Advanced chronic liver disease in the last year of life: a mixed methods study to understand how care in a specialist liver unit could be improved

Objective: To identify the limitations in palliative care provision in the last year of life for people with liver cirrhosis and potential barriers to and enablers of palliative care. / Design: Mixed methods, including a retrospective case note review, qualitative focus groups and individual interviews. / Setting: A tertiary referral liver centre in the south of England (UK). / Participants: Purposively selected case notes of 30 people with cirrhosis who attended the tertiary referral liver centre and died during an 18-month period; a purposive sample of 22 liver health professionals who participated in either focus groups or individual interviews. / Primary and secondary outcomes: Data collected from case notes included hospital admissions, documented discussions of prognosis and palliative care provision. Qualitative methods explored management of people with cirrhosis, and barriers to and enablers of palliative care. / Results: Participants had high rates of hospital admissions and symptom burden. Clinicians rarely discussed prognosis or future care preferences; they lacked the skills and confidence to initiate discussions. Palliative care provision occurred late because clinicians were reluctant to refer due to their perception that reduced liver function is reversible, poor understanding of the potential of a palliative approach; palliative care was perceived negatively by patients and families. / Conclusions: People dying with cirrhosis have unpredictable trajectories, but share a common pathway of frequent admissions and worsening symptoms as death approaches. The use of clinical tools to identify the point of irreversible deterioration and joint working between liver services and palliative care may improve care for people with cirrhosis

Palliative care for cirrhosis: a UK survey of health professionals' perceptions, current practice and future needs

Objective: To determine the knowledge and practice patterns of a UK cohort of relevant healthcare professionals (HCPs) about delivering palliative care in cirrhosis, and to inform priorities for future research. / Design: An on-line questionnaire survey with closed and open responses. / Setting: HCPs identified from the mailing list of special interest groups in hepatology and gastroenterology (liver), general practice and specialist palliative care (SPC) across the UK. / Results: Of the 6181 potential contacts identified, 517 HCPs responded. Most believed a role exists for SPC in caring for people with cirrhosis, but many SPC HCPs felt ill prepared to provide good care to those facing death. Further training was needed in managing liver-related symptoms, symptom control and end of life issues. All HCP groups wished to increase community provision of palliative care support, but many general practitioners felt unable to manage advanced cirrhosis in the community. There were differences in the optimal trigger for SPC referral with liver HCPs less likely to refer at symptom deterioration. Prognostication, symptom management and service configuration were key areas identified for future research. / Conclusions: All who responded acknowledged the role of SPC in caring for those dying with cirrhosis and need for further training to improve confidence and enable joint working between SPC, general practice and liver teams. Low response rates make it difficult to generalise these findings, which require further validation

National survey of feasibility of NIV trials for management of children with bronchiolitis.

Background: Bronchiolitis is a major cause of admission to hospital in children. Non-invasive ventilation (NIV) support with continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) oxygen is routinely used for infants in the UK with bronchiolitis. Objective: To establish UK paediatric practice regarding management of bronchiolitis, and to explore issues pertinent to the design of a potential future randomised controlled trial of NIV. Design: Screening logs were completed in hospitals in England capturing information on paediatric bronchiolitis admissions. An online national survey of clinical practice was disseminated to healthcare professionals (HCPs) across the UK to ascertain current management strategies. Results: Screening logs captured data on 393 infants from 8 hospitals. Reasons for admission were most commonly respiratory distress and/or poor fluid intake. Oxygen was administered for 54% of admissions. Respiratory (CPAP and HFNC) and non-respiratory support administered varied considerably. The national survey was completed by 111 HCPs from 76 hospitals. Data were obtained on criteria used to commence and wean NIV, responsibilities for altering NIV settings, minimum training requirements for staff managing a child on NIV, and numbers of trained staff. Most centres were interested in and capable of running a trial of NIV, even out of normal office hours. Conclusions: Respiratory and non-respiratory management of bronchiolitis in UK centres varies widely. A trial of HFNC oxygen therapy in this group of patients is feasible and HCPs would be willing to randomise patients into such a trial. Future work should focus on defining trial eligibility criteria

Establishing and augmenting views on the acceptability of a paediatric critical care randomised controlled trial (the FEVER trial): a mixed methods study

OBJECTIVE: To explore parent and staff views on the acceptability of a randomised controlled trial investigating temperature thresholds for antipyretic intervention in critically ill children with fever and infection (the FEVER trial) during a multi-phase pilot study. DESIGN: Mixed methods study with data collected at three time points: (1) before, (2) during and (3) after a pilot trial. SETTING: English, Paediatric Intensive Care Units (PICUs). PARTICIPANTS: (1) Pre-pilot trial focus groups with pilot site staff (n=56) and interviews with parents (n=25) whose child had been admitted to PICU in the last 3 years with a fever and suspected infection, (2) Questionnaires with parents of randomised children following pilot trial recruitment (n=48 from 47 families) and (3) post-pilot trial interviews with parents (n=19), focus groups (n=50) and a survey (n=48) with site staff. Analysis drew on Sekhon et al's theoretical framework of acceptability. RESULTS: There was initial support for the trial, yet some held concerns regarding the proposed temperature thresholds and not using paracetamol for pain or discomfort. Pre-trial findings informed protocol changes and training, which influenced views on trial acceptability. Staff trained by the FEVER team found the trial more acceptable than those trained by colleagues. Parents and staff found the trial acceptable. Some concerns about pain or discomfort during weaning from ventilation remained. CONCLUSIONS: Pre-trial findings and pilot trial experience influenced acceptability, providing insight into how challenges may be overcome. We present an adapted theoretical framework of acceptability to inform future trial feasibility studies. TRIAL REGISTRATION NUMBERS: ISRCTN16022198 and NCT03028818

Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We aimed to develop and evaluate a pathway for management of patients with non-alcoholic fatty liver disease (NAFLD) using blood tests to stratify patients in primary care to improve detection of cases of advanced fibrosis and cirrhosis, and avoid unnecessary referrals to secondary care. METHODS: This was a prospective longitudinal cohort study with before-and-after analysis and comparison to unexposed controls. We used a two-step algorithm combining the use of FIB-4 followed by the ELF test if required RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (OR=5.18; 95%CI=2.97 to 9.04; p<0.0001). Unnecessary referrals from primary care to secondary care fell by 81% (OR=0.193; 95%CI 0.111 to 0.337; p<0.0001). Three times more cases of cirrhosis were diagnosed (OR=3.14; 95%CI=1.57 to 24; p=0.00011). Although it was used for only 48% of referrals, significant benefits were observed across all referrals from the practices exposed to the pathway. Unnecessary referrals fell by 77% (OR=0.23; 95% CI=0.658 to 0.082; p=0.006) with a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR=4.32; 95% CI=1.52 to 12.25; p=0.006). Compared to referrals made before introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%) representing an 88% reduction in unnecessary referrals when the pathway was followed (OR=0.12; 95%CI=0.042 to 0.349; p<0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis to stratify patients with NAFLD improves the detection of cases of advanced fibrosis and cirrhosis and reduces unnecessary referrals to secondary care of patients with lesser degrees of liver fibrosis. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease to reduce unnecessary referrals by 80% and improve the detection of cases of advanced fibrosis 5 fold and cirrhosis 3 fold

TRAIL Receptor Signaling Regulation of Chemosensitivity In Vivo but Not In Vitro

Background: Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear. Methodology/Principal Findings: To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model. Conclusions: These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs a

Origin matters: Using a local reference genome improves measures in population genomics.

Genome sequencing enables answering fundamental questions about the genetic basis of adaptation, population structure and epigenetic mechanisms. Yet, we usually need a suitable reference genome for mapping population-level resequencing data. In some model systems, multiple reference genomes are available, giving the challenging task of determining which reference genome best suits the data. Here, we compared the use of two different reference genomes for the three-spined stickleback (Gasterosteus aculeatus), one novel genome derived from a European gynogenetic individual and the published reference genome of a North American individual. Specifically, we investigated the impact of using a local reference versus one generated from a distinct lineage on several common population genomics analyses. Through mapping genome resequencing data of 60 sticklebacks from across Europe and North America, we demonstrate that genetic distance among samples and the reference genomes impacts downstream analyses. Using a local reference genome increased mapping efficiency and genotyping accuracy, effectively retaining more and better data. Despite comparable distributions of the metrics generated across the genome using SNP data (i.e. π, Tajima's D and FST ), window-based statistics using different references resulted in different outlier genes and enriched gene functions. A marker-based analysis of DNA methylation distributions had a comparably high overlap in outlier genes and functions, yet with distinct differences depending on the reference genome. Overall, our results highlight how using a local reference genome decreases reference bias to increase confidence in downstream analyses of the data. Such results have significant implications in all reference-genome-based population genomic analyses