Northern Hemisphere Glaciation during the Globally Warm Early Late Pliocene

The early Late Pliocene (3.6 to ~3.0 million years ago) is the last extended interval in Earth's history when atmospheric CO2 concentrations were comparable to today's and global climate was warmer. Yet a severe global glaciation during marine isotope stage (MIS) M2 interrupted this phase of global warmth ~3.30 million years ago, and is seen as a premature attempt of the climate system to establish an ice-age world. Here we propose a conceptual model for the glaciation and deglaciation of MIS M2 based on geochemical and palynological records from five marine sediment cores along a Caribbean to eastern North Atlantic transect. Our records show that increased Pacific-to-Atlantic flow via the Central American Seaway weakened the North Atlantic Current and attendant northward heat transport prior to MIS M2. The consequent cooling of the northern high latitude oceans permitted expansion of the continental ice sheets during MIS M2, despite near-modern atmospheric CO2 concentrations. Sea level drop during this glaciation halted the inflow of Pacific water to the Atlantic via the Central American Seaway, allowing the build-up of a Caribbean Warm Pool. Once this warm pool was large enough, the Gulf Stream–North Atlantic Current system was reinvigorated, leading to significant northward heat transport that terminated the glaciation. Before and after MIS M2, heat transport via the North Atlantic Current was crucial in maintaining warm climates comparable to those predicted for the end of this century

THU0334 LASER SPECKLE CONTRAST ANALYSIS FOR MEASUREMENT OF PERIPHERAL BLOOD PERFUSION IN SYSTEMIC SCLEROSIS PATIENTS: CAN IT PREDICT FUTURE ISCHEMIC DIGITAL TROPHIC LESIONS?

Background:Vasculopathy is a hallmark of systemic sclerosis (SSc). Laser speckle contrast analysis (LASCA) is a research tool to assess peripheral blood perfusion (PBP) (1). At this moment, its reliability has been attested in SSc patients, but its predictive value for future ischemic digital trophic lesions (DTL) is unknown (1).Objectives:To investigate in an unselected, prospective SSc cohort if baseline LASCA PBP measurements can discriminate between patients who will develop ischemic DTL (iDTL) and those who will not.Methods:Patients (fulfilling 2013 ACR/EULAR criteria and/or 2001 LeRoy and Medsger criteria) were recruited during the period of December 2017 to September 2018. LASCA was performed at baseline, in standardized conditions (1). Regions of interest (ROIs) (diameter 1 cm) were outlined at the 2nd-5thfingertip both volar and dorsal. The 'average PBP' of these ROIs was calculated (expressed in arbitrary perfusion units [PU]). A monthly telephone survey was conducted for 1 year to investigate DTL occurrence. DTL were considered 'ischemic' if not related to calcinosis. Logistic regression and ROC analysis were used to assess if average PBP is predictive of future iDTL.Results:Of the 106 patients with complete follow-up (92 women [86,8%]; 18 limited SSc [17,0%], 82 limited cutaneous SSc [77,4%], 6 diffuse cutaneous SSc [5,7%]), 29 patients (27,4%) had a DTL history. Forty-nine patients (46,2%) were on vasodilator therapy. Only 7 patients developed at least 1 iDTL during follow-up (6,6%) (Figure 1a). Performing univariate logistic regression (ULR), average PBP was not predictive for future iDTL (Table 1). Of note, analyzing only the patients not taking vasodilators, average PBP in the 'iDTL group' (n = 3) was median 46,8 PU (min. 45,6 - max. 68,8) vs. median 141,4 PU (min. 24,4 - max. 269,5) in the 'no iDTL group' (n = 54) (Figure 1b). In this subgroup, all 3 patients who developed iDTL (100%) had an average PBP ≤ 70 PU whereas only 9 of the 54 patients without iDTL development (16,7%) had such PBP values.Table 1.Results of ULRSummary statisticsULRVariableiDTL cases(n = 7)Non-iDTL cases(n = 99)ParameterOR(95% CI)pROC AUC(95% CI)Average PBP (PU) mean (+/- SD)123,0 (74,6)142,9 (61,9)Average PBP (linear)0,995(0,982-1,007)0,4180,597(0,352-0,843)Conclusion:In this pilot study with an unselected day-to-day SSc population, where patients were allowed to continue vasodilators, there was an unexpected low iDTL incidence, undermining the power of our study. Even though, the observations in the subgroup of patients not taking vasodilators deserve future investigation to assess whether low PBP values, as measured by LASCA, are associated with a higher iDTL incidence.References:[1]Cutolo M, Vanhaecke A, et al. Autoimmun Rev. 2018;17(8):775-80.Figure 1.Distribution of 'average PBP' as measured by LASCA for 'no iDTL group' and 'iDTL group'Disclosure of Interests:Claire Debusschere: None declared, Amber Vanhaecke: None declared, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha, Ellen Deschepper: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Spr

The Physical Projector and Topological Quantum Field Theories: U(1) Chern-Simons Theory in 2+1 Dimensions

The recently proposed physical projector approach to the quantisation of gauge invariant systems is applied to the U(1) Chern-Simons theory in 2+1 dimensions as one of the simplest examples of a topological quantum field theory. The physical projector is explicitely demonstrated to be capable of effecting the required projection from the initially infinite number of degrees of freedom to the finite set of gauge invariant physical states whose properties are determined by the topology of the underlying manifold.Comment: 24 pages, no figures, plain LaTeX file; one more reference added. Final version to appear in Jour. Phys.

L1cam as an e-selectin ligand in colon cancer

Metastasis is the main cause of death among colorectal cancer (CRC) patients. E-selectin and its carbohydrate ligands, including sialyl Lewis X (sLeX) antigen, are key players in the binding of circulating tumor cells to the endothelium, which is one of the major events leading to organ invasion. Nevertheless, the identity of the glycoprotein scaffolds presenting these glycans in CRC remains unclear. In this study, we firstly have characterized the glycoengineered cell line SW620 transfected with the fucosyltransferase 6 (FUT6) coding for the \u3b11,3-fucosyltransferase 6 (FUT6), which is the main enzyme responsible for the synthesis of sLeX in CRC. The SW620FUT6 cell line expressed high levels of sLeX antigen and E-selectin ligands. Moreover, it displayed increased migration ability. E-selectin ligand glycoproteins were isolated from the SW620FUT6 cell line, identified by mass spectrometry, and validated by flow cytometry and Western blot (WB). The most prominent E-selectin ligand we identified was the neural cell adhesion molecule L1 (L1CAM). Previous studies have shown association of L1CAM with metastasis in cancer, thus the novel role as E-selectin counter-receptor contributes to understand the molecular mechanism involving L1CAM in metastasis formation

Exploring wind direction and SO2 concentration by circular-linear density estimation

The study of environmental problems usually requires the description of variables with different nature and the assessment of relations between them. In this work, an algorithm for flexible estimation of the joint density for a circular-linear variable is proposed. The method is applied for exploring the relation between wind direction and SO2 concentration in a monitoring station close to a power plant located in Galicia (NW-Spain), in order to compare the effectiveness of precautionary measures for pollutants reduction in two different years.Comment: 17 pages, 7 figures, 2 table

L1cam as an e-selectin ligand in colon cancer

POCI-01-0145-FEDER-007728 ref. 140_596817822Metastasis is the main cause of death among colorectal cancer (CRC) patients. E-selectin and its carbohydrate ligands, including sialyl Lewis X (sLeX) antigen, are key players in the binding of circulating tumor cells to the endothelium, which is one of the major events leading to organ invasion. Nevertheless, the identity of the glycoprotein scaffolds presenting these glycans in CRC remains unclear. In this study, we firstly have characterized the glycoengineered cell line SW620 transfected with the fucosyltransferase 6 (FUT6) coding for the α1,3-fucosyltransferase 6 (FUT6), which is the main enzyme responsible for the synthesis of sLeX in CRC. The SW620FUT6 cell line expressed high levels of sLeX antigen and E-selectin ligands. Moreover, it displayed increased migration ability. E-selectin ligand glycoproteins were isolated from the SW620FUT6 cell line, identified by mass spectrometry, and validated by flow cytometry and Western blot (WB). The most prominent E-selectin ligand we identified was the neural cell adhesion molecule L1 (L1CAM). Previous studies have shown association of L1CAM with metastasis in cancer, thus the novel role as E-selectin counter-receptor contributes to understand the molecular mechanism involving L1CAM in metastasis formation.publishersversionpublishe

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial

Copyright @ Queen’s Printer and Controller of HMSO 2012. This work was produced by Sharples et al. under the terms of a commissioning contract issued by the Secretary of State for Health.Objective: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. Design: A prospective, international, open-label, randomised controlled study, with a trialbased economic analysis. Setting: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals,Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. Participants: Inclusion criteria: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. Exclusion criteria: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. Interventions: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. Main outcome measures: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost–utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. Results: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI –£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI –0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. Conclusions: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUSFNA or EBUS-TBNA by suitably trained chest physicians.This project was funded by the NIHR Health Technology Assessment programm

MHC class I stability is modulated by cell surface sialylation in human dendritic cells

PD/BD/52472/2014 project (Ref. 38870) POCI-01-0145-FEDER-007728Maturation of human Dendritic Cells (DCs) is characterized by increased expression of antigen presentation molecules, and overall decreased levels of sialic acid at cell surface. Here, we aimed to identify sialylated proteins at DC surface and comprehend their role and modulation. Mass spectrometry analysis of DC’s proteins, pulled down by a sialic acid binding lectin, identified molecules of the major human histocompatibility complex class I (MHC-I), known as human leucocyte antigen (HLA). After desialylation, DCs showed significantly higher reactivity with antibodies specific for properly folded MHC-I-β2-microglobulin complex and for β2-microglobulin but showed significant lower reactivity with an antibody specific for free MHC-I heavy chain. Similar results for antibody reactivities were observed for TAP2-deficient lymphoblastoid T2 cells, which express HLA-A*02:01. Using fluorescent peptide specifically fitting the groove of HLA-A*02:01, instead of antibody staining, also showed higher peptide binding on desialylated cells, confirming higher surface expression of MHC-I complex. A decay assay showed that desialylation doubled the half-life of MHC-I molecules at cell surface in both DCs and T2 cells. The biological impact of DC´s desialylation was evaluated in co-cultures with autologous T cells, showing higher number and earlier immunological synapses, and consequent significantly increased production of IFN-γ by T cells. In summary, sialic acid content modulates the expression and stability of complex MHC-I, which may account for the improved DC-T synapses.publishersversionpublishe

Prevalence of skin pressure injury in critical care patients in the UK: results of a single-day point prevalence evaluation in adult critically ill patients.

OBJECTIVES: Hospital-acquired pressure injuries (PIs) are a source of morbidity and mortality, and many are potentially preventable. DESIGN: This study prospectively evaluated the prevalence and the associated factors of PIs in adult critical care patients admitted to intensive care units (ICU) in the UK. SETTING: This service evaluation was part of a larger, international, single-day point prevalence study of PIs in adult ICU patients. Training was provided to healthcare givers using an electronic platform to ensure standardised recognition and staging of PIs across all sites. PARTICIPANTS: The characteristics of the ICUs were recorded before the survey; deidentified patient data were collected using a case report form and uploaded onto a secure online platform. PRIMARY AND SECONDARY OUTCOME MEASURES: Factors associated with ICU-acquired PIs in the UK were analysed descriptively and using mixed multiple logistic regression analysis. RESULTS: Data from 1312 adult patients admitted to 94 UK ICUs were collected. The proportion of individuals with at least one PI was 16% (211 out of 1312 patients), of whom 8.8% (n=115/1312) acquired one or more PIs in the ICU and 7.3% (n=96/1312) prior to ICU admission. The total number of PIs was 311, of which 148 (47.6%) were acquired in the ICU. The location of majority of these PIs was the sacral area, followed by the heels. Braden score and prior length of ICU stay were associated with PI development. CONCLUSIONS: The prevalence and the stage of severity of PIs were generally low in adult critically ill patients admitted to participating UK ICUs during the study period. However, PIs are a problem in an important minority of patients. Lower Braden score and longer length of ICU stay were associated with the development of injuries; most ICUs assess risk using tools which do not account for this. TRIAL REGISTRATION NUMBER: NCT03270345

Do you think it's a disease? a survey of medical students

Background: The management of medical conditions is influenced by whether clinicians regard them as "disease" or "not a disease". The aim of the survey was to determine how medical students classify a range of conditions they might encounter in their professional lives and whether a different name for a condition would influence their decision in the categorisation of the condition as a 'disease' or 'not a disease'. Methods. We surveyed 3 concurrent years of medical students to classify 36 candidate conditions into "disease" and "non-disease". The conditions were given a 'medical' label and a (lay) label and positioned where possible in alternate columns of the survey. Results: The response rate was 96% (183 of 190 students attending a lecture): 80% of students concurred on 16 conditions as "disease" (eg diabetes, tuberculosis), and 4 as "non- disease" (eg baldness, menopause, fractured skull and heat stroke). The remaining 16 conditions (with 21-79% agreement) were more contentious (especially obesity, infertility, hay fever, alcoholism, and restless leg syndrome). Three pairs of conditions had both a more, and a less, medical label: the more medical labels (myalgic encephalomyelitis, hypertension, and erectile dysfunction) were more frequently classified as 'disease' than the less medical (chronic fatigue syndrome, high blood pressure, and impotence), respectively, significantly different for the first two pairs. Conclusions: Some conditions excluded from the classification of "disease" were unexpected (eg fractured skull and heat stroke). Students were mostly concordant on what conditions should be classified as "disease". They were more likely to classify synonyms as 'disease' if the label was medical. The findings indicate there is still a problem 30 years on in the concept of 'what is a disease'. Our findings suggest that we should be addressing such concepts to medical students