Effect of recipient age on prioritisation for liver transplantation in the UK: a population-based modelling study.

BACKGROUND: Following the introduction of an algorithm aiming to maximise life-years gained from liver transplantation in the UK (the transplant benefit score [TBS]), donor livers were redirected from younger to older patients, mortality rate equalised across the age range and short-term waiting list mortality reduced. Understanding age-related prioritisation has been challenging, especially for younger patients and clinicians allocating non-TBS-directed livers. We aimed to assess age-related prioritisation within the TBS algorithm by modelling liver transplantation prioritisation based on data from a UK transplant unit and comparing these data with other regions. METHODS: In this population-based modelling study, serum parameters and age at liver transplantation assessment of patients attending the Scottish Liver Transplant Unit, Edinburgh, UK, between December, 2002, and November, 2023, were combined with representative synthetic data to model TBS survival predictions, which were compared according to age group (25-49 years vs ≥60 years), chronic liver disease severity, and disease cause. Models for end-stage liver disease (UKELD [UK], MELD [Eurotransplant region], and MELD 3.0 [USA]) were used as validated comparators of liver disease severity. FINDINGS: Of 2093 patients with chronic liver disease, 1808 (86%) had complete datasets and liver disease parameters consistent with eligibility for the liver transplant waiting list in the UK (UKELD ≥49). Disease severity as assessed by UKELD, MELD, and MELD 3.0 did not differ by age (median UKELD scores of 56 for patients aged ≥60 years vs 56 for patients aged 25-49 years; MELD scores of 16 vs 16; and MELD 3.0 scores of 18 vs 18). TBS increased with advancing age (R=0·45, p<0·0001). TBS predicted that transplantation in patients aged 60 years or older would provide a two-fold greater net benefit at 5 years than in patients aged 25-49 years (median TBS 1317 [IQR 1116-1436] in older patients vs 706 [411-1095] in younger patients; p<0·0001). Older patients were predicted to have shorter survival without transplantation than younger patients (263 days [IQR 144-473] in older patients vs 861 days [448-1164] in younger patients; p<0·0001) but similar survival after transplantation (1599 days [1563-1628] vs 1573 days [1525-1614]; p<0·0001). Older patients could reach a TBS for which a liver offer was likely below minimum criteria for transplantation (UKELD <49), whereas many younger patients were required to have high-urgent disease (UKELD >60). US and Eurotransplant programmes did not prioritise according to age. INTERPRETATION: The UK liver allocation algorithm prioritises older patients for transplantation by predicting that advancing age increases the benefit from liver transplantation. Restricted follow-up and biases in waiting list data might limit the accuracy of these benefit predictions. Measures beyond overall waiting list mortality are required to fully capture the benefits of liver transplantation. FUNDING: None.

Phosphorus Removal from Dirty Farmyard Water by Activated Anaerobic-Digestion-Derived Biochar.

The management of anaerobic digestate is important to realize the value of the waste and enhance the whole system sustainability of anaerobic digestion. In this study, the phosphorus treatment of dirty irrigation water by biochar samples derived from digestate of anaerobic digestion were investigated. The biochars were further activated by steam activation with different duration time and KOH activation with different introducing ratios; the textural properties of biochars were optimized after activation from the aspect of biochar characterization. Notably, AD-N2 demonstrates a remarkable adsorption effect of phosphorus, with an adsorption efficiency of 8.99 mg g-1. Besides the effect of biochar dosage on phosphorus removal, adsorption kinetics and thermodynamic isotherms are studied. According to the adsorption kinetics, the adsorption of phosphorus from dirty water fits the Elovich equation (R2 = 0.95). Furthermore, the thermodynamic isotherm results illustrate the process of phosphorus removal by biochar is endothermic (ΔH0 = 17.93 kJ mol-1) and spontaneous (ΔS = 96.24 J mol-1 K-1). Therefore, this work suggests a promising solution to phosphorus-related environmental challenges in industry and agriculture.

Endoscopic management of Bouveret syndrome with electrohydraulic lithotripsy.

Video 1Endoscopic management of Bouveret syndrome with electrohydraulic lithotripsy.

A comparative life-cycle assessment and cost analysis of biofilters amended with sludge-based activated carbon and commercial activated carbon for stormwater treatment.

Environmental and economic issues resulting from the unsustainable management of sewage sludge from wastewater have necessitated the development of eco-friendly sewage sludge disposal methods, whereas stormwater effluent contains tremendous amounts of pollutants. This study compares the feasibility and environmental impacts associated with incorporating biofilters with sludge-based activated carbon (SBAC) versus commercial activated carbon (CAC) for stormwater treatment. The results demonstrate that the construction and disposal life-cycle stages are the dominant contributors to several environmental impact categories, including resource scarcity, carcinogenic toxicity, terrestrial ecotoxicity, and ozone formation indicators. Across multiple impact categories, the incorporation of biofilters with SBAC can reduce the negative environmental impacts associated with biofilter construction and disposal by 40% over a 50-year analysis period. In contrast, the most significant improvement is on construction-dominant indicators, where the decreased need for biofilter reconstruction results in a higher reduction in environmental impacts. Economically, amending the biofilter with SBAC can increase profits by up to 66% due to extending its lifespan. This study shows that SBAC has similar performance as CAC for lowering the negative environmental impacts resulting from biofilter construction, while increasing the overall net profits of the system. However, converting sewage sludge to an effective sorbent (SBAC) and incorporating SBAC into a biofilter to capture pollutants from stormwater is an economically and environmentally sustainable solution available to practitioners to manage sewage sludge and stormwater effluent. This solution protects the environment in a cost efficient, sustainable manner.

Protection from T cell-dependent colitis by the helminth-derived immunomodulatory mimic of transforming growth factor-ß, Hp-TGM.

In animal models of inflammatory colitis, pathology can be ameliorated by several intestinal helminth parasites, including the mouse nematode Heligmosomoides polygyrus. To identify parasite products that may exert anti-inflammatory effects in vivo, we tested H. polygyrus excretory-secretory (HES) products, as well as a recombinantly expressed parasite protein, transforming growth factor mimic (TGM), that functionally mimics the mammalian immunomodulatory cytokine TGF-ß. HES and TGM showed a degree of protection in dextran sodium sulphate-induced colitis, with a reduction in inflammatory cytokines, but did not fully block the development of pathology. HES also showed little benefit in a similar acute trinitrobenzene sulphonic acid-induced model. However, in a T cell transfer-mediated model with recombination activation gene (RAG)-deficient mice, HES-reduced disease scores if administered throughout the first 2 or 4 weeks following transfer but was less effective if treatment was delayed until 14 days after T cell transfer. Recombinant TGM similarly dampened colitis in RAG-deficient recipients of effector T cells, and was effective even if introduced only once symptoms had begun to be manifest. These results are a promising indication that TGM may replicate, and even surpass, the modulatory properties of native parasite HES.

Delivering teaching in dentistry at Queen's University, Belfast for 100 years.

Dental education has been delivered in Queen's University for just over 100 years, with the Dental School celebrating its centenary in 2020. During that time, the undergraduate curriculum has evolved greatly, through innovations in the delivery of teaching and assessment driven by changes in educational practice, developing technologies and, most recently, the COVID-19 pandemic. Throughout all of these changes, our focus remains on our students, their wellbeing, and their development as lifelong learners for a career in the dental profession.

The effect of biochar and acid activated biochar on ammonia emissions during manure storage.

Animal manure contains valuable plant nutrients which need to be stored until field application. A significant proportion of slurry nitrogen is volatilized in the form of ammonia (NH3) during storage. This impacts human health, biodiversity, air and water quality and thus urgent action is needed to reduce NH3 emissions. In this experiment, we evaluated the NH3 emission mitigation potential of biochars derived from miscanthus (MB) and solid separated anaerobic digestate (DB), and orthophosphoric acid activated MB (AMB) and DB (ADB) as well as lightweight expanded clay aggregate (LECA) during four months of liquid manure storage. A slurry without amendment was included as a control (Ctrl). Acid activated and non-activated biochars were applied on top of the slurry maintaining a 7 mm thick surface layer, while LECA was applied in a 2 cm thick layer. NH3 emissions were measured by photoacoustic analyzer. In comparison to Ctrl, acid activated biochar decreased (p < 0.05) NH3 emissions during the slurry storage. Activated biochar reduced the emissions by 37-51% within the first month of slurry storage and achieved a 25-28% emissions reduction efficiency throughout the four month period due to the reduction in emission mitigation efficiency as the storage period progressed. LECA reduced NH3 emissions by 21% during storage. Losses of NH3 as a percentage of total ammoniacal N were 29-31% for activated biochars, 35-39% for non-activated biochars and 33% for LECA. In conclusion, acid activated biochars and LECA could be good floating-covers to mitigate NH3 emissions during manure storage, but activated biochars may have better mitigation potential than LECA.

From Haphazard to a Sustainable Normothermic Regional Perfusion Service: A Blueprint for the Introduction of Novel Perfusion Technologies.

Normothermic Regional Perfusion (NRP) has shown encouraging clinical results. However, translation from an experimental to routine procedure poses several challenges. Herein we describe a model that led to the implementation of NRP into standard clinical practice in our centre following an iterative process of refinement incorporating training, staffing and operative techniques. Using this approach we achieved a four-fold increase in trained surgical staff and a 6-fold increase in competent senior organ preservation practitioners in 12 months, covering 93% of the retrieval calls. We now routinely provide NRP throughout the UK and attended 186 NRP retrievals from which 225 kidneys, 26 pancreases and 61 livers have been transplanted, including 5 that were initially declined by all UK transplant centres. The 61 DCD(NRP) liver transplants undertaken exhibited no primary non-function or ischaemic cholangiopathy with up to 8 years of follow-up. This approach also enabled successful implementation of ex situ normothermic liver perfusion which together with NRP contributed 37.5% of liver transplant activity in 2021. Perfusion technologies (in situ and ex situ) are now supported by a team of Advanced Perfusion and Organ Preservation Specialists. The introduction of novel perfusion technologies into routine clinical practice presents significant challenges but can be greatly facilitated by developing a specific role of Advanced Perfusion and Organ Preservation Specialist supported by a robust education, training and recruitment programme.

Modelling and experimental investigation of small-scale gasification CHP units for enhancing the use of local biowaste.

Small-scale gasification Combined Heat and Power systems, fed by biowaste resources, have the potential to enhance local renewable energy production, reduce carbon emissions and address the challenges of waste disposal. However, there is a lack of understanding on the influence of challenging feedstocks, such as, for example, digestate, poultry litter and municipal solid waste, on the syngas quality and the incidence of the drying stage in the overall process. This paper addresses this gap by analysing and comparing 40 samples of the most common biowaste feedstocks. We developed a stoichiometric-thermodynamic one stage equilibrium model that was experimentally validated and calibrated by laboratory results, with a maximum error of 15% between real and predicted values. Simulation results show that the low heating value of the syngas produced from biowaste resources analysed ranges from 3.1 to 5.4 MJ/Nm3 on a dry basis. Working at the optimal equivalence ratio increases the electricity and thermal output by up to 20%. To achieve a feedstock moisture content of 10%, the drying process may require up to 60% of the heat produced. Furthermore, results show that downdraft gasification based combined heat and power, is a feasible and interesting option to deal with biowaste resources which can potentially avoid the cost, risk and externalities of landfilling while it contributes to the increase of local electricity and heat production from renewable energy sources, both for grid and off-grid applications.

COVID-19 in liver transplant candidates: pretransplant and post-transplant outcomes - an ELITA/ELTR multicentre cohort study.

OBJECTIVE: Explore the impact of COVID-19 on patients on the waiting list for liver transplantation (LT) and on their post-LT course. DESIGN: Data from consecutive adult LT candidates with COVID-19 were collected across Europe in a dedicated registry and were analysed. RESULTS: From 21 February to 20 November 2020, 136 adult cases with laboratory-confirmed SARS-CoV-2 infection from 33 centres in 11 European countries were collected, with 113 having COVID-19. Thirty-seven (37/113, 32.7%) patients died after a median of 18 (10-30) days, with respiratory failure being the major cause (33/37, 89.2%). The 60-day mortality risk did not significantly change between first (35.3%, 95% CI 23.9% to 50.0%) and second (26.0%, 95% CI 16.2% to 40.2%) waves. Multivariable Cox regression analysis showed Laboratory Model for End-stage Liver Disease (Lab-MELD) score of ≥15 (Model for End-stage Liver Disease (MELD) score 15-19, HR 5.46, 95% CI 1.81 to 16.50; MELD score≥20, HR 5.24, 95% CI 1.77 to 15.55) and dyspnoea on presentation (HR 3.89, 95% CI 2.02 to 7.51) being the two negative independent factors for mortality. Twenty-six patients underwent an LT after a median time of 78.5 (IQR 44-102) days, and 25 (96%) were alive after a median follow-up of 118 days (IQR 31-170). CONCLUSIONS: Increased mortality in LT candidates with COVID-19 (32.7%), reaching 45% in those with decompensated cirrhosis (DC) and Lab-MELD score of ≥15, was observed, with no significant difference between first and second waves of the pandemic. Respiratory failure was the major cause of death. The dismal prognosis of patients with DC supports the adoption of strict preventative measures and the urgent testing of vaccination efficacy in this population. Prior SARS-CoV-2 symptomatic infection did not affect early post-transplant survival (96%).

Vibration improves gait biomechanics linked to posttraumatic knee osteoarthritis following anterior cruciate ligament injury.

Anterior cruciate ligament reconstruction (ACLR) incurs a high risk of posttraumatic knee osteoarthritis (PTOA). Aberrant gait biomechanics contribute to PTOA and are attributable in part to quadriceps dysfunction. Vibration improves quadriceps function following ACLR, but its effects on gait biomechanics are unknown. The purpose of this study was to evaluate the effects of whole-body vibration (WBV) and local muscle vibration (LMV) on gait biomechanics in individuals with ACLR. Seventy-five volunteers (time since ACLR 27 ± 16 months) were randomized to WBV, LMV, or Control interventions. Walking biomechanics were assessed prior to and following a single exposure to the interventions. Outcomes included pre-post change scores in the ACLR limb for the peak vertical ground reaction force (vGRF) and its loading rate, peak internal knee extension (KEM) and abduction moments, and peak knee flexion and varus angles. LMV produced a significant decrease in the vGRF loading rate (-3.6 BW/s) that was greater than the changes in the WBV (-0.3 BW/s) and Control (0.5 BW/s) groups. Additionally, WBV produced an increase in the peak KEM (0.27% BW × Ht) that was greater than the change in the Control group (-0.17% BW × Ht) but not the LMV group (0.01% BW × Ht). Lower KEM and greater loading rates have been linked to declines in joint health following ACLR. WBV acutely increased the peak KEM and LMV decreased loading rates. These data suggest that vibration has the potential to mitigate aberrant gait biomechanics, and may represent an effective approach for reducing PTOA risk following ACLR.

The Helminth Parasite Heligmosomoides polygyrus Attenuates EAE in an IL-4Rα-Dependent Manner.

Helminth parasites are effective in biasing Th2 immunity and inducing regulatory pathways that minimize excessive inflammation within their hosts, thus allowing chronic infection to occur whilst also suppressing bystander atopic or autoimmune diseases. Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory lesions within the central nervous system; there are very limited therapeutic options for the progressive forms of the disease and none are curative. Here, we used the experimental autoimmune encephalomyelitis (EAE) model to examine if the intestinal helminth Heligmosomoides polygyrus and its excretory/secretory products (HES) are able to suppress inflammatory disease. Mice infected with H. polygyrus at the time of immunization with the peptide used to induce EAE (myelin-oligodendrocyte glycoprotein, pMOG), showed a delay in the onset and peak severity of EAE disease, however, treatment with HES only showed a marginal delay in disease onset. Mice that received H. polygyrus 4 weeks prior to EAE induction were also not significantly protected. H. polygyrus secretes a known TGF-ß mimic (Hp-TGM) and simultaneous H. polygyrus infection with pMOG immunization led to a significant expansion of Tregs; however, administering the recombinant Hp-TGM to EAE mice failed to replicate the EAE protection seen during infection, indicating that this may not be central to the disease protecting mechanism. Mice infected with H. polygyrus also showed a systemic Th2 biasing, and restimulating splenocytes with pMOG showed release of pMOG-specific IL-4 as well as suppression of inflammatory IL-17A. Notably, a Th2-skewed response was found only in mice infected with H. polygyrus at the time of EAE induction and not those with a chronic infection. Furthermore, H. polygyrus failed to protect against disease in IL-4Rα-/- mice. Together these results indicate that the EAE disease protective mechanism of H. polygyrus is likely to be predominantly Th2 deviation, and further highlights Th2-biasing as a future therapeutic strategy for MS.

The trials and tribulations of liver allocation.

Allocation policies are necessary to ensure a fair distribution of a scarce resource. The goal of any liver transplant allocation policy is to achieve the best possible outcomes for the waiting list population, irrespective of the indication for transplant, whilst maximizing organ utilization. Organ allocation for liver transplantation has evolved from simple centre-based approaches driven by local issues, to complex, evidence-based algorithm prioritizing according to need. Despite the rapid evolution of allocation policies, there remain a number of challenges and new approaches are required to ensure transparency and equity on the decision-making process and the best possible outcomes for patients on the waiting list. New ways of modelling, together with novel outcome criteria, will be required to enable a dynamic adaptability of the allocation policies to the ever changing demographics of the donor population and the changing landscape of indications for transplantation.

Somatosensory Function Influences Aberrant Gait Biomechanics Following Anterior Cruciate Ligament Reconstruction.

Osteoarthritis is common following anterior cruciate ligament reconstruction (ALCR), and aberrant gait biomechanics are considered a primary contributor. Somatosensory dysfunction potentially alters gait biomechanics, but this association is unclear. Therefore, the purposes of this investigation were to compare somatosensory function between limbs and evaluate associations between somatosensory function and gait biomechanics linked to osteoarthritis development in individuals with ALCR. Seventy-three volunteers with ALCR participated. Gait biomechanics (peak vertical ground reaction force magnitude and loading rate, peak internal knee extension and valgus moments, peak knee flexion and varus angles, and quadriceps/hamstrings co-activation) were assessed as subjects walked at their preferred speed. The somatosensory function was assessed via joint position sense error (knee flexion) and vibratory perception threshold (femoral epicondyles, malleoli, and first metatarsal). Though somatosensory function did not differ between the ACLR and contralateral limbs, poorer joint position sense in the ACLR limb was associated with lower loading rates and internal knee extension moments, and greater co-activation. Poorer vibratory perception at the medial and lateral malleoli and first metatarsal head in the ACLR limb was associated with lower loading rates, greater internal knee valgus moments and varus angles, and greater co-activation. Poorer vibratory perception at the medial malleolus and first metatarsal head in the contralateral limb was associated with greater peak knee varus angles and internal knee valgus moments. These results suggest that future research evaluating rehabilitation approaches for improving somatosensory function is warranted as a potential approach for restoring normal gait biomechanics and reducing osteoarthritis risk. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:620-628, 2020.

Co-activation during gait following anterior cruciate ligament reconstruction.

BACKGROUND: Heightened co-activation of the quadriceps and hamstrings has been reported following anterior cruciate ligament reconstruction during various tasks, and may contribute to post-traumatic osteoarthritis risk. However, it is unclear if this phenomenon occurs during walking or how co-activation influences gait biomechanics linked to changes in joint health. METHODS: Co-activation and gait biomechanics were assessed in 50 individuals with ACLR and 25 healthy controls. Biomechanical outcomes included knee flexion displacement, peak vertical ground reaction force magnitude and rate, peak internal knee extension and valgus moments and rates, sagittal knee stiffness, and the heelstrike transient. Co-activation was calculated for the flexors and extensors collectively (i.e. composite), the medial musculature, and the lateral musculature. FINDINGS: Composite co-activation was greater in the ACLR limb compared to the contralateral limb and the control cohort during the preparatory and heelstrike phases of gait, and co-activation of the medial musculature was greater in the ACLR limb compared to the control cohort during the heelstrike phase. Greater co-activation in multiple gait phases was associated with less knee flexion displacement (r = -0.293 to -0.377), smaller peak vertical ground reaction force magnitude (r = -0.291), smaller peak internal knee extension moment (r = -0.291 to -0.328), and greater peak internal knee valgus moment (r = 0.317). INTERPRETATION: Individuals with ACLR displayed heightened co-activation during walking which was associated with biomechanical outcomes that have been linked to negative changes in joint health following ACLR. These data suggest that excessive co-activation may contribute to the mechanical pathogenesis of post-traumatic osteoarthritis. ClinicalTrials.gov Identifier: NCT02605876.

Exploratory study on modification of sludge-based activated carbon for nutrient removal from stormwater runoff.

Nutrients (P, N) in stormwater runoff are a major cause of eutrophication and algal blooms. A promising solution to this problem is to amend the rain garden growing medium (RGGM) with sewage sludge-based activated carbon (SBAC). To optimize the SBAC production process, different metals, pyrolysis conditions (temperature, heating time, carrier gas), and post-treatments were explored. When pyrolyzed at 400 °C for two hours, Zn-activated SBAC removed up to 41% of PO4-P (initial concentration of 1 mg/L) and 72% of NO3-N (initial concentration of 2 mg/L), at a dose of 1 g sorbent/L of nutrient-spiked distilled water. When the same dosage was applied to stormwater leachate made from RGGM and spiked with nutrients, the removal efficiencies were reduced to 20% for PO4-P and 38% for NO3-N. These reductions were probably caused by competition from other leachate components. Increasing the dosage to 3 g/L leachate improved PO4-P removal to 31% and NO3-N to 72%, while also resulting in the removal of 46% of total organic carbon. The major energy cost of producing such sorbents is estimated to be ∼$0.76 CAD/kg SBAC.

DEMONSTRATION OF THE ANTHELMINTIC POTENCY OF MARIMASTAT IN THE HELIGMOSOMOIDES POLYGYRUS RODENT MODEL.

In the course of a structure based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodelling enzymes that the parasites require for the developmentally essential moulting process. This discovery prompted an investigation of the compound's effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus faecal egg and larval load showed that marimastat effected a consistent and significant reduction in egg laying, and a consistent but minor reduction in adult worm load when administered every day, starting on the first day of infection. However, the drug failed to have any significant effect on egg counts or worm burdens when administered to mice with established infections. Therefore, marimastat does not appear to show promise as an anthelmintic in gastrointestinal nematode infections, although other metalloproteases such as batimastat may prove more effective.

A structurally distinct TGF-ß mimic from an intestinal helminth parasite potently induces regulatory T cells.

Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-ß signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-ß mimic (Hp-TGM) that replicates the biological and functional properties of TGF-ß, including binding to mammalian TGF-ß receptors and inducing mouse and human Foxp3+ Treg cells. Hp-TGM has no homology with mammalian TGF-ß or other members of the TGF-ß family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host.