There is a limited access to liver transplantation, however, many organs are discarded based on subjective assessment only. Here we report the VITTAL clinical trial (ClinicalTrials.gov number NCT02740608) outcomes, using normothermic machine perfusion (NMP) to objectively assess livers discarded by all UK centres meeting specific high-risk criteria. Thirtyone livers were enroled and assessed by viability criteria based on the lactate clearance to levels ≤2.5 mmol/L within 4 h. The viability was achieved by 22 (71%) organs, that were transplanted after a median preservation time of 18 h, with 100% 90-day survival. During the median follow up of 542 days, 4 (18%) patients developed biliary strictures requiring retransplantation. This trial demonstrates that viability testing with NMP is feasible and in this study enabled successful transplantation of 71% of discarded livers, with 100% 90-day patient and graft survival; it does not seem to prevent non-anastomotic biliary strictures in livers donated after circulatory death with prolonged warm ischaemia.

Individuals with cystic fibrosis (CF) are commonly colonized with Pseudomonas aeruginosa. The chronic infections caused by P. aeruginosa are punctuated by acute exacerbations of the lung disease, which lead to significant morbidity and mortality. As regulators of virulence determinants, P. aeruginosa quorum-sensing systems may be active in the chronic lung infections associated with CF. We have examined the levels of autoinducer molecules and transcript accumulation from the bacterial populations found in the lungs of patients with CF. We detected biologically active levels of N-(3-oxododecanoyl)-L-homoserine (3-oxo-C12-HSL) and N-butyryl-L-homoserine lactone (C4-HSL) in sputum from CF patients. Interestingly, it appears that C4-HSL is less frequently detected than 3-oxo-C12-HSL in the lungs of patients with CF. We also examined the transcription of the autoinducer synthase gene lasI and showed that it is frequently expressed in the lungs of patients with CF. We observed a significant correlation between the expression of lasI and four target genes of the Las quorum-sensing system. Taken together, our results indicate that quorum-sensing systems are active and may control virulence factor expression in the lungs of patients with CF.Quorum-sensing signaling systems allow bacteria to regulate gene expression in a population-dependent manner. Quorumsensing regulatory mechanisms are widespread; they have been described in numerous gram-positive (18) as well as gramnegative (9, 42) bacteria. In acyl-homoserine lactone-based systems, growing bacteria produce small signaling molecules (autoinducers) that accumulate in the surrounding environment. At a specific cell density, the concentration of autoinducer becomes sufficient to interact with the autoinducer-dependent transcriptional activator protein and alter gene expression.In Pseudomonas aeruginosa, quorum-sensing systems have been extensively studied. Two acyl-homoserine lactone-based systems, the las (10) and rhl (25) systems, have been described. These operate in a hierarchical fashion along with a recently described quinolone signaling system (33) to regulate as much as 4% of the genome (45). LasI and RhlI synthesize the autoinducers N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) (29) and N-butyryl-L-homoserine lactone (C4-HSL) (30), respectively. LasR and RhlR bind DNA to modify transcription of target genes only after a threshold level of their respective autoinducers is reached.Quorum-sensing systems are believed to be central to the pathogenesis of P. aeruginosa (reviewed by Rumbaugh et al. [34]). One such infection in which quorum sensing may play an important role is the P. aeruginosa lung infections associated with cystic fibrosis (CF). These infections may be the perfect environment for the expression of the quorum-sensing systems, as the lungs are a spatially limited environment and P. aeruginosa can grow to high densities (10 7 to 10 8 /ml) (40) in sputum. These conditions should be sufficient to induce expression of P. aeruginosa quorum-sens...

Increased use of high‐risk allografts is critical to meet the demand for liver transplantation. We aimed to identify criteria predicting viability of organs, currently declined for clinical transplantation, using functional assessment during normothermic machine perfusion (NMP). Twelve discarded human livers were subjected to NMP following static cold storage. Livers were perfused with a packed red cell–based fluid at 37°C for 6 hours. Multilevel statistical models for repeated measures were employed to investigate the trend of perfusate blood gas profiles and vascular flow characteristics over time and the effect of lactate‐clearing (LC) and non‐lactate‐clearing (non‐LC) ability of the livers. The relationship of lactate clearance capability with bile production and histological and molecular findings were also examined. After 2 hours of perfusion, median lactate concentrations were 3.0 and 14.6 mmol/L in the LC and non‐LC groups, respectively. LC livers produced more bile and maintained a stable perfusate pH and vascular flow >150 and 500 mL/minute through the hepatic artery and portal vein, respectively. Histology revealed discrepancies between subjectively discarded livers compared with objective findings. There were minimal morphological changes in the LC group, whereas non‐LC livers often showed hepatocellular injury and reduced glycogen deposition. Adenosine triphosphate levels in the LC group increased compared with the non‐LC livers. We propose composite viability criteria consisting of lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance. These have been tested successfully in clinical transplantation. In conclusion, NMP allows an objective assessment of liver function that may reduce the risk and permit use of currently unused high‐risk livers.