Predicting Early Allograft Function After Normothermic Machine Perfusion.

BACKGROUND: Normothermic ex situ liver perfusion is increasingly used to assess donor livers, but there remains a paucity of evidence regarding criteria upon which to base a viability assessment or criteria predicting early allograft function. METHODS: Perfusate variables from livers undergoing normothermic ex situ liver perfusion were analyzed to see which best predicted the Model for Early Allograft Function score. RESULTS: One hundred fifty-four of 203 perfused livers were transplanted following our previously defined criteria. These comprised 84/123 donation after circulatory death livers and 70/80 donation after brain death livers. Multivariable analysis suggested that 2-h alanine transaminase, 2-h lactate, 11 to 29 mmol supplementary bicarbonate in the first 4 h, and peak bile pH were associated with early allograft function as defined by the Model for Early Allograft Function score. Nonanastomotic biliary strictures occurred in 11% of transplants, predominantly affected first- and second-order ducts, despite selection based on bile glucose and pH. CONCLUSIONS: This work confirms the importance of perfusate alanine transaminase and lactate at 2-h, as well as the amount of supplementary bicarbonate required to keep the perfusate pH > 7.2, in the assessment of livers undergoing perfusion. It cautions against the use of lactate as a sole indicator of viability and also suggests a role for cholangiocyte function markers in predicting early allograft function

Cardiac output Optimisation following Liver Transplant (COLT) trial: study protocol for a feasibility randomised controlled trial

Abstract Background Patients with liver cirrhosis undergoing liver transplantation have a hyperdynamic circulation which persists into the early postoperative period making accurate assessment of fluid requirements challenging. Goal-directed fluid therapy (GDFT) has been shown to reduce morbidity and mortality in a number of surgery settings. The impact of GDFT in patients undergoing liver transplantation is unknown. A feasibility trial was designed to determine patient and clinician support for recruitment into a randomised controlled trial of GDFT following liver transplantation, adherence to a GDFT protocol, participant withdrawal, and to determine appropriate endpoints for a subsequent larger trial to evaluate the efficacy of GDFT in patients undergoing liver transplantation. Methods The Cardiac output Optimisation following Liver Transplant (COLT) trial is designed as a prospective, single-centre, randomised controlled study to assess the feasibility and safety of GDFT in liver transplantation for patients with cirrhosis. Consenting adults (aged between 18 and 80 years) with biopsy-proven liver cirrhosis who have been selected to undergo a first liver transplantation will be included in the trial and randomised into GDFT or standard care starting immediately after surgery and continuing for the first 12 h thereafter. Both groups will have cardiac output and stroke volume monitored using the FloTrac (EV1000) device. The intervention will consist of a protocolised GDFT approach to patient management, using stroke volume optimisation. The control group will receive standard care, without stroke volume and cardiac output measurement. After 12 h the patient’s fluid management will revert to standard of care. The primary endpoint of this study is feasibility. Secondary endpoints will include a safety assessment of the intervention, graft and patient survival, liver function, postoperative complications graded by Clavien-Dindo criteria, length of intensive care and hospital stay and quality of life across the intervention and control groups. Discussion There is a growing body of evidence that the use of perioperative GDFT in surgical patients can improve outcomes; however, signals of harm have also been detected. Patients with liver cirrhosis undergoing liver transplantation have markedly different cardiovascular physiology than general surgical patients. If GDFT is proven to be feasible and safe in this patient group, then a multicentre trial to demonstrate efficacy and cost-effectiveness will be required. Trial registration International Standard Randomised Controlled Trial Registry, ID: ISRCTN10329248. Registered on 4 April 2016

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRASV12, or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of α-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRASV12-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation — a common feature of aging — has the potential to limit aging-associated oncogenesis

Post‐HCV cure self‐reported changes in physical activity, eating behaviours, and fatigue in people living with HIV (ANRS CO13 HEPAVIH)

International audienc

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old