eIF4F complex dynamics are important for the activation of the integrated stress response.

In response to stress, eukaryotes activate the integrated stress response (ISR) via phosphorylation of eIF2α to promote the translation of pro-survival effector genes, such as GCN4 in yeast. Complementing the ISR is the target of rapamycin (TOR) pathway, which regulates eIF4E function. Here, we probe translational control in the absence of eIF4E in Saccharomyces cerevisiae. Intriguingly, we find that loss of eIF4E leads to de-repression of GCN4 translation. In addition, we find that de-repression of GCN4 translation is accompanied by neither eIF2α phosphorylation nor reduction in initiator ternary complex (TC). Our data suggest that when eIF4E levels are depleted, GCN4 translation is de-repressed via a unique mechanism that may involve faster scanning by the small ribosome subunit due to increased local concentration of eIF4A. Overall, our findings suggest that relative levels of eIF4F components are key to ribosome dynamics and may play important roles in translational control of gene expression.

Assessing the role of an artificial intelligence assessment tool for thoracic aorta diameter on routine chest CT.

OBJECTIVE: To assess the diagnostic accuracy and clinical impact of automated artificial intelligence (AI) measurement of thoracic aorta diameter on routine chest CT. METHODS: A single-centre retrospective study involving three cohorts. 210 consecutive ECG-gated CT aorta scans (mean age 75 ± 13) underwent automated analysis (AI-Rad Companion Chest CT, Siemens) and were compared to a reference standard of specialist cardiothoracic radiologists for accuracy measuring aortic diameter. A repeated measures analysis tested reporting consistency in a second cohort (29 patients, mean age 61 ± 17) of immediate sequential pre-contrast and contrast CT aorta acquisitions. Potential clinical impact was assessed in a third cohort of 197 routine CT chests (mean age 66 ± 15) to document potential clinical impact. RESULTS: AI analysis produced a full report in 387/436 (89%) and a partial report in 421/436 (97%). Manual vs AI agreement was good to excellent (ICC 0.76-0.92). Repeated measures analysis of expert and AI reports for the ascending aorta were moderate to good (ICC 0.57-0.88). AI diagnostic performance crossed the threshold for maximally accepted limits of agreement (>5 mm) at the aortic root on ECG-gated CTs. AI newly identified aortic dilatation in 27% of patients on routine thoracic imaging with a specificity of 99% and sensitivity of 77%. CONCLUSION: AI has good agreement with expert readers at the mid-ascending aorta and has high specificity, but low sensitivity, at detecting dilated aortas on non-dedicated chest CTs. ADVANCES IN KNOWLEDGE: An AI tool may improve the detection of previously unknown thoracic aorta dilatation on chest CTs vs current routine reporting.

Impact of an ultra-low dose unenhanced planning scan on CT coronary angiography scan length and effective radiation dose.

Objective: Imaged scan length (z-axis coverage) is a simple parameter that can reduce CT dose without compromising image quality. In CT coronary angiography (CTCA), z-axis coverage may be planned using non-contrast calcium score scan (CaCS) to identify the relevant coronary anatomy. However, standardised Agatston CaCS is acquired at 120 kV which adds a relatively high contribution to total study dose and CaCS is no longer routinely recommended in UK guidelines. We evaluate an ultra-low dose unenhanced planning scan on CTCA scan length and effective radiation dose. Methods: An ultra-low dose tin filter (Sn-filter) planning scan (100 kVp, maximum iterative reconstruction) was performed and used to plan the z-axis coverage on 48 consecutive CTCAs (62% men, 62 ± 13 years) compared with 47 CTCA planned using a localiser alone (46% men, 59 ± 12 years) between May and June 2019. Excess scanning beyond the ideal scan length was calculated for both groups. Estimations of radiation dose were also compared between the two groups. Results: Addition of an ultra-low dose unenhanced planning scan to CTCA protocol was associated with reduction in overscanning with no impact on image quality. There was no significant difference in total study effective dose with the addition of the planning scan, which had an average dose-length product of 3 mGy.cm. (total study dose: Protocol A 2.1 mSv vs Protocol B 2.2 mSv, p = 0.92). Conclusion: An ultra-low dose unenhanced planning scan facilitates optimal scan length for the diagnostic CTCA, reducing overscanning and preventing incomplete cardiac imaging with no significant dose penalty or impact on image quality. Advances in knowledge: An ultra-low dose CTCA planning is feasible and effective at optimising scan length.

Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.

BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.

Artificial intelligence can detect left ventricular dilatation on contrast-enhanced thoracic computer tomography relative to cardiac magnetic resonance imaging.

OBJECTIVES: To assess the diagnostic accuracy of an automated algorithm to detect left ventricular (LV) dilatation on non-ECG gated CT, using cardiac magnetic resonance (CMR) as reference standard. METHODS: Consecutive patients with contrast-enhanced CT thorax and CMR within 31 days (2016-2020) were analysed (n = 84). LV dilatation was defined against age-, sex- and body surface area-specific values for CMR. CTs underwent automated artificial intelligence(AI)-derived analysis that segmented ventricular chambers, presenting maximal LV diameter and volume. Area under the receiver operator curve (AUC-ROC) analysis identified CT thresholds with ≥90% sensitivity and highest specificity and ≥90% specificity with highest sensitivity. Youden's Index was used to identify thresholds with optimised sensitivity and specificity. RESULTS: Automated diameter analysis was feasible in 92% of cases (77/84; 45 men, age 61 ± 14 years, mean CT to CMR interval 10 ± 8 days). Relative to CMR as a reference standard, 45% had LV dilatation. In males, an automated LV diameter measurement of ≥55.5 mm was ≥90% specific for CMR-defined LV dilatation (positive predictive value (PPV) 85.7%, negative predictive value (NPV) 61.2%, accuracy 68.9%). In females, an LV diameter of ≥49.7 mm was ≥90% specific for CMR-defined LV dilatation (PPV 66.7%, NPV 73.1%, accuracy 71.9%). AI CT volumetry data did not significantly improve AUC performance. CONCLUSION: Fully automated AI-derived analysis LV dilatation on routine unselected non-gated contrast-enhanced CT thorax studies is feasible. We have defined thresholds for the detection of LV dilatation on CT relative to CMR, which could be used to routinely screen for dilated cardiomyopathy at the time of CT. ADVANCES IN KNOWLEDGE: We show, for the first time, that a fully-automated AI-derived analysis of maximal LV chamber axial diameter on non-ECG-gated thoracic CT is feasible in unselected real-world cases and that the derived measures can predict LV dilatation relative to cardiac magnetic resonance imaging, the non-invasive reference standard for determining cardiac chamber size. We have derived sex-specific cut-off values to screen for LV dilatation on routine contrast-enhanced thoracic CT. Future work should validate these thresholds and determine if technology can alter clinical outcomes in a cost-effective manner.

Automated calculation of the right ventricle to left ventricle ratio on CT for the risk stratification of patients with acute pulmonary embolism.

OBJECTIVES: To assess the feasibility and reliability of the use of artificial intelligence post-processing to calculate the RV:LV diameter ratio on computed tomography pulmonary angiography (CTPA) and to investigate its prognostic value in patients with acute PE. METHODS: Single-centre, retrospective study of 101 consecutive patients with CTPA-proven acute PE. RV and LV volumes were segmented on 1-mm contrast-enhanced axial slices and maximal ventricular diameters were derived for RV:LV ratio using automated post-processing software (IMBIO LLC, USA) and compared to manual analysis in two observers, via intraclass coefficient correlation analysis. Each CTPA report was analysed for mention of the RV:LV ratio and compared to the automated RV:LV ratio. Thirty-day all-cause mortality post-CTPA was recorded. RESULTS: Automated RV:LV analysis was feasible in 87% (n = 88). RV:LV ratios ranged from 0.67 to 2.43, with 64% (n = 65) > 1.0. There was very strong agreement between manual and automated RV:LV ratios (ICC = 0.83, 0.77-0.88). The use of automated analysis led to a change in risk stratification in 45% of patients (n = 40). The AUC of the automated measurement for the prediction of all-cause 30-day mortality was 0.77 (95% CI: 0.62-0.99). CONCLUSION: The RV:LV ratio on CTPA can be reliably measured automatically in the majority of real-world cases of acute PE, with perfect reproducibility. The routine use of this automated analysis in clinical practice would add important prognostic information in patients with acute PE. KEY POINTS: • Automated calculation of the right ventricle to left ventricle ratio was feasible in the majority of patients and demonstrated perfect intraobserver variability. • Automated analysis would have added important prognostic information and altered risk stratification in the majority of patients. • The optimal cut-off value for the automated right ventricle to left ventricle ratio was 1.18, with a sensitivity of 100% and specificity of 54% for the prediction of 30-day mortality.

Chest X-ray in suspected lung cancer is harmful.

OBJECTIVES: The aim of this study was to analyse the use of the chest radiograph (CXR) as the first-line investigation in primary care patients with suspected lung cancer. METHODS: Of 16,945 primary care referral CXRs (June 2018 to May 2019), 1,488 were referred for suspected lung cancer. CXRs were coded as follows: CX1, normal but a CT scan is recommended to exclude malignancy; CX2, alternative diagnosis; or CX3, suspicious for cancer. Kaplan-Meier survival analysis was undertaken by stratifying patients according to their CX code. RESULTS: In the study period, there were 101 lung cancer diagnoses via a primary care CXR pathway. Only 10% of patients with a normal CXR (CX1) underwent subsequent CT and there was a significant delay in lung cancer diagnosis in these patients (p < 0.001). Lung cancer was diagnosed at an advanced stage in 50% of CX1 patients, 38% of CX2 patients and 57% of CX3 patients (p = 0.26). There was no survival difference between CX codes (p = 0.42). CONCLUSION: Chest radiography in the investigation of patients with suspected lung cancer may be harmful. This strategy may falsely reassure in the case of a normal CXR and prioritises resources to advanced disease. KEY POINTS: • Half of all lung cancer diagnoses in a 1-year period are first investigated with a chest X-ray. • A normal chest X-ray report leads to a significant delay in the diagnosis of lung cancer. • The majority of patients with a normal or abnormal chest X-ray have advanced disease at diagnosis and there is no difference in survival outcomes based on the chest X-ray findings.

Computed tomography appearances of the lung parenchyma in pulmonary hypertension.

Computed tomography (CT) is a valuable tool in the workup of patients under investigation for pulmonary hypertension (PH) and may be the first test to suggest the diagnosis. CT parenchymal lung changes can help to differentiate the aetiology of PH. CT can demonstrate interstitial lung disease, emphysema associated with chronic obstructive pulmonary disease, features of left heart failure (including interstitial oedema), and changes secondary to miscellaneous conditions such as sarcoidosis. CT also demonstrates parenchymal changes secondary to chronic thromboembolic disease and venous diseases such as pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). It is important for the radiologist to be aware of the various manifestations of PH in the lung, to help facilitate an accurate and timely diagnosis. This pictorial review illustrates the parenchymal lung changes that can be seen in the various conditions causing PH.

Modulation of sulfur assimilation metabolic toxicity overcomes anemia and hemochromatosis in mice.

Sulfur assimilation is an essential metabolic pathway that regulates sulfation, amino acid metabolism, nucleotide hydrolysis, and organismal homeostasis. We recently reported that mice lacking bisphosphate 3'-nucleotidase (BPNT1), a key regulator of sulfur assimilation, develop iron-deficiency anemia (IDA) and anasarca. Here we demonstrate two approaches that successfully reduce metabolic toxicity caused by loss of BPNT1: 1) dietary methionine restriction and 2) overproduction of a key transcriptional regulator hypoxia inducible factor 2α (Hif-2a). Reduction of methionine in the diet reverses IDA in mice lacking BPNT1, through a mechanism of downregulation of sulfur assimilation metabolic toxicity. Gaining Hif-2a acts through a different mechanism by restoring iron homeostatic gene expression in BPNT1 deficient mouse intestinal organoids. Finally, as loss of BPNT1 impairs expression of known genetic modifiers of iron-overload, we demonstrate that intestinal-epithelium specific loss of BPNT1 attenuates hepatic iron accumulation in mice with homozygous C282Y mutations in homeostatic iron regulator (HFEC282Y), the most common cause of hemochromatosis in humans. Overall, our study uncovers genetic and dietary strategies to overcome anemia caused by defects in sulfur assimilation and identifies BPNT1 as a potential target for the treatment of hemochromatosis.

Conformations of peptoids in nanosheets result from the interplay of backbone energetics and intermolecular interactions.

The conformations adopted by the molecular constituents of a supramolecular assembly influence its large-scale order. At the same time, the interactions made in assemblies by molecules can influence their conformations. Here we study this interplay in extended flat nanosheets made from nonnatural sequence-specific peptoid polymers. Nanosheets exist because individual polymers can be linear and untwisted, by virtue of polymer backbone elements adopting alternating rotational states whose twists oppose and cancel. Using molecular dynamics and quantum mechanical simulations, together with experimental data, we explore the design space of flat nanostructures built from peptoids. We show that several sets of peptoid backbone conformations are consistent with their being linear, but the specific combination observed in experiment is determined by a combination of backbone energetics and the interactions made within the nanosheet. Our results provide a molecular model of the peptoid nanosheet consistent with all available experimental data and show that its structure results from a combination of intra- and intermolecular interactions.

Solid-State NMR Structural Characterization of Self-Assembled Peptides with Selective 13C and 15N Isotopic Labels.

For the structural characterization methods discussed here, information on molecular conformation and intermolecular organization within nanostructured peptide assemblies is discerned through analysis of solid-state NMR spectral features. This chapter reviews general NMR methodologies, requirements for sample preparation, and specific descriptions of key experiments. An attempt is made to explain choices of solid-state NMR experiments and interpretation of results in a way that is approachable to a nonspecialist. Measurements are designed to determine precise NMR peak positions and line widths, which are correlated with secondary structures, and probe nuclear spin-spin interactions that report on three-dimensional organization of atoms. The formulation of molecular structural models requires rationalization of data sets obtained from multiple NMR experiments on samples with carefully chosen 13C and 15N isotopic labels. The information content of solid-state NMR data has been illustrated mostly through the use of simulated data sets and references to recent structural work on amyloid fibril-forming peptides and designer self-assembling peptides.

Evidence for cis Amide Bonds in Peptoid Nanosheets.

Peptoid nanosheets are supramolecular protein-mimetic materials that form from amphiphilic polypeptoids with aromatic and ionic side chains. Nanosheets have been studied at the nanometer scale, but the molecular structure has been difficult to probe. We report the use of 13C-13C dipolar recoupling solid-state NMR measurements to reveal the configuration of backbone amide bonds selected by 13C isotopic labeling of adjacent α-carbons. Measurements on the same molecules in the amorphous state and in nanosheets revealed that amide bonds in the center of the amino block of peptoid (NaeNpe)7-(NceNpe)7 (B28) favor the trans configuration in the amorphous state and the cis configuration in the nanosheet. This unexpected result contrasts with previous NMR and theoretical studies of short solvated peptoids. Furthermore, examination of the amide bond at the junction of the two charged blocks within B28 revealed a mixture of both cis and trans configurational states, consistent with the previously predicted brickwork-like intermolecular organization.

Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis.

Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3'-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3'-phosphoadenosine 5'-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis.

The incompatibility of healthcare services and end-of-life needs in advanced liver disease: A qualitative interview study of patients and bereaved carers.

BACKGROUND: Liver disease represents the third commonest cause of death in adults of working age and is associated with an extensive illness burden towards the end of life. Despite this, patients rarely receive palliative care and are unlikely to be involved in advance care planning discussions. Evidence addressing how existing services meet end-of-life needs, and exploring attitudes of patients and carers towards palliative care, is lacking. AIM: To explore the needs of patients and carers with liver disease towards the end of life, evaluate how existing services meet need, and examine patient and carer attitudes towards palliative care. DESIGN: Qualitative study - semi-structured interviews analysed using thematic analysis. Settings/participants: A total of 17 participants (12 patients, 5 bereaved carers) recruited from University Hospitals Bristol. RESULTS: Participants described escalating physical, psychological and social needs as liver disease progressed, including disabling symptoms, emotional distress and uncertainty, addiction, financial hardship and social isolation. End-of-life needs were incompatible with the healthcare services available to address them; these were heavily centred in secondary care, focussed on disease modification at the expense of symptom control and provided limited support after curative options were exhausted. Attitudes towards palliative care were mixed, however, participants valued opportunities to express future care preferences (particularly relating to avoidance of hospital admission towards the end of life) and an increased focus on symptomatic and logistical aspects of care. CONCLUSION: The needs of patients with liver disease and their carers are frequently incompatible with the healthcare services available to them towards the end of life. Novel strategies, which recognise the life-limiting nature of liver disease explicitly and improve coordination with community services, are required if end-of-life care is to improve.

Self-assembly pathways and polymorphism in peptide-based nanostructures.

Dipeptide derivative molecules can self-assemble into space-filling nanofiber networks at low volume fractions (<1%), allowing the formation of molecular gels with tunable mechanical properties. The self-assembly of dipeptide-based molecules is reminiscent of pathological amyloid fibril formation by naturally occurring polypeptides. Fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) is the most widely studied such molecule, but the thermodynamic and kinetic phenomena giving rise to Fmoc-FF gel formation remain poorly understood. We have previously presented evidence that the gelation process is a first order phase transition characterized by low energy barriers to nucleation, short induction times, and rapid quasi-one-dimensional crystal growth, stemming from solvent-solute interactions and highly specific molecular packing. Here, we discuss the phase behavior of Fmoc-FF in different solvents. We find that Fmoc-FF gel formation can be induced in apolar solvents, in addition to previously established pathways in aqueous systems. We further show that in certain solvent systems anisotropic crystals (nanofibers) are an initial metastable state, after which macroscopic crystal aggregates with no preferred axis of growth are formed. The molecular conformation is sensitive to solvent composition during assembly, indicating that Fmoc-FF may be a simple model system to study complex thermodynamic and kinetic phenomena involved in peptide self-assembly.

Cirrhosis with ascites in the last year of life: a nationwide analysis of factors shaping costs, health-care use, and place of death in England.

BACKGROUND: Liver disease mortality increased by 400% in the UK between 1970 and 2010, resulting in rising pressures on acute hospital services, and an increasing need for end-of-life care. We aimed to assess the effect of demographic, clinical, and health-care factors on costs, patterns of health-care use, and place of death in a national cohort of patients with cirrhosis and ascites in their last year of life. METHODS: We did a retrospective, nationwide analysis of all patients who died from cirrhosis in England between 2013 and 2015, who required large-volume paracentesis in their last year of life. The outcomes measured were health-care costs accrued in the last year of life, number of inpatient days in last year of life, 30-day readmission rate, and occurrence of unplanned hospital death (probability of dying in hospital after unplanned admission). Using generalised linear and logistic regression models, we examined the effect of 12 independent variables on each outcome: sex, ethnicity, age at death, index of multiple deprivation quintile, year of death, liver disease causing death, place of death, time from index presentation in last year of life to death, whether enrolled in a day-case paracentesis service (care group), paracentesis ratio (number of day-case large-volume paracentesis procedures as a proportion of the total number of procedures in the last year of life), number of hospital episodes in the last year of life (not involving large-volume paracentesis), and number of large-volume paracentesis procedures in the last year of life. FINDINGS: Between Jan 1, 2013, and Dec 31, 2015, 13 818 people in England died from liver disease and had large-volume paracentesis within their last year of life. For all patients, mean cost of the last year of life was £21 113 (SD 16 881), 17 888 (52·5%) of 34 068 readmissions occurred within 30 days of discharge, and 10 341 (74·8%) of 13 818 deaths occurred in hospital, of which 10 045 (97·1%) followed an emergency hospital admission. Patients who attended a day-case large-volume paracentesis service within their last year of life had significant reductions in cost (-£4240, 95% CI -4829 to -3651; p<0·0001), number of inpatient bed days (-16·98 days, -18·45 to -15·51; p<0·0001), probability of early readmission (odds ratio [OR] 0·35, 95% CI 0·31 to 0·40; p<0·0001), and probability of dying in hospital after unplanned admission (0·31, 0·27 to 0·34; p<0·0001), compared with patients who had unplanned care. For patients enrolled in day-case services, improvements in outcomes correlated with the proportion of large-volume paracentesis procedures done in a day-case (vs unplanned) setting. INTERPRETATION: The use of day-case large-volume paracentesis services in the last year of life was associated with lower costs, reduced pressure on acute hospital services, and a lower probability of dying in hospital, compared with patients who received exclusively unplanned care in their last year of life. Wider adoption of day-case models of care could reduce costs and improve outcomes in the last year of life. FUNDING: David Telling Charitable Trust.

Increased sediment load during a large-scale dam removal changes nearshore subtidal communities.

The coastal marine ecosystem near the Elwha River was altered by a massive sediment influx-over 10 million tonnes-during the staged three-year removal of two hydropower dams. We used time series of bathymetry, substrate grain size, remotely sensed turbidity, scuba dive surveys, and towed video observations collected before and during dam removal to assess responses of the nearshore subtidal community (3 m to 17 m depth). Biological changes were primarily driven by sediment deposition and elevated suspended sediment concentrations. Macroalgae, predominantly kelp and foliose red algae, were abundant before dam removal with combined cover levels greater than 50%. Where persistent sediment deposits formed, macroalgae decreased greatly or were eliminated. In areas lacking deposition, macroalgae cover decreased inversely to suspended sediment concentration, suggesting impacts from light reduction or scour. Densities of most invertebrate and fish taxa decreased in areas with persistent sediment deposition; however, bivalve densities increased where mud deposited over sand, and flatfish and Pacific sand lance densities increased where sand deposited over gravel. In areas without sediment deposition, most invertebrate and fish taxa were unaffected by increased suspended sediment or the loss of algae cover associated with it; however, densities of tubeworms and flatfish, and primary cover of sessile invertebrates increased suggesting benefits of increased particulate matter or relaxed competition with macroalgae for space. As dam removal neared completion, we saw evidence of macroalgal recovery that likely owed to water column clearing, indicating that long-term recovery from dam removal effects may be starting. Our results are relevant to future dam removal projects in coastal areas and more generally to understanding effects of increased sedimentation on nearshore subtidal benthic communities.

Integration of palliative and supportive care in the management of advanced liver disease: development and evaluation of a prognostic screening tool and supportive care intervention.

BACKGROUND AND OBJECTIVES: Patients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life-limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention. DESIGN: Clinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. 'Plan-Do-Study-Act' (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention. RESULTS: 73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poor-prognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with decompensated cirrhosis, with the supportive care intervention (developed simultaneously) instigated for appropriate patients. CONCLUSIONS: We describe a model of care which identifies inpatients with cirrhosis at significant risk of dying over the coming year, and describe development of a supportive care intervention, which can be offered to suitable patients in parallel to ongoing active management.

Comorbidities and medications of patients with chronic hepatitis C under specialist care in the UK.

Designing services with the capacity and expertise to meet the needs of the chronic hepatitis C (CHC) population in the era of direct acting antivirals (DAAs), and widening access to such treatments, requires detailed understanding of the characteristics and healthcare needs of the existing patient population. In this retrospective analysis of data from the National HCV Research UK Biobank between March 2012 and October 2014, the characteristics of the CHC population currently under specialist care in the UK were evaluated-with specific focus upon use of medications, adverse lifestyle choices, and comorbidities. Demographic data, risk factors for CHC acquisition, HCV genotype, liver disease status, lifestyle factors, comorbidities, and medication classes were collected. Data were analyzed by history of injecting drug use (IDU), age, and severity of liver disease. A total of 6278 patients (70.5% white; median age, 52 years) from 59 UK specialist centres were included; 59.1% of patients had acquired HCV through IDU. The prevalence of adverse lifestyle factors was significantly lower in non-IDU compared with previous IDU or recent IDU patients. Depression was common in the previous (50.8%) and recent IDU (68.1%) groups, compared with 27.6% in non-IDU patients. Cirrhosis was common (23.6%), and prevalence increased with age. We describe a heterogeneous, polymorbid, and aging population of CHC patients in secondary care, and demonstrate underrepresentation of injecting drug users within the current system. The implications of this present significant challenges to physicians and healthcare commissioners in designing services which are fit for purpose inthe DAA era.