The Legally Disruptive Nature of Climate Change

Climate change gives rise to disputes and problems not easily addressed by existing legal doctrines and frameworks. This is because it is a polycentric problem; the assessment of future climate impacts must deal with uncertainty; climate change is socio-politically controversial; and addressing climate change requires recognising a dynamic physical environment. As such, climate change can be thought of as legally disruptive in that it requires lawyers and legal scholars to reconcile the legal issues raised by climate change with existing legal orders. The legal disruption catalysed by climate change has not only led to the creation of new legal regimes but also given rise to a multitude of legal disputes that require adjudication. A study of some of these cases highlights the need for active and deliberate reflection about the nature of adjudication and the legal reasoning embedded in it when confronted by a disruptive phenomenon like climate change

Curcumin inhibits activation of TRPM2 channels in rat hepatocytes

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Oxidative stress is a hallmark of many liver diseases including viral and drug-induced hepatitis, ischemia-reperfusion injury, and non-alcoholic steatohepatitis. One of the consequences of oxidative stress in the liver is deregulation of Ca(2+) homeostasis, resulting in a sustained elevation of the free cytosolic Ca(2+) concentration ([Ca(2+)]c) in hepatocytes, which leads to irreversible cellular damage. Recently it has been shown that liver damage induced by paracetamol and subsequent oxidative stress is, in large part, mediated by Ca(2+) entry through Transient Receptor Potential Melastatin 2 (TRPM2) channels. Involvement of TRPM2 channels in hepatocellular damage induced by oxidative stress makes TRPM2 a potential therapeutic target for treatment of a range of oxidative stress-related liver diseases. We report here the identification of curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a natural plant-derived polyphenol in turmeric spice, as a novel inhibitor of TRPM2 channel. Presence of 5µM curcumin in the incubation medium prevented the H2O2- and paracetamol-induced [Ca(2+)]c rise in rat hepatocytes. Furthermore, in patch clamping experiments incubation of hepatocytes with curcumin inhibited activation of TRPM2 current by intracellular ADPR with IC50 of approximately 50nM. These findings enhance understanding of the actions of curcumin and suggest that the known hepatoprotective properties of curcumin are, at least in part, mediated through inhibition of TRPM2 channels

Who Treats Patients with Diabetes and Compensated Cirrhosis

Increasingly, patients with multiple chronic conditions are being managed in patient-centered medical homes (PCMH) that coordinate primary and specialty care. However, little is known about the types of providers treating complex patients with diabetes and compensated cirrhosis

COVID-19 and liver disease: mechanistic and clinical perspectives

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity. © 2021, Springer Nature Limited

Trends in Characteristics of Patients Listed for Liver Transplantation Will Lead to Higher Rates of Waitlist Removal Due to Clinical Deterioration

BACKGROUND: Changes in the epidemiology of end-stage liver disease may lead to increased risk of dropout from the liver transplant waitlist. Anticipating the future of liver transplant waitlist characteristics is vital when considering organ allocation policy. METHODS: We performed a discrete event simulation to forecast patient characteristics and rate of waitlist dropout. Estimates were simulated from 2015 to 2025. The model was informed by data from the Organ Procurement and Transplant Network, 2003 to 2014. National data are estimated along with forecasts for 2 regions. RESULTS: Nonalcoholic steatohepatitis will increase from 18% of waitlist additions to 22% by 2025. Hepatitis C will fall from 30% to 21%. Listings over age 60 years will increase from 36% to 48%. The hazard of dropout will increase from 41% to 46% nationally. Wait times for transplant for patients listed with a Model for End-Stage Liver Disease (MELD) between 22 and 27 will double. Region 5, which transplants at relatively higher MELD scores, will experience an increase from 53% to 64% waitlist dropout. Region 11, which transplants at lower MELD scores, will have an increase in waitlist dropout from 30% to 44%. CONCLUSIONS: The liver transplant waitlist size will remain static over the next decade due to patient dropout. Liver transplant candidates will be older, more likely to have nonalcoholic steatohepatitis and will wait for transplantation longer even when listed at a competitive MELD score. There will continue to be significant heterogeneity among transplant regions where some patients will be more likely to drop out of the waitlist than receive a transplant

Determining risk factors for mortality in liver transplant patients with COVID-19

We read with great interest the Correspondence from Bhoori and colleagues1 describing the effect of coronavirus disease 2019 (COVID-19) on their centre's adult liver transplant population.1 Within their cohort of over 150 transplant recipients, the authors identified six patients with COVID-19, including three resulting deaths. Each of those who died was transplanted over 10 years previously and were older than 65 years, male, overweight, and had hypertension and diabetes. The authors speculated as to whether these characteristics might be major risk factors for mortality

Declining liver graft quality threatens the future of liver transplantation in the United States

National liver transplantation (LT) volume has declined since 2006, in part because of worsening donor organ quality. Trends that degrade organ quality are expected to continue over the next 2 decades. We used the United Network for Organ Sharing (UNOS) database to inform a 20-year discrete event simulation estimating LT volume from 2010 to 2030. Data to inform the model were obtained from deceased organ donors between 2000 and 2009. If donor liver utilization practices remain constant, utilization will fall from 78% to 44% by 2030, resulting in 2230 fewer LTs. If transplant centers increase their risk tolerance for marginal grafts, utilization would decrease to 48%. The institution of "opt-out" organ donation policies to increase the donor pool would still result in 1380 to 1866 fewer transplants. Ex vivo perfusion techniques that increase the use of marginal donor livers may stabilize LT volume. Otherwise, the number of LTs in the United States will decrease substantially over the next 15 years. In conclusion, the transplant community will need to accept inferior grafts and potentially worse posttransplant outcomes and/or develop new strategies for increasing organ donation and utilization in order to maintain the number of LTs at the current level

Changing shape of disease: Nonalcoholic fatty liver disease in Crohnʼs disease—A case series and review of the literature:

With improvements in therapy for inflammatory bowel disease (IBD) and changes in the prevalence of obesity, the phenotype of Crohn's Disease (CD) is changing. These changes may herald an increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in this population

Time to Rethink Antiviral Treatment for Hepatitis C in Patients with Coexisting Mental Health/Substance Abuse Issues

A new era has dawned in the treatment of chronic hepatitis C (HCV) virus with the use of direct-acting antiviral medications augmenting combination therapy. Unfortunately, the significant impact of improvements may not be realized if antiviral treatment is not expanded to include a larger proportion of patients, many of whom have coexisting mental health and/or substance abuse issues and have been historically deferred from treatment