Variation in proliferative and cell cycle markers in Barrett's esophagus in relation to circumferential and axial location in the esophagus.

BACKGROUND: Adenocarcinoma in Barrett's esophagus (BE) occurs more frequently between 12 and 3 o'clock at the gastroesophageal junction (GEJ). METHODS: BE patients were prospectively recruited from December 2013 to July 2016. Expression of p53, Ki-67, cyclin-D1, COX-2 and p21 was assessed in quadrantic biopsies from the proximal and distal margins of the BE segments. Cell cycle marker association with current or subsequent dysplasia or adenocarcinoma was examined. RESULTS: 110 patients: median age 64 (IQR, 56-71) years; median BE segment length C4M6; and a median follow-up of 4.7 (IQR, 3.6-5.7) years. In total 13 (11.8%) had evidence of dysplasia or neoplasia (2.7% indefinite for dysplasia, 5.5% low grade, 1.8% high grade and 1.8% adenocarcinoma) at index endoscopy. Six (7%) developed dysplasia or neoplasia (1 low grade, 2 high grade and 3 adenocarcinoma) during follow-up. Ki-67 expression was highest at 3 o'clock, and overall was 49.6% higher in the 12-6 o'clock position compared to 6-12 o'clock [odds ratio (OR), 1.42 (95% confidence interval (CI), 1.00-2.12)]. A similar pattern was found with p21 [1.82 (1.00-3.47)]. There was increased expression of several markers in distal BE biopsies; cyclin-D1 [1.74 (1.29-2.34)]; Cyclo-oxygenase 2 [2.03 (1.48-2.78]) and p21 [2.06 (1.16-3.68)]. Expression of Ki-67 was lower in distal compared to proximal biopsies [0.58 (0.43-0.78)]. P53 expression had high specificity (93.8%) for subsequent low-grade dysplasia, high-grade dysplasia or adenocarcinoma. CONCLUSION: Increased cellular proliferation was seen at 12-6 o'clock at the GEJ. Cell-cycle marker expression was increased at the GEJ compared to the proximal BE segment. These findings mirror reflux esophagitis and suggest ongoing reflux contributes to the progression of dysplasia and malignancy in BE.

Blood Lactate Responses of Male and Female Players Across an International Rugby Sevens Tournament.

PURPOSE: This study investigated within- and between-matches blood lactate (La-) responses across an international Rugby Sevens tournament (5 matches over 2 d) in male and female players. METHODS: Earlobe blood samples were taken from 25 professional players around matches: before warm-up (PRE), immediately upon finishing match participation (POST), and 30 minutes postmatch (30 min). RESULTS: POST [La-] (mean [SD], range) for males was 10.3 (3.2; 2.9-20.2) mmol·L-1 and for females was 9.1 (2.3; 3.4-14.6) mmol·L-1. Linear mixed-effects models revealed a decrease in POST [La-] after match 5, compared to match 1. Increased PRE [La-] was found before match 2 (+0.8 [0.6-1.1] mmol·L-1), match 3 (+0.8 [0.5-1.1] mmol·L-1), and match 5 (+0.6 [0.4-0.9] mmol·L-1) compared to match 1 (all P < .001). The [La-] remained elevated at 30 min, compared to PRE (+1.7 [1.4-2.0] mmol·L-1, P < .001), with ∼20% of values persisting >4 mmol·L-1. Higher POST was observed in males compared to females (+1.6 [0.1-3.2] mmol·L-1, P = .042); however, no differences between sexes were found across 30 min or PRE [La-]. No [La-] differences between positions (backs and forwards) were identified. CONCLUSIONS: Lactate concentrations above 10 mmol·L-1 are required to effectively simulate the anaerobic demands of international Rugby Sevens matches. Practitioners are advised to individualize anaerobic training prescription due to the substantial variability observed within positional groups. Additionally, improving athletes' metabolic recovery capacity through training, nutrition, and recovery interventions may enhance physical preparation for subsequent matches within a day, where incomplete lactate clearance was observed.

The public sector and co-creation in turbulent times: A systematic literature review on robust governance in the COVID-19 emergency.

The capacity of public sector of co-creating with other stakeholders is challenged by the increasing presence of disruptive turbulent events, such as the COVID-19. At this regard, robustness has been identified as a suitable response to deal with this kind of events. Through a systematic literature review, we analyzed how public sector organizations have co-created with other actors during the COVID-19 and what have been the contribution of robust governance strategies. Our findings point firstly to the empirical validity of the robustness concept, providing evidence of the extensive use of robust governance strategies into the co-creation processes. Second, we identified a configurational approach to robustness, with governments co-creating by simultaneously employing several robust strategies. Thirdly, we observed a more active involvement of societal stakeholders, with emergence of proto-institutions and potential threats to the political system.

Assessment of the role of the Edinburgh dysphagia score in referral triage in a national service evaluation of the urgent suspected upper gastrointestinal cancer pathway.

BACKGROUND: The British Society of Gastroenterology has recommended the Edinburgh Dysphagia Score (EDS) to risk-stratify dysphagia referrals during the endoscopy COVID recovery phase. AIMS: External validation of the diagnostic accuracy of EDS and exploration of potential changes to improve its diagnostic performance. METHODS: A prospective multicentre study of consecutive patients referred with dysphagia on an urgent suspected upper gastrointestinal (UGI) cancer pathway between May 2020 and February 2021. The sensitivity and negative predictive value (NPV) of EDS were calculated. Variables associated with UGI cancer were identified by forward stepwise logistic regression and a modified Cancer Dysphagia Score (CDS) developed. RESULTS: 1301 patients were included from 19 endoscopy providers; 43% male; median age 62 (IQR 51-73) years. 91 (7%) UGI cancers were diagnosed, including 80 oesophageal, 10 gastric and one duodenal cancer. An EDS ≥3.5 had a sensitivity of 96.7 (95% CI 90.7-99.3)% and an NPV of 99.3 (97.8-99.8)%. Age, male sex, progressive dysphagia and unintentional weight loss >3 kg were positively associated and acid reflux and localisation to the neck were negatively associated with UGI cancer. Dysphagia duration <6 months utilised in EDS was replaced with progressive dysphagia in CDS. CDS ≥5.5 had a sensitivity of 97.8 (92.3-99.7)% and NPV of 99.5 (98.1-99.9)%. Area under receiver operating curve was 0.83 for CDS, compared to 0.81 for EDS. CONCLUSIONS: In a national cohort, the EDS has high sensitivity and NPV as a triage tool for UGI cancer. The CDS offers even higher diagnostic accuracy. The EDS or CDS should be incorporated into the urgent suspected UGI cancer pathway.

The outcomes of emergency hospital admissions with non-malignant upper gastrointestinal bleeding in England between 2003 and 2015.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common medical emergency with significant mortality. Despite developments in endoscopic and clinical management, only minor improvements in outcomes have been reported. METHODS: This was a retrospective cohort study of patients with non-malignant UGIB emergency admissions in England between 2003 and 2015, using Hospital Episode Statistics. Multilevel logistic regression analysis examined the associations with mortality. RESULTS: 242 796 patients with an UGIB admission were identified (58.8 % men; median age 70 [interquartile range (IQR) 53 - 81]). Between 2003 and 2015, falls occurred in both 30-day mortality (7.5 % to 7.0 %; P < 0.001) and age-standardized mortality (odds ratio (OR) 0.74, 95 % confidence interval [CI] 0.69 - 0.80; P < 0.001), including from variceal bleeding (OR 0.63, 95 %CI 0.45 - 0.87; P < 0.005). Increasing co-morbidity (Charlson score > 5, OR 2.94, 95 %CI 2.85 - 3.04; P < 0.001), older age (> 83 years, OR 6.50, 95 %CI 6.09 - 6.94; P < 0.001), variceal bleeding (OR 2.03, 95 %CI 1.89 - 2.18; P < 0.001), and a weekend admission (Sunday, OR 1.18, 95 %CI 1.12 - 1.23; P < 0.001) were associated with 30-day mortality. Of deaths at 30 days, 8.9 % were from ischemic heart disease (IHD) and the cardiovascular age-standardized mortality rate following UGIB was high (IHD deaths within 1 year, 1188.4 [95 %CI 1036.8 - 1353.8] per 100 000 men in 2003). CONCLUSIONS: Between 2003 and 2015, 30-day mortality among emergency admissions with non-malignant UGIB fell by 0.5 % to 7.0 %. Mortality was higher among UGIB admissions at the weekend, with important implications for service provision. Patients with UGIB had a much greater risk of subsequently dying from cardiovascular disease and addressing this risk is a key management step in UGIB.

Synthesis and characterization of molybdenum disulfide nanoparticles in Shewanella oneidensis MR-1 biofilms.

Shewanella oneidensis MR-1 is a dissimilatory metal-reducing bacterium capable of reducing various metal and sulfur compounds and precipitating them in nanoparticulate form. Here, we report the synthesis of molybdenum disulfide nanomaterials at the site of S. oneidensis biofilms grown in the presence of molybdenum trioxide and sodium thiosulfate. Samples from the growth medium were imaged using scanning electron microscopy and characterized using transmission electron microscopy, energy-dispersive x-ray spectroscopy, absorbance spectroscopy, and x-ray diffraction. These methods revealed the presence of molybdenum disulfide nanoparticle aggregates 50-300 nm in diameter with both hexagonal and rhombohedral polytypes. As a biosynthesis method for molybdenum sulfide, the use of S. oneidensis offers the advantage of significantly reduced heat and chemical solvent input compared to conventional methods of synthesizing molybdenum disulfide nanoparticles.

The outcomes of biliary drainage by percutaneous transhepatic cholangiography for the palliation of malignant biliary obstruction in England between 2001 and 2014: a retrospective cohort study.

INTRODUCTION: Relieving obstructive jaundice in inoperable pancreato-biliary cancers improves quality of life and permits chemotherapy. Percutaneous transhepatic cholangiography with drainage and/or stenting relieves jaundice but can be associated with significant morbidity and mortality. Percutaneous transhepatic biliary drainage (PTBD) in malignant biliary obstruction was therefore examined in a national cohort to establish risk factors for poor outcomes. METHODS: Retrospective study of adult patients undergoing PTBD for palliation of pancreato-biliary cancer in England between 2001 and 2014 identified from Hospital Episode Statistics. Multivariate logistic regression analysis was used to examine associations with mortality and the need for a repeat PTBD within 2 months. RESULTS: 16 822 patients analysed (median age 72 (range 19-104) years, 50.3% men). 58% pancreatic and 30% biliary tract cancer. In-hospital and 30-day mortality were 15.3% (95% CI 14.7% to 15.9%) and 23.1% (22.4%-23.8%), respectively. 20.2% suffered a coded complication within 3 months. Factors associated with 30-day mortality: age (≥81 years OR 2.68 (95% CI 2.37 to 3.03), p<0.001), increasing comorbidity (Charlson score 20+, 3.10 (2.64-3.65), p<0.001), pre-existing renal dysfunction (2.37 (2.12-2.65), p<0.001) and non-pancreatic cancer (unspecified biliary tract 1.28 (1.08-1.52), p=0.004). Women had lower mortality (0.91 (0.84-0.98), p=0.011), as did patients undergoing PTBD in a 'higher volume' provider (84-180 PTBDs per year 0.68 (0.58-0.79), p<0.001). CONCLUSIONS: In patients undergoing PTBD for the palliation of malignant biliary obstruction, 30-day mortality was high at 23.1%. Mortality was higher in older patients, men, those with increasing comorbidity, a cancer site other than pancreas and at 'lower-volume' PTBD providers.

The Outcomes of Emergency Admissions With Ulcerative Colitis Between 2007 and 2017 in England.

BACKGROUND AND AIMS: Patients with ulcerative colitis [UC] may present as emergencies and require rapid escalation of therapy. This study aimed to assess the mortality, colectomy, and readmission risks, during and following a first emergency admission with UC. METHODS: Using Hospital Episode Statistics, subjects aged between 18 and 60 years, coded with a first emergency admission with UC, were identified between 2007 and 2017. Influences of demographic factors, comorbidity, anti-tumour necrosis factor [TNF] therapy, and provider UC activity on mortality and colectomy were examined. RESULTS: A total of 10 051 subjects (46% female; median age 33 years [interquartile range [IQR] 25-44]) were identified. Mortality was 0.2% in hospital and 0.5% at 12 months and, following colectomy during acute admission, it was 1.4% in hospital and 2.1% at 12 months. Females had reduced risk of colectomy during admission: odds ratio [OR] 0.73 (95% confidence interval [CI] 0.62-0.85). Comparing the period 2007-2011 with 2012-2017, the rate of colectomy fell during acute admissions: OR 0.85 [0.72-0.99], p = 0.038 and at 12 months after admission: OR 0.73 [0.61-0.87]. Anti-TNF therapy increased 4-fold in acute UC admissions from 2007-2017. Those receiving anti-TNF therapy had a 70% increased risk of colectomy during index admission compared with those not receiving anti-TNF: OR 1.72 [1.29-2.31]. Increased time to colectomy during first admission was associated with female sex: hazard ratio [HR] 0.84 [0.72-0.98] and Asian ethnicity: HR 0.61 [0.44-0.85], whereas reduced time was associated with increased comorbidity, lower deprivation, and high provider volume of colectomies for UC: HR 1.59 [1.31-1.93]. CONCLUSIONS: Mortality following colectomy was 1.4% in hospital and 2.1% at 12 months, and no significant change over time was observed. Colectomy during emergency admission for UC was less common in females. Rates of anti-TNF therapy during emergency admission for UC have increased and overall colectomy rates have fallen. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Outcomes of colorectal stents when used as a bridge to curative resection in obstruction secondary to colorectal cancer.

BACKGROUND: Up to 25% of colorectal cancers present with bowel obstruction. Metal stents (MS) can provide a bridge to surgery by relieving obstruction and allowing the subject's condition to improve pre-operatively. METHODS: Hospital Episode Statistics (HES) is a database of all NHS funded secondary care episodes in England. Subjects admitted with bowel obstruction secondary to colorectal cancer without metastases were identified and subdivided into two groups: MS insertion prior to surgery and surgery only. Due to demographic differences between the groups, propensity score matching was used to analyse procedural outcomes, mortality and readmission within 30 days in left-sided cancers based upon age, sex and Charlson co-morbidity score. RESULTS: Over 10 years, 4571 subjects were identified; 401 received a MS and 4170 underwent surgery only. Median age of MS subjects was 71 (IQR 62-79) years; 226 (56.4%) were male. Median age of surgery-only subjects was 73 (64-81); 2165 (51.9%) were male. Following propensity matching 375 MS and 375 surgery-only subjects remained; MS had fewer readmissions within 30 days (28 (7.5%) versus 44 (11.7%), p = 0.047), fewer respiratory complications (< 6 (< 1.5%) versus 28 (7.5%), p < 0.001), lower stoma rates (49 (13.1%) versus 159 (42.4%), p < 0.001) and higher rates of laparoscopic surgery (154 (41.1%) versus 25 (6.7%), p < 0.001). Mortality was lower in the MS group at 30 days (7 (1.9%) versus 33 (8.8%), p < 0.001) and 1 year (37 (9.9%) versus 71 (19.0%), p < 0.001). CONCLUSIONS: In subjects presenting with obstructing colorectal cancer outcomes including respiratory complications, readmission and mortality appear to be better in subjects undergoing MS as a bridge to surgery compared to surgery alone.

The ultrasound neck imaging for tracheostomy study: A study prompting ultrasound screening prior to percutaneous tracheostomy procedures to improve patient outcomes.

INTRODUCTION: Percutaneous tracheostomy procedures are commonplace in intensive care units worldwide. Haemorrhagic complications, though potentially fatal, are thought to be under-reported. Ultrasonography use has not established itself in these procedures. This study assesses the prevalence and characteristics of pre-tracheal blood vessels, to aid intensivists on potential procedural hazards. METHOD: A retrospective, observational study was performed in the UK. Computed tomography angiograms from January 2012 to October 2014 were randomly retrieved and analysed for vessel data. RESULTS: A total of 343 adult patients were included (mean age: 65 (inter-quartile range 52-79), male: 63%). Forty-one percent of patients demonstrated a vessel overlying percutaneous tracheostomy insertion sites (C6-T1); veins were more common than arteries (69%, p = 0.001). Males were more likely to display veins (78 vs. 53%, p < 0.001). DISCUSSION: A substantial proportion of patients exhibited pre-tracheal vessels. Front-of-neck ultrasonography has huge potential to identify these. Based on these data, we believe ultrasonography may be an effective screening tool for percutaneous tracheostomy procedures to reduce complications. Further research is required to study outcomes.

Contribution of the voluntary sector to mental health crisis care in England: protocol for a multimethod study.

INTRODUCTION: Timely access to the right kind of support for people experiencing a mental health crisis can be problematic. The voluntary sector (VS) plays a key role in providing support and enabling access, but there is a knowledge gap concerning its contribution and interface with public services in mental health crisis care. This study aims to address this. METHODS AND ANALYSIS: The study has three empirical elements: (1) a national survey of voluntary sector organisations (VSOs) in England and national stakeholder interviews to develop a typology of organisations and interventions provided by VSOs; (2) detailed mapping of VS services in two regions through interviews and extending the national survey; (3) four case studies, identified from the regional mapping, of VS mental health crisis services and their interface with National Health Service (NHS) and local authority services, at both a system and individual level. Data collection will involve interviews with commissioners; VSO and NHS or local authority providers; and focus groups with people who have experience of VSO crisis support, both service users and carers; and mapping the crisis trajectory of 10 service users in each study site through narrative interviews with service users and informal carers to understand the experience of VSO crisis care and its impact. ETHICS AND DISSEMINATION: The University of Birmingham Humanities and Social Sciences Ethical Review Committee granted ethical approval (reference ERN_16-1183) for the national and regional elements of the study. Ethical review by the Health Research Authority will be required for the case study research once the sites have been identified from the first two elements of the study. A range of methods including a policy seminar, publication in academic journals and a tool kit for commissioners and practitioners will be produced to maximise the impact of the findings on policy and practice.

The 2015 upper gastrointestinal "Be Clear on Cancer" campaign: its impact on gastroenterology services and malignant and premalignant diagnoses.

OBJECTIVE: To assess the impact of the upper gastrointestinal 'Be Clear on Cancer' campaign launched by Public Health England between January and February 2015 on open-access gastroscopy referrals, incidence of target diagnoses (oesophagogastric cancer and Barrett's oesophagus), cancer staging at presentation, 1-year survival and cost per additional diagnosis. DESIGN: We performed a retrospective study of patients referred for 2-week-wait (2WW), open-access endoscopy 3 months following the campaign with diagnoses, endoscopic findings, staging and 12-month survival compared with data from corresponding months in 2014. SETTING: Three adjacent National Health Service trusts in the West Midlands with a combined population of 1.34 million in 2015. RESULTS: 2WW open-access referrals increased by 48% (95% CI 1.35 to 1.61, p<0.001). The proportion of target diagnoses fell from 6.7% to 6.1% (p=0.62). There were no significant overall increases in target diagnoses (OR 1.35, 95% CI 0.95 to 1.92, p=0.11) or cancer (OR 1.30, 95% CI 0.80 to 2.07, p=0.36). There was no change in tumour, node, metastasis (TNM) staging for oesophageal or gastric cancer. Overall 1-year survival did not alter significantly (HR 1.10, 95% CI 0.56 to 2.19, p=0.76). DISCUSSION: The 'Be Clear on Cancer' campaign led to a 48% increase in demand for 2WW gastroscopies but did not significantly affect the incidence of target diagnoses, cancer staging or 1-year survival.

Support for All in the UK Work Programme? Differential Payments, Same Old Problem.

The UK has been a high profile policy innovator in welfare-to-work provision which has led in the Coalition government's Work Programme to a fully outsourced, 'black box' model with payments based overwhelmingly on job outcome results. A perennial fear in such programmes is providers' incentives to 'cream' and 'park' claimants, and the Department for Work and Pensions has sought to mitigate such provider behaviours through Work Programme design, particularly via the use of claimant groups and differential pricing. In this article, we draw on a qualitative study of providers in the programme alongside quantitative analysis of published performance data to explore evidence around creaming and parking. The combination of the quantitative and qualitative evidence suggest that creaming and parking are widespread, seem systematically embedded within the Work Programme, and are driven by a combination of intense cost-pressures and extremely ambitious performance targets alongside overly diverse claimant groups and inadequately calibrated differentiated payment levels.

Evidence for the proximity of the extreme N-terminus of the neurokinin-2 (NK2) tachykinin receptor to Cys167 in the putative fourth transmembrane helix.

Neurokinin-2 receptor (NK(2)R) binding of [(3)H]-SR48968, a piperidinyl antagonist, is inhibited by methanethiosulfonate ethylammonium (MTSEA) in a time- and concentration-dependent manner. By the systematic alanine replacement of putative loop and transmembrane region cysteine residues (Cys(4), Cys(81), Cys(167), Cys(262), Cys(281), Cys(308), and Cys(309)), we have determined that MTSEA perturbs [(3)H]-SR48968 binding by modifying Cys(167) in transmembrane helix 4. Data were substantiated using glycine, serine, and threonine substitutions of Cys(167). MTSEA preferentially modifies cysteine residues that are in proximity to a negatively charged environment. Hence, aspartate and glutamate residues were systematically substituted with leucine or valine, respectively, and the inhibitory effects of MTSEA on [(3)H]-SR48968 binding were reevaluated to determine those acidic residues close to the MTSEA binding crevice. Most significantly, substitution of Asp(5) in the receptor's extreme N-terminus abolished the effects of MTSEA on [(3)H]-SR48968 binding. Therefore, our data would suggest close association of the extreme N-terminus with the extracellular surfaces of helices 4 and 3 in the NK(2)R in forming a binding crevice for MTSEA. The inhibition of SR48968 binding appears to result from loss of the SR48968 binding conformation of Gln(166) induced by MTSEA when it is coupled to Cys(167). Hence, it is proposed that there is mutually exclusive hydrogen bonding of SR48968 and MTSEA to Gln(166).