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Severe coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infection in vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications.Clinical perspectiveSevere COVID-19 manifests as a microvascular syndrome, but whether SARS-CoV-2 infects and damages heart vascular pericytes (PCs) remains unknown.We provide evidence that cardiac PCs are not infected by SARS-CoV-2. Importantly, we show that the recombinant S protein alone elicits cellular signalling through the CD147 receptor in cardiac PCs, thereby inducing cell dysfunction and microvascular disruption in vitro.This study suggests that soluble S protein can potentially propagate damage to organs distant from sites of infection, promoting microvascular injury. Blocking the CD147 receptor in patients may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.

IntroductionDexamethasone has been shown to reduce mortality for patients hospitalised with acute COVID-19 pneumonia. However, a significant proportion of patients suffer persistent symptoms following COVID-19 and little is known about the longer-term impact of this intervention on symptom burden.MethodsPatients initially hospitalised with COVID-19 were prospectively recruited to an observational study (April-August 2020) with follow-up at 8 months (Dec 2020-April 2021) post-admission. A review of ongoing symptoms using a standardised systems-based proforma was performed alongside health-related quality of life assessment. In the UK, patients with COVID-19 (requiring oxygen) only received dexamethasone following the pre-print of the RECOVERY trial (June 2020), or as part of randomisation to that trial, allowing for a comparison between patients treated and not treated with dexamethasone.ResultsBetween April to August 2020, 198 patients were recruited to this observational study. 87 required oxygen and were followed up at 8-months, so were eligible for this analysis. Of these 39 received an inpatient course of dexamethasone (cases) and 48 did not (controls). The groups were well matched at baseline in terms of age, comorbidity and frailty score. Over two-thirds of patients reported at least 1 ongoing symptom at 8-month follow-up. Patients in the dexamethasone group reported fewer symptoms (n=73, 1.9 per patient) than the non-dexamethasone group (n=152, 3.2 per patient) (p = 0.01).ConclusionsIn conclusion, in this case-control observational study, patients who received oral dexamethasone for hospitalised COVID-19 were less likely to experience persistent symptoms at 8-month follow-up. These are reassuring results for physicians administering dexamethasone to this patient group.

Preservatives play an essentially role in ensuring that cosmetic formulations remain safe for use via control of microbial contamination. Commonly used preservatives include organic acids, alcohols and phenols and these play an essential role in controlling the growth of bacteria, fungi and moulds in substrates that can potentially act as a rich food source for microbial contaminants. Whilst the activity of these compounds is clear, both in vitro and in formulation, little information exists on the potential impact that common preservative systems, in full formulation, have on the skin’s resident microbiome. Dysbiosis of the skin’s microbiome has been associated with a number of cosmetic conditions but there currently are no in vivo studies investigating the potential for preservative ingredients, when included in personal care formulations under normal use conditions, to impact the cutaneous microbiome. Here we present an analysis of four in vivo studies that examine the impact of different preservation systems in full formulation, in different products formats, with varying durations of application. This work demonstrates that despite the antimicrobial efficacy of the preservatives in vitro, the skin microbiome is not impacted by preservative containing products in vivo.

Background Solitary fibrous tumours of the pleura (SFTP) are rare and account for around 5% of pleural based tumours with rates of malignancy of around 30%. Published data primarily includes histologically proven SFTP, but there is little evidence regarding the outcomes of radiologically diagnosed SFTP. Methods A service evaluation of radiologically diagnosed SFTP was completed in 12 UK centres, searching the local radiology database reports for the terms ‘Pleural fibroma’ OR ‘fibrous tumour of the pleura’ OR ‘SFTP’ between 01/01/2005 and 31/12/2015. Scans were determined to demonstrate a ‘typical’ SFTP, ‘unlikely’ SFTP or SFTP that was ‘within the differential diagnosis’. Data were collected to establish subsequent diagnoses and what follow up was undertaken. Results A total of 246 cases were included, table 1 exhibits the outcomes in each radiological group. Of patients with typical appearances for SFTP, 20/44 were histologically confirmed to represent a fibroma, 19/44 underwent radiological follow up only and 4/44 were confirmed not to represent SFTP. Of the patients who underwent radiological follow-up; there were 9 deaths, none of which were known to be related to SFTP, the median longest diameter was 30 mm (IQR 25–40) and the median follow-up time was 62 months (IQR 17–106). Of the 61 cases histologically confirmed SFTP, 17/61 were malignant, 37/61 benign and 7/61 unknown. A total of 26 patients died, 5 secondary to SFTP, 12 unrelated to SFTP and 9 of unknown cause. Conclusion A large proportion of patients with radiologically typical SFTP features do not undergo biopsy or resection and did not have SFTP related adverse outcomes in this small series. Further analysis is needed to determine whether any radiological features can predict clinical outcomes.

Pleural empyema represents a significant healthcare burden due to extended hospital admissions and potential requirement for surgical intervention. This study aimed to assess changes in incidence and management of pleural empyema in England over the past 10 years and the potential impact of influenza on rates. Hospital Episode Statistics data were used to identify patients admitted to English hospitals with pleural empyema between 2008 and 2018. Linear regression was used to analyse the relationship between empyema rates and influenza incidence recorded by Public Health England. The relationship between influenza and empyema was further explored using serological data from a prospective cohort study of patients presenting with pleural empyema. Between April 2008 and March 2018 there were 55 530 patients admitted with pleural empyema. There was male predominance (67% versus 33%), which increased with age. Cases have increased significantly from 4447 in 2008 to 7268 in 2017. Peaks of incidence correlated moderately with rates of laboratory-confirmed influenza in children and young adults (r=0.30). For nine of the 10 years studied, the highest annual point incidence of influenza coincided with the highest admission rate for empyema (with a 2-week lag). In a cohort study of patients presenting to a single UK hospital with pleural empyema/infection, 24% (17 out of 72) had serological evidence of recent influenza infection, compared to 7% in seasonally matched controls with simple parapneumonic or cardiogenic effusions (p, Rates of pleural empyema are increasing in English hospitals without any improvement in patient outcomes. This study also found that male predominance of empyema increased with age, and rates increased in winter and during peaks of influenza. https://bit.ly/3oiJ870

Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient’s persistent symptoms and radiological changes.

BackgroundIschaemic stroke and myocardial infarction (MI) are common after pneumonia and are associated with long-term mortality. Aspirin may attenuate this risk and should be explored as a therapeutic option.MethodsWe extracted all patients with pneumonia (aged over 50 years) from the Clinical Practice Research Datalink (CPRD), a large UK primary care database, from inception until January 2019. We then performed a prior event rate ratio (PERR) analysis with propensity score matching (PSM), an approach that allows for control of measured and unmeasured confounding, with aspirin usage as the exposure and ischaemic events as the outcome. The primary outcome was the combined outcome of ischaemic stroke and MI. Secondary outcomes were ischaemic stroke and MI individually. Relevant confounders (smoking, comorbidities, age and gender) were included in the analysis.Findings48 743 patients were eligible for matching. Of these, 9864 were aspirin users who were matched to 9864 non-users. Aspirin users had a reduced risk of the primary outcome (adjusted hazard ratio 0.64, 95% CI 0.52–0.79) in the PERR analysis. For both secondary outcomes, aspirin use was also associated with a reduced risk for MI (hazard ratio 0.46, 95% CI 0.30–0.72) and stroke (hazard ratio 0.70, 95% CI 0.55–0.91), respectively.InterpretationThis study provides supporting evidence that aspirin use is associated with reduced ischaemic events after pneumonia in a primary care setting. This drug may have a future clinical role in preventing this important complication.

RATIONALE: Parapneumonic effusions have a wide clinical spectrum. The majority settle with conservative management but some progress to complex collections requiring intervention. For decades, physicians have relied on pleural fluid pH to determine the need for chest tube drainage despite a lack of prospective validation and no ability to predict the requirement for fibrinolytics or thoracic surgery.OBJECTIVES: To study the ability of soluble urokinase Plasminogen Activator Receptor (suPAR), a potential biomarker of pleural fluid loculation, to predict the need for invasive management compared to conventional fluid biomarkers (pH, glucose, LDH) in parapneumonic effusions.METHODS: Patients presenting with pleural effusions were prospectively recruited to an observational study with biological samples stored at presentation. Pleural fluid and serum suPAR levels were measured using the suPARnosticTM double-monoclonal antibody sandwich ELISA on 93 patients with parapneumonic effusions and 47 controls (benign and malignant effusions).MEASUREMENTS AND MAIN RESULTS: Pleural suPAR levels were significantly higher in effusions that loculated versus non-loculated parapneumonic effusions (median 132ng/ml vs 22ng/ml, pCONCLUSIONS: Raised pleural suPAR was predictive of patients receiving more invasive management of parapneumonic effusions and added value to conventional biomarkers. These results need validation in a prospective multicenter trial.

Background: Risk stratification tools (RSTs) are used in healthcare settings to identify patients at risk of sepsis and subsequent adverse outcomes. In practice RSTs are used on admission and thereafter as ‘trigger’ tools prompting sepsis management. However, studies investigating their performance report scores at a single timepoint which varies in relation to admission. The aim of this meta-analysis was to determine if the predictive performance of RSTs is altered by the timing of their use. Methods: We conducted a systematic review and meta-regression analysis of studies published from inception to 31 October 2018, using EMBASE and PubMed databases. Any cohort studies investigating the ability of an RST to predict mortality in adult sepsis patients admitted to hospital, from which a 2x2 table was available or could be constructed, were included. The diagnostic performance of RSTs in predicting mortality was the primary outcome. Sensitivity, specificity, positive predictive value, negative predictive value and area under the receiver-operating curve (AUROC) were the primary measures, enabling further meta-regression analysis. Results: 47 studies were included, comprising 430,427 patients. Results of bivariate meta-regression analysis found tools using a first-recorded score were less sensitive than those using worst-recorded score (REML regression coefficient 0.57, 95% CI 0.07-1.08). Using worst-recorded score led to a large increase in sensitivity (summary sensitivity 0.76, 95% CI 0.67-0.83, for worst-recorded scores vs. 0.64 (0.57-0.71) for first-recorded scores). Scoring system type did not have a significant relationship with studies’ predictive ability. The most analysed RSTs were qSOFA (n=37) and EWS (n=14). Further analysis of these RSTs also found timing of their use to be associated with predictive performance. Conclusion: The timing of any RST is paramount to their predictive performance. This must be reflected in their use in practice, and lead to prospective studies in future.

Background The BTS pleural disease guidelines recommend all patients with an undiagnosed unilateral pleural undergo computed tomography (CT) of the thorax with contrast.1 However, there is no consensus on whether to include the abdomen and pelvis in the initial examination, with the BTS mesothelioma guidelines recommending this as an area that requires further research.2 Methods We performed a cross-sectional study using prospectively collected data between March 2008 and September 2018 of patients presenting with an undiagnosed pleural effusion. All patients consented for this study, underwent CT thorax, abdomen and pelvis as part of their standard work up and were followed for 12 months or until death, to ensure a robust diagnosis. Results 249 patients were included; mean age 72 (IQR 66–80), 167 (67%) male, WHO PS 0–1 (62%), 2–3 (37%), 190 (76%) out-patients, 147 (59%) right sided, 87 (35%) previous asbestos exposure. The final diagnosis was malignancy in 159 (64%). The CT thorax alone was consistent with the final diagnosis in 171 (69%). There were clinically significant findings below the costophrenic recesses in 59 patients (23.6%). Including the abdomen increased the diagnostic yield of clinically significant findings by 11.6% (n=29). Within the malignant group additional findings were of a primary tumour (6), upstaging of disease (19) and alternative biopsy sites (2). Including the pelvis resulted in 30 additional findings (12%), primary tumours (11), upstaging of disease (13) and alternative biopsy sites (3). 14 (5.6%) had an underlying ovarian cancer – 86% would have been missed if only CT chest and abdomen was performed. In females the pelvic CT revealed additional findings in 18 (22%). Conclusion CT thorax, abdomen and pelvis has a considerably higher diagnostic yield than more limited sequences in the work up of unilateral pleural effusions and this paper lends support to its inclusion for standard of care.

The use of thoracic CT for patients presenting with a unilateral pleural effusion is well established. However, there is no consensus with regard to the inclusion of the entire abdomen and pelvis in the initial imaging protocol. In this prospective UK-based study, 249 patients presenting with a unilateral effusion had a CT thorax/abdomen/pelvis performed. The prevalence of malignancy on thoracic CT was 56% (140/249). Clinically significant findings below the diaphragm were identified in 59 patients (24%). Integrating this approach into standard practice allows more rapid identification of the primary malignancy, upstaging lesions or alternative sites for biopsy.

Introduction: Several factors imply a viral role in the development of pleural infection including low yield on bacterial culture and seasonal variation. The relationship between respiratory viruses and pneumococcal pneumonia is well known but no studies have tested the association with pleural infection. Additionally, Epstein-Barr virus (EBV) has been implicated as a possible cause of ‘undiagnosed effusions’ without being validated. Methods: We analysed serum and pleural fluid (pf) from a prospective cohort of patients with effusions due to infection and biopsy-proven inflammatory pleuritis (IP). Nucleic acids were extracted from pf using the QIAsymphony DSP Virus/Pathogen Kit. Real-time PCR was performed using TaqMan array with 48 pathogen targets. Serum complement fixation testing using influenza and RSV antigen was performed alongside EBV serological tests. Results: From 193 patients including 60 empyema, 50 parapneumonic, 28 IP and 55 cardiac transudates (controls) there were no significant respiratory viral titres in pf. In patients with infective effusions, 21% had serological evidence of recent viral infection (Influenzas A&B or RSV). EBV was present at low levels in 22 pf samples (11%). There was no evidence of acute or re-activated EBV infection in the sera of patients with EBV DNA in pf. Conclusion: This is the first prospective study to test for the presence of viruses in pleural infection. We found no evidence of respiratory viruses within the effusions of either infection or control groups. However, there was serological evidence of recent flu/RSV infection in patients with pleural infection indicating a precedent illness. Results from pf EBV analysis demonstrated latent infection in 11% but no causative role.

Introduction: Increasingly, research is performed on routinely recorded clinical data, such as hospital episode statistics (HES). In uncommon diseases like pleural empyema, this data would be useful in assessing epidemiology. Also, empyema has a significant healthcare tariff and accurate coding ensures appropriate reimbursement. We aimed to assess the accuracy of coding for empyema across three separate UK hospitals. Methods: HES data (J86 code) was extracted for 1 year (Aug 2017 to Aug 2018) from 3 UK hospitals. Cases were verified to assess accuracy using medical notes, radiology, and microbiology. Empyema was defined using BTS criteria. To assess coding sensitivity, data from screened participants in the Pleural Infection Longitudinal Outcome (PILOT) study, for which our hospital was a recruitment centre, was extracted. The coding of these ‘confirmed cases’ was cross checked with hospital data from the same period. Results: Overall, 182 patients with a coded diagnosis of empyema were identified: 124 from a surgical centre. This coding was accurate in 158 cases (86%). Limiting the codes to exclude elective admissions increased the accuracy of coding (to 93%). This also excluded the vast majority (14/21) of empyema secondary to cardiothoracic or upper GI surgery. In patients with a confirmed empyema from the PILOT study, coding was 72% sensitive (18/25). The most common replacement code was ‘effusion otherwise unspecified’. Conclusion: Empyema coding was specific, with >85% of HES codes recorded accurately. However, in a prospectively collected cohort of patients, known clinically to have empyema, coding was around 70% sensitive. Excluding codes for elective admissions removed 2/3 of post-surgical cases.

Summary Background Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. Methods COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. Findings Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55–0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47–0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. Interpretation High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. Funding University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Introduction Acute presentations of COVID-19 infection vary, ranging from asymptomatic carriage through to severe clinical manifestations including acute respiratory distress syndrome (ARDS). Longer term sequelae of COVID-19 infection includes lung fibrosis in a proportion of patients. Krebs von den Lungen 6 (KL-6) is a mucin like glycoprotein that has been proposed as a marker of pulmonary epithelial cell injury. We sought to determine whether KL-6 was a marker of 1) the severity of acute COVID-19 infection, or 2) the persistence of symptoms/radiological abnormalities at medium term follow up. Methods Prospective single centre observational study. Results Convalescent KL-6 levels were available for 93 patients (male 63%, mean age 55.8 years) who attended an 12-week follow up appointment after being admitted to hospital with COVID-19. For 67 patients a baseline KL-6 result was available for comparison. There was no significant correlations between baseline KL-6 and the admission CXR severity score or clinical severity NEWS score. Furthermore, there was no significant difference in the baseline KL-6 level and an initial requirement for oxygen on admission or the severity of acute infection as measured at 28 days. There was no significant difference in the 12-week KL-6 level and the presence or absence of subjective breathlessness but patients with abnormal CT scans at 12 weeks had significantly higher convalescent KL-6 levels compared to the remainder of the cohort (median 1101 IU/ml vs 409 IU/ml). Conclusions The association between high KL-6 levels at 12 weeks and persisting CT abnormalities (GGO/fibrosis), is a finding that requires further exploration. Whether KL-6 may help differentiate those patients with persisting dyspnoea due to complications rather than deconditioning or dysfunctional breathing alone, is an important future research question.

Background: Radiological monitoring of malignant pleural mesothelioma (MPM) using modified RECIST criteria is limited by low sensitivity and inter-observer variability. Serial serum mesothelin measurement has shown utility in the assessment of treatment response during chemotherapy but has never been assessed in the longer term follow up of patients.Methods: This is a single centre study of consecutive patients diagnosed with MPM who received chemotherapy or best supportive care (BSC). Serum mesothelin measurements with paired 6 monthly CT scans were performed following the completion of chemotherapy, or from baseline in the BSC group. Changes in mesothelin were correlated with radiological progression and overall survival.Results: Forty-one patients with MPM were recruited and followed up for a minimum of 12 months (range 12-21 months). The majority of patients (n=23) received chemotherapy with pemetrexed and cisplatin. Across the cohort a 10% rise in serum mesothelin could predict radiological progression with a sensitivity of 96% (IQR; 79-100) and specificity of 74% (IQR; 50-91). Sensitivity fell to 80% in sarcomatoid only disease. Patients with a rising mesothelin at 6 months had significantly worse overall survival (175 days) compared to stable/falling levels (448 days) (p=0.003).Conclusions: This is the first study to assess serum mesothelin’s ability to detect progression of MPM following chemotherapy or during BSC. A 10% rise in serum mesothelin level showed excellent sensitivity at predicting progressive disease. Mesothelin measurement has several advantages over serial CT imaging including reducing hospital visits and cost.

Mesothelioma is an aggressive cancer of pleural and peritoneal cells that is difficult to diagnose and monitor. Numerous studies have attempted to identify a blood- or pleural fluid-based biomarker that could be used in the diagnostic pathway. More recently, there has been interest in the ability of serum/plasma biomarkers to monitor mesothelioma, given the development of newer treatments and limitations of radiological assessment. The majority of research has focused on soluble mesothelin, a soluble glycoprotein expressed by mesothelial cells. Although soluble mesothelin lacks the sensitivity to be used as a standalone diagnostic marker, serial measurements may be informative, with rising concentrations indicating disease progression and poor survival. High concentrations of other soluble glycoproteins, such as osteopontin, fibulin-3 and vascular endothelial growth factor are independently associated with poor prognosis at baseline, although further research is required to ascertain any role outside of clinical trials. More recent literature has focused on the development of novel biomarkers from discovery cohorts. Although many DNA and mRNA biomarkers show promise in the diagnosis or screening of mesothelioma, none have been prospectively evaluated for use in clinical practice. In this review article, we highlight the potential utility of biomarkers and evaluate the existing literature.

Background: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. Method: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. Results: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. Conclusions: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

Background Radiological monitoring of malignant pleural mesothelioma (MPM) using modified RECIST criteria is limited by low sensitivity and inter-observer variability. Serial serum mesothelin measurement has shown utility in the assessment of treatment response during chemotherapy but has never been assessed in the longer term follow up of patients. Methods This is a single centre study of consecutive patients diagnosed with MPM who received chemotherapy or best supportive care (BSC). Serum mesothelin measurements with paired 6 monthly CT scans were performed following the completion of chemotherapy, or from baseline in the BSC group. Changes in mesothelin were correlated with radiological progression and overall survival. Results Forty-one patients with MPM were recruited and followed up for a minimum of 12 months (range 12–21 months). The majority of patients (n=23) received chemotherapy with pemetrexed and cisplatin. Across the cohort a 10% rise in serum mesothelin could predict radiological progression with a sensitivity of 96% (IQR; 79–100) and specificity of 74% (IQR; 50–91) (figure 1). Sensitivity fell to 80% in sarcomatoid only disease. Patients with a rising mesothelin at 6 months had significantly worse overall survival (175 days) compared to stable/falling levels (448 days) (p=0.003). Conclusions This is the first study to assess serum mesothelin’s ability to detect progression of MPM following chemotherapy or during BSC. A 10% rise in serum mesothelin level showed excellent sensitivity at predicting progressive disease. Mesothelin measurement has several advantages over serial CT imaging including reducing hospital visits and cost.

Purpose of review Malignant pleural mesothelioma is an aggressive malignancy with a very poor prognosis. The majority of patients require pleural procedures for diagnostic or fluid management purposes. Damage to the pleura during these procedures can lead to procedure tract metastases (PTMs), with increasing risk from larger interventions. Prophylactic radiotherapy to these sites is a controversial topic with conflicting results from trial data. In this review, we summarize the recent evidence. Recent findings Four RCTs have been published on this topic, with another in follow-up. The earliest, from a cohort of 40 patients, strongly advocated the use of prophylactic radiotherapy. More recent trials, most notably the Surgical and large bore procedures in Malignant pleural mesothelioma And Radiotherapy Trial (SMART) (which randomized over 200 patients) did not demonstrate any benefit, especially when patient report symptoms and cost-effectiveness are considered. Certain subgroups demand further investigation, such as those not receiving systematic chemotherapy or with surgical intervention sites. The soon to be published Prophylactic Irradiation of Tracts (PIT) trial may help to further clarify best practice. Summary Recent studies have shown that prophylactic radiotherapy should not be routinely used to prevent PTMs in mesothelioma. Instead patients should undergo careful clinical follow-up to ensure PTMs are identified and treated promptly to minimize symptoms.

Indwelling pleural catheters (IPCs) have an established role in the management of recurrent pleural effusions due to malignancy. They are typically used in patients with trapped lung, those who have previously failed an attempted talc pleurodesis, or as first-line therapy. Experience of, and evidence for, IPC use in this setting is well established. In contrast, IPC use in patients with recurrent pleural effusions due to benign disease is limited, and there are no randomized studies evaluating their efficacy and safety in this patient group. Retrospective data suggest that IPCs may be effective at reducing breathlessness with acceptable complication rates, comparable to those seen in malignant effusions. This paper summarizes the epidemiology, pathophysiology and treatment options for benign pleural effusions, and reviews the published data assessing IPC use in this population.

Background: Radiological markers of treatment response and prognostication in malignant pleural mesothelioma have limitations due to the morphology of the disease. Serum or pleural fluid biomarkers that could act as an adjunct to radiological assessment would be of significant value. The aim of this review was to collate and summarise the literature relating to this topic. Methods: A systematic review was performed on the databases Pubmed and EMBASE to identify relevant studies. Two independent researchers read the abstracts and used the Quality in Prognostic Studies tool to assess the quality of the evidence. Results: Forty-five studies were identified from the current literature. Twenty studies investigated the role of serum soluble mesothelin with majority suggesting that it has variable utility as a baseline test but when measured serially correlates with treatment response and prognosis. Several studies demonstrated that serum osteopontin correlated with survival at baseline. Other biomarkers have shown prognostic utility in individual studies but are yet to be reproduced in large cohort studies. Conclusions: From the available literature no serum or pleural fluid biomarker was identified that could be recommended currently for routine clinical practice. However, a falling serum soluble mesothelin might correlate with treatment response and improved survival.

Internet-derived health care information is increasingly accessed by patients, yet its quality and accuracy is variable and unregulated. The aim of this study was to assess the information available regarding common gastrointestinal cancers via three internet search engines (Google, Yahoo and Bing). The top 30 websites for each of the terms: oesophageal, gastric, pancreatic, colon and rectal cancer were evaluated (University of Michigan Consumer Health Website Checklist) and scored [−80 (poor) to 90 (excellent)]. The median score was 53 (−7 to 81) and was significantly higher for oesophageal (61) and pancreatic (65) cancer websites, compared with gastric (49), colon (48) and rectal cancer (50) (p = 0.014). Median scores related to charitable organisations were significantly better than academic, commercial, news agency, care provider, layperson and medical information websites collectively (79 vs. 42, p < 0.0001). Overall quality of internet-derived gastrointestinal cancer information remains poor and patients and clinicians should be aware.

The vast majority of undiagnosed unilateral pleural effusions have fluid sent for cytological analysis. Despite widespread use, there is uncertainty about its sensitivity to diagnose malignant pleural effusions (MPEs). Our aim was to ascertain the utility of cytology using a large prospective cohort.Consecutive patients presenting with an undiagnosed unilateral pleural effusion were recruited to this UK-based study. All had pleural fluid sent for cytological analysis. Cytological sensitivity was based on the final diagnosis at 12 months, confirmed by two consultants.Over 8 years, 921 patients were recruited, of which 515 had a MPE. Overall sensitivity of fluid cytology to diagnose malignancy was 46% (95% CI 42–58%). There was variation in sensitivity depending on cancer primary, with mesothelioma (6%) and haematological malignancies (40%) being significantly lower than adenocarcinomas (79%). MPEs secondary to ovarian cancer had high pick-up rates (95%). In asbestos-exposed males with exudative effusions, the risk of MPE was 60%, but cytological sensitivity was 11%.This is the largest prospective study of pleural fluid cytology and informs discussions with patients about the likely requirement for investigations following thoracentesis. In patients presenting with a clinical suspicion of mesothelioma, cytological sensitivity is low, so more definitive investigations could be performed sooner.

Background: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. Methods: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil–lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. Findings: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR

Introduction Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. Methods Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. Results Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732–1.000). Discussion This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.

Background Adenocarcinoma of the vermiform appendix is rare. It constitutes less than 0.5% of all gastrointestinal malignancies. Pathologically, appendiceal neoplasms are categorized into various subtypes depending on cell lineage. Patients and Methods We considered a case series of appendiceal invasive adenocarcinomas from 2004 to 2013 managed in a teaching hospital. We discuss our management dilemmas, given the lack of randomized controlled trial data that exist. A detailed look at the histopathology, case series, and literature is presented. Results Ideal standards ought to be constructed for the management of this rare pathology, with a particular focus on exploring the indications and potential benefits, as well as difficulties, of ileocolic lymphadenectomy. Conclusion Appendiceal adenocarcinoma ought to be managed in the same way as a cecal adenocarcinoma.

Objective To evaluate mildly abnormal liver function test (LFT) results in general practice among patients who do not have known liver disease. Design Prospective cohort study of people with abnormal LFT results identified in primary care. Participants were intensively investigated using a common protocol and followed up for 2 years. Substudies investigated the psychological sequelae of abnormal test results, clinicians' reasons for testing, decision options when LFT results were abnormal and early detection of liver fibrosis. Setting Eleven primary-care practices: eight in Birmingham and three in Lambeth. Participants Adults with abnormal LFT results who did not have pre-existing or obvious liver disease. Eight analytes were included in the panel of LFTs. Main outcome measures Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFT results and (1) specific viral, genetic and autoimmune diseases, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis; (2) a range of other serious diseases, such as metastatic cancer and hypothyroidism; (3) ‘fatty liver’ not associated with the above; and (4) the absence of detectable disease. Results Fewer than 5% of people with abnormal LFT results had a specific disease of the liver, and many of these were unlikely to need treatment. The diagnostic potential of the LFT panel is largely subsumed into just two analytes: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Gamma-glutamyltransferase (GGT) offers a small increase in sensitivity at the margin at the cost of a large loss of specificity. Eighty-four per cent of abnormal LFT results remain abnormal on retesting 1 month later. In many cases, carrying out a definitive or specific test will be more efficient than repeating LFTs, with a view to specific testing only if the test remains abnormal. An ultrasound diagnosis of ‘fatty liver’ was present in nearly 40% of patients with abnormal LFTs and a small amount of weight loss over 2 years was associated with a reduced incidence of liver fat. There was a J-shaped relationship between alcohol intake and fatty liver in men. An abnormal LFT result causes temporary anxiety, which does not appear to promote sustained behaviour change. Conclusions Liver disease is rare among people with abnormal LFT results in primary care. Only two analytes (ALT and ALP) are helpful in identifying the majority of liver disease. GGT adds little information in return for a high false-positive rate but it is sensitive to alcohol intake. LFT results seldom revert from abnormal to normal over a 1-month period, and modelling shows that repeating an abnormal LFT panel, as recommended in the current guidelines, is inefficient. LFTs are often undertaken to meet perceived patient need for a blood test, but as they are neither specific nor indicative of any particular disease they are among the least suitable tests for this purpose. Obesity and raised ALT provide strong evidence for a presumptive diagnosis of ‘fatty’ liver. Abnormal LFTs and ‘fatty’ liver provoke only short-term anxiety and neither is associated with sustained weight loss. Even a small amount of weight loss reduces liver fat. Future work recommendations (1) the cases of ‘fatty liver’ and controls should be followed up in the long term to identify features that predict development of hepatosteatosis and then cirrhosis; (2) the acceptability of replacing the traditional six- to eight-analyte LFT panel with a drop down menu including the ALT/ALP combination should be evaluated. Funding The National Institute for Health Research Health Technology Assessment programme.

Laparoscopic cholecystectomy has traditionally been performed using multiple small sites. Single-incision laparoscopic surgery has emerged as an alternative technique to improve cosmesis and minimize complications associated with multiple incisions. A retrospective study was performed of all patients who underwent laparoscopic cholecystectomy by a single surgeon (DTA) from April 2008 to August 2011. Charts were reviewed for surgical indication, operative technique (multiple vs. single transumbilical incision), operative time, length of stay, and surgical complications. Sixty-three patients underwent laparoscopic cholecystectomy using a traditional approach of four skin incisions, while 62 patients underwent a single-incision transumbilical approach. Average age and sex were comparable between the two groups. Indications for surgery included cholelithiasis, cholecystitis, biliary dyskinesia, biliary pancreatitis, and porcelain gallbladder. Of those undergoing single-incision cholecystectomy, 85% (53/62) went home the same day, compared with 70% (44/63) of those undergoing four-incision cholecystectomy (P = 0.03). Among those not discharged on the same day of surgery, the average length of stay trended shorter in the single-incision group (2.8 days, range 1–6) compared with the four-incision group (3.3 days, range 1–12; P = NS). Operative time was slightly longer for those undergoing single-incision surgery (65 minutes, range 35–141) versus traditional four-incision surgery (51 minutes, range 41–109) (P < 0.001). With this single surgeon's single-incision transumbilical technique, costs were comparable between the two groups. One patient who underwent traditional four-incision cholecystectomy was readmitted for biliary pancreatitis and bacteremia on postoperative day 3. In the single-incision group, one patient was readmitted 1 month later with pancreatitis. In conclusion, single-incision transumbilical laparoscopic cholecystectomy can be an effective alternative to traditional four-incision cholecystectomy, with the added benefit of minimized scarring and a shorter length of stay. A longer operative time may be needed initially to adjust for a learning curve. This technique can be performed safely for patients with a multitude of gallbladder diseases without resulting in additional complications.

Aims To compare the outcomes of stage-directed surgical therapy and chemoradiotherapy (CRT) for oesophageal cancer and to determine if a significant age–treatment interaction exists to guide therapy. Materials and methods Five hundred and eight consecutive patients with oesophageal cancer suitable for radical treatment based on radiological stage and performance status were studied (275 surgery; 93 surgery alone, 131 neoadjuvant chemotherapy, 51 neoadjuvant CRT and 233 definitive CRT). The primary measure of outcome was survival. Results Thirty-day mortality rates and 2-year survival after surgery and CRT in patients P =0.207) and 47.3% ( P =0.011), respectively. Thirty-day mortality rates and 2-year survival after surgery and CRT in patients ≥70 years were 7.0 and 45.1%, respectively, compared with 0 ( P =0.029) and 46.3% ( P =0.992), respectively. Multivariate analysis including only surgical patients in the model revealed three factors to be independently and significantly associated with survival; endoscopic ultrasound (EUS) T stage ( P =0.033), EUS lymph node metastasis count (≥2 versus 0: hazard ratio 1.67, 95% confidence interval 1.06–2.92, P =0.026), and age ≥70 years (hazard ratio 1.51, 95% confidence interval 1.05–2.16, P =0.025). Conclusion Overall survival for patients treated with surgery was strongly age dependent around the age of 70 years, and patients ≥70 years with oesophageal cancer should be aware that outcomes after CRT are similar to those after surgery.

Introduction Numerous studies have assessed the diagnostic ability of pleural adenosine deaminase (ADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in the UK (UK) ADA is not routinely used in the investigation of a patient with a pleural effusion, mainly due to a lack of evidence as to its utility in areas where tuberculosis (TB) incidence is low. Methods Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study, in which baseline pleural fluid samples were collected and stored. Samples from consecutive patients with robust 12-month follow up data and confirmed diagnoses were sent for ADA analysis. Results Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All 7 TB effusions were lymphocyte predominant with a median ADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). Using the established cut off of 35 IU/L, ADA was shown to have a negative predictive value (NPV) of 99.7% (95% CI; 98.2–99.9%) for the exclusion of TB, and sensitivity of 85.7% (95% CI; 42.2–97.6%) with an area under the curve of 0.88 (95% CI; 0.732–1.000). In the context of a lymphocytic effusion an ADA over 35 IU/L had a sensitivity and positive predictive value of 85.7% (95% CI; 42.2–97.6%), see figure. Bacterial pleural infection was the main alternative cause of raised ADA in our cohort. Discussion This is the first study examining the diagnostic utility of pleural fluid ADA in a low TB incidence area. The chance of an effusion with an ADA under 35 IU/L being of tuberculous aetiology was negligible and empirical anti-TB therapy could be avoided in such cases. A pleural ADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of tuberculous aetiology. In patients who are unsuitable for more invasive procedures this could be used as an indication to start therapy.

Background The NHS End of Life Care Council advises that end of life (EoL) discussions should be offered to patients with chronic obstructive pulmonary disease (COPD) who have certain poor prognostic markers. EoL conversations with advanced care planning can reduce a patient9s anxiety during an exacerbation, allow informed decisions about what treatment they would (or would not) like to receive in the future, reduce unnecessary or unwanted hospital admissions, and enable patients to die in their preferred place. Aims To assess whether patients who are admitted to a respiratory ward with exacerbations of COPD, who fulfill the criteria, have been offered the opportunity to have such discussions. Secondary aims included (i) patient engagement, (ii) communication of outcomes (iii) communication of DNACPR orders. Methods Audit of all patients admitted to a respiratory ward with an exacerbation of COPD, within a 3 month period. Specifically looking for evidence of EoL conversations during the current admission, previous admission or clinic appointments. Results Of 48 patients admitted with an exacerbation of COPD, 20 fulfilled the criteria to be offered EoL conversations. The 3 month mortality of these 20 patients was 25%. Three patients (15%) had documented EoL conversations. One lead to the formation of an advance directive not to return to hospital, one described a patient9s wish to have no further non-invasive ventilation, and one where a patient wanted full treatment escaltion in the future. Seventeen of the 20 patients were made DNACPR, however, only 4 had this communicated to the GP. Recommendations Identify patients on hospital board rounds that may be suitable for end of life discussions. If patients engage with EoL discussions this should be documented in the medical notes as well as the discharge summary. Further use of an existing “Poor prognostic indicators” letter, which is sent to the GP, noting engagement in EoL discussions and decisions around DNACPR orders.

ObjectivesEarly Warning Scores are used to evaluate patients in many hospital settings. It is not clear if these are accurate in predicting mortality in sepsis. We performed a systematic review and meta-analysis of multiple studies in sepsis. Our aim was to estimate the accuracy of EWS for mortality in this setting.MethodsPubMED, CINAHL, Cochrane, Web of Science and EMBASE were searched to October 2016. Studies of adults with sepsis who had EWS calculated using any appropriate tool (e.g. NEWS, MEWS) were eligible for inclusion. Study quality was assessed using QUADAS-2. Summary estimates were derived using HSROC analysis.ResultsSix studies (4298 participants) were included. Results suggest that EWS cannot be used to predict which patients with sepsis will (positive likelihood ratio 1.79, 95% CI 1.53 to 2.11) or will not die (negative likelihood ratio 0.59, 95% CI 0.45 to 0.78). Two studies were rated as low risk of bias and one as unclear risk of bias on all domains. The other three studies were judged at high risk of bias in one domain.ConclusionEarly Warning Scores are not sufficiently accurate to rule in or rule out mortality in patients with sepsis, based on the evidence available, which is generally poor quality.

Background Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. Methods This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Results Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Conclusions Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population.