Mid Essex Hospital Services NHS Trust

BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

OBJECTIVE: The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes. DESIGN AND SETTING: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the ICU, ED, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the US, Europe, and South America. Elements of the guidelines were "bundled" into two sets of targets to be completed within 6 h and within 24 h. An analysis was conducted on data submitted from January 2005 through March 2008. MAIN RESULTS: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years (P<0.0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 years (P = 0.008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37 to 30.8% over 2 years (P = 0.001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 years (95% CI, 2.5-8.4%). CONCLUSIONS: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

BACKGROUND AND AIMS: Approximately 10% of adults experience gastro-oesophageal reflux symptoms with a variable oesophageal response. A total of 60% have no endoscopic abnormality, 30% have oesophagitis, and 10% have Barrett's oesophagus. We investigated whether the inflammatory cell infiltrate and cytokine profiles of these clinical phenotypes merely vary in severity or are fundamentally different. METHODS: Patients with reflux symptoms and a normal oesophagus (n=18), oesophagitis (n=26), and Barrett's oesophagus (n=22 newly diagnosed, n=28 surveillance) were recruited. Endoscopic and histopathological degrees of inflammation were scored. Cytokine expression was determined by competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: In oesophagitis, endoscopic and histopathological grades of inflammation correlated highly. mRNA expression of proinflammatory interleukin (IL)-1beta, IL-8, and interferon gamma (IFN-gamma) were increased 3-10-fold compared with non-inflamed squamous or Barrett's oesophageal samples. There was a modest increase in anti-inflammatory IL-10 but no increase in IL-4. In Barrett's oesophagus, 29/50 had no endoscopic evidence of inflammation and histopathological inflammation was mild in 17/50 and moderate in 24/50, independent of acid suppressants. Expression of IL-1beta, IL-8, and IFN-gamma was similar to non-inflamed squamous mucosa. IL-10 was increased 1.6-fold similar to oesophagitis. IL-4 was increased fourfold, with 100-fold increase in IL-4/T cell receptor expression, compared with squamous oesophagus or oesophagitis. CONCLUSIONS: Barrett's oesophagus is characterised by a distinct Th-2 predominant cytokine profile compared with the proinflammatory nature of oesophagitis. The specific oesophageal immune responses may influence disease development and progression.

OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement. DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008. SETTING: 187 acute trusts in England and Wales. INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004. MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections). RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10,000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P < 0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P < 0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P = 0.02) and C difficile infection (0.75, 0.67 to 0.84; P < 0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit. CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.

INTRODUCTION: Barrett's oesophageal epithelium (BE) is clinically important due to the associated inflammatory and malignant complications which are unevenly distributed throughout the BE segment. As the immunoregulatory environment may influence disease manifestations, we analysed the inflammatory and cytokine responses throughout the BE mucosa. We then investigated whether the inflammatory gradient is related to the distribution of metaplastic cell subtypes, epithelial exposure to the components of refluxate, or squamocolumnar cell interactions. METHODS: Fifty consecutive patients with long segment BE were recruited. The segmental degree of endoscopic and histopathological inflammation was graded, and expression of interleukin (IL)-1 beta, IL-8, IL-4, and IL-10 were determined by ELISA following organ culture with or without addition of acid or bile salts. Mucin staining and IL-10 immunohistochemistry were performed. The effect of squamocolumnar interactions on cytokine expression were analysed using cocultures of squamous (OE-21) and BE (TE7) carcinoma cell lines. RESULTS: There was a histopathological inflammatory gradient in BE. Inflammation was maximal at the new squamocolumnar junction with > or = 2-fold increase in proinflammatory IL-8 and IL-1 beta expression. The proximal proinflammatory response could not be explained by the distribution of metaplastic subtypes. Pulsatile exposure of BE to acid and bile, as well as juxtaposition of BE to squamous epithelial cells in culture, increased expression of IL-1 beta. In contrast, inflammation was minimal distally with a significant increase in anti-inflammatory IL-10 expression and 4/6 cancers occurred distally. CONCLUSIONS: Specific cytokine responses may contribute to the localisation of inflammatory and malignant complications within BE.

The use of biologic therapies has transformed the management of inflammatory arthritis (IA). In contrast to conventional systemic DMARDs (csDMARDs) traditionally used to treat inflammatory disease, these agents offer a targeted approach, and their widespread use has resulted in disease remission becoming an increasingly achievable goal. Biologic therapies are not without potential risk, and hence it is important that clinicians are aware of these risks and ensure that appropriate precautions are taken to minimize them. Information on the safety of biologic therapies continues to be collected through national registries, clinical and cohort studies and case series and reports.<br/><br/>NICE has accredited the process used by the BSR to produce its guidance on the safety of biologic DMARDs in inflammatory arthritis. Accreditation is valid for 5 years from 10 June 2013<br/><br/>This guideline supersedes the previous BSR/BHPR anti-TNF [1], rituximab (RTX) [2] and tocilizumab (TCZ) [3] guidelines and has been developed in line with the BSR Guidelines Protocol.

INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10-13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards. CONCLUSION: Despite difficulties in implementation, intention-to-treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN65246961.

BACKGROUND: Fluorescent angiography (FA) has been useful for assessing blood flow and assessing tissue perfusion in ophthalmology and other surgical disciplines for decades. In plastic surgery, indocyanine green (ICG) dye-based FA is a relatively novel imaging technology with high potential in various applications. We review the various FA detector systems currently available and critically appraise its utility in breast reconstruction. METHODS: A review of the published English literature dating from 1950 to 2015 using databases, such as PubMed, Medline, Web of Science, and EMBASE was undertaken. RESULTS: In comparison to the old fluorescein dye, ICG has a superior side effect profile and can be accurately detected by various commercial devices, such as SPY Elite (Novadaq, Canada), FLARE (Curadel LLC, USA), PDE-Neo (Hamamatsu Photonics, Japan), Fluobeam 800 (Fluoptics, France), and IC-View (Pulsion Medical Systems AG, Germany). In breast reconstruction, ICG has established as a safer, more accurate tracer agent, in lieu of the traditional blue dyes, for detection of sentinel lymph nodes with radioactive isotopes ((99m)-Technetium). In prosthesis-based breast reconstruction, intraoperative assessment of the mastectomy skin flap to guide excision of hypoperfused areas translates to improved clinical outcomes. Similarly, in autologous breast reconstructions, FA can be utilized to detect poorly perfused areas of the free flap, evaluate microvascular anastomosis for patency, and assess SIEA vascular territory for use as an alternative free flap with minimal donor site morbidity. CONCLUSIONS: ICG-based FA is a novel, useful tool for various applications in breast reconstruction. More studies with higher level of evidence are currently lacking to validate this technology.

BACKGROUND: We report on the hepatitis C virus (HCV) epidemic among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) in the United Kingdom and model its trajectory with or without scaled-up HCV direct-acting antivirals (DAAs). METHODS: A dynamic HCV transmission model among HIV-diagnosed MSM in the United Kingdom was calibrated to HCV prevalence (antibody [Ab] or RNA positive), incidence, and treatment from 2004 to 2011 among HIV-diagnosed MSM in the UK Collaborative HIV Cohort (UK CHIC). The epidemic was projected with current or scaled-up HCV treatment, with or without a 20% behavioral risk reduction. RESULTS: HCV prevalence among HIV-positive MSM in UK CHIC increased from 7.3% in 2004 to 9.9% in 2011, whereas primary incidence was flat (1.02-1.38 per 100 person-years). Over the next decade, modeling suggests 94% of infections are attributable to high-risk individuals, comprising 7% of the population. Without treatment, HCV chronic prevalence could have been 38% higher in 2015 (11.9% vs 8.6%). With current treatment and sustained virological response rates (status quo), chronic prevalence is likely to increase to 11% by 2025, but stabilize with DAA introduction in 2015. With DAA scale-up to 80% within 1 year of diagnosis (regardless of disease stage), and 20% per year thereafter, chronic prevalence could decline by 71% (to 3.2%) compared to status quo in 2025. With additional behavioral interventions, chronic prevalence could decline further to <2.5% by 2025. CONCLUSIONS: Epidemiological data and modeling suggest a continuing HCV epidemic among HIV-diagnosed MSM in the United Kingdom driven by high-risk individuals, despite high treatment rates. Substantial reductions in HCV transmission could be achieved through scale-up of DAAs and moderately effective behavioral interventions.

We performed a systematic review of epidemiological, diagnostic, and therapeutic outcomes of esophageal perforations. A systematic review was performed in PubMed database using the key-phrase 'esophageal perforation'. All studies regarding acute esophageal perforations were reviewed and parameters of epidemiology, diagnosis, and management published in the literature from 2005 up to 2015 were included in the study. Studies of postoperative esophageal leaks were excluded. Two researchers performed individually the research, while quality assessment was performed according to GRADE classification. Main outcomes and exposure were overall mortality, perforation-to-admission interval, anatomical position, cause, prevalent symptom at admission, diagnostic tests used, type of initial management (conservative or surgery), healing rate, and fistula complication. There were 1319 articles retrieved, of which 52 studies including 2,830 cases finally met inclusion criteria. Mean duration of study period was 15.2 years. Mean patient age was 58.4 years. Out of 52 studies included, there were 43 studies of very low or low quality included. The overall mortality rate according to extracted data was 13.3% (n = 214, 1,644 patients, 39 studies). Admission before 24 hours was reported in 58.1% of patients (n = 514). Position was thoracic in 72.6% of patients (n = 813, 1,120 patients, 20 studies). Mean cause of perforation was iatrogenic in 46.5% of patients (n = 899, 1,933 patients, 40 studies). Initial management was conservative in 51.3% of cases (n = 904, 1,762 patients, 41 studies) CT confirmed diagnosis in 38.7% of overall cases in which it was used as imaging diagnostic procedure (n = 266), X-ray in 36.6% (n = 231), and endoscopy in 37.4% (n = 343). Sepsis on admission was observed in 23.3% of cases (209 out of 898 patients, 16 studies). The present systematic review highlighted the significant proportion of cases diagnosed with delay over 24 hours, mortality rates ranging over 10% and no consensus regarding optimal therapeutic approach and optimal diagnostic management. As esophageal perforation represents a high-risk clinical condition without consensus regarding optimal management, there should be large multicenter prospective studies or Randomized Controlled Trial (RCT)s performed in order to advance diagnostic and therapeutic approach of such challenging pathology.

Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.

Delays in cancer diagnosis and treatment due to the COVID-19 pandemic is a widespread source of concern, but the scale of the challenge for different tumour sites is not known. Routinely collected NHS England Cancer Waiting Time data were analysed to compare activity for breast cancer in the first 6 months of 2020 compared to the same time period in 2019. The number of referrals for suspected breast cancer was 28% lower (N = 231,765 versus N = 322,994), and the number of patients who received their first treatment for a breast cancer diagnosis was 16% lower (N = 19,965 versus N = 23,881). These data suggest that the number of breast cancers diagnosed during the first half of 2020 is not as low as initially feared, and a substantial proportion of the shortfall can be explained by the suspension of routine screening in March 2020. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.

<h3>Objectives</h3> Immigrants with common mental disorders (CMDs) are reported to have a higher risk of disability pension (DP) compared with native residents; however, the reasons for this are not fully understood. This study aimed to investigate (1) differences in morbidity (3 measures) and socioeconomic status in native Swedes, ‘Western’ and ‘non-Western’ immigrants with CMDs and (2) interactions between morbidity and socioeconomic status and immigrant status regarding subsequent DP. <h3>Design</h3> The study was a prospective population-based cohort study using national register data. Crude and multivariate HRs with 95% CIs were calculated using the Cox regression (2007–2010). <h3>Participants</h3> All individuals aged 18–59 with an incident sick-leave spell due to CMDs during 2006 were included in the study (N=66 097). The study population was divided into 3 groups based on country of birth: (1) Sweden, (2) immigrants from ‘Western’ countries (EU25, Norway, Iceland, North America and Oceania) and (3) immigrants from ‘non-Western’ countries (east Europe, Africa, Asia and South America). <h3>Results</h3> Particularly, immigrants born in non-Western countries had higher levels of morbidity and lower socioeconomic status than natives (p&gt;0.001). No significant differences in the associations between specialised psychiatric and somatic care with regard to subsequent DP were found between immigrants and native Swedes. Being prescribed more than 1 type of psychiatric medication was associated with higher HRs for DP in immigrants from Western (HR 3.34; CI 2.3 to 4.9) and non-Western countries (3.6; 1.9 to 6.4) than in native Swedes (2.55; 2.3 to 2.8) (p_interaction=0.003). Low education was a marginally stronger predictor for DP in non-Western immigrants than in native Swedes and Western immigrants (p_interaction=0.03). <h3>Conclusions</h3> Morbidity measured by medication, but not by specialised healthcare, was a stronger predictor for DP in immigrants than in native Swedes, warranting scrutiny of differences in care and treatment in immigrants and native Swedes with CMDs.

In this study, the authors explored how a group of young people aged 16 to 26 years (who identified themselves as having engaged in deliberate self-harm) made sense of the self by conducting two online focus groups and four e-mail interviews. They analyzed data using interpretive phenomenological analysis. The concept of validation was the primary means of making sense of the self and concerned the desire to be considered legitimate and of worth. This desire was clearly evident across three realms of conflict: (a) the intrinsic or extrinsic self, which marked the distinction between objective fact and subjective opinion; (b) the accepted or denied self; and (c) the notion of normality. It is possible that having one’s denied self validated online might lead to an exacerbation of an individual’s self-harming behavior. Further work is needed to explore the effects of online discussion forums on such taboo forms of behavior.

[No abstract]

PURPOSE: The aim of this study is to determine the optimal range of cephalic vein and radial artery diameter following preoperative duplex imaging to enhance maturation and primary patency of Brescia-Cimino radiocephalic arteriovenous fistula. METHODS: A systematic review and meta-aggregation of literature from 1966 to January 2015 in English language and adult subjects in Pubmed, OVID, CINHAL and Cochrane database was conducted. RESULTS: This search produced a total of thirty-six (n = 36) articles. Following the application of recruitment criteria, only twelve articles (n = 12) were found eligible. Their quality was assessed by Oxford Critical Appraisal skills Programme (CASP) and their recommendation for practice was examined through National Institute for Health and Care Excellence (NICE). CONCLUSIONS: The current literature suggests that the optimal range of radial artery for maximum performance (maturation and primary patency) of RCAVF is at least 2 mm (level 2, grade a). The cephalic vein diameter of at least 2 mm (non-augmented) can result in best maturation and primary patency outcomes (level 2, grade a) and threshold below 1.5 mm is not advocated (level 2, grade b).

INTRODUCTION: The benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis. METHODS: Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups. RESULTS: A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47). CONCLUSIONS: Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.

OBJECTIVE: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. METHODS: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. RESULTS: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. CONCLUSIONS: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.

BACKGROUND: Throughout the Ebola virus disease (EVD) epidemic in West Africa, field laboratory testing for EVD has relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays; an accurate sample-to-answer RT-PCR test would reduce time to results and potentially increase access to testing. We evaluated the performance of the Cepheid GeneXpert Ebola assay on clinical venipuncture whole blood (WB) and buccal swab (BS) specimens submitted to a field biocontainment laboratory in Sierra Leone for routine EVD testing by RT-PCR ("Trombley assay"). METHODS AND FINDINGS: This study was conducted in the Public Health England EVD diagnostic laboratory in Port Loko, Sierra Leone, using residual diagnostic specimens remaining after clinical testing. EDTA-WB specimens (n = 218) were collected from suspected or confirmed EVD patients between April 1 and July 20, 2015. BS specimens (n = 71) were collected as part of a national postmortem screening program between March 7 and July 20, 2015. EDTA-WB and BS specimens were tested with Xpert (targets: glycoprotein [GP] and nucleoprotein [NP] genes) and Trombley (target: NP gene) assays in parallel. All WB specimens were fresh; 84/218 were tested in duplicate on Xpert to compare WB sampling methods (pipette versus swab); 43/71 BS specimens had been previously frozen. In all, 7/218 (3.2%) WB and 7/71 (9.9%) BS samples had Xpert results that were reported as "invalid" or "error" and were excluded, leaving 211 WB and 64 BS samples with valid Trombley and Xpert results. For WB, 22/22 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 84.6%-100%), and 181/189 Trombley-negative samples were Xpert-negative (specificity 95.8%, 95% confidence interval (CI) 91.8%-98.2%). Seven of the eight Trombley-negative, Xpert-positive (Xpert cycle threshold [Ct] range 37.7-43.4) WB samples were confirmed to be follow-up submissions from previously Trombley-positive EVD patients, suggesting a revised Xpert specificity of 99.5% (95% CI 97.0%-100%). For Xpert-positive WB samples (n = 22), Xpert NP Ct values were consistently lower than GP Ct values (mean difference -4.06, 95% limits of agreement -6.09, -2.03); Trombley (NP) Ct values closely matched Xpert NP Ct values (mean difference -0.04, 95% limits of agreement -2.93, 2.84). Xpert results (positive/negative) for WB sampled by pipette versus swab were concordant for 78/79 (98.7%) WB samples, with comparable Ct values for positive results. For BS specimens, 20/20 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 83.2%-100%), and 44/44 Trombley-negative samples were Xpert-negative (specificity 100%, 95% CI 92.0%-100%). This study was limited to testing residual diagnostic samples, some of which had been frozen before use; it was not possible to test the performance of the Xpert Ebola assay at point of care. CONCLUSIONS: The Xpert Ebola assay had excellent performance compared to an established RT-PCR benchmark on WB and BS samples in a field laboratory setting. Future studies should evaluate feasibility and performance outside of a biocontainment laboratory setting to facilitate expanded access to testing.