Single-cell transcriptomics stratifies organoid models of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test new therapies are indispensable. While recently, human liver organoid models have emerged to assess steatotic liver disease, a systematic evaluation of their translational potential is still missing. Here, we evaluated human liver organoid models of MASLD, comparatively testing disease induction in three conditions: oleic acid, palmitic acid, and TGF-ß1. Through single-cell analyses, we find that all three models induce inflammatory signatures, but only TGF-ß1 promotes collagen production, fibrosis, and hepatic stellate cell expansion. In striking contrast, oleic acid ameliorates fibrotic signatures and reduces the hepatic stellate cell population. Linking data from each model to gene expression signatures associated with MASLD disease progression further demonstrates that palmitic acid and TGF-ß1 more robustly model inflammation and fibrosis. Our findings highlight the importance of stratifying MASLD organoid models by signatures of clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

Working with suicidal mothers during the perinatal period: a reflexive thematic analysis study with mental health professionals.

BACKGROUND: Suicide is the leading cause of death in mothers postpartum and one of the most common causes of death during pregnancy. Mental health professionals who work in perinatal services can offer insights into the factors they perceive as being linked to mothers' suicidal ideation and behaviour, support offered to mothers and improvements to current practices. We aimed to explore the experiences and perceptions of perinatal mental health professionals who have worked with suicidal mothers during the perinatal period. METHOD: Semi-structured interviews were conducted face-to-face or via telephone with mental health professionals working in perinatal mental health inpatient or community services across England. Data were analysed using reflexive thematic analysis. RESULTS: From the professionals' (n = 15) accounts three main themes were developed from their interview data. The first, factors linked to suicidal ideation and behaviour, overarched two sub-themes: (1.1) the mother's context and (1.2) what the baby represents and what this means for the mother. These sub-themes described factors that professionals assessed or deemed contributory in relation to suicidal ideation and behaviour when a mother was under their care. The second main theme, communicating about and identifying suicidal ideation and behaviour, which outlined how professionals enquired about, and perceived, different suicidal experiences, encapsulated two sub-themes: (2.1) how to talk about suicide and (2.2) types of suicidal ideation and attempts. The third main theme, reducing suicidal ideation through changing how a mother views her baby and herself, focused on how professionals supported mothers to reframe the ways in which they viewed their babies and in turn themselves to reduce suicidal ideation. CONCLUSION: Professionals highlighted many factors that should be considered when responding to a mother's risk of suicide during the perinatal period, such as the support around her, whether the pregnancy was planned and what the baby represented for the mother. Professionals' narratives stressed the importance of adopting a tailored approach to discussing suicidal experiences with mothers to encourage disclosure. Our findings also identified psychological factors that professionals perceived as being linked to suicidal outcomes for mothers, such as self-efficacy; these factors should be investigated further.

Resection of NAFLD/NASH-related Hepatocellular Carcinoma (HCC): Clinical Features and Outcomes Compared with HCC Due to Other Etiologies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the leading causes of hepatocellular carcinoma (HCC) worldwide. Limited data exist on surgical outcomes for NAFLD/NASH-related HCC compared with other HCC etiologies. We evaluated differences in clinicopathological characteristics and outcomes of patients undergoing surgical resection for NAFLD/NASH-associated HCC compared with other HCC etiologies. METHODS: Demographic, clinicopathological features, and survival outcomes of patients with surgically resected HCC were collected. NAFLD activity score (NAS) and fibrosis score were assessed by focused pathologic review in a subset of patients. RESULTS: Among 492 patients screened, 260 met eligibility (NAFLD/NASH [n = 110], and other etiologies [n = 150]). Median age at diagnosis was higher in the NAFLD/NASH HCC cohort compared with the other etiologies cohort (66.7 vs. 63.4 years, respectively, P = .005), with an increased percentage of female patients (36% vs. 18%, P = .001). NAFLD/NASH-related tumors were more commonly >5 cm (66.0% vs. 45%, P = .001). There were no significant differences in rates of lymphovascular or perineural invasion, histologic grade, or serum AFP levels. The NAFLD/NASH cohort had lower rates of background liver fibrosis, lower AST and ALT levels, and higher platelet counts (P < .01 for all). Median overall survival (OS) was numerically shorter in NAFLD/NASH vs other etiology groups, however, not statistically significant. CONCLUSIONS: Patients with NAFLD/NASH-related HCC more commonly lacked liver fibrosis and presented with larger HCCs compared with patients with HCC from other etiologies. No differences were seen in rates of other high-risk features or survival. With the caveat of sample size and retrospective analysis, this supports a similar decision-making approach regarding surgical resection for NAFLD/NASH and other etiology-related HCCs.

Application of the Latest Advances in Evidence-Based Medicine in Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune liver disease that can progress to end-stage liver disease and its complications. A previous expert review panel collaborated on a consensus document for gastroenterologists and other healthcare professionals regarding the care of patients with PBC. Subsequently, there have been several recent important developments in the diagnosis, treatment, and monitoring of patients with PBC. These include updates to prognostic models on risk stratification, new noninvasive tools for staging of disease, updates to the appropriate use of and long-term treatment results with obeticholic acid as a second-line treatment, the emerging therapeutic role of fibrates, and the advancement of investigational agents for managing PBC. In this updated expert consensus document, we provide updates on staging, the use of noninvasive prognostic tools, and a treatment algorithm to provide evidence-based and practical tools for clinicians who manage PBC, with the ultimate goal to improve the long-term outcomes for patients with this chronic liver disease.

The interplay between suicidal experiences, psychotic experiences and interpersonal relationships: a qualitative study.

BACKGROUND: Suicidal thoughts, acts, plans and deaths are considerably more prevalent in people with non-affective psychosis, including schizophrenia, compared to the general population. Social isolation and interpersonal difficulties have been implicated in pathways which underpin suicidal experiences in people with severe mental health problems. However, the interactions between psychotic experiences, such as hallucinations and paranoia, suicidal experiences, and the presence, and indeed, absence of interpersonal relationships is poorly understood and insufficiently explored. The current study sought to contribute to this understanding. METHODS: An inductive thematic analysis was conducted on transcripts of 22, individual, semi-structured interviews with adult participants who had both non-affective psychosis and recent suicidal experiences. A purposive sampling strategy was used. Trustworthiness of the analysis was assured with researcher triangulation. RESULTS: Participants relayed both positive and negative experiences of interpersonal relationships. A novel conceptual model is presented reflecting a highly complex interplay between a range of different suicidal experiences, psychosis, and aspects of interpersonal relationships. Three themes fed into this interplay, depicting dynamics between perceptions of i. not mattering and mattering, ii. becoming disconnected from other people, and iii. constraints versus freedom associated with sharing suicidal and psychotic experiences with others. CONCLUSION: This study revealed a detailed insight into ways in which interpersonal relationships are perceived to interact with psychotic and suicidal experiences in ways that can be both beneficial and challenging. This is important from scientific and clinical perspectives for understanding the complex pathways involved in suicidal experiences. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03114917), 14th April 2017. ISRCTN (reference ISRCTN17776666 .); 5th June 2017). Registration was recorded prior to participant recruitment commencing.

What makes a perinatal woman suicidal? A grounded theory study.

BACKGROUND: Suicide is a leading cause of maternal death during pregnancy and up to a year after birth. Psychological and psychosocial risk factors for maternal suicide ideation and behaviour have been identified but do not account for why mothers begin to experience suicidal thoughts. Qualitative research offers a way of identifying what might drive mothers to initially consider suicide and then go on to act on such thoughts; crucial for the development of assessments to identify, and interventions to target, maternal suicide ideation and behaviour. We aimed to develop a grounded theory outlining what makes women think about suicide and/or engage in suicidal behaviour during pregnancy and the first 12 months following birth? METHOD: Semi-structured interviews were conducted with 12 mothers in the UK who had suicidal thoughts during pregnancy and/or the first year following birth. A constructivist approach to grounded theory was adopted which guided the data collection and analysis processes. RESULTS: We developed a model outlining the theorised process of psychological factors that culminates in mothers experiencing suicidal thoughts and then making a suicide attempt during the perinatal period. The process was initiated when mothers felt attacked by motherhood which led to feeling like a failure, self-identifying as a "bad mother" and subsequent appraisals of entrapment and/or defeat. When nothing resolved the distress and as mothers collated reasons for why they perceived they needed to die, suicidal behaviour became a viable and appealing option. We theorised that mothers might make a suicide attempt when they entered a state of intense "darkness" brought on by a trigger, followed by a temporary lapse in the conflict between the desire to live and desire to die and an opportunity to attempt. CONCLUSIONS: Participants stressed the rapid onset of suicidal thoughts. We suggest that healthcare professionals enquire about the mother's feelings towards the baby and of isolation, how she views herself as a mother, feelings of entrapment and defeat during routine contacts to aid identification and prevention of suicidal ideation/behaviour. Suggested interventions to prevent suicidal thoughts and behaviour include helping women manage their expectations for pregnancy and the postpartum period.

A positive mental imagery intervention for targeting suicidal ideation in university students: A pilot study.

OBJECTIVES: Suicide is a major public health concern and is now considered to be the leading cause of death in young people. Suicidal ideation within student populations has recently increased. The Broad-Minded Affective Coping (BMAC) offers a brief psychological intervention targeting suicidal ideation by enabling access to competing positive emotions and thoughts using guided imagery. Its acceptability and feasibility in student populations are unclear. DESIGN: A single arm pilot study investigated the feasibility and acceptability of a six-session BMAC intervention for university students experiencing suicidal ideation. METHOD: Recruitment took place from university counselling services. Suicidal ideation and emotional states were assessed at baseline and after 6 and 12 weeks. Participants also completed corresponding sessional measures. RESULTS: Twelve eligible participants consented to take part with 11 receiving the intervention. Ten participants completed post treatment and follow up assessments. Retention to treatment was high with participants attending an average of 5.2 (87%; SD = 1.54) out of six intervention sessions. There were also good completion rates of the BMAC technique between sessions. Participants reported high levels of satisfaction with the intervention. There was an associated reduction across a range of clinical outcomes, including suicidal ideation, with large effect sizes. DISCUSSION: This pilot study showed promising results on the feasibility and acceptability of the BMAC intervention in students experiencing suicidal ideation. However, the study had a small sample size and no comparator control group. Further exploration of the BMAC intervention is warranted.

The relationship between the therapeutic alliance in psychotherapy and suicidal experiences: A systematic review.

It is well established that there is a fundamental need to develop a robust therapeutic alliance to achieve positive outcomes in psychotherapy. However, little is known as to how this applies to psychotherapies which reduce suicidal experiences. The current narrative review summarizes the literature which investigates the relationship between the therapeutic alliance in psychotherapy and a range of suicidal experiences prior to, during and following psychotherapy. Systematic searches of MEDLINE, PsycINFO, Web of Science, EMBASE and British Nursing Index were conducted. The search returned 6472 studies, of which 19 studies were eligible for the present review. Findings failed to demonstrate a clear link between suicidal experiences prior to or during psychotherapy and the subsequent development and maintenance of the therapeutic alliance during psychotherapy. However, a robust therapeutic alliance reported early on in psychotherapy was related to a subsequent reduction in suicidal ideation and attempts. Study heterogeneity, varied sample sizes and inconsistent reporting may limit the generalizability of review findings. Several recommendations are made for future psychotherapy research studies. Training and supervision of therapists should not only highlight the importance of developing and maintaining the therapeutic alliance in psychotherapy when working with people with suicidal experiences but also attune to client perceptions of relationships and concerns about discussing suicidal experiences during therapy.

An investigation of whether emotion regulation mediates the relationship between attachment insecurity and suicidal ideation and behaviour.

OBJECTIVE: The aim of this research was to examine relationships between attachment insecurity and suicidal ideation and behaviour. Secondary aims were to explore the mediating role of emotion dysregulation and the moderating role of betrayal trauma in explaining hypothesised relationships. METHOD: Sixty-five participants with experience of suicidal ideation completed questionnaire measures assessing attachment security, suicide ideation, emotion regulation, betrayal trauma, depressive symptoms and hopelessness. RESULTS: A direct relationship was found between avoidant attachment and suicide ideation after controlling for age and gender. Multiple suicide attempters had higher anxious attachment. Anxious and avoidant attachment, suicide ideation and betrayal trauma were associated with emotion dysregulation. The relationship between attachment insecurity and suicide ideation was not mediated by emotion dysregulation. In the mediation model, only anxious attachment remained a significant predictor of emotion regulation and there was no significant effect of emotion regulation nor betrayal trauma, on suicide ideation. CONCLUSION: Suicidal individuals may benefit from therapeutic intervention that explores attachment-related difficulties and therapies such as dialectical behavioural therapy, which support skills in emotional regulation. Future longitudinal research should identify other important mediators of the association between attachment and suicidality to develop more targeted psychological interventions for suicidality.

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA.

BACKGROUND & AIMS: Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. METHODS: This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). RESULTS: At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p <0.001 vs. placebo) and by -40.6±17.4% in the elafibranor 120 mg group (p <0.001) compared to a +3.2±14.8% increase in the placebo group. The composite endpoint of ALP ≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. CONCLUSION: In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. LAY SUMMARY: Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT03124108.

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19), the illness caused by the SARS-CoV-2 virus, is rapidly spreading throughout the world. Hospitals and healthcare providers are preparing for the anticipated surge in critically ill patients, but few are wholly equipped to manage this new disease. The goals of this document are to provide data on what is currently known about COVID-19, and how it may impact hepatologists and liver transplant providers and their patients. Our aim is to provide a template for the development of clinical recommendations and policies to mitigate the impact of the COVID-19 pandemic on liver patients and healthcare providers. APPROACH AND RESULTS: This article discusses what is known about COVID-19 with a focus on its impact on hepatologists, liver transplant providers, patients with liver disease, and liver transplant recipients. We provide clinicians with guidance for how to minimize the impact of the COVID-19 pandemic on their patients' care. CONCLUSIONS: The situation is evolving rapidly, and these recommendations will need to evolve as well. As we learn more about how the COVID-19 pandemic impacts the care of patients with liver disease, we will update the online document available at https://www.aasld.org/about-aasld/covid-19-and-liver.

Hepatology Consultants Often Disagree on Etiology of Abnormal Liver Biochemistries in COVID-19 but Agree on Management.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with elevated liver biochemistries in approximately half of hospitalized patients, with many possible etiologies. AIM: To assess agreement on the etiology of abnormal liver biochemistries and diagnostic recommendations in COVID-19. METHODS: Twenty hepatology consultations were reviewed by three senior hepatologists who provided a differential diagnosis and diagnostic recommendations. Kappa agreement on the primary etiology was calculated. RESULTS: Kappa agreement between hepatologists on the primary etiology of elevated liver biochemistries was 0.10 (p = 0.03). Agreement was greater around drug-induced liver injury 0.51 (p < 0.0001) and SARS-CoV-2-related liver injury 0.17 (p = 0.03). Serial liver biochemistries were recommended in all consultations over other evaluations. CONCLUSION: In COVID-19, elevated liver biochemistries present a diagnostic challenge and can often be monitored conservatively.

Involving an individual with lived-experience in a co-analysis of qualitative data.

BACKGROUND: People with lived-experience of the phenomenon under investigation are seldom involved in the analysis of qualitative data, and there exists little guidance for those wishing to involve contributors at this stage of research. AIMS: To critically reflect on the process of involving people with lived-experience in a thematic analysis and to offer direction to other researchers. METHODS: An individual with lived-experience of residing in prison contributed to a co-analysis of qualitative data using thematic analysis. This paper reports on involvement at each stage of a thematic analysis and follows an established reporting checklist. RESULTS: A number of challenges and benefits were encountered in the process of co-analysing the data. These are discussed in relation to previous research and how to overcome the challenges encountered. CONCLUSIONS: The paper concludes by giving recommendations and guidance for future researchers wishing to involve people with lived-experience in qualitative data analysis.

The relationship between self-criticism and suicide probability.

The relationship of self-to-self relating and suicide has received attention in explanatory models of suicide. However, exploration of specific types of self-relationships, namely feelings of inadequacy (associated with perfectionism), self-attacking and the ability to be kind and nurturing towards the self has received limited attention in a suicidal population. The present study assessed the relative contribution of self-criticism to suicide probability, alongside established predictors of suicidal ideation; hopelessness, depression, defeat and entrapment. Participants completed measures of inadequacy, self-attacking, self-reassurance, defeat, entrapment, depression and hopelessness (N = 101). A correlation, regression and mediation analysis was undertaken. Results demonstrated that self-attacking has a direct relationship with suicide probability, alongside established predictors; entrapment and hopelessness. Depressive symptomology was not found to be a significant predictor of suicide probability in this population. Addressing particularly hostile forms of self-criticism may be a promising area in terms of future research and clinical practice. Entrapment continues to be a significant predictor of suicide risk and interventions that target this experience should be explored.

Immediate administration of antiviral therapy after transplantation of hepatitis C-infected livers into uninfected recipients: Implications for therapeutic planning.

The practice of transplanting hepatitis C (HCV)-infected livers into HCV-uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct-acting antivirals (DAAs) provide an opportunity to treat donor-derived HCV-infection and should be administered early in the posttransplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV-positive donor organs. We report the results of a trial in which 14 HCV-negative patients underwent successful liver transplantation from HCV-positive donors. Nine patients received viremic (nucleic acid testing [NAT]-positive) livers and started a 12-week course of oral glecaprevir-pibrentasvir within 5 days of transplant. Five patients received livers from HCV antibody-positive nonviremic donors and were followed using a reactive approach. Survival in NAT-positive recipients is 100% at a median follow-up of 46 weeks. An immediate treatment approach for HCV NAT-positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the posttransplant course could enable need-based allocation of HCV-positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Gut-homing lymphocytes that express the integrin α4ß7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4ß7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD. METHODS: We collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes. RESULTS: In the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation. CONCLUSIONS: In an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.

A psychological intervention for suicide applied to non-affective psychosis: the CARMS (Cognitive AppRoaches to coMbatting Suicidality) randomised controlled trial protocol.

BACKGROUND: Suicide is a leading cause of death globally. Suicide deaths are elevated in those experiencing severe mental health problems, including schizophrenia. Psychological talking therapies are a potentially effective means of alleviating suicidal thoughts, plans, and attempts. However, talking therapies need to i) focus on suicidal experiences directly and explicitly, and ii) be based on testable psychological mechanisms. The Cognitive AppRoaches to coMbatting Suicidality (CARMS) project is a Randomised Controlled Trial (RCT) which aims to investigate both the efficacy and the underlying mechanisms of a psychological talking therapy for people who have been recently suicidal and have non-affective psychosis. METHODS: The CARMS trial is a two-armed single-blind RCT comparing a psychological talking therapy (Cognitive Behavioural Suicide Prevention for psychosis [CBSPp]) plus Treatment As Usual (TAU) with TAU alone. There are primary and secondary suicidality outcome variables, plus mechanistic, clinical, and health economic outcomes measured over time. The primary outcome is a measure of suicidal ideation at 6 months after baseline. The target sample size is 250, with approximately 125 randomised to each arm of the trial, and an assumption of up to 25% attrition. Hence, the overall recruitment target is up to 333. An intention to treat analysis will be used with primary stratification based on National Health Service (NHS) recruitment site and antidepressant prescription medication. Recruitment will be from NHS mental health services in the North West of England, UK. Participants must be 18 or over; be under the care of mental health services; have mental health problems which meet ICD-10 non-affective psychosis criteria; and have experienced self-reported suicidal thoughts, plans, and/or attempts in the 3 months prior to recruitment. Nested qualitative work will investigate the pathways to suicidality, experiences of the therapy, and identify potential implementation challenges beyond a trial setting as perceived by numerous stake-holders. DISCUSSION: This trial has important implications for countering suicidal experiences for people with psychosis. It will provide definitive evidence about the efficacy of the CBSPp therapy; the psychological mechanisms which lead to suicidal experiences; and provide an understanding of what is required to implement the intervention into services should it be efficacious. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03114917), 14th April 2017. ISRCTN (reference ISRCTN17776666 https://doi.org/10.1186/ISRCTN17776666); 5th June 2017). Registration was recorded prior to participant recruitment commencing.

The role of psychological and social factors in the relationship between attachment and suicide: A systematic review.

Insecure attachment is widely accepted to be a risk factor for suicidal thoughts and behaviour. To increase our understanding of this distal association, the current systematic review aimed to evaluate empirical evidence that has investigated the role of psychosocial mechanisms within this relationship. Sixteen original research articles were identified, with the majority carrying out mediational analyses to test their hypotheses. Substantial heterogeneity was found across studies with regards to their theoretical approach to assessing attachment, suicide-related outcomes, sample population, statistical analyses, and the psychological factors under investigation. Nevertheless, this emergent evidence base indicates that a range of predisposing, precipitating, and crisis-state factors may mediate the association between attachment security and suicidality. Studies that investigated moderating factors did not report significant findings, and the mediating role for psychiatric diagnoses remains unclear. Furthermore, this emerging research base is limited by an over-reliance on cross-sectional designs and self-reported data. Longitudinal and experimental designs are required to verify causal pathways and to investigate whether trait vulnerabilities interact with acute stressors to increase suicide risk. Finally, disorganized attachment has been overlooked so far and should be given greater consideration going forward.