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From the Editor's Desk…

A New Year is begun: 2013 was a difficult year. Patients faced cuts in personal benefits and services, and there were new commissioning arrangements, all at the time of a financial crisis; alongside these the Francis Inquiry (http://www.rcpsych.ac.uk/ usefulresources/rcpsychenewsletters/enewsletters2013/january2013/ francisinquiry.aspx) revealed severe failings in NHS care practices, revitalising the need for compassion in care and exposing shamefully poor care. A more honest appraisal of the quality of care and confronting the limitations of services seem to be the hallmark of 2014. Professionals complain that they had invested much in complex and intensive models of care over decades, for these largely to be remodelled or reorganised because of the economic crisis; and that no evidence-based evaluations preceded these crisis responses. Professionals may be tempted to indulge in demoralisation and despair. They must not. Patients need to know that they will experience safe, evidence-based, and high-quality care from committed and empathic professionals who can help them reconcile the dilemmas of becoming ill, accept available treatments, while protecting dignity and emotional resources. An essential element of care is to sustain and encourage optimism and hope, while sharing knowledge about how to overcome symptoms and the financial and social implications of developing and living with a mental illness. Studies of hope and optimism in psychiatric care are rare. Given the economic crisis, new models of care are needed but new professional attitudes and approaches must accompany these, in order to avoid inadvertently perpetuating institutionalised practices that serve the organisation and not the patient. What is the role of psychiatric research and practice in supporting health systems to adopt evidence-based transitions that protect patients, and eradicate uncaring practices, which undermine hope? Hope and optimism are essential elements of the therapeutic encounter. Research that helps to stratify the risks of medical disorders is in itself a hopeful activity that encourages patients and the public to commit themselves to prevention and effective early treatment, for example, of breast cancer. In cancer care, much is being done to generate more research funding, reduce stigma, and instil collective optimism within society as well as the scientific community. The prevailing narrative is of improvements in treatment outcomes as a consequence of new research. The relationship between psychiatry and medicine remains the subject of lively hopeful discussion. The closer alignment of psychiatry with neurology has already been proffered as a solution, yet this is challenged on the basis that psychiatry needs to rid itself of illusory technological solutions in favour of addressing experiences of coherence and meaning, including hope, in the social world. Integration of social/environmental and health services research alongside neurobiological evidence offers better solutions. New research is forcing amendments to diagnostic and health systems, and consequently the notion of what constitutes an intervention has to change. For example, amid these controversies, researchers are teasing out causal interconnections between what were considered to be discrete psychiatric disorders, revealing shared genetic markers and cortical networks that are causally implicated – see papers by Rees et al (pp. 108–114), Rose et al (pp. 115–121) and Duffy et al (pp. 122–128) in this issue. Editorials by Sharpe (pp. 91–92), Craddock & Mynors-Wallis (pp. 93–95) and Barrett (pp. 96–97) grapple with the relationship between psychiatry and medicine (as do Heylens and colleagues, pp. 151–156), and then take up the implications for diagnosis and treatment in a wide range of conditions and contexts. The research findings in this month’s Journal take us a step further towards better treatments that do not discriminate between mind and body. These are already instilling hope, hand in hand with the rapidly expanding knowledge about psychological processes, empathy, cognition and neuroanatomical localisation of healthy and unhealthy brain function (see Lloyd et al (pp. 129–136), Carnegie et al (pp. 137–143), Menchetti et al (pp. 144–150) and Gould et al (pp. 98–107). However, public attitudes perhaps do not fully reflect these advances and we must do a better job of communicating to a wider audience that psychiatric illness is treatable, and that treatment includes instilling hope and restoring meaning as well as the generation and application of new knowledge. Although deliberations about hope can be restricted to people with multiple forms of stigma, social exclusion and comorbidities, its importance is now accepted more widely for all populations and venues of psychiatric practice. Indeed, even in the recently updated edition of Jerome Frank’s seminal volume Persuasion and Healing, there are elegant neuroanatomical diagrams and in-depth argumentation about the neural and evolutionary basis of hope and its place as a target of intervention. This hopeful enterprise is necessary to promote resilience, creativity, and concern among practitioners, scientists, and the public, and consequently offers direct benefits to patients, so underpinning the future of a hopeful personalised psychiatry.

In this issue, Cai Q. et al. evaluated the clinical characteristics of patients with COVID-19 and abnormal liver tests. Clinical records and laboratory results were obtained from 417 patients with laboratory confirmed COVID-19 who were admitted to the only referral hospital in Shenzhen, China. Of 417 patients with COVID-19, 318 (76.3%) had abnormal liver tests and 90 (21.5%) had liver injury during hospitalisation. The presence of abnormal liver tests became more pronounced during hospitalisation. The use of lopinavir/ritonavir was found to lead to increased odds of liver injury. Patients with abnormal liver tests of hepatocellular type or mixed type at admission were at greater risk of progressing to severe disease. The authors stated that the potential detrimental effects on liver injury mainly related to drugs used during hospitalisation, which should be monitored. The global obesity epidemic affects liver health across generations. Sun and coworkers now demonstrate, in multi-generational obesity models in mice, that maternal obesity caused susceptibility of offspring to diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC). Using sophisticated methods, the authors identified the microRNA miR-27a-3p as crucial for this process. This microRNA was upregulated in obese mouse mothers and passed on to the offspring, where it enhanced liver tumour incidence by regulating the expression levels of Acsl1 and Aldh2 genes. This fascinating over-generational mechanism of obesity-induced HCC susceptibility warrants further studies in human cohorts.
Autophagy and necroptosis are coregulated and interlinked in hepatocytes during fatty liver disease Autophagy is a highly conserved intracellular process for the ordered degradation of cellular components in lysosomes, which provides energy and recycled substrates (amino acids, glucose, fatty acids) to the cell. Insufficient autophagy in hepatocytes has been implicated in non-alcoholic fatty liver disease (NAFLD). Wu and coworkers now provide an in-depth series of experimental data revealing a co-regulatory mechanism between necroptosis and autophagy in NAFLD. Mlkl-dependent, but Rip3-independent, signalling contributed to "Western diet"-induced liver injury and inflammation through inhibition of autophagy. This new link from mouse models may provide novel targets for intervening in the pathogenesis of NAFLD.

Gut-liver axis revisited: How intestinal Paneth cells influence angiogenesis and portal hypertension
Paneth cells in the epithelium of the small intestine produce antimicrobial peptides and balance the intestinal microbiota.
Hassan and coworkers now demonstrate the involvement of Paneth cells in the haemodynamic changes caused by experimental portal hypertension. Using mouse models with Paneth cell depletion as well as intestinal organoids, this study revealed that Paneth cells produce angiogenic moleculespartly in response to signals from the intestinal microbiotathat impact intestinal and mesenteric angiogenesis and regulate portal hypertension. This study raises the perspective that intestinal cells could be a novel target to alleviate portal hypertension.

Cytotoxic functions of MAIT cells in human liver during acute viral hepatitis
Mucosal-associated invariant T (MAIT) cells are abundantly present "innate-like T cells" in human liver, but their role is poorly understood. Rha and coworkers studied many paired samples from blood and liver in human patients, characterising these cells in healthy liver and demonstrating an as yet unrecognised mechanism of MAIT cell activation in acute viral hepatitis. MAIT cell activation by IL-15 results in an NKG2D-dependent cytotoxicity and contributes to immune-mediated liver injury in acute hepatitis A. MAIT cells might therefore represent an interesting target to either reduce immune-mediated injury in acute hepatitis or to increase the elimination of virus-infected cells.

Chronic hyperammonaemia induces peripheral inflammation
In this paper Balzano T. et al. tested the hypothesis that chronic hyperammonaemia would induce peripheral inflammation which, in turn, would induce neuro-inflammation and cognitive impairment. The effects of chronic hyperammonaemia, induced by feeding rats with an ammonia-containing diet, on peripheral inflammation, neuro-inflammation and cognitive impairment were analysed before and after the administration of an anti-TNFa agent (Infliximab). Rats with hyperammonaemia showed a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNFa and IL-6. Peripheral anti-TNFa treatment prevented peripheral inflammation induction, the increase in IL-1b and TNFa and microglia activation in the hippocampus of the rats, which remained hyperammonaemic. This was associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory. The authors stated that peripheral inflammation may be a mechanism by which hyperammonaemia induces cognitive impairment. Thus, they hypothesised that reducing peripheral inflammation could improve cognitive function in patients with hepatic encephalopathy.

VIRAL HEPATITIS
C19orf66 is an interferon-induced inhibitor of HCV replication pregnancies with other CLD or no CLD. On multivariate analysis, NAFLD was independently associated with hypertensive complications, postpartum haemorrhage and pre-term birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counselling and pregnancy care.
Genome-wide association study of NAFLD and NASH Most genome-wide association studies (GWASs) in NAFLD assessed hepatic triglyceride content as a reference phenotype but lacked detailed histological classification for other lesions with prognostic value. Anstee et al. performed GWAS in 1,483 European NAFLD cases recruited from several European tertiary care centres and 17,781 genetically matched population controls. A replication Italian cohort of 559 NAFLD cases and 945 controls was also included. A majority (78%) of liver pathology slides were scored by a central pathologist and the remainder but the local one. This study confirmed PNPLA3, TM6SF2 and HSD17B13 variants as the major risk factors for disease susceptibility. A combined genetic risk score based on summing the allele count had a statistically significant relationship with the semi-quantitative steatosis/NAS/fibrosis scores, with the most significant relationship detected for fibrosis stage. This result was replicated in the Italian cohort. They also identified a signal in the gene coding for PYGO1 (a transcription factor that contributes to Wnt signalling) with close to genome-wide significance for steatosis. Additional case-control analyses were undertaken but did not identify other traits with genome-wide significance. This study also confirmed that the newly identified HSD17B13 isoform (lacking the exon 6 in the liver) had a protective effect against NAFLD. Importantly, there were no significant associations of any genotype with disease activity when considered separately from steatosis.

LIVER CANCER
Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with cirrhosis Over the last 4 years, there has been intense controversy regarding the possibility that DAAs could increase the chances of newly diagnosed or recurrent HCC in a fraction of patients. The subgroup at risk was allegedly enriched in patients with pre-existing indeterminate liver nodules. Sangiovanni et al. led a prospective multicentre study on 1,285 consecutive cirrhotic patients treated with DAAs, Among cirrhotics without HCC, de novo tumours appeared in 48 patients (yearly incidence 3.1/100 patients-year, 77% in early stages), with a 2-year cumulative incidence of 5.4% in patients with no nodules and 13.6% in patients with undefined/non-malignant nodules (UNMNs). UNMNs, prior ascites and alpha-fetoprotein levels were independently associated with the incidence of de novo HCC on multivariate analysis. Among cirrhotics with HCC in complete response, recurrence occurred in 40 patients (yearly incidence 29.9/100 patients-year, 83% in early stages), with a 2-year cumulative incidence of 42.9%. A peak of instant incidence was observed at 7.7 months. The authors concluded that an early peak of incidence for both de novo HCC in patients with UNMNs and recurrent HCC was observed in cirrhotic patients treated with DAAs, but increased incidence was not associated with increased tumour aggressiveness.

CIRRHOSIS AND LIVER FAILURE
Changes in frailty are associated with waitlist mortality in patients with cirrhosis: A multicentre cohort study Lai J.C. et al. aimed to evaluate change in frailty over time (DLFI) and its association with death/delisting for sickness. A total of 1,093 outpatients with cirrhosis without HCC, listed for liver transplantation at 8 centres in the US underwent ambulatory longitudinal frailty testing with the liver frailty index (LFI). A multilevel linear mixed effects regression was used to model and predict DLFI per 3 months based on age, gender, MELDNa, ascites, and hepatic encephalopathy. Patients were categorised into 4 groups by frailty trajectories. The impact of baseline LFI and predicted DLFI on death/delisting, was evaluated with transplantation as the competing risk. After a median follow-up of 11 months, 223 (20%) of the overall cohort of patients died/ were delisted for sickness. The cumulative incidence of death/delisting increased by worsening DLFI group. In competing risk regression, a 0.1 unit change in DLFI per 3 months was associated with a 2-fold increased risk of death/delisting. The authors stated that changes in frailty were significantly associated with death/delisting independent of baseline frailty and MELDNa in patients with cirrhosis. Thus, they supported the longitudinal measurement of frailty, using the LFI, and interventional work aimed at reversing frailty in these patients.

CHOLESTATIC DISEASE
Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis In most liver transplant centres, ursodeoxycholic acid (UDCA) is generally employed after the diagnosis of recurrent primary biliary cholangitis (PBC) has been established. In this longitudinal, retrospective analysis of a very large, multicentre, international cohort Corpechot et al. attempted to understand whether prophylactic administration of UDCA is beneficial. They included 780 patients transplanted for PBC and followed-up for a median of 11 years; 190 patients received preventive UDCA (10-15 mg/kg/d). During follow-up, 30% of patients exhibited PBC recurrence and this accounted for a quarter of liver-related deaths and lower rates of patient and graft survivals. Despite patient baseline differences between those who did or did not receive UDCA and large differences between centres, preventive administration of UDCA was associated with a lower risk of disease recurrence, graft loss, liver-related death, and all-cause death. Interestingly, cyclosporine rather than tacrolimus use added to the preventive effect of UDCA against PBC recurrence, graft loss and all-cause death. These results strongly favour initiation of UDCA therapy soon after LT for PBC, as this may not only prevent PBC recurrence but also reduce its long-term negative impact.