The impact of chronic liver disease on critically ill patients

In the UK, mortality from liver disease has increased by 400% between 1970 and 2010 with death rates for those under 65 having risen by almost 500% (1). Up to 75% of deaths related to chronic liver disease have an underlying aetiology of alcohol and are preventable (1, 2). Advanced chronic liver disease leads to multi-system clinical manifestations, many of which will require critical care. Evidence supporting this claim is seen in the increase in admissions to critical care for those patients with cirrhosis (3). These patients have higher rates of readmission to ICU (Intensive Care Unit), longer length of ICU stay and have an increased requirement for organ support (4). Despite this, both ICU and hospital mortality in those with cirrhosis have improved since the 1980s where mortality was reported to be up to 100% (5-7). With fewer beds compared to the USA or other European countries the existing demand on critical care capacity in the UK is increasing. There remains a need for a greater number of centres offering both critical care and hepatology input, with a significant number of hospitals nationwide lacking any hepatology input (8). Assessment of critically ill patients with cirrhosis is challenging, with many prognostic scoring systems in use. To date, no scoring system has been demonstrated to be superior in stratifying which patients would benefit from ICU admission. With the existing pressure on limited critical care beds within the UK and the increased demand to support critically ill patients, identifying those patients who merit admission to critical care will become an increasingly important challenge. This thesis focuses on the factors used in the decision to admit a patient with advanced chronic liver disease or cirrhosis to critical care, their long-term survival and quality of life. Attention is given to the utility of the Child-Pugh score and when it should be assessed. As the majority of deaths due to chronic liver disease have an underlying aetiology of alcohol, this thesis will also address how an alcohol use disorder can be assessed in the critically ill. The first investigation of this thesis explores the criteria used in the decision to escalate a patient to intensive care. This is explored through 2 Scottish surveys of consultant gastroenterologists and intensivists. Results highlighted agreement by both specialities on the importance of Child-Pugh score measured when a patient was clinically stable. Inconsistencies were evident in the escalation of therapy with intensivists more likely to offer intensive care and multi-organ support as compared to gastroenterologists. In response to these findings, the timing and utility of Child-Pugh score was investigated. This observational cohort study compared Child-Pugh score measured on ICU admission with the score when a patient was clinically stable and short-term mortality. Only Child-Pugh score measured at time of ICU admission was associated with hospital mortality, which contradicted the findings of the previous chapter. The degree of change in Child-Pugh score between these time points was associated with mortality. Given that the majority of deaths due to chronic liver disease in the UK are primarily caused by alcohol, challenges exist in identifying alcohol use disorders in the critically ill. A prospective study examined the use of a proxy to report an alcohol use disorder in critically ill patients and suggested that a proxy could be used as a reliable historian. Whilst short-term survival of critically ill cirrhotics has improved, there is a paucity of studies reporting long-term outcomes. An observational cohort study investigated survival at 12 months for cirrhotic patients admitted to a general ICU in the UK. Long-term survival following an ICU stay has improved, in keeping with other studies. When measured on admission to ICU, Child-Pugh class was demonstrated to stratify patients into 3 distinct groups for long-term survival. With the improvement in survival, the sequelae of an ICU stay were investigated. A prospective observational cohort study explored the long-term quality of life and prevalence of sleep disturbance. A number of survivors reported that their quality of life was worse than, or equal to death. Quality of life and sleep disturbance were influenced by pre-existing comorbidity and events during their ICU. In this study, there was no association found between QOL and insomnia in those with liver cirrhosis. This thesis addresses the decision to admit a patient with advanced chronic liver disease or cirrhosis to critical care, reports their long-term survival and quality of life and explores how one preventable cause of chronic liver disease can be assessed in the critically ill by use of a proxy

Feasibility of testing effectiveness of an interactive film to improve wellbeing in young people at school settings in the North of England

Background Adolescence is a period of heightened vulnerability for the onset of mental illness and 75% of all mental health problems are established before 18 years old. The North East and North Cumbria (NENC) Child Health and Wellbeing Network worked with local filmmakers TryLife to create an interactive film to support young people’s wellbeing. Interactive films potentially offer an accessible and cost-effective preventative tool, but there is lack of evidence evaluating effectiveness of such interventions. Methods This mixed-methods feasibility trial aimed to evaluate acceptability and feasibility of a randomised controlled trial of the interactive film intervention aimed to build resilience, enhance mental wellbeing and help-seeking attitudes for young people (14-18) in NENC school settings. Primary outcomes were key parameters of the trial, including willingness of schools to participate, participant recruitment, and retention. Secondary outcomes were mental wellbeing, resilience and help-seeking attitudes, analysed descriptively and with a two-way ANOVA. Three schools were recruited and randomised to condition 1) watching the film in class 2) watching the film in class supported by youth workers or 3) class as usual without watching the film. Between November 2021 and December 2022, 172 students completed surveys about mental wellbeing, help-seeking and resilience before watching the film, and at 3- and 6-month follow-up. Acceptability was assessed qualitatively through three focus groups with students and teacher interviews (n=3). Findings Recruitment of schools was challenging due to resource issues and impact of the pandemic. Retention to Follow-up 2 was high in year 10 (96%), but considerably worse in year 12 (60%). Qualitative data indicated acceptability of the intervention and project. Pupils and teachers supported using the film as an intervention in schools, and particularly liked the interactive element to stimulate discussion. Data demonstrated that communication about the project and resource issues within schools were challenges to be remedied before beginning a larger-scale trial. Preliminary analyses showed no significant differences (CI 95%) on wellbeing, resilience and help-seeking outcomes between conditions. Conclusion Some trial aspects worked well, including data collection and analysis. However, recruitment, retention and communication with schools were challenging. Participants offered positive feedback both on the film and trial. Although secondary outcomes did not indicate significant differences between groups, sample sizes were small and further analyses need to be conducted to confirm results. Future research could help to understand the film’s impact to support young people’s wellbeing further. However, potential challenges need addressing ahead of a larger-scale trial

Feasibility of testing effectiveness of an interactive film to improve wellbeing in young people at school settings in the North of England

Background Adolescence is a period of heightened vulnerability for the onset of mental illness and 75% of all mental health problems are established before 18 years old. The North East and North Cumbria (NENC) Child Health and Wellbeing Network worked with local filmmakers TryLife to create an interactive film to support young people’s wellbeing. Interactive films potentially offer an accessible and cost-effective preventative tool, but there is lack of evidence evaluating effectiveness of such interventions. Methods This mixed-methods feasibility trial aimed to evaluate acceptability and feasibility of a randomised controlled trial of the interactive film intervention aimed to build resilience, enhance mental wellbeing and help-seeking attitudes for young people (14-18) in NENC school settings. Primary outcomes were key parameters of the trial, including willingness of schools to participate, participant recruitment, and retention. Secondary outcomes were mental wellbeing, resilience and help-seeking attitudes, analysed descriptively and with a two-way ANOVA. Three schools were recruited and randomised to condition 1) watching the film in class 2) watching the film in class supported by youth workers or 3) class as usual without watching the film. Between November 2021 and December 2022, 172 students completed surveys about mental wellbeing, help-seeking and resilience before watching the film, and at 3- and 6-month follow-up. Acceptability was assessed qualitatively through three focus groups with students and teacher interviews (n=3). Findings Recruitment of schools was challenging due to resource issues and impact of the pandemic. Retention to Follow-up 2 was high in year 10 (96%), but considerably worse in year 12 (60%). Qualitative data indicated acceptability of the intervention and project. Pupils and teachers supported using the film as an intervention in schools, and particularly liked the interactive element to stimulate discussion. Data demonstrated that communication about the project and resource issues within schools were challenges to be remedied before beginning a larger-scale trial. Preliminary analyses showed no significant differences (CI 95%) on wellbeing, resilience and help-seeking outcomes between conditions. Conclusion Some trial aspects worked well, including data collection and analysis. However, recruitment, retention and communication with schools were challenging. Participants offered positive feedback both on the film and trial. Although secondary outcomes did not indicate significant differences between groups, sample sizes were small and further analyses need to be conducted to confirm results. Future research could help to understand the film’s impact to support young people’s wellbeing further. However, potential challenges need addressing ahead of a larger-scale trial

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification