text: DSpace Community: http://hdl.handle.net/2381/9550 2017-01-18T08:39:27Z The frailty syndrome http://hdl.handle.net/2381/39196 Title: The frailty syndrome Authors: Conroy, Simon; Elliott, Amy Abstract: Frailty is an important geriatric syndrome with a high prevalence in the community population. It can be seen as a state of extreme vulnerability and loss of resistance to external stressors resulting in an increased risk of several adverse outcomes. Although linked with ageing, disability and co-morbidity, many consider frailty as a distinct clinical and pathophysiological entity. A problem with this concept is the search for a suitable operational definition that can be used in clinical practice. Many definitions exist in literature, but there is no agreement on the best measure. The more popular of these definitions include Fried's model of frailty and the Frailty Index. Identification of frailty is recommended to target interventions and help improve outcomes. Description: Embargo of 12 months. 2017-01-17T16:29:10Z Amplification of human platelet activation by surface pannexin-1 channels http://hdl.handle.net/2381/39195 Title: Amplification of human platelet activation by surface pannexin-1 channels Authors: Taylor, K. A.; Wright, J. R.; Vial, C.; Evans, R. J.; Mahaut-Smith, M. P. Abstract: Background: Pannexin-1 (Panx1) forms an anionselective channel with a permeability up to ~1 kDa and represents a non-lytic, non-vesicular ATP release pathway in erythrocytes, leukocytes and neurons. Related connexin gap junction proteins have been reported in platelets; however, the expression and function of the pannexins remain unknown. Objective: To determine the expression and function of pannexins in human platelets, using molecular, cellular and functional techniques. Methods: Panx1 expression in human platelets was determined using qPCR and antibody-based techniques. Contributions of Panx1 to agonist-evoked efflux of cytoplasmic calcein, Ca2+ influx, ATP release and aggregation were assessed in washed platelets under conditions where the P2X1 receptor response was preserved (0.32 U mL 1 apyrase). Thrombus formation in whole blood was assessed in vitro using a shear chamber assay. Two structurally unrelated and widely used Panx1 inhibitors, probenecid and carbenoxolone, were used throughout this study, at concentrations that do not affect connexin channels. Results: PANX1, but not PANX2 or PANX3, mRNA was detected in human platelets. Furthermore, Panx1 protein is glycosylated and present on the plasma membrane of platelets, and displays weak physical association with P2X1 receptors. Panx1 inhibition blocked thrombinevoked efflux of calcein, and reduced Ca2+ influx, ATP release, platelet aggregation and thrombus formation under arterial shear rates in vitro. The Panx1-dependent contribution was not additive to that of P2X1 receptors. Conclusions: Panx1 is expressed on human platelets and amplifies Ca2+ influx, ATP release and aggregation 2017-01-17T16:09:33Z Nucleoside triphosphate diphosphohydrolase-1 ectonucleotidase is required for normal vas deferens contraction and male fertility through maintaining P2X1 receptor function. http://hdl.handle.net/2381/39194 Title: Nucleoside triphosphate diphosphohydrolase-1 ectonucleotidase is required for normal vas deferens contraction and male fertility through maintaining P2X1 receptor function. Authors: Kauffenstein, G.; Pelletier, J.; Lavoie, E. G.; Kukulski, F.; Martín-Satué, M.; Dufresne, S. S.; Frenette, J.; Ribas Fürstenau, C.; Sereda, Michal J.; Toutain, B.; Henrion, D.; Sullivan, R.; Vial, Catherine; Sévigny, J. Abstract: In this work, we report that Entpd1(-/-) mice, deficient for the ectonucleotidase nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), produce smaller litters (27% reduction) compared with wild-type C57BL6 animals. This deficit is linked to reduced in vivo oocyte fertilization by Entpd1(-/-) males (61 ± 11% versus 88 ± 7% for Entpd1(+/+)). Normal epididymal sperm count, spermatozoa morphology, capacitation, and motility and reduced ejaculated sperm number (2.4 ± 0.5 versus 3.7 ± 0.4 million for Entpd1(+/+)) pointed to vas deferens dysfunction. NTPDase1 was localized by immunofluorescence in the tunica muscularis of the vas deferens. Its absence resulted in a major ATP hydrolysis deficiency, as observed in situ by histochemistry and in primary smooth muscle cell cultures. In vitro, Entpd1(-/-) vas deferens displayed an exacerbated contraction to ATP, a diminished response to its non-hydrolysable analog αβMeATP, and a reduced contraction to electrical field stimulation, suggesting altered P2X1 receptor function with a propensity to desensitize. This functional alteration was accompanied by a 3-fold decrease in P2X1 protein expression in Entpd1(-/-) vas deferens with no variation in mRNA levels. Accordingly, exogenous nucleotidase activity was required to fully preserve P2X1 receptor activation by ATP in vitro. Our study demonstrates that NTPDase1 is required to maintain normal P2X1 receptor functionality in the vas deferens and that its absence leads to impaired peristalsis, reduced spermatozoa concentration in the semen, and, eventually, reduced fertility. This suggests that alteration of NTPDase1 activity affects ejaculation efficacy and male fertility. This work may contribute to unveil a cause of infertility and open new therapeutic potentials. 2017-01-17T16:04:36Z Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a meta-analysis. http://hdl.handle.net/2381/39190 Title: Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a meta-analysis. Authors: Charbonnel, B.; Bertolini, M.; Tinahones, F. J.; Domingo, M. P.; Davies, Melanie Abstract: AIMS: The efficacy of the once-daily prandial GLP-1 receptor agonist lixisenatide plus basal insulin in T2DM was assessed by pooling results of phase III trials. METHODS: A meta-analysis was performed of results from three trials in the GetGoal clinical program concerning lixisenatide or placebo plus basal insulin with/without OADs. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints were change in PPG, FPG, insulin dose, and weight from baseline to week 24. Hypoglycemia rates and several composite endpoints were assessed. RESULTS: Lixisenatide plus basal insulin was significantly more effective than basal insulin alone at reducing HbA1c at 24 weeks. Composite and secondary endpoints were improved significantly with lixisenatide plus basal insulin, with the exception of FPG, which showed no significant difference between the groups. Lixisenatide plus basal insulin was associated with an increased incidence of hypoglycemia versus basal insulin alone. CONCLUSIONS: Lixisenatide plus basal insulin resulted in significant improvement in glycemic control versus basal insulin alone, particularly in terms of controlling PPG. Prandial lixisenatide in combination with basal insulin is a suitable option for treatment intensification in patients with T2DM insufficiently controlled with basal insulin, as these agents have complementary effects on PPG and FPG, respectively. Description: ClinicalTrials.gov identifier: for each of the trials included in the meta-analysis: GetGoal-Duo1, NCT00975286; GetGoal-L, NCT00715624; GetGoal-L-Asia, NCT00899958. 2017-01-17T15:37:04Z Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes. http://hdl.handle.net/2381/39186 Title: Cardiovascular risk factors and incident albuminuria in screen-detected type 2 diabetes. Authors: Webb, D. R.; Zaccardi, F.; Davies, M. J.; Griffin, S. J.; Wareham, N. J.; Simmons, R. K.; Rutten, G. E.; Sandbaek, A.; Lauritzen, T.; Borch-Johnsen, K.; Khunti, K. Abstract: BACKGROUND: It is unclear whether cardiovascular risk factor modification influences the development of renal disease in people with type 2 diabetes identified through screening. We determined predictors of albuminuria five years after a diagnosis of screen-detected diabetes within the ADDITION-Europe study, a pragmatic cardiovascular outcome trial of multifactorial cardiovascular risk management. METHODS: In 1,826 participants with newly diagnosed, screen-detected diabetes without albumiuria, we explored associations between risk of new albuminuria (≥2.5 mg mmol(-1) males and ≥3.5 mg mmol(-1) females) and: 1) baseline cardio-metabolic risk factors and 2) changes from baseline to one year in systolic blood pressure (∆SBP) and glycated haemoglobin (∆HbA1c ) using logistic regression. RESULTS: Albuminuria developed in 268 (15%) participants; baseline body mass index and active smoking were independently associated with new onset albuminuria in the five years after detection of diabetes. In a model adjusted for age, gender, and baseline HbA1c and blood pressure, a 1% decrease in HbA1c and 5 mmHg decrease in SBP during the first year were independently associated with lower risks of albuminuria (Odds Ratio (OR), 95% confidence interval: 0.76, 0.62 to 0.91 and 0.94, 0.88 to 1.01, respectively). Further adjustment did not materially change these estimates. There was no interaction between ΔSBP and ΔHBA1c in relation to albuminuria risk, suggesting likely additive effects on renal microvascular disease. CONCLUSIONS: Baseline measurements and changes in HbA1c and SBP a year after diagnosis of diabetes through screening independently associate with new onset albuminuria four years later. Established multifactorial treatment for diabetes applies to cases identified through screening. 2017-01-17T14:27:55Z Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension. http://hdl.handle.net/2381/39184 Title: Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension. Authors: Ott, C.; Lobo, M. D.; Sobotka, P. A.; Mahfoud, F.; Stanton, A.; Cockcroft, J.; Sulke, N.; Dolan, E.; van der Giet, M.; Hoyer, J.; Furniss, S. S.; Foran, J. P.; Witkowski, A.; Januszewicz, A.; Schoors, D.; Tsioufis, K.; Rensing, B. J.; Saxena, M.; Scott, B.; Ng, G. André; Achenbach, S.; Schmieder, R. E.; ROX CONTROL HTN Investigators Abstract: BACKGROUND: Options for interventional therapy to lower blood pressure (BP) in patients with treatment-resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the ROX coupler. It has been shown that BP response after renal denervation is greater in patients with combined hypertension (CH) than in patients with isolated systolic hypertension (ISH). We analyzed the effect of ROX coupler implantation in patients with CH as compared with ISH. METHODS AND RESULTS: The randomized, controlled, prospective ROX Control Hypertension Study included patients with true treatment-resistant hypertension (office systolic BP ≥140 mm Hg, average daytime ambulatory BP ≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with CH (n=31) and ISH (n=11). Baseline office systolic BP (177±18 mm Hg versus 169±17 mm Hg, P=0.163) and 24-hour ambulatory systolic BP (159±16 mm Hg versus 154±11 mm Hg, P=0.463) did not differ between patients with CH and those with ISH. ROX coupler implementation resulted in a significant reduction in office systolic BP (CH: -29±21 mm Hg versus ISH: -22±31 mm Hg, P=0.445) and 24-hour ambulatory systolic BP (CH: -14±20 mm Hg versus ISH: -13±15 mm Hg, P=0.672), without significant differences between the two groups. The responder rate (office systolic BP reduction ≥10 mm Hg) after 6 months was not different (CH: 81% versus ISH: 82%, P=0.932). CONCLUSIONS: Our data suggest that creation of an arteriovenous anastomosis using the ROX coupler system leads to a similar reduction of office and 24-hour ambulatory systolic BP in patients with combined and isolated systolic hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498. 2017-01-17T14:02:04Z Use of single molecule sequencing for comparative genomics of an environmental and a clinical isolate of Clostridium difficile ribotype 078. http://hdl.handle.net/2381/39183 Title: Use of single molecule sequencing for comparative genomics of an environmental and a clinical isolate of Clostridium difficile ribotype 078. Authors: Hargreaves, Katherine R.; Thanki, Anisha M.; Jose, Bethany R.; Oggioni, Marco R.; Clokie, Martha R. J. Abstract: BACKGROUND: How the pathogen Clostridium difficile might survive, evolve and be transferred between reservoirs within the natural environment is poorly understood. Some ribotypes are found both in clinical and environmental settings. Whether these strains are distinct from each another and evolve in the specific environments is not established. The possession of a highly mobile genome has contributed to the genetic diversity and ongoing evolution of C. difficile. Interpretations of genetic diversity have been limited by fragmented assemblies resulting from short-read length sequencing approaches and by a limited understanding of epigenetic regulation of diversity. To address this, single molecule real time (SMRT) sequencing was used in this study as it produces high quality genome sequences, with resolution of repeat regions (including those found in mobile elements) and can generate data to determine methylation modifications across the sequence (the methylome). RESULTS: Chromosomal rearrangements and ribosomal operon duplications were observed in both genomes. The rearrangements occurred at insertion sites within two mobile genetic elements (MGEs), Tn6164 and Tn6293, present only in the M120 and CD105HS27 genomes, respectively. The gene content of these two transposons differ considerably which could impact upon horizontal gene transfer; differences include CDSs encoding methylases and a conjugative prophage only in Tn6164. To investigate mechanisms which could affect MGE transfer, the methylome, restriction modification (RM) and the CRISPR/Cas systems were characterised for each strain. Notably, the environmental isolate, CD105HS27, does not share a consensus motif for (m4)C methylation, but has one additional spacer when compared to the clinical isolate M120. CONCLUSIONS: These findings show key differences between the two strains in terms of their genetic capacity for MGE transfer. The carriage of horizontally transferred genes appear to have genome wide effects based on two different methylation patterns. The CRISPR/Cas system appears active although perhaps slow to evolve. Data suggests that both mechanisms are functional and impact upon horizontal gene transfer and genome evolution within C. difficile. Description: The two SMRT generated genomes of M120 and CD105HS27 have been deposited in the ENA in study PRJEB13565 and have accession numbers ERS1242840 and ERS1242839, respectively. The methylation data has been deposited for each isolate in REBASE as organisms #19242 and #19243, respectively. 2017-01-17T12:59:51Z ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle. http://hdl.handle.net/2381/39182 Title: ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle. Authors: Bousquet, J.; Hellings, P. W.; Agache, I.; Bedbrook, A.; Bachert, C.; Bergmann, K. C.; Bewick, M.; Bindslev-Jensen, C.; Bosnic-Anticevitch, S.; Bucca, C.; Caimmi, D. P.; Camargos, P. A.; Canonica, G. W.; Casale, T.; Chavannes, N. H.; Cruz, A. A.; De Carlo, G.; Dahl, R.; Demoly, P.; Devillier, P.; Fonseca, J.; Fokkens, W. J.; Guldemond, N. A.; Haahtela, T.; Illario, M.; Just, J.; Keil, T.; Klimek, L.; Kuna, P.; Larenas-Linnemann, D.; Morais-Almeida, M.; Mullol, J.; Murray, R.; Naclerio, R.; O'Hehir, R. E.; Papadopoulos, N. G.; Pawankar, R.; Potter, P.; Ryan, D.; Samolinski, B.; Schunemann, H. J.; Sheikh, A.; Simons, F. E.; Stellato, C.; Todo-Bom, A.; Tomazic, P. V.; Valiulis, A.; Valovirta, E.; Ventura, M. T.; Wickman, M.; Young, I.; Yorgancioglu, A.; Zuberbier, T.; Aberer, W.; Akdis, C. A.; Akdis, M.; Annesi-Maesano, I.; Ankri, J.; Ansotegui, I. J.; Anto, J. M.; Arnavielhe, S.; Asarnoj, A.; Arshad, H.; Avolio, F.; Baiardini, I.; Barbara, C.; Barbagallo, M.; Bateman, E. D.; Beghé, B.; Bel, E. H.; Bennoor, K. S.; Benson, M.; Białoszewski, A. Z.; Bieber, T.; Bjermer, L.; Blain, H.; Blasi, F.; Boner, A. L.; Bonini, M.; Bonini, S.; Bosse, I.; Bouchard, J.; Boulet, L. P.; Bourret, R.; Bousquet, P. J.; Braido, F.; Briggs, A. H.; Brightling, C. E.; Brozek, J.; Buhl, R.; Bunu, C.; Burte, E.; Bush, A.; Caballero-Fonseca, F.; Calderon, M. A.; Camuzat, T.; Cardona, V.; Carreiro-Martins, P.; Carriazo, A. M.; Carlsen, K. H.; Carr, W.; Cepeda Sarabia, A. M.; Cesari, M.; Chatzi, L.; Chiron, R.; Chivato, T.; Chkhartishvili, E.; Chuchalin, A. G.; Chung, K. F.; Ciprandi, G.; de Sousa, J. C.; Cox, L.; Crooks, G.; Custovic, A.; Dahlen, S. E.; Darsow, U.; Dedeu, T.; Deleanu, D.; Denburg, J. A.; De Vries, G.; Didier, A.; Dinh-Xuan, A. T.; Dokic, D.; Douagui, H.; Dray, G.; Dubakiene, R.; Durham, S. R.; Du Toit, G.; Dykewicz, M. S.; Eklund, P.; El-Gamal, Y.; Ellers, E.; Emuzyte, R.; Farrell, J.; Fink Wagner, A.; Fiocchi, A.; Fletcher, M.; Forastiere, F.; Gaga, M.; Gamkrelidze, A.; Gemicioğlu, B.; Gereda, J. E.; van Wick, R. G.; González Diaz, S.; Grisle, I.; Grouse, L.; Gutter, Z.; Guzmán, M. A.; Hellquist-Dahl, B.; Heinrich, J.; Horak, F.; Hourihane, J. O.; Humbert, M.; Hyland, M.; Iaccarino, G.; Jares, E. J.; Jeandel, C.; Johnston, S. L.; Joos, G.; Jonquet, O.; Jung, K. S.; Jutel, M.; Kaidashev, I.; Khaitov, M.; Kalayci, O.; Kalyoncu, A. F.; Kardas, P.; Keith, P. K.; Kerkhof, M.; Kerstjens, H. A.; Khaltaev, N.; Kogevinas, M.; Kolek, V.; Koppelman, G. H.; Kowalski, M. L.; Kuitunen, M.; Kull, I.; Kvedariene, V.; Lambrecht, B.; Lau, S.; Laune, D.; Le, L. T.; Lieberman, P.; Lipworth, B.; Li, J.; Lodrup Carlsen, K. C.; Louis, R.; Lupinek, C.; MacNee, W.; Magar, Y.; Magnan, A.; Mahboub, B.; Maier, D.; Majer, I.; Malva, J.; Manning, P.; De Manuel Keenoy, E.; Marshall, G. D.; Masjedi, M. R.; Mathieu-Dupas, E.; Maurer, M.; Mavale-Manuel, S.; Melén, E.; Melo-Gomes, E.; Meltzer, E. O.; Mercier, J.; Merk, H.; Miculinic, N.; Mihaltan, F.; Milenkovic, B.; Millot-Keurinck, J.; Mohammad, Y.; Momas, I.; Mösges, R.; Muraro, A.; Namazova-Baranova, L.; Nadif, R.; Neffen, H.; Nekam, K.; Nieto, A.; Niggemann, B.; Nogueira-Silva, L.; Nogues, M.; Nyembue, T. D.; Ohta, K.; Okamoto, Y.; Okubo, K.; Olive-Elias, M.; Ouedraogo, S.; Paggiaro, P.; Pali-Schöll, I.; Palkonen, S.; Panzner, P.; Papi, A.; Park, H. S.; Passalacqua, G.; Pedersen, S.; Pereira, A. M.; Pfaar, O.; Picard, R.; Pigearias, B.; Pin, I.; Plavec, D.; Pohl, W.; Popov, T. A.; Portejoie, F.; Postma, D.; Poulsen, L. K.; Price, D.; Rabe, K. F.; Raciborski, F.; Roberts, G.; Robalo-Cordeiro, C.; Rodenas, F.; Rodriguez-Mañas, L.; Rolland, C.; Roman Rodriguez, M.; Romano, A.; Rosado-Pinto, J.; Rosario, N.; Rottem, M.; Sanchez-Borges, M.; Sastre-Dominguez, J.; Scadding, G. K.; Scichilone, N.; Schmid-Grendelmeier, P.; Serrano, E.; Shields, M.; Siroux, V.; Sisul, J. C.; Skrindo, I.; Smit, H. A.; Solé, D.; Sooronbaev, T.; Spranger, O.; Stelmach, R.; Sterk, P. J.; Strandberg, T.; Sunyer, J.; Thijs, C.; Triggiani, M.; Valenta, R.; Valero, A.; van Eerd, M.; van Ganse, E.; van Hague, M.; Vandenplas, O.; Varona, L. L.; Vellas, B.; Vezzani, G.; Vazankari, T.; Viegi, G.; Vontetsianos, T.; Wagenmann, M.; Walker, S.; Wang, D. Y.; Wahn, U.; Werfel, T.; Whalley, B.; Williams, D. M.; Williams, S.; Wilson, N.; Wright, J.; Yawn, B. P.; Yiallouros, P. K.; Yusuf, O. M.; Zaidi, A.; Zar, H. J.; Zernotti, M. E.; Zhang, L.; Zhong, N.; Zidarn, M. Abstract: The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease. 2017-01-17T12:54:40Z A185 Infrared thermal imaging of the hand during vascular occlusion in healthy volunteers http://hdl.handle.net/2381/39177 Title: A185 Infrared thermal imaging of the hand during vascular occlusion in healthy volunteers Authors: Charlton, M.; Tonks, L.; Mclelland, L.; Coats, T. J.; Thompson, J. P.; Sims, M. R.; Papetti, M; Tang, KB; Maghsudi, B; SICM NICER Group; EXODUS-investigators; Horton, A; Saeed, S; Aktepe, O; Medina, RS; Beerepoot, M; Weblin, J; Bar, S; Redondo, E; Souza, RB; Liu, CP; Toral, CM; Pereira, T; Lygnos, M; Murbach, LD; Alvarez-Lerma, F.; Clermont, G.; Vlasenko, R; Thickett, D. R.; Creagh-Brown, B; Wojnicka, AG; Kousha, O.; Malheiro, DT; Mid-Norway Sepsis Research Center; Zhang, J; Cavalheiro, AM; Grieco, DL; Lucena, F; Elbers, PW; Wood, M; Elbahr, M; Colombo, D; Guerrero, J. E.; Bauer, A; Morris, P. E.; Arafa, MY; El-Adawy, A; López, M. I.; Hart, N.; Fanelli, V; Carton, E; Erdogdu, B; Valsø, Å; Ruiz-Perea, A; Watts, S; Cornara, P; Meddeb, K; Beltramelli, V; Vikulova, D.; Piers, R.; Urbano, A.; Šímová, D; Rusinova, K.; Auzias, G; Ziaian, B; Swart, E. L.; Candeias, C.; Lilot, M.; Giovanni, L.; Dolgikova, Y; Babel, J.; Lundin, S; Salido-Díaz, L; Reine, J; Lesimple, B; Nakamura, MA; Meert, A. P.; Singer, M; Young, N.; GRAVITY-VAP TRIAL NETWORK; Kox, M; Appleton, R; Schmid, RM; Akkoc, T; García-Alcántara, A; Urbino, R; Gibson, A.; Treso-Geira, M; Elmenshawy, AM; Park, MJ; Cressoni, M; Chau, CM; Reyners, A. K.; Kauts, V; Wilson, A; Forsberg, S; Matilla, CI; Rubio, RJ; Long, NW; Chico-Fernández, M; Balci, C; Pogson, D; Gilles, M.; Ritter, C.; Gundogan, K.; Zýková, I; Wang, CH; Hjortrup, PB; Guerci, P.; Hasanin, A; Langer, T; Mercier, R; Benten, D; Fernández-Porcel, A; Sánchez, JS; Chan, K. S.; Khader, H; Arango-Dávila, CA; Marenghi, C; Paulsen, J; Shingo, I.; Martins, A. M.; Quiñonez, E; Grzeskowiak, E; Ben-Ghezala, H; Fletcher, N.; Costa, A.; Güell, E.; Grzeskowiak, E; Castellanos, MA; Sklar, M; Trepte, CJ; Ko, J. I.; Sungur, M.; Yeter, H; Ghorbani, M; Tánczos, K; Dementienko, M.; Carroll, G.; Pennington, J; Touw, HR; Blakey, JD; Velez, N; Seller-Pérez, G.; Williams, D; Cabrera, AR; Findeisen, M; Romano, SM; Abentroth, LR; Cheng, CC; Li, S. H.; Blackwood, B; Dyson, A; Scaramuzza, A; Hartog, CS; Akkoc, T; Kompanje, E.; Varas, JL; Gouva, M.; Orford, C; Thomas-Rueddel, DO; Nedergaard, HK; Ince, C.; Kenji, F; Frantzeskaki, F.; Dres, M; Decruyenaere, J.; Tuinman, P. R.; Garcia-Garcia, M; Kuharic, J; Lehmann, M; FINNAKI Study Group; Hravnak, M.; Huschens, B; Falk, AC; Molnár, Z.; Turrini, C; Granillo, JF; Raafat, A; Phelan, D; Vallone, CS; Beam, AL; Bern, R; Gerrard, CS; Masjedi, M; Pinel, AC; Okada, M; Schultz, M. J.; Bienert, A; Slama, M; Petramfar, P; de Murillas, RG; Huang, WC; Gusarov, V.; Quiney, N; Mercat, A.; Nijsten, MW; Lavault, S.; Kwon, IS; Lauretta, MP; Capitanio, G.; Villarejo, P; Ghorbani, M.; Brodska, H; Hollinger, A; Koh, Y; Samuel, JL; Fenner, L; Plata-Menchaca, EP; Barreto, J; Bringue, J; Antok, E; Calini, A; Grasso, S.; Nakamae, M. N.; Kara, I; Guirgis, AH; Bakhshi-Raiez, F; Berthelsen, R. E.; Wennervirta, J; Rufo-Tejeiro, O; Érces, D.; Grandbois, M; Richecoeur, J; Howells, P. A.; Singer, M; Sarret, P; de Mast, Q; Lambermont, B.; Knudsen, H.; Borthwick, M; Meierhans, R.; Izurieta, JR; Wright, C; Alves, J; Alvarez, A; Åsvold, BO; Souza, R. B.; Vergani, G; Cámara-Sola, E; Torres, A.; Thomas, G; Mehl, A; Okumus, N; Mansouri, P.; Hernandez, G; Simioni, P.; Guven, M.; Harjola, VP; Cabeza, EM; Xie, Z; Sarıca, LT; Dos Santos, ER; Gaibor, ND; Soriano-Orozco, R; Ranieri, VM; Masclans, J. R.; Dubin, A.; Sma, N; Citerio, G; Gomez-Gonzalez, N; Plaud, B; Armaganidis, A; Paldusová, B; Aguilar, AL; Zhivotneva, I.; Etman, M; Martínez-Martínez, M.; Kunze-Szikszay, N.; Maltesen, R. G.; Pelenz, M; Zand, F.; Bousselmi, K; Suh, GY; Coskun, R.; Gallego-Lara, S; Villén, LM; Martín-Loeches, I.; Dieperink, W; Barea-Mendoza, J; Hatib, F; Tomic, I; Andersson, AE; Chanzu, NM; Laborías, PM; Pérez-Fernández, XL; Jiménez, G. J.; Mojoli, F; Consonni, D.; Urbanaviciute, I; Meixensberger, J; Corcia-Palomo, Y.; Blaffart, F.; Legrand, M; Fernandes, SM; Gil, CP; Toscani, L; Molnár, Z; de Boer, R; Haberlandt, T; Nakane, M; Okada, M; Quintana, S; Jaillette, E.; Fraj, N; Singer, M; Javadpour, S; Güllü, Z; Koh, I. H.; Herranz, UA; Pettilä, V.; Uusvel, G.; Érces, D; Frencken, J.; Aisling, B.; Rodriguez, CG; Parker, R. S.; Salem, M; ARIAM-CARDIAC SURGERY PROJECT AUTHORS; Haftacı, E; Antonelli, M; Dawson, D.; Kleyman, A.; Fouad, AZ; Chiumello, D; Herpain, A; Masjedi, M.; Bonastre, J.; Koh, I. H.; Tagliaferri, F.; Zani, G; Sánchez, MS; Camprubí-Rimblas, M; Roushdy, DZ; de la Torre, M. C.; Skogstad, L; Riccio, FC; Verbrugge, SJ; Marijon, E; Tullo, L; Pereira, B; Olona, M; Laoveeravat, P; Kong, HH; Lee, CT; Baldwin, C. E.; Grounds, R. 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M.; Sánchez, B; Padilla, C; Sipman, FS; Amilien, V.; Tsvetanova-Spasova, T; Schuepbach, R.; Laoveeravat, P.; Pérez-Carrasco, M.; Murza, A; NEFROCON Investigators; de Haan, RJ; Cinel, L; Riccio, F; Bakker, J; Linde-Zwirble, W.; Khedher, A.; Afshari, R; Chiou, KR; Lorne, E; Roman, JA; Vogel, G; Hadavi, MR; Marin, J; Kadioglu, A; Trojanowska, I; Besserve, P.; Cote, J; Hartmann, J; Ruiz-Rodriguez, JC; Simeone, P; Gutiérrez-Pizarraya, A.; Neuzner, J; Jensen, J. U.; Velly, L; Cardiac Arrest Group HUVR; Sousa, M; Muhtaroglu, S.; Assis, R; Gonen, C; Brazzi, L; Le Bars, D; Panarello, G.; Hilasque, C; Perkins, G. 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A.; Greiwe, G; Antonia, V; Alkan, A; Ylikoski, E; Bertini, P; Dubrawski, A.; Verrier, N; Khaliq, W.; Polidano, E; Acuna, JM; Arnulf, I.; Snell, G; Hamimy, WI; van Achterberg, T.; Herrera-Gutierrez, M. E.; Asadpour, E.; Passouant, O; Palomo, YC; Kao, KC; Jorge, AC; Milazzo, F; Taba, S; Wright, AD; Mignolet, K; Ogasawara, SM; Lim, YJ; Sartori, G.; García-de la Torre, A; Michalsen, A.; Altintas, ND; Antonelli, M; Koulouras, V.; Kim, S; Ledoux, G.; Amato, MB; Chaari, A; Montravers, P; Gemmell, ML; Gager, M; Kezyte, G; Blaser, A. R.; de Jonge, M; Gaite, F. B.; Llopar-Valdor, E.; Mitsi, E; Fagerdahl, AM; Sotosek-Tokmazic, V; Hsu, YC; Martin, JC; Garcia, AC; Haftacı, E; Fan, E.; Skorniakov, I.; Marshall, JC; Olaniran, KO; Lynch, S. J.; Rozemeijer, S; Filho, CA; Andreotti, A.; Hernandez, G; Blomqvist, H; Forni, L.; E Silva, Z. C.; Stapleton, P; Santana, JD; Chouchene, I; Rahamat-Langedoen, J; Hubert, R.; Gommers, D. 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F.; Ferrer, M.; Mar, GY; Norkiene, I; Tonon, D; Pronina, AM; Baldirà, J; Echeverry, GJ; Kalaiselvan, M. S.; Colombo, A; Gommers, DA; DeWan, A; Benoit, D.; Bäcklund, M; Balicco, B; Rizk, A; Ferrone, G; Carranza, ML; Fernandez-Delgado, E.; Mcgaughey, J; Koch, R; Jones, N; El Maraghi, S.; Leijte, GP; Lopez, MA; Costa, R; Cinel, I; Schweingruber, T; Chao, A; Luciani, A; Georger, J. F.; Carlesso, E; Lagunes, L; de Grooth, H. J.; Pike, F.; MacEachern, KN; Christensen, D. F.; Schloesser, J; Shah, A.; Hong, CW; Jonnada, S; Tachaboon, S; KARISMA; Mercurio, G.; Savo, D; Ballantyne, J; Tiranathanagul, K; Murbach, LD; Matilla, CI; Bousselmi, K; Hansell, D.; Mills, GH; Gibbons, FK; Bouneb, R; Kauts, V; Mortimore, J.; O'Loughlin, C; Caballero, CH; LUNG SAFE Investigators and the ESICM Trials Group; Crimella, F; Hamdaoui, Y; Lange, C; Whiteley, C.; Malmgren, J.; Trenado, J; Hakim, KA; Scott, J; Chang, CH; Filippini, C; Messina, A; Mukhtar, AM; Lorente, MJ; Ralston, MR; Arias-Verdú, D.; Rooyackers, O.; Nweze, K.; Cartanya Ferré, M; Black, E; Muñoz-Bono, J.; Diaz, DD; Acebes, S. R.; Conti, G; Huber, W; Gritsan, A; Ribeiro, J. M.; Santos, A. C.; van Lieshout, EJ; Alzola, LM; Lee, RM; Kawamae, K; Schreiner, F; Masclans, J. R.; Rose, L; Di Molfetta, P; Fischer, L; Galvez-Blanco, GA; Venetsanou, K; Dupont, H; Gascón, L. M.; Ferguson, AJ; Kompanje, E.; Bourdeaux, D; Holst, R; Chiang, CC; Romero, I; Smedberg, M.; Pinsky, M. 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O.; Kashiwagi, Y; Hahnenkamp, K.; Tungsanga, K; Hung, WT; Chen, CJ; Creteur, J; Pogson, D; Alejo, GC; Wernerman, J.; Chan, A; Wright, C; Paratz, J; Alklit, A.; Rueda-Molina, C; Lim, BC; Iesu, E; Cerrato, S. G.; Hinojosa, R.; Eiam-Ong, S.; Granja, C; Vazin, A; Muñoz, A. O.; Baño, DM; Massari, D; Torres, A.; Zakaria, E; Preiser, JC; Elazizy, HM; Dyson, A; MacKay, A; Ataman, S.; Coloma-Gomez, B; Jensen, J. F.; Kleinpell, R; Nahas, RA; Nassar, H; Tonilo, A; H1N1 SEMICYUC/GETGAG Working Group; Gelee, B; Bitker, L; Chang, C. H.; Oudemans-van Straaten, H. M.; Kauts, V; Hilbert, G; Hung, SM; Grainger, E.; Rehal, M. S.; Richter, P; Ori, C.; Palomera, E.; Brettner, F; Oliva, I; Longbottom, E. R.; Woo, S; Bassi, G. L.; Campello, E.; Vidal-Perez, R; Rueda-Molina, C; de la Gandara, AM; Öhman, T; Clinical Intensive Care Research Basel; Monnet, X; Talmor, D.; Paños-Espinosa, C; Cremer, O.; Markopoulou, D; Moise, G.; Mudersbach, E; Kang, Y. R.; De Santis, P; Rossi, S; Srisawat, N; Öveges, N; Wallin, A; Martinez, ML; Kaunisto, M. A.; Sperlinga, R; Schultz, MJ; Ozcan, N; Irie, H; Suzuki, H; Dupont, H.; Oerding, H; Berry, A; Srisawat, N; Tsvetanova-Spasova, T; Sari, A; Papatella, R.; Franchi, F; Kurmukov, IA; Pi-Guerrero, M; Egerod, I; Pezza, B; Hanifa, M.; Kuo, FY; Vanheule, S.; Tudor, B; Nitzschke, R; Vazquez, AL; Sanguino, VD; de la Torre-Prados, MV; Artigas, A; Martínez, M. P.; Ayman, E; Martins, A. M.; Kristensen, S. R.; Solligård, E; Demeter, G; Rodriguez, CG; Oldner, A; Marshall, DC; Gil, CP; Romagnoli, S; Vaara, S. T.; Piers, R.; Hinds, R; Mcauley, DF; Zanella, A.; Wang, D; Quinty, F; Houston, S; Kwon, SJ; Decruyenaere, J.; Wimmer, R.; Bodí, M; Pinnschmidt, H; Ospina-Tascón, GA; Joelsson-Alm, E; Park, JS; Atkinson, D; de la Torre-Prados, M; Fernández-Porcel, A; Lynch, S. J.; Hinds, CJ; Vidal-Perez, R; Berry, W; LUNG SAFE investigators and the ESICM study group; Montejo-González, JC; Mastromauro, I; Sauerlaender, S; Ergin, B; Sabetian, G.; Krag, M; Pasko, N.; Kao, K. C.; Soliman, MS; Ayachi, J; Kang, PL; Gonen, C; Facchin, F.; Garrigue, P; García-Fuentes, C; de la Torre-Prados, MV; Pesenti, A; Dominguez-Aguado, H; Fernández, IF; Chagnon, F; Elghonemi, MO; Ruiz, BL; Launay, JM; Spoelstra-de Man, A. M.; Shih, PY; Christodoulopoulou, T.; Noone, K.; Yan, LS; Livigni, S.; Petrikov, S; Pickkers, P; Kubitz, JC; Masjedi, M; Ziaian, B; Moolenaar, DL; Loghmari, D.; Krajčová, A.; Ista, E.; Costa, CR; Ghorbani, M.; Schouten, LR; Fusari, M; Levitt, J; Palmaccio, A; Alonso, DC; Pedersen, S.; Charris-Castro, L.; Salvail, D; Dehghanrad, F.; Ori, C; Spoelstra-de Man, A. M.; Longares, MD; Pizza, A; Campbell, C; Rietdijk, W; Connolly, B. C.; Naumann, D; Mendez, R.; Yarici, M.; Gonzalez, V; Storm, H; Gerretsen, J; Froe, F.; Yan, Z; Sainsily, X; Na, S; Lemarié, J; Aydoğan, BB; Greaves, J; Choo, W. P.; Miglioranza, D; Paz, ES; Hagar, F.; Mulier, J. L.; Barbrel, B; Obukhova, O; Pettenuzzo, T.; Vieira, J. C.; Nesterova, E.; Alphonsine, J; Granillo, JF; Rosato, R; Zubek, L.; Aron, J.; Chang, YF; Cariou, A; Vroom, MB; van der Jagt, M.; Akcan-Arikan, A; Jensen, J. F.; Owen, H. C.; Waldauf, P.; Guiga, A; Mezquita, MV; Trepte, C; Koeneman, B; Gemmell, L; Martins, A; Hung, WT; Funcke, S; Garnacho-Montero, J.; Gusarov, V.; Lévy, B; Xe-HYPOTHECA study group; McGrath, B.; Adriaanse, M; Álvarez-Lerma, F.; Martínez, L; Dell'Anna, AM; Verboom, D.; Bromberg, I; Egbaria, W; Alabart-Segura, Y; Møller, MH; Cheng, YJ; Casals, X. N.; Sarris, SJ; Prada, R; Yıldırım, F; Lim, MP; Canabal, A; Major, E; Chrysanthopoulou, E; Hasanin, A; Bailón, AM; El-Sherif, R; Scaravilli, V; Kooner, G; Uz, Z.; Toft, P; West, T; Viegas, E; Demircioglu, E; Gibson, D; Aksun, S; Tchir, M.; Benoit, D.; Wright, C; Gul, F; Gimeno-Raga, M; Rustøen, T; Boussarsar, M; Díaz, F. J.; Lapinsky, SE; Sedes, PR; Balan, C; Trogrlic, Z; Reuter, DA; Hutchings, SD; Starkopf, J.; Frantzeskaki, F; Diamantakis, A.; Pesenti, A.; Trásy, D.; Irigoyen, JL; Trojette, F; Muller, L.; Amirian, A; Zamyatin, M.; Lumley, G.; Campos, PC; Puppo-Moreno, A; Christopher, KB; Hajjar, LA; Brochard, L.; Berra, L.; Cressoni, M; Ayachi, J.; Rooyackers, O.; Taccone, FS; Stanworth, S. 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L.; Malmgren, J.; Sandiumenge, A; Arzapalo, MF; Schmidle, P; Rajam, G; Türkoğlu, M; Kaszaki, J.; Silversides, JA; Hoppmann, P; Silva, JS; Tenaglia, T; Cannesson, M; Nader, J.; Simioni, P.; Rossi, S.; Knox, C.; Guillamat-Prats, R; Schmid, RM; Marin-Corral, J.; Naldrett, I; Andreas, D.; Dashti, AS; Pereira, M. 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C.; Damås, JK; Onodera, Y; Redondo, E; Villeret, L.; Bernal, JB; Zöllner, C; Tomas, E; Sugiura, A; Shaikh, O.; Müller-Engelmann, J; González-Gay, M. A.; Grasselli, G; Ades, EW; Brohi, K; Moore, MJ; Oudemans-van Straaten, HM; Lingsma, H; Valencia, JD; Aydoğdu, M; Cecconi, M.; Lai, C; Hu, HC; De-Diós-Chacón, I.; Forfori, F; Sabetian, G; Lebák, G.; Zand, F.; Mauricio, MD; Bartkowska-Sniatkowska, A; Colombo, E; Vazin, A.; CAPCRI Study; Ramirez, CS; Schwedhelm, E; Marques, R; Cheng, X; Maroto-Monserrat, F; Yan, WW; Mahmoud, TM; Ozcan, A; Fernández-Porcel, A; Sahatjian, J.; Armaganidis, A.; Montrasio, E; Ben-Ghezala, H; Dhadwal, K.; Aguilera, P; Chao, CC; Settels, J; Helmy, M.; Pifferi, B; de Acilu, MG; Busch, T; Sigurta, A; Bousselmi, K; Norberg, Å.; Trepte, CJ; Abougabal, A; Torrini, F; Garcia, M; Hakim, KA; Aicha, NB; Mann, EE; Martínez, M; Shulman, R; Tesio, R; Garda, RF; Parker, R; Herrera-Gutierrez, M; Askim, Å; Rhodes, A; Trásy, D; Carreira, S.; Ismail, M; Sousa, P; Salido-Díaz, L; Doree, C.; Wiczling, P; Jakob, H; Sedes, PR; Meisner, S; Balik, M; Pollen, SJ; Maldonado, C.; Costa, CR; Toft, P; Dissayabutra, T; Bazin, JE; Romdhani, S; Ceccato, A.; Bermúdez, RM; Sutherasan, Y; Sandgren, A; Paterska, M; Canales, H. S.; Li, S. H.; Nuevo-Ortega, P; Öveges, N.; Souza, VA; Nakanishi, M; Guarasa, IM; Corbett, C; Hansen, JO; D'Antona, L; Karanjia, N; O'Dywer, M. J.; Amatu, A.; Latthaprecha, K.; Castro, S; Mukhtar, A; de Lucas, EH; Azoulay, E.; Torrents, E; Masclans, J. R.; Chiu, L. C.; Mazo, C; König, C; Khaled, M. M.; El Bahr, M; Stapel, SN; Lopes, N; Rose, L; Martínez, M. G.; Tuzzolino, F.; Fukuoka, T; Traille, M; Tanaka, H; Leivas, AF; Arzapalo, MF; Glossop, A; van der Jagt, M; Guanziroli, M; Koster-Brouwer, M.; Quesada-García, G.; Rooyackers, O.; László, I.; Morbeck, RA; Lloyd, J; Matsa, R; Liberatore, AM; Stroud, JS; Kostalas, M; Titeca, D; Tavazzi, G; Vera, IG; Chrysanthopoulou, E.; Martinez-Reyes, L; Li, H; Valles, SL; Yu, W; Rodriguez, A.; Eiam-Ong, S; Nsiala, J; Maia, P.; Neidecker, J.; Hynninen, M; Tang, Z; Wickerts, CJ; Duran, S.; Gönderen, K; Rehberg, S.; Nuevo-Ortega, P; Kiers, D; Jaitner, J; Kilembe, A; Navarrete, O; Chiumello, D; Cambiaghi, B.; Abdelfattah, ME; Aguilar-Alonso, E.; Taccone, P; Sakka, S; Dovbish, N; Blackwood, B; Vollmer, M.; Cabrera, JL; Parrini, V.; Lee, JW; Park, CM; Schoonderbeek, JF; Németh, M.; Martucci, G.; Heitschmidt, M; Zerman, A; Casey, WF; Lynch, M; Runciman, N; Kontogiorgi, M.; Hassen, BG; Rodriguez, RG; Komaromi, A.; Németh, M; RAPIT Group; Saleh, MH; Young, L; Szerkus, O; Wong, A; Kokot, Z; Galas, FR; Ogasawara, SM; Habchi, S; Fernandez, HS; Bansal, V; Price, G.; Svensen, C; Hjortrup, PB; Edul, V. S.; McWilliams, D; Charlton, M; Cremer, OL; Sackey, P; Santana-Santos, E; Bermejo-Martín, J. F.; Ahmad, N; Silva, ZC; Caus, T.; Kalafati, M; Chen, HL; Kuhn, S. O.; De Brito-Ashurst, I.; de Murillas, RG; Ince, C; Rageb, D.; Kontogiorgi, M; H1N1 SEMICYUC/GETGAG working group; Blanch, L; Neitzke, NM; Zahrte, C; Gattinoni, L; Wallace, S.; Filipe, E; Philippon-Jouve, B; Jiménez, FJ; Theerawit, P; Kobayashi, T; Escoval, A; Mclelland, L; de Waard, MC; Pinsky, MR; Tiranathanagul, K.; Vazir, A; Liberatore, AM; Rongen, G; Villagrán-Ramírez, F; Duran, S; Zepeda, EM; Devroey, M; Aicha, N. B.; Abril, RR; Jian, Z; Marsault, E; Gustafsson, T; Ralston, M; Bongiovanni, F; MacKay, A; Juárez, P; Cheng, CC; Fellahi, J. L.; Lesur, O; Liu, CP; Shivkumar, R. L.; Sims, MR; De Cassai, A; Gürsel, G; Van den Bulcke, B.; Laffey, J.; Colmenero-Ruiz, M; Vidal, M. V.; Mayaux, J.; Reuter, DA; Prudden, S.; Temmerman, W; Argandoña, R; Hayashi, K; Bonicolini, E; Cai, C; Chakarian, JC; Pietilä, M; Aliaga, S. M.; Pessoa, L; Christodoulopoulou, T; Hung, C. Y.; Enberg, L; Vilà, C.; Boyacı, N; Nikandish, R.; Pozzi, M; Liou, YJ; Prina, E.; Fernández-Porcel, A; Six, S.; Zakharchenko, M; Elsayed, MA; Delgado, CP; Hatib, F; Haase, N; Hung, CY; Solligård, E; Pauwels, J; Sharman, M; Riksen, NP; Kirakli, C.; Hakim, KA; Ferrara, G.; Gomes, M; Giolitti, C; Wallin, M; Nunes, SL; Brioni, M; Leite, MA; Sanchez, PC; Koch, A; Dan, WX; Brugger, S. C.; Bulgarelli, P; Campello, E.; Campillo, N.; Rooyackers, O; Wøien, H; de Keizer, NF; Masjedi, M; Pivkina, A.; Gaygısız, Ü; Lee, JY; Meyhoff, TS; Wodack, KH; Lingsma, H.; Goffi, A; Liberatore, A. M.; Algieri, I; Grönlund, J; Damås, JK; Tong, L; Silva, D; Araujo, JA; Diamantakis, A; Shakotko, A; Duarte, PA; Viegas, E.; Galfo, F; Catorze, N; Arboleda-Sánchez, J. A.; Huber, W; Reyners, A. K.; Lucino, NM; Cortina-Gutiérrez, A.; Roozeman, J. P.; Giménez, NC; Lam, KN; Moktar, AM; Böhm, SH; Janssen, N.; Darang, N.; Ahn, JY; Starkopf, L.; Augustin, P; Champigneulle, B; Wu, Q; Kontar, L; Martínez, Á. F.; Romero, OM; Pozo, M. O.; MacKay, A; Rodi, G; Fossum, M; Ferreira, DM; Mazzeo, AT; Lai, CH; Richardson, A; Grainger, E.; Montero, RM; Roberts, S; Su, F; Akimoto, R; de Tymowski, C; Coats, TJ; Ten Kate, D.; Gabarrus, A.; Möller, M; Schultz, M.; Arık, G; Marçal, R.; Salido-Díaz, L; Rimmer, A; Riera, J; Günter, J; Wallace, S.; Khedher, A; Dunn, M.; Houard, M.; Barker, G; Kamikawa, M; Vansteelandt, S.; Pérez, EV; Malmgren, JA; Hinds, C. J.; Gattinoni, L; Tomas, E.; Kim, DH; Bouneb, R; Cheikh, AB; Dickenmann, M; Williamson, M; Longbottom, ER; Khalili, F; Schouten, L. R.; Panigada, M; Morasert, T; Fortes, C; Oudemans, HM; Richard, C; Harm, S; Kawamae, K; Verbrugge, S. J.; Carollo, T.; Tomlin, M; Scheer, C.; Kirkman, E; Marharaj, R; Velly, L; Meddeb, K.; Fornier, W.; Hamidova, L; Vergani, G; Preti, J; Tong, L; Sundin, Ø; Hong, G; Serrano, AL; Savvidou, S.; Coll, N. R.; Milliken, D.; Jimenez-Herrera, MF; Shalhoub, J; Auger-Messier, M; Bienert, A; Kaymak, C; Tant, E; Ergin, B.; Sheikh, O; Grässler, MF; Hou, P; Aya, H. D.; Tánczos, K.; Møller, K; Aldasoro, M; Ince, C.; Sörberg, M; Morgan, P; Scicluna, B.; Arunkumar, A. S.; Bos, LD; Dogan, E.; van der Heijden, W; Pennington, SH; Pearse, R. M.; Laddomada, T; Sánchez, VM; Hu, H. C.; Rossi, M; Marzorati, C; Vidaur, L.; Aya, HD; Mukhtar, A; Mulero, F. R.; Movsisyan, V; Paz, ES; El Sakka, A; Kertmegi, I; Chouchene, I; Paary, TT; González, LR; Leon, P; Simonis, F. D.; Tang, Z; Bernardo, JM; Anido, U; Sustic, A; Theodorakopoulou, M; Omengo, P; Duška, F.; Merghani, M; Kennedy, C. E.; Moreno, JL; Fehmi, AM; Jockers, F; Valeiras-Valero, A; Marchio, P; Gomez-Gonzalez, C; Lin, KC; Hernandez, G; Soliman, R. A.; Nedved, P; Brugger, S. C.; Kombak, E; Ukere, A; Ferretti-Rebustini, RE; Ince, Y; Nashan, B; Betbese-Roig, A; Suh, G.; Pisani, L.; Lin, SC; Cecconi, M; Gripenberg, L. G.; Gao, F.; Yoon, SY; Carroll, G; Sánchez, JS; Tardif, N; Dondorp, A. M.; Rauseo, M; Chung, CR; Maia, P.; Reay, M.; Maghsudi, B; Tang, S; Gemmell, L; Kerr, C; Alamanos, I; Dongelmans, DA; Hafes, R.; Taggu, A.; Gagliardone, MP; Rossi, S.; Barsam, E.; Guarracino, F; Petosic, A; Mirabella, L; Winkelmann, T; Suarez-Sipmann, F; Kaliszan, R; Giangregorio, A.; Price, J.; Antonio, AC; Arthur, A; Guzman, CI; Buddi, S; García, RC; Granger, C. L.; Ho, CK; Jee, YK; Souza, R. B.; Longares, MD; Chen, L.; Olafsen, K; Lopez, CM; Muñoz-Bermúdez, R.; Colella, V; Luque, S.; van Eijk, LT; Simón, JM; Ruiz, ER; Boer, C; Yébenes, J. C.; Cauley, RP; Lujan, CV; Chong, CT; Denehy, L.; Leite, MA; Yeh, YC; Hallbäck, M; Doesburg, F; Williams, J; Bein, B; Delgado, MR; Abd El Halim, MA; Topeli, A; Almirall, J.; Rosada-Kurasinska, J; Isgro, G; Meert, A. P.; Schettler, A; Ballin, A.; Kim, J; Azoulay, E.; Piñol-Tena, A; Marutyan, Z; Gonzalez-Juanatey, JR; Guanziroli, M; Fleischmann, C; Kox, M; Thürk, F; Vallero, ME; Xiang, ZY; Bermudez, WF; Ponssen, H. H.; García-Alcántara, A; Swinnen, W; Mackay, A; Åsvold, BO; Pannier, E; Bihry, N; Huber, W.; Suberbiola, B.; El Messaoudi, S; Ribeiro, H; Talan, L.; Adhikari, NK; Terragni, PP; Filipe, F; Zarantonello, F.; Thompson, JP; Massant, C; Tsvetanova-Spasova, T; Warzybok, J; Siluk, D; Boussarsar, M; Cinnella, G; Smuszkiewicz, P; Ferrazza, V.; Rusinova, K.; Elsaid Hafez, MH; Lenoire, A; Mauri, T; Sautou, V; Airaksinen, J; Payá, J. M.; Keating, S.; Altıntas, N. D.; Cho, J; Filippou, L; Palmeiro, Y; Climent, C.; Bult, W; Reboul, M; Buche, D; Marc, J; Sinclair, A; Coquerel, D; Adams, P; Vallejo-Báez, A; Theodorakopoulou, M.; Gurarda, H; Björne, H; Dunatov, S; Ana, B; Bestle, M. H.; Beuret, P; de Gopegui Miguelena, PR; Gonzalo, G; Tuinman, PR; Sabetian, G; ARIAM-SEMICYUC Registry Investigators; García-Garmendia, JL; Volbeda, M.; Varenne, O; Lahmer, T; Schwarzkopf, D; Parry, S. M.; Park, MR; Ponssen, HH; Torkomian, G; Cressoni, M.; Eichhorn, V; Gattinoni, L.; Mira, JP; Masclans, JR; Martin, MC; Tøien, K; Cilloniz, C.; United States Critical Illness and Injury Trials Group/LIPS-B investigators; Talmor, D.; Papiol, E.; Perner, A; Colombo, A; Silva-Medina, R; Suh, G. J.; Llaurado-Serra, M; Van der Hoeven, S. M.; Dumont, L; Socolovsky, CS; Lin, YS; Cho, J.; Chouchène, I.; Lee, C; Puthucheary, Z. A.; Moro, G; Sim, K; Akimoto, R; Fayed, AM; Los, F; Kittiskulnam, P; Tuksavul, F.; El Ayashi, M; Bouafia, N; Shrestha, S; Dono, L.; Maitre, B.; Citton, G.; Richard, JC; P-INFECT; Ebm, C; D'Amico, M; Thomas, M; Bento, H; Terenzoni, M; Giannakou, M.; Groves, C.; Zand, F; Boots, R; Pieri-Davies, S.; Wirotwan, T. O.; Kattan, E; Behem, CR; Kaniusas, E; Gonzalez-Carrillo, PL; Kuzovlev, A.; De Gaudio, AR; Nseir, S.; Colón-Pallarés, C; Praditpornsilpa, K; Festic, E.; Rodriguez, MD; Iaquaniello, C; Escoresca-Ortega, A.; Morawiec, E.; Sadoune, M; Laitio, T; Mondino, M; Bovento, B.; Uysupova, I; Riche, M.; Sunde, K; Frank, R; Laitio, R; Stacke, A; Kim, K.; Buscetti, M. G.; Pereira, A; Lipman, J.; Sharpe, G.; Franco, M; Tonks, L; Mulero, M. D.; Hoekstra, M.; Costa, A; García, IP; Boyko, Y; Sykes, MC; Norberg, Å.; Kang, Y; Park, YB Abstract: Vascular occlusion tests (VOT) have been utilized alongside near infrared spectroscopy as a means of dynamically investigating microcirculatory function (1), with correlation demonstrated between derangement in muscle tissue oxygenation and mortality (2). Human skin has an exquisite microcirculatory blood supply which can be visualized by means of infrared thermography. Thermography may therefore be a potentially useful non-contact, real-time monitor of microcirculatory function. 2017-01-17T12:00:47Z Targeted Sequencing of Lung Function Loci in Chronic Obstructive Pulmonary Disease Cases and Controls http://hdl.handle.net/2381/39175 Title: Targeted Sequencing of Lung Function Loci in Chronic Obstructive Pulmonary Disease Cases and Controls Authors: Soler Artigas, María; Wain, Louise V.; Shrine, Nick; McKeever, T. M.; UK BiLEVE; Sayers, I.; Hall, I. P.; Tobin, Martin D. Abstract: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; smoking is the main risk factor for COPD, but genetic factors are also relevant contributors. Genome-wide association studies (GWAS) of the lung function measures used in the diagnosis of COPD have identified a number of loci, however association signals are often broad and collectively these loci only explain a small proportion of the heritability. In order to examine the association with COPD risk of genetic variants down to low allele frequencies, to aid fine-mapping of association signals and to explain more of the missing heritability, we undertook a targeted sequencing study in 300 COPD cases and 300 smoking controls for 26 loci previously reported to be associated with lung function. We used a pooled sequencing approach, with 12 pools of 25 individuals each, enabling high depth (30x) coverage per sample to be achieved. This pooled design maximised sample size and therefore power, but led to challenges during variant-calling since sequencing error rates and minor allele frequencies for rare variants can be very similar. For this reason we employed a rigorous quality control pipeline for variant detection which included the use of 3 independent calling algorithms. In order to avoid false positive associations we also developed tests to detect variants with potential batch effects and removed them before undertaking association testing. We tested for the effects of single variants and the combined effect of rare variants within a locus. We followed up the top signals with data available (only 67% of collapsing methods signals) in 4,249 COPD cases and 11,916 smoking controls from UK Biobank. We provide suggestive evidence for the combined effect of rare variants on COPD risk in TNXB and in sliding windows within MECOM and upstream of HHIP. These findings can lead to an improved understanding of the molecular pathways involved in the development of COPD. 2017-01-17T11:51:10Z Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension. http://hdl.handle.net/2381/39173 Title: Increased NBCn1 expression, Na+/HCO3- co-transport and intracellular pH in human vascular smooth muscle cells with a risk allele for hypertension. Authors: Liang Ng, F.; Boedtkjer, E.; Witkowska, K.; Ren, M.; Zhang, R.; Tucker, A.; Aalkjær, C.; Caulfield, M. J.; Ye, Shu Abstract: Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na(+)/HCO3 co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na(+)/H(+) exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pH i regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure. 2017-01-17T11:40:04Z Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice. http://hdl.handle.net/2381/39172 Title: Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice. Authors: Minnema, D. J.; Travis, K. Z.; Breckenridge, C. B.; Sturgess, N. C.; Butt, M.; Wolf, J. C.; Zadory, D.; Beck, M. J.; Mathews, J. M.; Tisdel, M. O.; Cook, A. R.; Botham, P. A.; Smith, Lewis L. Abstract: Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators 'blinded' to the origin of the tissue. Neither dose of PQ·Cl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH(+)) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH(+) neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQ·Cl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc. 2017-01-16T17:22:57Z Opportunity for cardiovascular risk factor reduction in AAA surveillance programs: a systematic review and meta-analysis of cardiovascular mortality in patients with small AAA http://hdl.handle.net/2381/39170 Title: Opportunity for cardiovascular risk factor reduction in AAA surveillance programs: a systematic review and meta-analysis of cardiovascular mortality in patients with small AAA Authors: Bath, M.; Gokani, V.; Sidloff, D.; Jones, L.; Choke, E.; Sayers, R.; Bown, M. J. Abstract: Aim: Screening for abdominal aortic aneurysm (AAA) has dramatically reduced the rate of AAA-rupture, yet cardiovascular mortality remains a major cause of death in this patient group. A diagnosis of AAA is a powerful marker of cardiovascular risk, yet only 12.4% of patients use statins. The aim of this study was to assess the cardiovascular risk in patients with small AAA. Methods: Standard PRISMA guidelines were followed. A meta-regression analysis was performed for cardiovascular mortality in small AAA patients and a qualitative synthesis of the prevalence of concurrent cardiovascular diseases. Results: A total 2323 patients with small AAA were identified (median follow-up 5 years). A total of 335 cardiovascular deaths occurred, 37 of which from AAA-rupture, showing a cardiovascular mortality risk of 3.00% per year in small AAA patients (R2 = 0.902, p < 0.001). The prevalence of ischaemic heart disease (44.9%), myocardial infarction (26.8%), heart failure (4.4%) and cerebrovascular disease (14.0%) were high in this patient group. Discussion: There is high cardiovascular risk in patients with small AAA, yet many may not be taking advantage of optimal cardiovascular risk factor modification. The diagnosis of a small AAA should be seen as a red-flag sign, triggering lifestyle change and pharmaco-vigilance against cardiovascular risk factors. 2017-01-16T17:07:43Z Oncogene driver mutations and copy number variation as markers for predicting drug resistance and disease outcome in NSCLC http://hdl.handle.net/2381/39168 Title: Oncogene driver mutations and copy number variation as markers for predicting drug resistance and disease outcome in NSCLC Authors: Jaber, Almahdi Abstract: Introduction: Worldwide, lung cancer is the leading cause of death. Non-small cell lung cancer (NSCLC) patients with KRAS mutations have a poor prognosis and show drug resistance, with MCL-1 implicated in this mechanism via evasion of apoptosis. This study is aimed at evaluating the relationship between key oncogene driver mutations, MCL-1 regulation and MCL-1-induced drug resistance. Methods: We analysed 39 adenocarcinomas (ADCs), 38 squamous cell carcinomas (SCCs), two large cell lung carcinomas (LCCs) and cell lines. A PNA-LNA-based TaqMan qPCR approach was performed for eight KRAS, one BRAF, three PIK3CA and one EGFR mutations. MCL-1, PIK3CA and SOX2 were analysed for copy number variation (CNV). Immunohistochemistry (IHC) and in situ hybridization (ISH) was performed for protein and mRNA, respectively. Alamar blue assay was used to evaluate drug responses. Results: KRAS mutations were detected in 36% of ADCs and 0% of SCCs, whereas PIK3CA mutation was most common in SCC (15.7%) and found in 5% of ADCs. MCL-1, PIK3CA and SOX2 amplification were detected in 13%, 74% and 86.6% of SCCs respectively, and were detected in 2.5%, 25.9% and 13.3% of ADCs respectively. MCL-1-amplified tumours demonstrated high expression of MCL-1 mRNA compared to non-amplified (p < 0.05). Cases with high phospho-ERK and phospho-AKT also showed high expression of MCL-1 mRNA. No growth inhibition was detected in cell lines treated with 5 μM of SH-4-54 inhibitor; however, 10 μM caused 99.9% growth inhibition. Ex vivo experiments mimicking the in vivo tumour environment demonstrated that NSCLCs are sensitive to cisplatin, one of which was MCL-1amplified. Conclusion: We have shown that KRAS mutation is common in ADC, whereas PIK3CA is more common in SCC. Importantly, we have highlighted that CNV of MCL-1 may be an important driver in resistance to chemotherapy. The JAK/STAT pathway was the key regulator for MCL-1 transcription. Resistance to cisplatin was observed in the KRAS mutant cell, MCL-1-amplified cell, cells harbouring MCL-1 gain and Chr1 polysomy but not the SOX2-amplified cell. 2017-01-16T16:55:56Z Drugs affecting the autonomic nervous system http://hdl.handle.net/2381/39154 Title: Drugs affecting the autonomic nervous system Authors: Charlton, Matthew; Thompson, Jonathan P. Abstract: The autonomic nervous system (ANS) is a complex system of nervous and humoral mechanisms that modulates the function of the autonomous or visceral organs. Autonomic control of organs aims to maintain homoeostasis in health. Many drugs used in clinical practice can have either primary or secondary effects on the function of autonomic nervous system. 2017-01-16T15:11:39Z Current challenges in vascular anaesthesia. http://hdl.handle.net/2381/39153 Title: Current challenges in vascular anaesthesia. Authors: Howell, S. J.; Thompson, J. P.; Irwin, M. G. Abstract: First paragraph: The British Journal of Anaesthesia is delighted to offer this special issue on Current Challenges in Vascular Anaesthesia. Vascular diseases are responsible for 17.3 million deaths per year worldwide; that is, 31% of global mortality. Cardiovascular disease remains a huge burden worldwide. Even as the rates of cardiovascular mortality have decreased in more economically developed countries, they have continued to increase elsewhere. Description: 12 months embargo 2017-01-16T15:07:45Z The Effects of Air Pollution on Respiratory Bacteria http://hdl.handle.net/2381/39149 Title: The Effects of Air Pollution on Respiratory Bacteria Authors: Hussey, Shane J. K. Abstract: Particulate Matter (PM), a major component of air pollution, is associated with a variety of cardiorespiratory diseases including acute lower respiratory tract infections. It is well established that PM has detrimental effects on the host, causing tissue damage, oxidative stress, and modulating the immune system. However there has been extremely limited research into the effects of PM on bacteria, the organisms responsible for the respiratory infections associated with PM exposure. This project investigated whether Black Carbon (BC), a major component of PM produced as a by-product of fossil fuel combustion, directly affects respiratory tract bacteria. Two model opportunistic pathogens of the respiratory tract were chosen for this investigation, Streptococcus pneumoniae and Staphylococcus aureus. BC was found to alter biofilm formation, structure, matrix composition, and functioning, of both S. pneumoniae and S. aureus, as well as inhibiting planktonic growth. Interestingly, these effects were strain-dependent. Furthermore, BC promoted dissemination of S. pneumoniae from the nasopharynx to the lower respiratory tract in an in vivo murine colonisation model. BC was not observed to alter the respiratory tract microbiota in this project, however a variety of limitations which may have prevented a definitive conclusion being reached are presented. This study provides the first evidence to show that bacteria are directly affected by PM, and thereby suggests that the adverse health effects of PM may not only be due to effects on host tissues, but that modulation of bacterial behaviour may also have a role. The findings of this study therefore show the potential importance of this overlooked field. 2017-01-16T11:37:12Z Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets http://hdl.handle.net/2381/39142 Title: Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets Authors: Wain, Louise V.; Shrine, Nick; Soler Artigas, María; Erzurumluoglu, A. Mesut; Noyvert, Boris; Bossini-Castillo, L.; Obeidat, M.; Henry, A. P.; Portelli, M. A .; Hall, R. J.; Billington, C. K.; Deary, I. J.; Harris, S. E.; Marten, J.; Rudan, I.; Enroth, S.; Gyllensten, U.; Kerr, S. M.; Polasek, O.; Kähönen, M.; Surakka, I.; Vitart, V.; Hayward, C.; Lehtimäki, T.; Raitakari, O.; Evans, D. M.; Henderson, A. J.; Pennell, C. E.; Wang, C. A.; Sly, P. D.; Wan, E. S.; Busch, R.; Hobbs, B. D.; Litonjua, A. A.; Sparrow, D. W.; Gulsvik, A.; Bakke, P. S.; Crapo, J. D.; Beaty, T. H.; Hansel, N. N.; Mathias, R. A.; Ruczinski, I.; Barnes, K. C.; Bossé, Y.; Joubert, P.; van den Berge, M.; Brandsma, C-A.; Paré, P. D.; Sin, D. D.; Nickle, D. C.; Hao, K.; Gottesman, O.; Dewey, F. E.; Bruse, S. E.; Carey, D. J.; Kirchner, H. L.; Geisinger-Regeneron DiscovEHR Collaboration; Jonsson, S.; Thorleifsson, G.; Jonsdottir, I.; Gislason, T.; Stefansson, K.; Schurmann, C.; Nadkarni, G.; Bottinger, E. P.; Loos, R. J. F.; Walters, R. G.; Chen, Z.; Millwood, I. Y.; Vaucher, J.; Kurmi, O. P.; Li, L.; Hansell, A. L.; Brightling, Chris; Zeggini, E.; Cho, M. H.; Silverman, E. K.; Sayers, I.; Trynka, G.; Morris, A. P.; Strachan, D. P.; Hall, I. P.; Tobin, Martin D.; Rimington, T. L.; Fenech, A. G.; John, Catherine; Blake, Tineka; Jackson, Victoria E.; Allen, Richard J.; Prins, B. P.; Understanding Society Scientific Group; Campbell, A.; Porteous, D. J.; Jarvelin, M-R.; Wielscher, M.; James, A. L.; Hui, J.; Wareham, N. J; Zhao, J. H.; Wilson, J. F.; Joshi, P. K.; Stubbe, B.; Rawal, R.; Schulz, H.; Imboden, M.; Probst-Hensch, N. M.; Karrasch, S.; Gieger, C. Abstract: Chronic Obstructive Pulmonary Disease (COPD) is characterised by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratios per standard deviation of the risk score (~6 alleles) (95% confidence interval) 1.24 (1.20-1.27), P=5.05x10^-49) and we observed a 3.7 fold difference in COPD risk between highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in development, elastic fibres and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications. Description: The stage 1 (UK BiLEVE) genome-wide association results for FEV1, FVC and FEV1/FVC are available from UK Biobank at http://www.ukbiobank.ac.uk/. The sources of all other data utilised in this study can be found in the Online Methods and Supplementary Note. 6 Months embargo from publication. 2017-01-16T10:03:37Z Circulating nucleic acids as biomarkers of breast cancer http://hdl.handle.net/2381/39137 Title: Circulating nucleic acids as biomarkers of breast cancer Authors: Rghebi, Basma Abstract: Background: Breast cancer is the commonest cancer and the second cause of cancer death among women. Two circulating biomarkers microRNAs (miRNAs) and circulating cell-free tumour DNA (cf-DNA) are currently under active investigation as a liquid biopsy for their utility in screening and management of breast cancer. Aims: The aim was to profile circulating miRNAs in plasma of breast cancer and compare to healthy controls to determine whether there were any miRNAs that differentially expressed in cancer. A second aim was to compare different methods to detect PIK3CA and TP53 mutations in breast cancer tissues DNA and cf-DNA. Methods: The expression level of 384 miRNAs in pooled plasma of breast cancer was compared to healthy controls using TaqMan microRNA array, followed by validation of specific miRNAs in single cancer and control plasma, using qPCR. Multiple different methods (qPCR, HRMC, ddPCR and Sanger sequencing) were compared for detection of PIK3CA or TP53 mutations in breast cancer tissue and matched plasma (cf-DNA). Results: 49 miRNAs (12.8%) showed significant expression change between pooled breast cancer plasma and controls. 11 of these were upregulated (P<0.05) in individual cancer plasma but there was wide variation in expression in controls. Overall, the ddPCR technology had higher sensitivity in detecting PIK3CA (0.1%) or TP53 (0.01%) mutations in cell line and breast cancer tissue than that achieved with other methods and overall 18 of 26 samples had a mutation in one or other gene. Conclusions: There was expression difference of a number of miRNAs in plasma of breast cancer compared to healthy controls, which needs further validation in other cohorts. The ddPCR was able to detect PIK3CA or TP53 mutations in breast cancer tissues with higher sensitivity than the other methods tested. 2017-01-13T15:23:47Z An assessment of learning in dogs in relation to cues conveyed by humans http://hdl.handle.net/2381/39135 Title: An assessment of learning in dogs in relation to cues conveyed by humans Authors: Ashton, Rebecca Louise Abstract: In some instances, dogs show proficient skill in search tasks involving object permanence and gestures from humans, yet it is unclear the extent to which they rely on associative learning to solve these tasks. To address this issue, the Mediational Learning Paradigm (Rumbaugh, 1984) was modified to include 1) object cues 2) human communicative cues and 3) non-social physical cues. In the initial discrimination, two containers were presented at locations A and B with reward contingency A+B-. Once a specified performance criterion was met, the rewarded location was switched and three conditions were presented: the original locations (A-B+), and each location paired with a novel location (A-C+, B+D-). Associative learning predicted low performance in A-B+ due to pre-existing tendency to search A and avoid B, where novel location conditions involve only one of these. Alternatively, associative strategy would predict equal performance in all conditions, as search is informed by object cues or human gestures. In the absence of any cues, dogs relied on associative learning, and the same was true when object cues were presented at the point of reversal. Communicative gestures from humans led dogs to shift away from associative processes, supporting the notion dogs have a comprehension in socio-communication with humans. However, after cue duration was matched with an object cue, dogs were also able to override associative learning without a socio-communicative cue. Additionally, non-social physical cues in the reversal phase were sufficient for dogs to override the effects of associative learning, but dogs were not able to discriminate based on these cues alone. These results suggest that when food location changes, dogs are prone to search the same location even when there are cues indicating the correct location. Dogs comprehend human pointing cues, but require explicit cues to break away from associative learning as a search strategy. Social cues maximise the chances of searching correctly, but they can also benefit from explicit non-social cues. 2017-01-13T15:11:47Z STRIDER: Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction--a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. http://hdl.handle.net/2381/39133 Title: STRIDER: Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction--a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Authors: Ganzevoort, W.; Alfirevic, Z.; von Dadelszen, P.; Kenny, L.; Papageorghiou, A.; van Wassenaer-Leemhuis, A.; Gluud, C.; Mol, B. W.; Baker, Philip N. Abstract: BACKGROUND: In pregnancies complicated by early-onset extreme fetal growth restriction, there is a high risk of preterm birth and an overall dismal fetal prognosis. Sildenafil has been suggested to improve this prognosis. The first aim of this review is to assess whether sildenafil benefits or harms these babies. The second aim is to analyse if these effects are modified in a clinically meaningful way by factors related to the women or the trial protocol. METHODS/DESIGN: The STRIDER (Sildenafil Therapy In Dismal prognosis Early-onset intrauterine growth Restriction) Individual Participant Data (IPD) Study Group will conduct a prospective IPD and aggregate data systematic review with meta-analysis and trial sequential analysis. The STRIDER IPD Study Group started trial planning and funding applications in 2012. Three trials will be launched in 2014, recruiting for three years. Further trials are planned to commence in 2015.The primary outcome for babies is being alive at term gestation without evidence of serious adverse neonatal outcome. The latter is defined as severe central nervous system injury (severe intraventricular haemorrhage (grade 3 and 4) or cystic periventricular leukomalacia, demonstrated by ultrasound and/or magnetic resonance imaging) or other severe morbidity (bronchopulmonary dysplasia, retinopathy of prematurity requiring treatment, or necrotising enterocolitis requiring surgery). The secondary outcomes are improved fetal growth velocity assessed by ultrasound abdominal circumference measurements, gestational age and birth weight (centile) at delivery, and age-adequate performance on the two-year Bayley scales of infant and toddler development-III (composite cognitive score and composite motor score). Subgroup and sensitivity analyses in the IPD meta-analysis include assessment of the influence of several patient characteristics: an abnormal or normal serum level of placental growth factor, absent/reversed umbilical arterial end diastolic flow at commencement of treatment, and other patient characteristics available at baseline such as gestational age and estimated fetal weight. The secondary outcomes for mothers include co-incidence and severity of the maternal syndrome of pre-eclampsia, mortality, and other serious adverse events. DISCUSSION: Trials are expected to start in 2013-2014 and end in 2016-2017. Data analyses of individual trials are expected to finish in 2019. Given the pre-planned and agreed IPD protocol, these results should be available in 2020. 2017-01-11T12:03:58Z α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. http://hdl.handle.net/2381/39132 Title: α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner. Authors: Yin, G.; Lopes da Fonseca, T.; Eisbach, S. E.; Anduaga, Ane Martín; Breda, Carlo; Orcellet, M. L.; Szegő, É. M.; Guerreiro, P.; Lázaro, D. F.; Braus, G. H.; Fernandez, C. O.; Griesinger, C.; Becker, S.; Goody, R. S.; Itzen, A.; Giorgini, Flaviano; Outeiro, T. F.; Zweckstetter, M. Abstract: Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction. Description: Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.nbd.2014.06.018. 2017-01-11T11:53:44Z RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility. http://hdl.handle.net/2381/39131 Title: RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility. Authors: Yu, Z. Y.; Tan, J. C.; McMahon, Aisling C.; Iismaa, S. E.; Xiao, X. H.; Kesteven, S. H.; Reichelt, M. E.; Mohl, M. C.; Smith, N. J.; Fatkin, D.; Allen, D.; Head, S. I.; Graham, R. M.; Feneley, M. P. Abstract: AIMS: To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility. BACKGROUND: We reported previously that transgenic mice with cardiac-restricted α1A-AR overexpression (α1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gαq/11-coupled receptor in hypertrophy. METHODS: Contractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from α1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after α1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. RESULTS: Hypercontractility without hypertrophy with α1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, α1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its Gαq/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the α1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective α1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without α1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. CONCLUSIONS: We report for the first time pleiotropic α1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart. 2017-01-11T10:25:07Z A multiplex microsatellite set for non-invasive genotyping and sexing of the osprey (Pandion haliaetus). http://hdl.handle.net/2381/39128 Title: A multiplex microsatellite set for non-invasive genotyping and sexing of the osprey (Pandion haliaetus). Authors: Dawson, D. A.; Kleven, O.; Dos Remedios, N.; Horsburgh, G. J.; Kroglund, R. T.; Santos, T.; Hewitt, Colin R. A. Abstract: During the 1950s and 1970s the osprey (Pandion haliaetus) experienced a dramatic population crash and remains of conservation concern in several parts of the world. We isolated 37 microsatellite loci and assessed these in ospreys sampled in the UK and Norway (using mouth swabs/feathers). From 26 loci variable in four ospreys, we selected 13, combined these into two multiplex-PCR sets and included a sex-typing marker. Additional markers confirmed sexes. In 17 ospreys, feather-sampled in central Norway, we found 3-10 alleles per locus. The 13 loci are autosomal (heterozygotes were present in both sexes) and observed heterozygosities ranged from 0.24 to 0.94. The combined probability of identity for the 13 loci was 8.0 × 10(-12). These microsatellite loci will be useful for genetic monitoring, parentage analysis and population genetic studies of the osprey. Description: The online version of this article (doi:10.1007/s12686-015-0497-4) contains supplementary material, which is available to authorized users. 2017-01-10T16:26:18Z A decision analytic model to investigate the cost-effectiveness of poisoning prevention practices in households with young children. http://hdl.handle.net/2381/39123 Title: A decision analytic model to investigate the cost-effectiveness of poisoning prevention practices in households with young children. Authors: Achana, F.; Sutton, Alex J.; Kendrick, D; Hayes, M; Jones, David R.; Hubbard, Stephanie J.; Cooper, Nicola J. Abstract: BACKGROUND: Systematic reviews and a network meta-analysis show home safety education with or without the provision of safety equipment is effective in promoting poison prevention behaviours in households with children. This paper compares the cost-effectiveness of home safety interventions to promote poison prevention practices. METHODS: A probabilistic decision-analytic model simulates healthcare costs and benefits for a hypothetical cohort of under 5 year olds. The model compares the cost-effectiveness of home safety education, home safety inspections, provision of free or low cost safety equipment and fitting of equipment. Analyses are conducted from a UK National Health Service and Personal Social Services perspective and expressed in 2012 prices. RESULTS: Education without safety inspection, provision or fitting of equipment was the most cost-effective strategy for promoting safe storage of medicines with an incremental cost-effectiveness ratio of £2888 (95 % credible interval (CrI) £1990-£5774) per poison case avoided or £41,330 (95%CrI £20,007-£91,534) per QALY gained compared with usual care. Compared to usual care, home safety interventions were not cost-effective in promoting safe storage of other household products. CONCLUSION: Education offers better value for money than more intensive but expensive strategies for preventing medicinal poisonings, but is only likely to be cost-effective at £30,000 per QALY gained for families in disadvantaged areas and for those with more than one child. There was considerable uncertainty in cost-effectiveness estimates due to paucity of evidence on model parameters. Policy makers should consider both costs and effectiveness of competing interventions to ensure efficient use of resources. Description: Additional files available via journal of record website 2017-01-10T13:49:24Z The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours http://hdl.handle.net/2381/39121 Title: The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours Authors: Kamata, Tamihiro; Jin, Hong; Giblett, Susan; Patel, Bipin; Patel, Falguni; Foster, Charles; Pritchard, Catrin Abstract: The tumour microenvironment is known to play an integral role in facilitating cancer progression at advanced stages, but its function in some pre-cancerous lesions remains elusive. We have used the V600EBRAF-driven mouse lung model that develop premalignant lesions to understand stroma–tumour interactions during pre-cancerous development. In this model, we have found that immature macrophage-lineage cells (IMCs) producing PDGFA, TGFβ and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 (CCR1)-dependent mechanisms. Stromal IMCs promote proliferation and transcriptional alterations suggestive of epithelial–mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for the maintenance of early-stage lung tumours in vivo. Furthermore, we have found that IMC recruitment to the microenvironment is restrained by the cholesterol-binding protein, Niemann-Pick type C2 (NPC2). Studies on isolated cells ex vivo confirm that NPC2 is secreted from tumour cells and is taken up by IMCs wherein it suppresses secretion of the CCR1 ligand CC chemokine 6 (CCL6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for the development of chemopreventive strategies in lung cancer. Description: Supplementary information for this article is available online: http://embomolmed.embopress.org 2017-01-10T13:30:24Z Psychology of game playing: Introduction to a special issue http://hdl.handle.net/2381/39120 Title: Psychology of game playing: Introduction to a special issue Authors: Colman, Andrew M.; Pulford, Briony D. Abstract: Game theory has focused attention on different problems at different times in its history. Currently, attention is devoted to investigating how human decision makers with bounded rationality choose strategies in interactive decisions. Behavioral economics, and more generally experimental games, have appeared in the literature with accelerating frequency since 1990, and this cannot continue indefinitely without a proportional expansion of journal space. This Special Issue includes contributions to behavioral economics, experimental games, and evolutionary game theory, using theoretical, experimental, and agent-based modeling techniques. 2017-01-10T13:23:40Z The challenges of amblyopia treatment. http://hdl.handle.net/2381/39117 Title: The challenges of amblyopia treatment. Authors: Maconachie, Gail D. E.; Gottlob, Irene Abstract: The treatment of amblyopia, particularly anisometropic (difference in refractive correction) and/or strabismic (turn of one eye) amblyopia has long been a challenge for many clinicians. Achieving optimum outcomes, where the amblyopic eye reaches a visual acuity similar to the fellow eye, is often impossible in many patients. Part of this challenge has resulted from a previous lack of scientific evidence for amblyopia treatment that was highlight by a systematic review by Snowdon et al. in 1998. Since this review, a number of publications have revealed new findings in the treatment of amblyopia. This includes the finding that less intensive occlusion treatments can be successful in treating amblyopia. A relationship between adherence to treatment and visual acuity has also been established and has been shown to be influenced by the use of intervention material. In addition, there is growing evidence of that a period of glasses wearing only can significantly improve visual acuity alone without any other modes of treatment. This review article reports findings since the Snowdon's report. 2017-01-10T11:54:55Z Serum C-reactive protein and C-reactive gene (-717C>T) polymorphism are not associated with periodontitis in Indonesian male patients http://hdl.handle.net/2381/39116 Title: Serum C-reactive protein and C-reactive gene (-717C>T) polymorphism are not associated with periodontitis in Indonesian male patients Authors: Suhartono, A. W.; Sulijaya, B.; Djamal, N. Z.; Masulili, S. L. C.; Talbot, Christopher; Auerkari, E. I. Abstract: Background: Periodontitis is an inflammatory disease caused by periodontal pathogens and influenced by multiple risk factors such as genetics, smoking habit, age and systemic diseases. The inflammatory cascade is characterized by the release of C-reactive protein (CRP). Periodontitis has been reported to have plausible links to increased level of CRP, which in turn has been associated to elevated risk of cardiovascular disease (CVD). Purpose: The purpose of this study was t o investigate the relationship amongst the severity of periodontitis, CRP level in blood and CRP (-717 C>T) gene polymorphism in male Indonesian smokers and non-smokers. Method: The severity of periodontitis was assessed for 97 consenting male Indonesian smokers and non-smokers. The CRP level of the subjects was determined by using immuno-turbidimetric assay performed in PARAHITA Diagnostic Center Laboratory ISO 9001: 2000 Cert No. 15225/2. The rate of CRP (-717C>T) gene polymorphism was determined by using PCR-RFLP in Oral Biology Laboratory, Faculty of Dentistry, Universitas Indonesia. Result: The results suggest that the CRP protein level is not significantly associated with the tested CRP gene polymorphism (p>0.05). Also, while the severity of periodontitis increased significantly with subject age, the CRP level in blood serum was not significantly related to the severity of periodontitis. The genotypes of the tested polymorphism did not show significant association with the severity of periodontitis either in smokers or in the combined population including smokers and non-smokers. The results naturally do not exclude such associations, but suggest that to discern the differences the sample size must be considerably increased. Conclusion: The CRP (-717C>T) gene polymorphism and CRP level in blood serum were not found to be associated with the severity of periodontitis in male smokers or in the combined population of smokers and non-smokers. 2017-01-10T11:42:01Z An algorithm to improve diagnostic accuracy in diabetes in computerised problem orientated medical records (POMR) compared with an established algorithm developed in episode orientated records (EOMR). http://hdl.handle.net/2381/39108 Title: An algorithm to improve diagnostic accuracy in diabetes in computerised problem orientated medical records (POMR) compared with an established algorithm developed in episode orientated records (EOMR). Authors: de Lusignan, S.; Liaw, S. T.; Dedman, D.; Khunti, Kamlesh; Sadek, K.; Jones, S. Abstract: BACKGROUND: An algorithm that detects errors in diagnosis, classification or coding of diabetes in primary care computerised medial record (CMR) systems is currently available. However, this was developed on CMR systems that are episode orientated medical records (EOMR); and do not force the user to always code a problem or link data to an existing one. More strictly problem orientated medical record (POMR) systems mandate recording a problem and linking consultation data to them. OBJECTIVE: To compare the rates of detection of diagnostic accuracy using an algorithm developed in EOMR with a new POMR specific algorithm. METHOD: We used data from The Health Improvement Network (THIN) database (N = 2,466,364) to identify a population of 100,513 (4.08%) patients considered likely to have diabetes. We recalibrated algorithms designed to classify cases of diabetes to take account of that POMR enforced coding consistency in the computerised medical record systems [In Practice Systems (InPS) Vision] that contribute data to THIN. We explored the different proportions of people classified as having type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) and with diabetes unclassifiable as either T1DM or T2DM. We compared proportions using chi-square tests and used Tukey's test to compare the characteristics of the people in each group. RESULTS: The prevalence of T1DM using the original EOMR algorithm was 0.38% (9,264/2,466,364), and for T2DM 3.22% (79,417/2,466,364). The prevalence using the new POMR algorithm was 0.31% (7,750/2,466,364) T1DM and 3.65% (89,990/2,466,364) T2DM. The EOMR algorithms also left more people unclassified 11,439 (12%), as to their type of diabetes compared with 2,380 (2.4%), for the new algorithm. Those people who were only classified by the EOMR system differed in terms of older age, and apparently better glycaemic control, despite not being prescribed medication for their diabetes (p < 0.005). CONCLUSION: Increasing the degree of problem orientation of the medical record system can improve the accuracy of recording of diagnoses and, therefore, the accuracy of using routinely collected data from CMRs to determine the prevalence of diabetes mellitus; data processing strategies should reflect the degree of problem orientation. 2017-01-10T09:59:05Z Monitoring asthma in childhood: management-related issues. http://hdl.handle.net/2381/39107 Title: Monitoring asthma in childhood: management-related issues. Authors: Rottier, B. L.; Eber, E.; Hedlin, G.; Turner, S.; Wooler, E.; Mantzourani, E.; Kulkarni, Neeta; ERS Task Force Monitoring Asthma in Children Abstract: Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patient's illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro-oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention. Description: This is a supporting document of the ERS Task Force Monitoring Asthma in Children published in the European Respiratory Journal: Pijnenburg MW, Baraldi E, Brand PLP, et al. Monitoring asthma in children. Eur Respir J 2015; 45: 906–925. 2017-01-10T09:52:52Z Community Providers of the NHS Health Check CVD Prevention Programme Target Younger and More Deprived People http://hdl.handle.net/2381/39106 Title: Community Providers of the NHS Health Check CVD Prevention Programme Target Younger and More Deprived People Authors: Woringer, M.; Cecil, E.; Watt, H.; Chang, K.; Hamid, F.; Khunti, Kamlesh Abstract: In April 2009, the Department of Health in England implemented the NHS Health Check Programme. NHS Health Check is a national risk assessment and management programme for those aged 40 to 74 living in England, who do not have an existing vascular disease, and who are not currently being treated for certain risk factors. It is aimed at preventing heart disease, stroke, diabetes and kidney disease and raising awareness of dementia for those aged 65-74. Patients identified as having preclinical symptoms of disease are referred for formal diagnosis and enter established care pathways. The remainder of the population is managed within the programme, either with a brief lifestyle intervention or signposting to local services for more intensive intervention.(1) The programme aims to reduce health inequalities associated with cardiovascular disease (CVD).(2) The NHS Health Check programme is delivered through contracts with service providers such as general practices and community providers. Whereas general practices offer the vast majority of their Health Checks by appointments, community providers offer opportunistic checks.(3) Between 2008 and 2013, PCT public health commissioners commissioned community providers using Health Options® software and Point of Care Testing (POCT) to deliver the Health Check Programme in pharmacies, community settings and businesses. These providers were commissioned to conduct Health Checks with the aim of reducing health inequalities by targeting more deprived individuals and more ethnic minorities. In 2013, Public Health England reasserted their commitment to strengthening the programme in deprived communities and among ethnic minorities.(4) There has been no national study assessing the impact of delivering the Health Check programme with community providers. The current analysis examined the effectiveness of community providers in targeting ethnic minorities and deprived communities. The analysis is based on a comparison of patient level data collected by outreach providers to the general population data in 8 regions of England across 29 local authorities (LAs). Target population included 41,570 individuals who received a Health Check carried out by community providers from the January 30 2008 to October 31, 2013. Office for National Statistics Census (2011) data was used as a reference for comparative analyses at the local authority level. Department for Communities and Local Government, Indices of Deprivation 2010 was used as a reference for comparative analysis of deprivation. Delivering the NHS Health Check Programme with community providers using Health Options® software and Point of Care Testing (POCT) allowed for community services to be integrated more closely with primary care. Unlike the standard data gathering systems in general practices used to deliver the Health Checks (e.g. EMIS, INPS-Vision, TPP-SystmOne), Health Options® software was developed specifically for the purpose of carrying out the Health Check programme. It was designed to enable a range of healthcare professionals to use it while communicating personalised CVD risk information to the patient. Technological innovation resulted in patient centred care when risk lowering scenarios were presented to the patient. Same day testing using POCT allowed for CVD risk to be communicated to the patient on the same day and minimised the loss to follow up observed in general practices lacking POCT devices. Health Checks results obtained by community providers were communicated to general practices. The mean IMD 2010 score across 29 LAs was 5.98 higher at p<0.05 compared to general population data using two sample t-tests. Twenty two of the 29 LAs were significantly more deprived at p<0.05 compared to the general population. Across the 29 LAs, no statistically significant difference was obtained in the mean proportion of ethnic minorities. The mean proportion of men was 11.3% lower at p<0.001. The mean proportion of 40-49 and 50-59 year olds was 10.79% and 5.15% higher at p<0.0001 and p=0.0021 respectively. Community providers effectively targeted deprived areas and communities. A substantial proportion of younger patients were recruited when the programme was offered outside of the normal business hours. This overcame the difficulty in recruiting working age populations in general practices as these do not offer Health Checks on evenings and weekends. Although more women than men were served by community providers, more young men took part in the programme. Outreach providers recruited a representative proportion of ethnic minorities from the local authorities that they served. The results of this study suggest that using outreach providers is an effective approach to targeting younger people, more deprived areas and communities while recruiting a representative proportion of ethnic minorities across England. If the Health Check programme is effective in preventing the onset of CVD disease, community provision of the programme may reduce health inequalities therein. Description: PowerPoint presentation http://integratedcarefoundation.org/resource/icic15-presentations 2017-01-10T09:47:43Z Let's Prevent Diabetes: From idea to implementation http://hdl.handle.net/2381/39104 Title: Let's Prevent Diabetes: From idea to implementation Authors: Gray, Laura J.; Troughton, Jacqui; Khunti, Kamlesh; Davies, Melanie J. Abstract: The prevention of Type 2 Diabetes Mellitus (T2DM) is a global health care priority. We describe a programme of work, which developed a method for identifying those with Non Diabetic Hyperglycaemia (NDH) (a high risk group in which T2DM is preventable) in primary care and developed and tested a prevention programme suitable for delivery within the NHS. The subsequent implementation of this programme as part of the NHS Diabetes Prevention Programme, which was launched in 2016, is then described. Description: 12 months embargo from publication 2017-01-10T09:29:06Z Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study. http://hdl.handle.net/2381/39103 Title: Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study. Authors: Ng, Leong L.; Squire, Iain B.; Jones, Donald J. L.; Cao, Thong Huy; Chan, Daniel C. S.; Sandhu, Jatinderpal K.; Quinn, Paulene A.; Davies, Joan E.; Struck, J.; Hartmann, O.; Bergmann, A.; Mebazaa, A.; Gayat, E.; Arrigo, M.; Akiyama, E.; Sabti, Z.; Lohrmann, J.; Twerenbold, R.; Herrmann, T.; Schumacher, C.; Kozhuharov, N.; Mueller, C.; GREAT Network Abstract: BACKGROUND: Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis. OBJECTIVES: This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome. METHODS: This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation. RESULTS: During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively. CONCLUSIONS: PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up. 2017-01-09T16:58:10Z Novel phage recombination pathways and their applications http://hdl.handle.net/2381/39100 Title: Novel phage recombination pathways and their applications Authors: Reddy, Thimma Rajkumar Abstract: No Abstract available 2017-01-09T16:27:35Z Molecular Characterization of N-glycan Degradation and Transport in Streptococcus pneumoniae and Its Contribution to Virulence. http://hdl.handle.net/2381/39090 Title: Molecular Characterization of N-glycan Degradation and Transport in Streptococcus pneumoniae and Its Contribution to Virulence. Authors: Robb, M.; Hobbs, J. K.; Woodiga, S. A.; Shapiro-Ward, S.; Suits, M. D.; McGregor, N.; Brumer, H.; Yesilkaya, H.; King, S. J.; Boraston, A. B. Abstract: The carbohydrate-rich coating of human tissues and cells provide a first point of contact for colonizing and invading bacteria. Commensurate with N-glycosylation being an abundant form of protein glycosylation that has critical functional roles in the host, some host-adapted bacteria possess the machinery to process N-linked glycans. The human pathogen Streptococcus pneumoniae depolymerizes complex N-glycans with enzymes that sequentially trim a complex N-glycan down to the Man3GlcNAc2 core prior to the release of the glycan from the protein by endo-β-N-acetylglucosaminidase (EndoD), which cleaves between the two GlcNAc residues. Here we examine the capacity of S. pneumoniae to process high-mannose N-glycans and transport the products. Through biochemical and structural analyses we demonstrate that S. pneumoniae also possesses an α-(1,2)-mannosidase (SpGH92). This enzyme has the ability to trim the terminal α-(1,2)-linked mannose residues of high-mannose N-glycans to generate Man5GlcNAc2. Through this activity SpGH92 is able to produce a substrate for EndoD, which is not active on high-mannose glycans with α-(1,2)-linked mannose residues. Binding studies and X-ray crystallography show that NgtS, the solute binding protein of an ABC transporter (ABCNG), is able to bind Man5GlcNAc, a product of EndoD activity, with high affinity. Finally, we evaluated the contribution of EndoD and ABCNG to growth of S. pneumoniae on a model N-glycosylated glycoprotein, and the contribution of these enzymes and SpGH92 to virulence in a mouse model. We found that both EndoD and ABCNG contribute to growth of S. pneumoniae, but that only SpGH92 and EndoD contribute to virulence. Therefore, N-glycan processing, but not transport of the released glycan, is required for full virulence in S. pneumoniae. To conclude, we synthesize our findings into a model of N-glycan processing by S. pneumoniae in which both complex and high-mannose N-glycans are targeted, and in which the two arms of this degradation pathway converge at ABCNG. Description: Coordinates and structure factors have been deposited with the following accession codes into the Protein Data Bank: SpGH92 in complex with mannose (5SWI); native NgtS (5SUO); NgtS in complex with Man1GlcNAc (5SWA); NgtS in complex with Man5GlcNAc (5SWB). 2017-01-09T14:56:15Z Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen http://hdl.handle.net/2381/39087 Title: Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen Authors: Dhariwal, J.; Cameron, A.; Trujillo-Torralbo, M.; del Rosario, A.; Bakhsoliani, E.; Paulsen, M.; Jackson, D. J.; Edwards, M. R.; Rana, B. M. J.; Cousins, David J.; Hansel, T. T.; Johnston, S. L.; Walton, R. P. Abstract: Rationale: Newly characterised type 2 innate lymphoid cells display potent type 2 effector functionality, however their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterise the airway mucosa is invasive, poorly tolerated and does not allow for sequential sampling. Objectives: To assess the role of type 2 innate lymphoid cells during nasal allergen challenge in subjects with allergic rhinitis, using novel non-invasive methodology. Methods: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of type 2 innate lymphoid cells and granulocytes to the upper airways of atopic and healthy subjects following allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. Measurements and Main Results: Following allergen challenge, atopic subjects displayed rapid induction of upper airway symptoms, an enrichment of type 2 innate lymphoid cells, eosinophils and neutrophils, along with increased production of interleukin-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared to healthy subjects. The most pronounced type 2 innate lymphoid cell recruitment was observed in patients with elevated serum IgE and airway eosinophilia. Conclusions: The rapid recruitment of type 2 innate lymphoid cells to the upper airways of allergic rhinitis patients, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergen in the airways. The novel methodology described herein enables the analysis of rare cell populations from non-invasive, serial tissue sampling. Description: Can be made available via LRA on publication. 2017-01-09T13:09:23Z Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. http://hdl.handle.net/2381/39086 Title: Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson's disease. Authors: Lehmann, Susann; Loh, Samantha H. Y.; Martins, L. Miguel Abstract: Familial forms of Parkinson's disease (PD) caused by mutations in PINK1 are linked to mitochondrial impairment. Defective mitochondria are also found in Drosophila models of PD with pink1 mutations. The co-enzyme nicotinamide adenine dinucleotide (NAD(+)) is essential for both generating energy in mitochondria and nuclear DNA repair through NAD(+)-consuming poly(ADP-ribose) polymerases (PARPs). We found alterations in NAD(+) salvage metabolism in Drosophila pink1 mutants and showed that a diet supplemented with the NAD(+) precursor nicotinamide rescued mitochondrial defects and protected neurons from degeneration. Additionally, a mutation of Parp improved mitochondrial function and was neuroprotective in the pink1 mutants. We conclude that enhancing the availability of NAD(+) by either the use of a diet supplemented with NAD(+) precursors or the inhibition of NAD(+)-dependent enzymes, such as PARPs, which compete with mitochondria for NAD(+) is a viable approach to preventing neurotoxicity associated with mitochondrial defects. 2017-01-09T12:36:05Z Enhanced purinergic contractile responses and P2X1 receptor expression in detrusor muscle during cycles of hypoxia-glucopenia and reoxygenation. http://hdl.handle.net/2381/39083 Title: Enhanced purinergic contractile responses and P2X1 receptor expression in detrusor muscle during cycles of hypoxia-glucopenia and reoxygenation. Authors: Elliott, R. A.; Tonnu, A.; Ghaffar, N.; Taylor, A. H.; Tincello, D. G.; Norman, R. I. Abstract: Bladders from patients with detrusor overactivity have an increased atropine-resistant contractile response to nerve stimulation. The bladder has also been shown to be very susceptible to hypoxia-glucopenia and reperfusion injury, leading to the hypothesis that episodes of hypoxia-glucopenia and reoxygenation result in increased atropine-resistant responses to nerve stimulation in the detrusor muscle. Detrusor muscle strips were suspended in a Perspex organ bath chamber of volume 0.2 ml perfused with Krebs solution at 37°C aerated with 21% O2, 5% CO2 and the balance nitrogen. Hypoxia-glucopenia was induced by switching perfusion to Krebs solution without glucose, gassed with 95% nitrogen and 5% CO2. Atropine-resistant contractile responses increased by 40.5 ± 7.3% after four cycles of hypoxia-glucopenia (10 min) and reoxygenation (1 h), whereas α,β-methylene ATP-resistant responses did not increase. Expression of P2X1 receptors in the bladder was increased after hypoxia-glucopenia and reoxygenation cycling, and ATP release from stimulated bladder strips during cycling was also increased. Other P2X receptor-mediated mechanisms may also be involved in the augmentation of bladder contraction during hypoxia-glucopenia and reoxygenation cycling, because a non-specific P2X antagonist blocked most of the augmented response, whereas a P2X1-specific antagonist prevented only part of the augmentation of contractile response induced by hypoxia-glucopenia and reoxygenation. In conclusion, four cycles of hypoxia-glucopenia and reoxygenation increased the purinergic, but not the cholinergic, contractile responses to nerve stimulation. Increased P2X1 receptor expression and ATP release may have contributed to the augmentation of contractile response induced by hypoxia-glucopenia and reoxygenation. Purinergic antagonists may, therefore, be a useful therapeutic option for the treatment of overactive bladder with increased purinergic-mediated contractions. 2017-01-09T11:58:34Z Reflecting on what 'you said' as a way of reintroducing difficult topics in child mental health assessments http://hdl.handle.net/2381/39074 Title: Reflecting on what 'you said' as a way of reintroducing difficult topics in child mental health assessments Authors: Kiyimba, N.; O'Reilly, M. Abstract: Background: In child and adolescent mental health assessments questions are integral to the process. There has been limited research focused on the assessment process, or on how questions are constructed within this clinical environment. Methods: We examined 28 naturally-occurring initial assessments, with particular attention to how practitioners used questions in their communication with children and young people. We utilised conversation analysis to examine the data. Results: Analysis revealed a particular type of question preface used to reintroduce a prior topic. This was achieved through the use of 'you said x' as a foundation for asking a followup question and demonstrated active listening. Conclusions: Arguably, this approach is a useful way of gathering assessment-relevant information in a child-centred way. Description: 12 Months embargo from publication 2017-01-06T16:15:32Z European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. http://hdl.handle.net/2381/39063 Title: European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Authors: Lucas, J. S.; Barbato, A.; Collins, S. A.; Goutaki, M.; Behan, L.; Caudri, D.; Dell, S.; Eber, E.; Escudier, E.; Hirst, Robert; Hogg, C.; Jorissen, M.; Latzin, P.; Legendre, M.; Leigh, M. W.; Midulla, F.; Nielsen, K. G.; Omran, H.; Papon, J. F.; Pohunek, P.; Redfern, B.; Rigau, D.; Rindlisbacher, B.; Santamaria, F.; Shoemark, A.; Snijders, D.; Tonia, T.; Titieni, A.; Walker, W. T.; Werner, C.; Bush, A.; Kuehni, C. E. Abstract: The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia. Description: This article has supplementary material available from erj.ersjournals.com 2017-01-04T16:58:14Z Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer. http://hdl.handle.net/2381/39045 Title: Mast cell phenotype, TNFα expression and degranulation status in non-small cell lung cancer. Authors: Shikotra, A.; Ohri, C. M.; Green, R. H.; Waller, D. A.; Bradding, P. Abstract: Mast cell infiltration of tumour islets represents a survival advantage in non-small cell lung cancer (NSCLC). The phenotype and activation status of these mast cells is unknown. We investigated the mast cell phenotype in terms of protease content (tryptase-only [MCT], tryptase + chymase [MCTC]) and tumour necrosis factor-alpha (TNFα) expression, and extent of degranulation, in NSCLC tumour stroma and islets. Surgically resected tumours from 24 patients with extended survival (ES; mean survival 86.5 months) were compared with 25 patients with poor survival (PS; mean survival 8.0 months) by immunohistochemistry. Both MCT and MCTC in tumour islets were higher in ES (20.0 and 5.6 cells/mm(2) respectively) compared to PS patients (0.0 cells/mm(2)) (p < 0.0001). Both phenotypes expressed TNFα in the islets and stroma. In ES 44% of MCT and 37% of MCTC expressed TNFα in the tumour islets. MCT in the ES stroma were more degranulated than in those with PS (median degranulation index = 2.24 versus 1.73 respectively) (p = 0.0022), and ES islet mast cells (2.24 compared to 1.71, p < 0.0001). Since both MCT and MCTC infiltrating tumour islets in ES NSCLC patients express TNFα, the cytotoxic activity of this cytokine may confer improved survival in these patients. Manipulating mast cell microlocalisation and functional responses in NSCLC may offer a novel approach to the treatment of this disease. 2017-01-04T14:29:31Z Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity http://hdl.handle.net/2381/39040 Title: Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity Authors: Mumme, K.; Gray, C.; Reynolds, C. M.; Vickers, M. H.; Harrison, C. J.; Stanley, J. L.; Ruggiero, K.; Villas-Bôas, S. G.; Baker, Philip N.; Sulek, K. Abstract: Introduction Maternal obesity is associated with a range of pregnancy complications, including fetal growth restriction (FGR), whereby a fetus fails to reach its genetically determined growth. Placental insufficiency and reduced nutrient transport play a role in the onset of FGR. Objectives Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth. Methods We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats were assigned to (a) control diet (CD; 1 % salt, 10 % kcal from fat), (b) high salt diet (SD; 4 % salt, 10 % kcal from fat), (c) high fat diet (HF; 1 % salt, 45 % kcal from fat) or (d) high-fat high-salt diet (HFSD; 4 % salt, 45 % kcal from fat) 21 days prior to pregnancy and during gestation. Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry. Results Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta. Polyunsaturated fatty acid metabolism was significantly altered in maternal and fetal liver by maternal fat intake. Conclusion Excess of linoleic and α-linoleic acid (essential fatty acids) may be detrimental during placentation and associated with a reduction in fetal weight. Additionally, maternal, placental and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity. Description: The online version of this article (doi:10.1007/s11306-016-1014-9) contains supplementary material, which is available to authorized users. 2017-01-03T15:50:23Z Imbalance between proliferation and apoptosis-related impaired GPR30 expression is involved in preeclampsia. http://hdl.handle.net/2381/39039 Title: Imbalance between proliferation and apoptosis-related impaired GPR30 expression is involved in preeclampsia. Authors: Li, J.; Chen, Z.; Zhou, X.; Shi, S.; Qi, H.; Baker, Philip N.; Zhang, H. Abstract: The proliferation and apoptosis of cells in the placenta play a critical role in preeclampsia (PE) in which estrogen has been implicated via estrogen receptors (ERs). A novel ER, G-protein-coupled receptor 30 (GPR30), has recently been shown to be involved in PE. We investigated the basic levels of proliferation and apoptosis in normal placentae and placentae with PE and compared GPR30 expression levels between the two groups. We demonstrated that low GPR30 expression levels, more apoptosis, and less proliferation were associated with PE. Moreover, our in vitro study showed that both the selective GPR30 agonist G1 and the general ER agonist 17-β-estradiol were able to protect the placenta from hypoxia-reoxygenation injuries, resulting in decreased apoptosis and increased proliferation. Furthermore, this protective effect was abolished by the addition of the selective GPR30 inhibitor G15. These results provide evidence that (1) GPR30 is involved in regulating cell proliferation and apoptosis; (2) pharmacologic upregulation of GPR30 is beneficial for PE management; (3) GPR30 may therefore be an interventional target for pregnancies complicated by PE. 2017-01-03T15:45:11Z The relationship between 25-hydroxyvitamin D concentration in early pregnancy and pregnancy outcomes in a large, prospective cohort. http://hdl.handle.net/2381/39038 Title: The relationship between 25-hydroxyvitamin D concentration in early pregnancy and pregnancy outcomes in a large, prospective cohort. Authors: Boyle, V. T.; Thorstensen, E. B.; Mourath, D.; Jones, M. B.; McCowan, L. M.; Kenny, L. C.; Baker, Philip N. Abstract: Vitamin D insufficiency and deficiency have been associated with an increased risk of adverse pregnancy outcomes. Controversy remains as findings have been inconsistent between disparate populations. The aim of this study was to investigate the relationship between vitamin D status and pregnancy outcomes in a large, prospective pregnancy cohort. 25-Hydroxyvitamin D concentration was analysed in serum samples collected at 15 weeks of gestation from 1710 New Zealand women participating in a large, observational study. Associations between vitamin D status and pre-eclampsia, preterm birth, small for gestational age (SGA) and gestational diabetes were investigated. The mean 25-hydroxyvitamin D concentration was 72·9 nmol/l. In all, 23 % had 25-hydroxyvitamin D concentrations 75 nmol/l (OR 2·3; 95 % CI 1·1, 5·1). However, this effect was not significant when adjustments were made for BMI and ethnicity (OR 1·8; 95 % CI 0·8, 4·2). 25-Hydroxyvitamin D concentration at 15 weeks was not associated with development of pre-eclampsia, spontaneous preterm birth or SGA infants. Pregnancy complications were low in this largely vitamin D-replete population. 2017-01-03T15:34:42Z Hypoxia upregulates neutrophil degranulation and potential for tissue injury. http://hdl.handle.net/2381/39035 Title: Hypoxia upregulates neutrophil degranulation and potential for tissue injury. Authors: Hoenderdos, K.; Lodge, K. M.; Hirst, Robert A.; Chen, C.; Palazzo, S. G.; Emerenciana, A.; Summers, C.; Angyal, A.; Porter, L.; Juss, J. K.; O'Callaghan, C.; Chilvers, E. R.; Condliffe, A. M. Abstract: BACKGROUND: The inflamed bronchial mucosal surface is a profoundly hypoxic environment. Neutrophilic airway inflammation and neutrophil-derived proteases have been linked to disease progression in conditions such as COPD and cystic fibrosis, but the effects of hypoxia on potentially harmful neutrophil functional responses such as degranulation are unknown. METHODS AND RESULTS: Following exposure to hypoxia (0.8% oxygen, 3 kPa for 4 h), neutrophils stimulated with inflammatory agonists (granulocyte-macrophage colony stimulating factor or platelet-activating factor and formylated peptide) displayed a markedly augmented (twofold to sixfold) release of azurophilic (neutrophil elastase, myeloperoxidase), specific (lactoferrin) and gelatinase (matrix metalloproteinase-9) granule contents. Neutrophil supernatants derived under hypoxic but not normoxic conditions induced extensive airway epithelial cell detachment and death, which was prevented by coincubation with the antiprotease α-1 antitrypsin; both normoxic and hypoxic supernatants impaired ciliary function. Surprisingly, the hypoxic upregulation of neutrophil degranulation was not dependent on hypoxia-inducible factor (HIF), nor was it fully reversed by inhibition of phospholipase C signalling. Hypoxia augmented the resting and cytokine-stimulated phosphorylation of AKT, and inhibition of phosphoinositide 3-kinase (PI3K)γ (but not other PI3K isoforms) prevented the hypoxic upregulation of neutrophil elastase release. CONCLUSION: Hypoxia augments neutrophil degranulation and confers enhanced potential for damage to respiratory airway epithelial cells in a HIF-independent but PI3Kγ-dependent fashion. Description: Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/thoraxjnl-2015-207604) 2017-01-03T15:05:13Z Major host transitions are modulated through transcriptome-wide reprograming events in Schistocephalus solidus, a threespine stickleback parasite. http://hdl.handle.net/2381/39034 Title: Major host transitions are modulated through transcriptome-wide reprograming events in Schistocephalus solidus, a threespine stickleback parasite. Authors: Hébert, F. O.; Grambauer, Stephan; Barber, Iain; Landry, C. R.; Aubin-Horth, N. Abstract: Parasites with complex life cycles have developed numerous phenotypic strategies, closely associated with developmental events, to enable the exploitation of different ecological niches and facilitate transmission between hosts. How these environmental shifts are regulated from a metabolic and physiological standpoint, however, still remain to be fully elucidated. We examined the transcriptomic response of Schistocephalus solidus, a trophically-transmitted parasite with a complex life cycle, over the course of its development in an intermediate host, the threespine stickleback, and the final avian host. Results from our differential gene expression analysis show major reprogramming events among developmental stages. The final host stage is characterized by a strong activation of reproductive pathways and redox homeostasis. The attainment of infectivity in the fish intermediate host - which precedes sexual maturation in the final host and is associated with host behaviour changes - is marked by transcription of genes involved in neural pathways and sensory perception. Our results suggest that un-annotated and S. solidus-specific genes could play a determinant role in host-parasite molecular interactions required to complete the parasite's life cycle. Our results permit future comparative analyses to help disentangle species-specific patterns of infection from conserved mechanisms, ultimately leading to a better understanding of the molecular control and evolution of complex life cycles. 2017-01-03T14:56:24Z Climate change and nesting behaviour in vertebrates: a review of the ecological threats and potential for adaptive responses. http://hdl.handle.net/2381/39033 Title: Climate change and nesting behaviour in vertebrates: a review of the ecological threats and potential for adaptive responses. Authors: Mainwaring, M. C.; Barber, Iain; Deeming, D. C.; Pike, D. A.; Roznik, E. A.; Hartley, I. R. Abstract: Nest building is a taxonomically widespread and diverse trait that allows animals to alter local environments to create optimal conditions for offspring development. However, there is growing evidence that climate change is adversely affecting nest-building in animals directly, for example via sea-level rises that flood nests, reduced availability of building materials, and suboptimal sex allocation in species exhibiting temperature-dependent sex determination. Climate change is also affecting nesting species indirectly, via range shifts into suboptimal nesting areas, reduced quality of nest-building environments, and changes in interactions with nest predators and parasites. The ability of animals to adapt to sustained and rapid environmental change is crucial for the long-term persistence of many species. Many animals are known to be capable of adjusting nesting behaviour adaptively across environmental gradients and in line with seasonal changes, and this existing plasticity potentially facilitates adaptation to anthropogenic climate change. However, whilst alterations in nesting phenology, site selection and design may facilitate short-term adaptations, the ability of nest-building animals to adapt over longer timescales is likely to be influenced by the heritable basis of such behaviour. We urgently need to understand how the behaviour and ecology of nest-building in animals is affected by climate change, and particularly how altered patterns of nesting behaviour affect individual fitness and population persistence. We begin our review by summarising how predictable variation in environmental conditions influences nest-building animals, before highlighting the ecological threats facing nest-building animals experiencing anthropogenic climate change and examining the potential for changes in nest location and/or design to provide adaptive short- and long-term responses to changing environmental conditions. We end by identifying areas that we believe warrant the most urgent attention for further research. 2017-01-03T14:49:40Z Adaptive and Behavioral Changes in Kynurenine 3-monooxygenase Knockout Mice: Relevance to Psychotic Disorders http://hdl.handle.net/2381/39031 Title: Adaptive and Behavioral Changes in Kynurenine 3-monooxygenase Knockout Mice: Relevance to Psychotic Disorders Authors: Erhardt, S.; Pocivavsek, A.; Repici, Mariaelena; Liu, X-C.; Imbeault, S.; Maddison, Daniel C.; Thomas, M. A. R.; Smalley, Joshua L.; Larsson, M. K.; Muchowski, P. J.; Giorgini, Flaviano; Schwarcz, R. Abstract: Background Kynurenine 3-monooxygenase (KMO) converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway - which is implicated as dysfunctional in various psychiatric disorders - towards enhanced synthesis of kynurenic acid (KYNA), an antagonist of both α7 nicotinic acetylcholine and NMDA receptors. Possibly as a result of reduced KMO activity, elevated central nervous system levels of KYNA have been found in patients with psychotic disorders, including schizophrenia (SZ). Methods In the present study, we investigated adaptive – and possibly regulatory – changes in mice with a targeted deletion of Kmo (Kmo-/-) and characterized the KMO-deficient mice using six behavioral assays relevant for the study of SZ. Results Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of SZ- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. KYNA levels were also increased in these brain regions in Kmo-/-mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo-/-mice exhibited impairments in contextual memory and spent less time than controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light-dark box. After a D-amphetamine challenge (5 mg/kg, i.p.), Kmo-/- mice showed potentiated horizontal activity in the open field paradigm. Conclusions Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders. 2017-01-03T12:48:45Z Understanding Clostridium Difficile and the Bacteriophages from the Environment http://hdl.handle.net/2381/39028 Title: Understanding Clostridium Difficile and the Bacteriophages from the Environment Authors: Rashid, Saroa Jamal Abstract: Clostridium difficile is an important nosocomial pathogen that causes significant human morbidity and mortality. The environment is a natural reservoir for C. difficile where it is found in soils, rivers, and other natural settings. It is not clear whether these strains are active, or present as a result of human contamination. To address this, the physiological characterisation of isogenic pairs was tested to determine if strains from the environment had different properties to those derived from a clinical setting. Clinical strains were less motile but produced more toxins and spores than environmental strains. Little is known about environmental strains of C. difficile outside Europe, the USA, and Australia. To explore new areas, C. difficile and phages were isolated from environmental samples collected in Kurdistan in northern Iraq. Sixty-one strains were isolated and classified into 9 ribotypes including a new ribotype, R691. The two strains examined from dominant ribotype R604, were non-toxigenic and related to each other but distinct from most described clades of C. difficile. Evidence for phages playing important roles in environmental C. difficile dynamics can be seen from the large diverse prophage carriage within strains, and the extensive CRISPR system. Seventeen new phages were isolated and shown to infect ribotype 078 for which few phages exist. Host-range analysis showed that these phages can infect most clinically relevant ribotypes including the novel observation that two myoviruses can infect R027. Genome analysis of three phages revealed that they are distinct but related to known C. difficile phages. Interestingly CDKM15 is the first phage isolated to have an active CRISPR system. This study suggests that the natural environment is a potential reservoir for genetically diverse C. difficile strains and phages that are regionally structured. This could play a role in the emergence of new strains in hospitals. 2016-12-21T16:27:35Z