Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

BACKGROUND: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects. AIMS: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC. METHODS: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. RESULTS: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. CONCLUSIONS: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. CLINICALTRIALS: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.

Golexanolone improves fatigue, motor incoordination and gait and memory in rats with bile duct ligation.

BACKGROUND AND AIMS: Many patients with the chronic cholestatic liver disease primary biliary cholangitis (PBC) show fatigue and cognitive impairment that reduces their quality of life. Likewise, rats with bile duct ligation (BDL) are a model of cholestatic liver disease. Current PBC treatments do not improve symptomatic alterations such as fatigue or cognitive impairment and new, more effective treatments are therefore required. Golexanolone reduces the potentiation of GABAA receptors activation by neurosteroids. Golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in rats with chronic hyperammonemia. The aims of the present study were to assess if golexanolone treatment improves fatigue and cognitive and motor function in cholestatic BDL rats and if this is associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. METHODS: Rats were subjected to bile duct ligation. One week after surgery, oral golexanolone was administered daily to BDL and sham-operated controls. Fatigue was analysed in the treadmill, motor coordination in the motorater, locomotor gait in the Catwalk, and short-term memory in the Y-maze. We also analysed peripheral inflammation, neuroinflammation, and GABAergic neurotransmission markers by immunohistochemistry and Western blot. RESULTS: BDL induces fatigue, impairs memory and motor coordination, and alters locomotor gait in cholestatic rats. Golexanolone improves these alterations, and this was associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. CONCLUSION: Golexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC.

Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's antipruritic effects and IL-31 and bile acid levels in patients with PBC. APPROACH AND RESULTS: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group. CONCLUSIONS: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar's antipruritic effects.

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.

Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells.

BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response.

Patient Priorities in Autoimmune Hepatitis: The Need for Better Treatments, More Education and Challenging Stigma.

BACKGROUND: Data show that patients with autoimmune hepatitis have significantly reduced quality-of-life and that corticosteroids carry marked side effects. AIMS: This study explored patients' experiences of autoimmune hepatitis and its treatments; key aspects for developing safe and effective new approaches to therapy. METHODS: An anonymised, internet-based survey collected data including patient demographics, treatments, side-effects, impact on day-to-day life, sources of support and attitudes towards autoimmune hepatitis between December 2019-January 2020. Semi-structured interviews were conducted with 13 patients to further explore their support networks, treatment experiences and health priorities. Descriptive and quantitative analyses were undertaken using R and free text responses were subject to thematic analysis. RESULTS: In total, 270 survey responses were received (median age 55 years and 94% female). Perceived medication side-effects were reported by 66% (169/257) and 73% responded negatively about their experience of corticosteroids. The majority (62·3% [(109/175]) would 'definitely' or 'probably' consider clinical trial participation to improve their care. Only 18·7% (31/166) reported access to a specialist liver nurse and nearly half were involved in support groups. Interview and survey data suggested that major issues were stigma, loss of control and fatigue. CONCLUSIONS: This study provides insights into the realities of living with autoimmune hepatitis with clear issues around lack of support networks, need for patient empowerment and stigma surrounding liver disease. Patient priorities are better therapies to slow disease progression, avoiding corticosteroids and minimising side-effects. Patient willingness to participate in trials suggests that they are achievable provided they have the right design and clinical endpoints.

Anti-Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct-Ligated Mice.

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

Quality of life and home parenteral nutrition: a survey of UK healthcare professionals' knowledge, practice and opinions.

BACKGROUND: There is increasing interest in the assessment of health-related quality of life (QoL) in the care of patients treated with home parenteral nutrition (HPN). However, it is not known whether healthcare professionals (HCPs) have embedded QoL assessment into routine clinical practice in line with current guidelines to favour a more holistic approach to HPN care. The aim of this study was to assess knowledge, current practice and the opinions of HCPs regarding QoL in care of patients on HPN. METHODS: An online survey was distributed via email to HCPs working with HPN patients throughout England, Scotland, Wales and Northern Ireland. Participants were identified using a mailing list for the British Intestinal Failure Alliance, a specialist group within the British Association for Parenteral and Enteral Nutrition. RESULTS: The survey was completed by 67 professionals comprising 24 dietitians, 17 nurses, 14 gastroenterologists, 6 pharmacists, 5 surgeons and 1 psychologist. Of these, 54 (80%) participants agreed that the measurement of QoL is useful. In contrast, 38 (57%) of all participants, including 27 (50%) of those participants who agreed that the measurement of QoL was useful, never measured QoL. Knowledge of QoL literature was rated as poor or very poor by 27 (40%) participants. CONCLUSIONS: Despite the perceived usefulness and importance of QoL assessment, very few HCPs embed it into clinical practice. Knowledge of QoL literature and QoL tools is variable, and there is significant variability in QoL practice. This is clear in terms of the frequency of QoL assessments and heterogeneity in methodology. In contrast, there was almost unanimous agreement that the complications associated with HPN contribute to poorer QoL. There is a need for specific, evidence-based, clinical practice guidelines detailing how to define and measure QoL in this patient population.

Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

Background and Aims: A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method: Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results: There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p < 0.001) but not healthy controls (r (39) = -0.21, p = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p = 0.02), emotional (u = 1374, p = 0.004), and itch (u = 795, p = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p = 0.001). Conclusion: Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.

The National Audit of Primary Biliary Cholangitis (PBC) in the United Kingdom: Defining the Audit Dataset and Data Collection System.

Primary biliary cholangitis (PBC) is a debilitating chronic liver disease that progresses to cirrhosis with attendant complications in a substantial proportion of patients. It is a major cause of liver-related morbidity and mortality in the United Kingdom (UK). The British Society of Gastroenterology (BSG) published guidelines on PBC management, which included key audit standards. Therefore, we propose the first UK-wide audit of the management of PBC, sanctioned by the BSG and the British Association for Study of the Liver (BASL), to benchmark NHS trusts and health boards against these audit standards as a guide to targeted improvement in the delivery of PBC-related health care.

The relationship between disease activity and UDCA response criteria in primary biliary cholangitis: A cohort study.

BACKGROUND: Uncertainty exists about how best to identify primary biliary cholangitis (PBC) patients who would benefit from second-line therapy. Existing, purely clinical, ursodeoxycholic acid (UDCA) response criteria accept degrees of liver biochemistry abnormality in responding patients, emerging data, however, suggest that any degree of ongoing abnormality may, in fact, be associated with an increased risk of adverse outcomes. This cohort study explores the link between response status, the biology of high-risk disease and its implications for clinical practice. METHODS: Proteomics, exploring 19 markers previously identified as remaining elevated in PBC following UDCA therapy, were performed on 400 serum samples, from participants previously recruited to the UK-PBC Nested Cohort between 2014 and 2019. All participants had an established diagnosis of PBC and were taking therapeutic doses of UDCA for greater than 12 months. UDCA response status was assessed using Paris 1, Paris 2 and the POISE criteria, with additional analyses using normal liver blood tests stratified by bilirubin level. Statistical analysis using parametric t tests and 1-way ANOVA. FINDINGS: Disease markers were statistically significantly higher in UDCA non-responders than in responders for all the UDCA response criteria, suggesting a meaningful link between biochemical disease status and disease mechanism. For each of the criteria, however, marker levels were also statistically significantly higher in responders with ongoing liver function test abnormality compared to those who had normalised their liver biochemistry. IL-4RA, IL-18-R1, CXCL11, 9 and 10, CD163 and ACE2 were consistently elevated across all responder groups with ongoing LFT abnormality. No statistically significant differences occurred between markers in normal LFT groups stratified by bilirubin level. INTERPRETATION: This study provides evidence that any ongoing elevation in alkaline phosphatase levels in PBC after UDCA therapy is associated with some degree of ongoing disease activity. There was no difference in activity between patients with normal LFT when stratified by bilirubin. These findings suggest that if our goal is to completely control disease activity in PBC, then normalisation of alkaline phosphatase and bilirubin should be the treatment target. This would also simplify messaging around goals of therapy in PBC, benefiting both patients and clinicians. FUNDING: Funding by the UK Medical Research Council (Stratified Medicine Programme) and an independent research grant by Pfizer. The study funders played no role in the study design, data collection, data analyses, data interpretation or manuscript writing.

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis.

BACKGROUND & AIMS: We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. METHODS: In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. RESULTS: Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. CONCLUSIONS: Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. GOV NUMBER: NCT02955602 CLINICALTRIALSREGISTER. EU NUMBER: 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.

Ten years of NIHR research training: who got an award? A retrospective cohort study.

OBJECTIVE: In 2017, the National Institute for Health Research (NIHR) academy produced a strategic review of training, which reported the variation in application characteristics associated with success rates. It was noted that variation in applicant characteristic was not independent of one another. Therefore, the aim of this secondary analysis was to investigate the inter-relationships in order to identify factors (or groups of factors) most associated with application numbers and success rates. DESIGN: Retrospective data were gathered from 4388 applications to NIHR Academy between 2007 and 2016. Multinominal logistic regression models quantified the likelihood of success depending on changes in the explanatory factors; relative risk ratios with 95% CIs. A classification tree analysis was built using exhaustive χ2 automatic interaction detection to better understand the effect of interactions between explanatory variables on application success rates. RESULTS: 936 (21.3%) applications were awarded. Applications from males and females were equally likely to be successful (p=0.71). There was an overall reduction in numbers of applications from females as award seniority increased from predoctoral to professorship. Applications from institutions with a medical school had a 2.6-fold increase in likelihood of success (p<0.001). Classification tree analysis revealed key predictors of application success: award level, type of programme, previous NIHR award experience and applying form a medical school. CONCLUSION: Success rates did not differ according to gender, and doctors were not more likely to be successful than applications from other professions. Taken together, these findings suggest an essential fairness in how the quality of a submitted application is assessed, but they also raise questions about variation in the opportunity to submit a high-quality application. The companion qualitative study (Burkshaw et al. (2021) BMJ Open) provides valuable insight into potential candidate mechanisms and discusses how research capacity development initiatives might be targeted in the future.

Widespread gaps in the quality of care for primary biliary cholangitis in UK.

OBJECTIVE: Primary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines. DESIGN: Data were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ2 analysis for variation in performance between trusts. RESULTS: 790 patients' medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297). CONCLUSION: Our findings identify a broad-based deficiency in 'real-world' PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.

The effects of different parenteral nutrition lipid formulations on clinical and laboratory endpoints in patients receiving home parenteral nutrition: A systematic review.

BACKGROUND: Home parenteral nutrition (HPN) is a life-sustaining therapy for individuals with intestinal failure in a community setting. It refers to the intravenous infusion of macronutrients, micronutrients, fluids and electrolytes. Routinely used HPN solutions contain different quantities of these components. Consequently, each HPN solution may have different impacts on metabolism, inflammation and oxidative stress. Long-term use of HPN can lead to a number of adverse health outcomes including the development of metabolic bone disease, intestinal failure associated liver disease and poor quality of life but whether, and how, the composition of HPN solutions contributes to these health sequelae is poorly understood. The aim of this study is to systematically review and evaluate the evidence for the differential effects of HPN solutions and to understand what features are associated with differences in clinical endpoints. METHODS: A systematic literature search was conducted between September and December 2020, and updated in July 2021 using the MEDLINE (Ovid), EMBASE, Scopus, and Web of Science databases. Studies were selected according to the following criteria (a) adult participants (>18 years old) dependent on HPN; (b) randomised controlled trials, prospective cohort and cross-sectional study designs; (c) primary research comparing two or more HPN solutions and (d) published in English language. Data were extracted and study quality assessed using Cochrane Collaboration's tools: Risk of Bias for Randomised Controlled Trials (RCTs); Risk of Bias in Non-Randomised Studies of Interventions; and the Newcastle Ottawa Scale for cross-sectional studies. RESULTS: Of the 5148 articles identified, seven RCTs, two prospective cohort and one cross-sectional study were included with a total of 295 participants. Studies varied in terms of duration (one to 60 months) and sample size (n = 5 to 88). Ten studies compared lipid emulsions (LE) and one study also compared LE with lipid-free HPN. No studies were found that compared the amino acid, vitamin, trace element or electrolyte components of HPN. In general, LE were well tolerated with no significant adverse effects. LE containing olive +/or fish oil were associated with a lower ω-6:ω-3 fatty acid ratio, positive reductions in markers of liver function, and changes in blood and cell fatty acid profiles. CONCLUSIONS: Despite the increasing use of HPN, there is surprisingly little evidence available to guide the provision of macro and micronutrients in the adult population requiring this therapy. Although LE containing olive +/or fish oil show promise with regards to liver function and blood and cell fatty acid profiles, further studies are needed before drawing definitive conclusions on the clinical value of these emulsions. It is likely that one type of HPN solution alone cannot be uniformly applied to patient care, and each patient should be assessed on an individual basis.

Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) can result in life-altering cholestatic pruritus and fatigue, but treatment options are limited. Seladelpar, a peroxisome proliferator-activated receptor-delta (PPARδ) agonist, has demonstrated potent anti-cholestatic effects in clinical studies. This open-label, uncontrolled phase 2 study in PBC patients evaluated the effects of 1-year of seladelpar treatment on measures of pruritus and quality of life. METHODS: Self-reported experiences of 101 PBC patients were collected at baseline and after 1 year of seladelpar treatment using the pruritus visual analog scale (VAS), 5D-itch scale, and PBC-40 questionnaires along with bile acid profiles. RESULTS: In patients with moderate-to-severe pruritus, substantial improvement in pruritus was seen in 58% and 93% of patients in 5/10 mg and 10 mg treatment groups, respectively. After 1 year, patients reporting improvement substantially outnumbered those who worsened in the total 5-D itch (including individual domains) and PBC-40 (itch and fatigue domains) questionnaires. Improvement in sleep disturbance at 1-year was reported in 81% (5/10 mg) and 78% (10 mg) of the patients with baseline itch-related sleep disturbance by 5-D itch score with similar results using the PBC-40 sleep questionnaire. Seladelpar-treated patients had significant reductions of 46% (5/10 mg) and 31% (10 mg) in the serum bile acid precursor C4 and reductions of up to 38% in serum bile acids. CONCLUSIONS: Seladelpar treatment for 1 year led to consistent improvement in both symptom burden and biochemical response, suggesting its potential as a single agent to address two key unmet needs in PBC patients.