Network evaluation of an innovation platform in continuous quality improvement in Australian Indigenous primary healthcare.

BACKGROUND: From 2014 to 2019, the Centre for Research Excellence in Integrated Quality Improvement (CRE-IQI) was evaluated as an innovation platform focusing on continuous quality improvement in Indigenous Australian primary healthcare. Although social network analysis (SNA) is a recognized method for evaluating the functioning, collaboration and effectiveness of innovation platforms, applied research is limited. This study applies SNA to evaluate the CRE-IQI's functioning as an innovation platform. METHODS: Two surveys (2017, 2019) were conducted using social survey and network methods. Survey items covered respondent characteristics, their perceptions of the CRE-IQI's performance, and its impact and sociometric relationships. Members' relationship information was captured for the CRE-IQI at three time points, namely start (retrospectively), midpoint and final year, on three network types (knew, shared information, collaborated). SNA software was used to compute standard network metrics including diameter, density and centrality, and to develop visualizations. Survey and network results were addressed in a workshop held by members to develop improvement strategies. RESULTS: The response rate was 80% in 2017 and 65% in 2019 (n = 49 and 47, respectively). Between 2017 and 2019, respondents' mean ratings of the CRE-IQI's functioning and achievements in meeting its goals were sustained. They perceived the CRE-IQI as multidisciplinary, having effective management and governance, and incorporating Indigenous research leadership, representation and ways of working. Respondents recognized high levels of trust amongst members, rated "good communication and coordination with participants" highly, and "facilitating collaboration" as the CRE's most strongly recognized achievement. In collaboration and information-sharing networks, average path length remained low in 2017 and 2019, indicating good small-world network properties for relaying information. On average, respondents shared information and collaborated with more CRE members in 2017 than 2019. However, in both 2017 and 2019 there were new collaborations and information-sharing outside of direct collaborations. CRE-IQI outcomes included: evidence generation; knowledge transfer and skills development in quality improvement; research capacity-building, career development; mentoring; grant support; development of new projects; health service support; and policy impact. CONCLUSIONS: This study shows the utility of network analysis in evaluating the functioning, and collaboration, at the individual, organizational and health system levels, of an innovation platform, and adds to our understanding of factors enabling successful innovation platforms.

Liver Transplantation for Acute Intermittent Porphyria.

Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.

The genome of Eucalyptus grandis.

Eucalypts are the world's most widely planted hardwood trees. Their outstanding diversity, adaptability and growth have made them a global renewable resource of fibre and energy. We sequenced and assembled >94% of the 640-megabase genome of Eucalyptus grandis. Of 36,376 predicted protein-coding genes, 34% occur in tandem duplications, the largest proportion thus far in plant genomes. Eucalyptus also shows the highest diversity of genes for specialized metabolites such as terpenes that act as chemical defence and provide unique pharmaceutical oils. Genome sequencing of the E. grandis sister species E. globulus and a set of inbred E. grandis tree genomes reveals dynamic genome evolution and hotspots of inbreeding depression. The E. grandis genome is the first reference for the eudicot order Myrtales and is placed here sister to the eurosids. This resource expands our understanding of the unique biology of large woody perennials and provides a powerful tool to accelerate comparative biology, breeding and biotechnology.

Transient Dissipation and Structural Costs of Physical Information Transduction.

A central result that arose in applying information theory to the stochastic thermodynamics of nonlinear dynamical systems is the information-processing second law (IPSL): the physical entropy of the Universe can decrease if compensated by the Shannon-Kolmogorov-Sinai entropy change of appropriate information-carrying degrees of freedom. In particular, the asymptotic-rate IPSL precisely delineates the thermodynamic functioning of autonomous Maxwellian demons and information engines. How do these systems begin to function as engines, Landauer erasers, and error correctors? We identify a minimal, and thus inescapable, transient dissipation of physical information processing, which is not captured by asymptotic rates, but is critical to adaptive thermodynamic processes such as those found in biological systems. A component of transient dissipation, we also identify an implementation-dependent cost that varies from one physical substrate to another for the same information processing task. Applying these results to producing structured patterns from a structureless information reservoir, we show that "retrodictive" generators achieve the minimal costs. The results establish the thermodynamic toll imposed by a physical system's structure as it comes to optimally transduce information.

Maxwell Demon Dynamics: Deterministic Chaos, the Szilard Map, and the Intelligence of Thermodynamic Systems.

We introduce a deterministic chaotic system-the Szilard map-that encapsulates the measurement, control, and erasure protocol by which Maxwellian demons extract work from a heat reservoir. Implementing the demon's control function in a dynamical embodiment, our construction symmetrizes the demon and the thermodynamic system, allowing one to explore their functionality and recover the fundamental trade-off between the thermodynamic costs of dissipation due to measurement and those due to erasure. The map's degree of chaos-captured by the Kolmogorov-Sinai entropy-is the rate of energy extraction from the heat bath. Moreover, an engine's statistical complexity quantifies the minimum necessary system memory for it to function. In this way, dynamical instability in the control protocol plays an essential and constructive role in intelligent thermodynamic systems.

The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster.

The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role of secondary metabolite gene clusters and their metabolites in fungal biology.

Genome sequencing provides insight into the reproductive biology, nutritional mode and ploidy of the fern pathogen Mixia osmundae.

Mixia osmundae (Basidiomycota, Pucciniomycotina) represents a monotypic class containing an unusual fern pathogen with incompletely understood biology. We sequenced and analyzed the genome of M. osmundae, focusing on genes that may provide some insight into its mode of pathogenicity and reproductive biology. Mixia osmundae has the smallest plant pathogenic basidiomycete genome sequenced to date, at 13.6 Mb, with very few repeats, high gene density, and relatively few significant gene family gains. The genome shows that the yeast state of M. osmundae is haploid and the lack of segregation of mating genes suggests that the spores produced on Osmunda spp. fronds are probably asexual. However, our finding of a complete complement of mating and meiosis genes suggests the capacity to undergo sexual reproduction. Analyses of carbohydrate active enzymes suggest that this fungus is a biotroph with the ability to break down several plant cell wall components. Analyses of publicly available sequence data show that other Mixia members may exist on other plant hosts and with a broader distribution than previously known.

Thermodynamic uncertainty theorem.

Thermodynamic uncertainty relations (TURs) express a fundamental lower bound on the precision (inverse scaled variance) of any thermodynamic charge-e.g., work or heat-by functionals of the average entropy production. Relying on purely variational arguments, we significantly extend TUR inequalities by incorporating and analyzing the impact of higher statistical cumulants of the entropy production itself within the general framework of time-symmetrically-controlled computation. We derive an exact expression for the charge that achieves the minimum scaled variance, for which the TUR bound tightens to an equality that we name the thermodynamic uncertainty theorem (TUT). Importantly, both the minimum scaled variance charge and the TUT are functionals of the stochastic entropy production, thus retaining the impact of its higher moments. In particular, our results show that, beyond the average, the entropy production distribution's higher moments have a significant effect on any charge's precision. This is made explicit via a thorough numerical analysis of "swap" and "reset" computations that quantitatively compares the TUT against previous generalized TURs.

Chronic pain education delivered with a virtual reality headset in outpatient physical therapy clinics: a multi-site exploratory trial.

OBJECTIVE: Chronic pain is multidimensional, requiring expanded interventions for optimal management. Pain education, mindfulness training, and virtual reality (VR) are showing promise, but barriers remain for implementation by clinicians. The purpose of this study was to explore the experiences with a pain education and mindfulness intervention for patients with chronic low back pain and their treating clinicians. METHODS: This was a prospectively designed exploratory trial registered at ClinicalTrials.gov: NCT04777877. Patients were identified by study staff and consented. Baseline and follow-up questionnaires and surveys were collected with quantitative and qualitative data. Patients viewed five videos explaining key pain concepts and guided imagery nature videos using a VR headset. RESULTS: Twenty patients consented, and 15 patients completed the intervention. Patients and clinicians rated their experiences with the program as excellent; however, concerns were raised related to logistical challenges around use of the VR headset in busy clinic settings. Percentage changes in patient pain knowledge occurred in the desired direction in 8 out of 9 key concepts. CONCLUSIONS: Delivering educational and mindfulness content with a VR headset to patients with chronic low back pain was feasible and acceptable to patients and clinicians. Concerns remain regarding the increased time burden with use of this technology in a busy clinic setting weighed against potential benefits. Alternative delivery methods are needed to reduce logistical challenges and increase patient access to content outside of the clinic setting.

Shortcuts to Thermodynamic Computing: The Cost of Fast and Faithful Information Processing.

Landauer's Principle states that the energy cost of information processing must exceed the product of the temperature, Boltzmann's constant, and the change in Shannon entropy of the information-bearing degrees of freedom. However, this lower bound is achievable only for quasistatic, near-equilibrium computations-that is, only over infinite time. In practice, information processing takes place in finite time, resulting in dissipation and potentially unreliable logical outcomes. For overdamped Langevin dynamics, we show that counterdiabatic potentials can be crafted to guide systems rapidly and accurately along desired computational paths, providing shortcuts that allow for the precise design of finite-time computations. Such shortcuts require additional work, beyond Landauer's bound, that is irretrievably dissipated into the environment. We show that this dissipated work is proportional to the computation rate as well as the square of the information-storing system's length scale. As a paradigmatic example, we design shortcuts to create, erase, and transfer a bit of information metastably stored in a double-well potential. Though dissipated work generally increases with operation fidelity, we show that it is possible to compute with perfect fidelity in finite time with finite work. We also show that the robustness of information storage affects an operation's energetic cost-specifically, the dissipated work scales as the information lifetime of the bistable system. Our analysis exposes a rich and nuanced relationship between work, speed, size of the information-bearing degrees of freedom, storage robustness, and the difference between initial and final informational statistics.

A biologically oriented algorithm for spatial sound segregation.

Listening in an acoustically cluttered scene remains a difficult task for both machines and hearing-impaired listeners. Normal-hearing listeners accomplish this task with relative ease by segregating the scene into its constituent sound sources, then selecting and attending to a target source. An assistive listening device that mimics the biological mechanisms underlying this behavior may provide an effective solution for those with difficulty listening in acoustically cluttered environments (e.g., a cocktail party). Here, we present a binaural sound segregation algorithm based on a hierarchical network model of the auditory system. In the algorithm, binaural sound inputs first drive populations of neurons tuned to specific spatial locations and frequencies. The spiking response of neurons in the output layer are then reconstructed into audible waveforms via a novel reconstruction method. We evaluate the performance of the algorithm with a speech-on-speech intelligibility task in normal-hearing listeners. This two-microphone-input algorithm is shown to provide listeners with perceptual benefit similar to that of a 16-microphone acoustic beamformer. These results demonstrate the promise of this biologically inspired algorithm for enhancing selective listening in challenging multi-talker scenes.

Van Allen Probes Observations of Symmetric Stormtime Compressional ULF Waves.

Previous spacecraft studies showed that stormtime poloidal ultralow-frequency (ULF) waves in the ring current region have an antisymmetric (second harmonic) mode structure about the magnetic equator. This paper reports Van Allen Probes observations of symmetric ULF waves in the postnoon sector during a moderate geomagnetic storm. The mode structure is determined from the presence of purely compressional magnetic field oscillations at the equator accompanied by strong transverse electric field perturbations. Antisymmetric waves were also detected but only very late in the recovery phase. The symmetric waves were detected outside the plasmasphere at L = 3.0-5.5 and had peak power at 4-10 mHz, lower than the frequency of the local fundamental toroidal standing Alfvén wave. During the wave events, the flux of protons was enhanced at energies below ∼5 keV, which appears to be a prerequisite for the waves. The protons may provide free energies to waves through drift resonance instability or drift compressional instability, which occur in the presence of radial gradients of plasma parameters.

Outcomes of incoming and outgoing second opinions from a UK liver transplant centre.

OBJECTIVE: Second transplant centre opinions (STCOs) for patients declined for liver transplantation are infrequent. We aimed to identify STCOs outcomes from a tertiary transplant centre. DESIGN: Referrals between 2012 and 2020 to Birmingham Unit were reviewed. Incoming: all referrals from out-of-region centres were collated. Outgoing: patients not listed in Birmingham were reviewed to identify referrals for STCOs to the other UK centres (A-F). RESULTS: 2535 patients were assessed for liver transplantation during the study period. Incoming: among 1751 referrals, 23 STCOs (17 unit A, 3 unit B, 1 unit C, 1 unit D and 1 unit E) were provided by Birmingham. Of the STCOs, 13/23 (57%) patients remained unsuitable for transplantation. Therefore, 10/23 (43%) underwent a second liver transplant assessment, of whom five (50%) were still deemed unsuitable, three (30%) listed (one transplanted) and two (20%) died preassessment. Outgoing: among 426 patients not listed, eight (1.8%) patients were referred for STCO (4 unit E, 2 unit B, 1 unit D, 1 unit A). Three (38%) were listed, two (25%) were assessed and declined, two (25%) were unsuitable for assessment and one (12.5%) died while waiting. Combining incoming and outgoing Birmingham STCOs (n=31), six (19%) of STCOs were listed in a second centre. CONCLUSION: Second transplant centre opinions are rare with the majority still deemed unsuitable for liver transplantation. This highlights potential resource implications especially when undergoing a full second formal assessment. A streamlined STCO process with sharing of investigations and use of telemedicine in appropriate patients may allow for greater transparency, quicker decision making and less use of labour-intensive resources.

Pharmacological agents for developmental stuttering in children and adolescents: a systematic review.

Stuttering affects approximately 5% of children up to the teenage years. There are many possible forms of intervention, one of which is pharmacotherapy. No review about the treatment of stuttering with pharmacological agents in children and adolescents has been undertaken. The objectives of this review were to determine the extent of previous research in this area and to assess the success of pharmacological agents in reducing the frequency of disfluency in child and adolescent stutterers (<18 years). A systematic search of MEDLINE, PsychInfo, Embase, and Cochrane Systematic Review databases was carried out to identify potential studies for the review. Studies that met specified criteria were selected for detailed examination, and the quality of evidence they provided was assessed according to 7 criteria that pertained to study design and data provision. Seven publications met the inclusion criteria for the review. Only 1 publication was classified as strong evidence quality, and this reported that clonidine did not reduce the frequency of disfluency in a group of 25 individuals who stuttered. All further publications were classified as either very low or low evidence quality. The agents examined were risperidone, olanzapine, clonidine, tiapride, haloperidol, and chlorpromazine.

Development of an Automated, Non-Enzymatic Nucleic Acid Amplification Test.

Among nucleic acid diagnostic strategies, non-enzymatic tests are the most promising for application at the point of care in low-resource settings. They remain relatively under-utilized, however, due to inadequate sensitivity. Inspired by a recent demonstration of a highly-sensitive dumbbell DNA amplification strategy, we developed an automated, self-contained assay for detection of target DNA. In this new diagnostic platform, called the automated Pi-powered looping oligonucleotide transporter, magnetic beads capture the target DNA and are then loaded into a microfluidic reaction cassette along with the other reaction solutions. A stepper motor controls the motion of the cassette relative to an external magnetic field, which moves the magnetic beads through the reaction solutions automatically. Real-time fluorescence is used to measure the accumulation of dumbbells on the magnetic bead surface. Left-handed DNA dumbbells produce a distinct signal which reflects the level of non-specific amplification, acting as an internal control. The autoPiLOT assay detected as little as 5 fM target DNA, and was also successfully applied to the detection of S. mansoni DNA. The autoPiLOT design is a novel step forward in the development of a sensitive, user-friendly, low-resource, non-enzymatic diagnostic test.

Basiliximab With Delayed Tacrolimus Improves Short-Term Renal Outcomes Post-Liver Transplantation-a Real-World Experience.

BACKGROUND: Acute kidney injury (AKI) is common after liver transplantation (LT). Induction with interleukin-2 receptor antagonists is often used as a "renal-sparing" strategy. The aim of this study was to assess this approach in a real-world setting in an LT center. METHODS: A retrospective cohort analysis of LTs between 2011 and 2018 was performed to assess the impact of a renal-sparing strategy using basiliximab in conjunction with mycophenolate mofetil and corticosteroids from day 0 post-LT along with delayed introduction of tacrolimus. This was compared with a group receiving tacrolimus, mycophenolate mofetil, and corticosteroids from the outset. RESULTS: The renal-sparing regimen was associated with significantly lower incidence of all-stage AKI at day 7 post-LT (36% vs 55%, P = .006) and less decline in renal function at 3 months (39% vs 57%, P = .01). No further significant differences in renal outcomes were observed at other time points on follow-up to 1 year post-LT. There was no significant difference in the incidence of acute cellular rejection, inpatient length of stay or graft survival. The decision to adopt a renal-sparing regimen was predominantly made on a clinically reactive basis within the first 24 hours post-LT in 77%, and was preordained in 23%. Cost-effectiveness analysis did not find evidence of a significant cost saving when using a renal-sparing strategy. CONCLUSION: This study provides real-world analysis of the use of a renal-sparing immunosuppression regimen in LT. Although improvements in incidence of AKI in the short term were demonstrated, this did not translate to cost savings or improved renal outcomes after 3 months.

Collaboration and knowledge generation in an 18-year quality improvement research programme in Australian Indigenous primary healthcare: a coauthorship network analysis.

OBJECTIVES: Though multidisciplinary research networks support the practice and effectiveness of continuous quality improvement (CQI) programmes, their characteristics and development are poorly understood. In this study, we examine publication outputs from a research network in Australian Indigenous primary healthcare (PHC) to assess to what extent the research network changed over time. SETTING: Australian CQI research network in Indigenous PHC from 2002 to 2019. PARTICIPANTS: Authors from peer-reviewed journal articles and books published by the network. DESIGN: Coauthor networks across four phases of the network (2002-2004; 2005-2009; 2010-2014; 2015-2019) were constructed based on author affiliations and examined using social network analysis methods. Descriptive characteristics included organisation types, Indigenous representation, gender, student authorship and thematic research trends. RESULTS: We identified 128 publications written by 308 individual authors from 79 different organisations. Publications increased in number and diversity over each funding phase. During the final phase, publication outputs accelerated for organisations, students, project officers, Indigenous and female authors. Over time there was also a shift in research themes to encompass new clinical areas and social, environmental or behavioural determinants of health. Average degree (8.1), clustering (0.81) and diameter (3) indicated a well-connected network, with a core-periphery structure in each phase (p≤0.03) rather than a single central organisation (degree centralisation=0.55-0.65). Academic organisations dominated the core structure in all funding phases. CONCLUSION: Collaboration in publications increased with network consolidation and expansion. Increased productivity was associated with increased authorship diversity and a decentralised network, suggesting these may be important factors in enhancing research impact and advancing the knowledge and practice of CQI in PHC. Publication diversity and growth occurred mainly in the fourth phase, suggesting long-term relationship building among diverse partners is required to facilitate participatory research in CQI. Despite improvements, further work is needed to address inequities in female authorship and Indigenous authorship.

Medical liver biopsy: background, indications, procedure and histopathology.

Histological analysis of liver tissue continues to play an important role in modern hepatological practice. This review explores the indications for medical liver biopsy in addition to the procedure itself, potential complications, preparation of tissue and routine staining. A broad selection of histological images is included to illustrate the appearance of liver tissue both in health and in several important diseases.

Road deaths relating to the attendance of medical appointments in Queensland.

Objective This study sought to estimate and observe the risks imposed on patients as they travel to hospital for referred treatment. Factors such as distance and remoteness were compared to understand how they affect this risk. Methods This study focused on Queensland residents attending specialist out-patient appointments in a Queensland public hospital throughout 2016. Deidentified information on all recipients of a specialist out-patient appointment in 2016 (n=2946584) were included in the study. This study also contained a theoretical component: using a data model to estimate the number of fatalities that could be expected from a travelling population of this size and complexity. The modelling results were compared with the frequency of actual fatalities among individuals travelling to receive treatment, as determined by a review of the Queensland Police Road Database. The data model and empirical values from police reports were used to independently measure what risk, if any, individuals travelling to obtain specialist out-patient treatment are exposed to. Differences between the model and observed values were evaluated using statistical tests. Results A direct relationship between increasing remoteness and travel risk was established in both the model and observed data (CV(RMSD)=0.660773). Conclusion Fatal risk is present in any road journey regardless of distance, duration or the purpose of travel. Individuals living in regional and remote Queensland are exposed to a larger risk than those living in the major cities of Queensland when travelling to obtain public health care. What is already known on this subject? Road safety remains one of Australia's most serious public health issues, with 1295 road-related fatalities recorded throughout Australia in 2016. Although the potential dangers of road travel are well understood, extended journeys by road to attend hospital appointments are often undertaken despite available alternatives to travel in some instances. What this paper adds? Travelling to attend medical appointments exposes a patient to a small but potentially catastrophic risk that can be observed in state road crash data. This risk is measurably greater for individuals in regional Queensland. What are the implications for practitioners? Clinical models of care that reduce patient travel may represent a new standard in patient safety when of the risks associated travel are considered.

The role of stem cells in liver injury and repair.

Introduction: Liver disease is an increasing cause of worldwide mortality, and currently the only curative treatment for end-stage liver disease is whole organ allograft transplantation. Whilst this is an effective treatment, there is a shortage of suitable grafts and consequently some patients die whilst on the waiting list. Cell therapy provides an alternative treatment to increase liver function and potentially ameliorate fibrosis. Areas covered: In this review, we discuss the different cellular sources for therapy investigated to date in humans including mature hepatocytes, hematopoietic stem cells, mesenchymal stromal cells and hepatic progenitor cells. Cells investigated in animals include embryonic stem cells, induced pluripotent stem cells and directly reprogrammed cells. We then appraise the experience and evidence base underlying each cell type. Expert opinion: We discuss how this field may evolve in the years to come focusing on opportunities to enhance the intrinsic regenerative response with therapeutic targets and cell therapies. Growing expertise in tissue engineering will likely lead to increasingly complex bio-reactors and bio-artificial livers, which open a further avenue to restore liver function and delay or prevent the need for transplantation.