transepithelial electrical resistance, while had higher FD-4 flux and the expression of MLCK, p-MLC, TJ proteins and P65 in the nucleus. PHGG pretreatment reversed the above effects induced by CLP or LPS treatment. Moreover, SN50, an NF-κB inhibitor, attenuated the above effects of LPS on Caco-2 cells. Overall, PHGG reduced inflammation, increased TJ protein expression and localization, and relieved damage to the TJ structure and intestinal permeability through suppression of the NF-κB/MLCK pathway. This study provides new insights into the role of PHGG in sepsis therapy.

Berberine hydrochloride-loaded dung beetle chitosan/sodium alginate microspheres ameliorate DSS-induced colitis and regulate gut microorganisms in mice.

Berberine hydrochloride (BH) has long been known for its therapeutic efficacy. In the present study, we aimed to treat mice with colitis using dung beetle chitosan (DCS) -transported BH. To achieve this, BH-loaded DCS/sodium alginate microspheres (SA-DCS-BH) were prepared. The SA-DCS-BH was characterized using SEM, DLS, FT-IR, and XRD, then was used for administration and anti-inflammatory examination in mice. SEM and DLS confirmed the surface morphology of the microspheres, and the particle size was relatively uniform. FT-IR and XRD results confirmed that BH was successfully loaded. In vitro and in vivo studies showed that SA-DCS-BH had slow-release ability. After treatment with SA-DCS-BH, DAI was significantly reduced, colon weight and length increased, spleen length and weight reduced, concentrations of pro-inflammatory cytokines in colonic tissues were reduced, and gut microbiota species abundance was modulated. In addition, this study found a correlation between specific microbes and colitis indicators, Muribaculaceae showed sequential growth after receiving BH, SA-CS-BH, and SA-DCS-BH treatments, respectively. It was concluded that SA-DCS-BH effectively delivered the BH to the intestine with slow-release ability and exhibited anti-inflammatory effects by immune response. Compared to commercial chitosan, DCS has potential for modulating intestinal microorganisms and more suitable carrier for intestinal drug delivery systems.

Exploring the optimal range of central venous pressure in sepsis and septic shock patients: A retrospective study in 208 hospitals.

BACKGROUND: The aim of this study was to investigate the optimal CVP range in sepsis and septic shock patients admitted to intensive care unit. METHODS: We performed a retrospective study with adult sepsis patients with CVP records based on the eICU Collaborative Research Database. Multivariable logistic regression was performed to explore the associations between CVP level and hospital mortality. Non-linear correlations and optimal CVP range were explored using restricted cubic splines (RCS). RESULTS: A total of 5302 sepsis patients were included in this study. Patients in 4-8 mmHg group owned the lowest odds ratio for raw hospital mortality (19.7%). The logistic regression analyses revealed that hospital death risk increased significantly when mean CVP level exceeds 12 mmHg compared to 4-8 mmHg level. U-shaped association of CVP with hospital mortality was revealed by RCS model in septic shock patients and the optimal range was 5.6-12 mmHg. While, there was a J-shaped trend for non-septic shock patients. For non-septic shock patients, patients had an increased risk of hospital death only if CVP exceeded 11 mmHg. CONCLUSIONS: We observed U-shaped association between mean CVP level and hospital mortality in septic shock patients and J-shaped association in non-septic shock patients. This may imply that patients with different severity of sepsis have different CVP requirements. We need to monitor and manage CVP according to the circulatory status of the sepsis patient.