2,177 results on '"Dg"'
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2. A longitudinal assessment of trial protocols approved by research ethics committees: the Adherance to SPIrit REcommendations in the UK (ASPIRE-UK) study
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Speich, B, Odutayo, A, Peckham, N, Ooms, A, Stokes, JR, Saccilotto, R, Gryaznov, D, von Niederhäusern, B, Copsey, B, Altman, DG, Briel, M, and Hopewell, S
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Clinical Trial Protocols as Topic ,Humans ,Guideline Adherence ,United Kingdom ,Ethics Committees, Research - Abstract
Background To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. Methods We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. Results The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6–69.2%) in 2012 to a median of 72.5% (IQR, 65.3–78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1–69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5–67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2–79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6–76.3%). Conclusions The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.
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- 2023
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3. SARS-CoV-2 lineage dynamics in England from September to November 2021: high diversity of Delta sub-lineages and increased transmissibility of AY.4.2
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Eales, O, Page, AJ, de Oliveira Martins, L, Wang, H, Bodinier, B, Haw, D, Jonnerby, J, Atchison, C, Robson, SC, Connor, TR, Loman, NJ, Golubchik, T, Nunez, RTM, Bonsall, D, Rambaut, A, Snell, LB, Livett, R, Ludden, C, Corden, S, Nastouli, E, Nebbia, G, Johnston, I, Lythgoe, K, Torok, ME, Goodfellow, IG, Prieto, JA, Saeed, K, Jackson, DK, Houlihan, C, Frampton, D, Hamilton, WL, Witney, AA, Bucca, G, Pope, CF, Moore, C, Thomson, EC, Harrison, EM, Smith, CP, Rogan, F, Beckwith, SM, Murray, A, Singleton, D, Eastick, K, Sheridan, LA, Randell, P, Jackson, LM, Ariani, CV, Gonçalves, S, Fairley, DJ, Loose, MW, Watkins, J, Moses, S, Nicholls, S, Bull, M, Amato, R, Smith, DL, Aanensen, DM, Barrett, JC, Aggarwal, D, Shepherd, JG, Curran, MD, Parmar, S, Parker, MD, Williams, C, Glaysher, S, Underwood, AP, Bashton, M, Pacchiarini, N, Loveson, KF, Byott, M, Carabelli, AM, Templeton, KE, de Silva, TI, Wang, D, Langford, CF, Sillitoe, J, Gunson, RN, Cottrell, S, O’Grady, J, Kwiatkowski, D, Lillie, PJ, Cortes, N, Moore, N, Thomas, C, Burns, PJ, Mahungu, TW, Liggett, S, Beckett, AH, Holden, MTG, Levett, LJ, Osman, H, Hassan-Ibrahim, MO, Simpson, DA, Chand, M, Gupta, RK, Darby, AC, Paterson, S, Pybus, OG, Volz, EM, de Angelis, D, Robertson, DL, Martincorena, I, Aigrain, L, Bassett, AR, Wong, N, Taha, Y, Erkiert, MJ, Chapman, MHS, Dewar, R, McHugh, MP, Mookerjee, S, Aplin, S, Harvey, M, Sass, T, Umpleby, H, Wheeler, H, McKenna, JP, Warne, B, Taylor, JF, Chaudhry, Y, Izuagbe, R, Jahun, AS, Young, GR, McMurray, C, McCann, CM, Nelson, A, Elliott, S, Lowe, H, Price, A, Crown, MR, Rey, S, Roy, S, Temperton, B, Shaaban, S, Hesketh, AR, Laing, KG, Monahan, IM, Heaney, J, Pelosi, E, Silviera, S, Wilson-Davies, E, Fryer, H, Adams, H, du Plessis, L, Johnson, R, Harvey, WT, Hughes, J, Orton, RJ, Spurgin, LG, Bourgeois, Y, Ruis, C, O’Toole, Á, Gourtovaia, M, Sanderson, T, Fraser, C, Edgeworth, J, Breuer, J, Michell, SL, Todd, JA, John, M, Buck, D, Gajee, K, Kay, GL, Peacock, SJ, Heyburn, D, Kitchman, K, McNally, A, Pritchard, DT, Dervisevic, S, Muir, P, Robinson, E, Vipond, BB, Ramadan, NA, Jeanes, C, Weldon, D, Catalan, J, Jones, N, da Silva Filipe, A, Fuchs, M, Miskelly, J, Jeffries, AR, Oliver, K, Park, NR, Ash, A, Koshy, C, Barrow, M, Buchan, SL, Mantzouratou, A, Clark, G, Holmes, CW, Campbell, S, Davis, T, Tan, NK, Brown, JR, Harris, KA, Kidd, SP, Grant, PR, Xu-McCrae, L, Cox, A, Madona, P, Pond, M, Randell, PA, Withell, KT, Graham, C, Denton-Smith, R, Swindells, E, Turnbull, R, Sloan, TJ, Bosworth, A, Hutchings, S, Pymont, HM, Casey, A, Ratcliffe, L, Jones, CR, Knight, BA, Haque, T, Hart, J, Irish-Tavares, D, Witele, E, Mower, C, Watson, LK, Collins, J, Eltringham, G, Crudgington, D, Macklin, B, Iturriza-Gomara, M, Lucaci, AO, McClure, PC, Carlile, M, Holmes, N, Storey, N, Rooke, S, Yebra, G, Craine, N, Perry, M, Alikhan, N - F, Bridgett, S, Cook, KF, Fearn, C, Goudarzi, S, Lyons, RA, Williams, T, Haldenby, ST, Durham, J, Leonard, S, Davies, RM, Batra, R, Blane, B, Spyer, MJ, Smith, P, Yavus, M, Williams, RJ, Mahanama, AIK, Samaraweera, B, Girgis, ST, Hansford, SE, Green, A, Beaver, C, Bellis, KL, Dorman, MJ, Kay, S, Prestwood, L, Rajatileka, S, Quick, J, Poplawski, R, Reynolds, N, Mack, A, Morriss, A, Whalley, T, Patel, B, Georgana, I, Hosmillo, M, Pinckert, ML, Stockton, J, Henderson, JH, Hollis, A, Stanley, W, Yew, WC, Myers, R, Thornton, A, Adams, A, Annett, T, Asad, H, Birchley, A, Coombes, J, Evans, JM, Fina, L, Gatica-Wilcox, B, Gilbert, L, Graham, L, Hey, J, Hilvers, E, Jones, S, Jones, H, Kumziene-Summerhayes, S, McKerr, C, Powell, J, Pugh, G, Taylor, S, Trotter, AJ, Williams, CA, Kermack, LM, Foulkes, BH, Gallis, M, Hornsby, HR, Louka, SF, Pohare, M, Wolverson, P, Zhang, P, MacIntyre-Cockett, G, Trebes, A, Moll, RJ, Ferguson, L, Goldstein, EJ, Maclean, A, Tomb, R, Starinskij, I, Thomson, L, Southgate, J, Kraemer, MUG, Raghwani, J, Zarebski, AE, Boyd, O, Geidelberg, L, Illingworth, CJ, Jackson, C, Pascall, D, Vattipally, S, Freeman, TM, Hsu, SN, Lindsey, BB, James, K, Lewis, K, Tonkin-Hill, G, Tovar-Corona, JM, Cox, MG, Abudahab, K, Menegazzo, M, MEng, BEWT, Yeats, CA, Mukaddas, A, Wright, DW, Colquhoun, R, Hill, V, Jackson, B, McCrone, JT, Medd, N, Scher, E, Keatley, J - P, Curran, T, Morgan, S, Maxwell, P, Smith, K, Eldirdiri, S, Kenyon, A, Holmes, AH, Price, JR, Wyatt, T, Mather, AE, Skvortsov, T, Hartley, JA, Guest, M, Kitchen, C, Merrick, I, Munn, R, Bertolusso, B, Lynch, J, Vernet, G, Kirk, S, Wastnedge, E, Stanley, R, Idle, G, Bradley, DT, Poyner, J, Mori, M, Jones, O, Wright, V, Brooks, E, Churcher, CM, Fragakis, M, Galai, K, Jermy, A, Judges, S, McManus, GM, Smith, KS, Westwick, E, Attwood, SW, Bolt, F, Davies, A, De Lacy, E, Downing, F, Edwards, S, Meadows, L, Jeremiah, S, Smith, N, Foulser, L, Charalampous, T, Patel, A, Berry, L, Boswell, T, Fleming, VM, Howson-Wells, HC, Joseph, A, Khakh, M, Lister, MM, Bird, PW, Fallon, K, Helmer, T, McMurray, CL, Odedra, M, Shaw, J, Tang, JW, Willford, NJ, Blakey, V, Raviprakash, V, Sheriff, N, Williams, L - A, Feltwell, T, Bedford, L, Cargill, JS, Hughes, W, Moore, J, Stonehouse, S, Atkinson, L, Lee, JCD, Shah, D, Alcolea-Medina, A, Ohemeng-Kumi, N, Ramble, J, Sehmi, J, Williams, R, Chatterton, W, Pusok, M, Everson, W, Castigador, A, Macnaughton, E, Bouzidi, KE, Lampejo, T, Sudhanva, M, Breen, C, Sluga, G, Ahmad, SSY, George, RP, Machin, NW, Binns, D, James, V, Blacow, R, Coupland, L, Smith, L, Barton, E, Padgett, D, Scott, G, Cross, A, Mirfenderesky, M, Greenaway, J, Cole, K, Clarke, P, Duckworth, N, Walsh, S, Bicknell, K, Impey, R, Wyllie, S, Hopes, R, Bishop, C, Chalker, V, Harrison, I, Gifford, L, Molnar, Z, Auckland, C, Evans, C, Johnson, K, Partridge, DG, Raza, M, Baker, P, Bonner, S, Essex, S, Murray, LJ, Lawton, AI, Burton-Fanning, S, Payne, BAI, Waugh, S, Gomes, AN, Kimuli, M, Murray, DR, Ashfield, P, Dobie, D, Ashford, F, Best, A, Crawford, L, Cumley, N, Mayhew, M, Megram, O, Mirza, J, Moles-Garcia, E, Percival, B, Driscoll, M, Ensell, L, Lowe, HL, Maftei, L, Mondani, M, Chaloner, NJ, Cogger, BJ, Easton, LJ, Huckson, H, Lewis, J, Lowdon, S, Malone, CS, Munemo, F, Mutingwende, M, Nicodemi, R, Podplomyk, O, Somassa, T, Beggs, A, Richter, A, Cormie, C, Dias, J, Forrest, S, Higginson, EE, Maes, M, Young, J, Davidson, RK, Jackson, KA, Turtle, L, Keeley, AJ, Ball, J, Byaruhanga, T, Chappell, JG, Dey, J, Hill, JD, Park, EJ, Fanaie, A, Hilson, RA, Yaze, G, Lo, S, Afifi, S, Beer, R, Maksimovic, J, McCluggage, K, Spellman, K, Bresner, C, Fuller, W, Marchbank, A, Workman, T, Shelest, E, Debebe, J, Sang, F, Zamudio, ME, Francois, S, Gutierrez, B, Vasylyeva, TI, Flaviani, F, Ragonnet-Cronin, M, Smollett, KL, Broos, A, Mair, D, Nichols, J, Nomikou, K, Tong, L, Tsatsani, I, O’Brien, PS, Rushton, S, Sanderson, R, Perkins, J, Cotton, S, Gallagher, A, Allara, E, Pearson, C, Bibby, D, Dabrera, G, Ellaby, N, Gallagher, E, Hubb, J, Lackenby, A, Lee, D, Manesis, N, Mbisa, T, Platt, S, Twohig, KA, Morgan, M, Aydin, A, Baker, DJ, Foster-Nyarko, E, Prosolek, SJ, Rudder, S, Baxter, C, Carvalho, SF, Lavin, D, Mariappan, A, Radulescu, C, Singh, A, Tang, M, Morcrette, H, Bayzid, N, Cotic, M, Balcazar, CE, Gallagher, MD, Maloney, D, Stanton, TD, Williamson, KA, Manley, R, Michelsen, ML, Sambles, CM, Studholme, DJ, Warwick-Dugdale, J, Eccles, R, Gemmell, M, Gregory, R, Hughes, M, Nelson, C, Rainbow, L, Vamos, EE, Webster, HJ, Whitehead, M, Wierzbicki, C, Angyal, A, Green, LR, Whiteley, M, Betteridge, E, Bronner, IF, Farr, BW, Goodwin, S, Lensing, SV, McCarthy, SA, Quail, MA, Rajan, D, Redshaw, NM, Scott, C, Shirley, L, Thurston, SAJ, Rowe, W, Gaskin, A, Le-Viet, T, Bonfield, J, Liddle, J, Whitwham, A, Ashby, D, Barclay, W, Taylor, G, Cooke, G, Ward, H, Darzi, A, Riley, S, Chadeau-Hyam, M, Donnelly, CA, Elliott, P, The COVID-19 Genomics UK (COG-UK) Consortium, Department of Health, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), Cancer Research UK, Commission of the European Communities, Wellcome Trust, National Institute for Health Research, and Imperial College Healthcare NHS Trust: Research Capability Funding (RCF)
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Delta variant ,Science & Technology ,SARS-CoV-2 ,COVID-19 ,1103 Clinical Sciences ,C500 ,Microbiology ,Genetic diversity ,B900 ,Infectious Diseases ,England ,COVID-19 Genomics UK (COG-UK) Consortium ,1108 Medical Microbiology ,Mutation ,Humans ,Transmission advantage ,Life Sciences & Biomedicine ,Phylogeny ,0605 Microbiology - Abstract
Background Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Genomic surveillance in regions of high immunity is crucial in detecting emerging variants that can more successfully navigate the immune landscape. Methods We present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. During round 14 (9 September–27 September 2021) and 15 (19 October–5 November 2021) lineages were determined for 1322 positive individuals, with 27.1% of those which reported their symptom status reporting no symptoms in the previous month. Results We identified 44 unique lineages, all of which were Delta or Delta sub-lineages, and found a reduction in their mutation rate over the study period. The proportion of the Delta sub-lineage AY.4.2 was increasing, with a reproduction number 15% (95% CI 8–23%) greater than the most prevalent lineage, AY.4. Further, AY.4.2 was less associated with the most predictive COVID-19 symptoms (p = 0.029) and had a reduced mutation rate (p = 0.050). Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. Conclusions As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.
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- 2022
4. Does clopidogrel change morbidity and mortality in ICU sepsis patients?
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Klepser, DG, Dobesh, PP, McGuire, TR, Roberts, DA, Himmelberg, AL, and Olsen, KM
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- 2014
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5. T-cell receptor activation-associated cytokine release is impaired in septic patients with faecal peritonitis
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Gore, DG, Preciado-Llanes, L, Mills, GH, Heath, AW, and Read, RC
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- 2014
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6. Blood product transfusions in septic patients are associated with mortality, ARDS, and more days on mechanical ventilation
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Dobesh, PP, Klepser, DG, McGuire, TR, Roberts, DA, Himmelberg, AL, and Olsen, KM
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- 2014
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7. Impact of obesity on outcomes in patients with sepsis
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Dobesh, PP, McGuire, TR, Klepser, DG, Himmelberg, AL, Roberts, DA, and Olsen, KM
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- 2014
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8. Identifying risk factors for readmission to the ICU: a qualitative approach
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Strange, DG, Tjelle, K, Lindhardt, A, and Jensen, K
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- 2013
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9. Repeatability of breast density visual assessment
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Walshaw, L, Sergeant, JC, Wilson, M, Steed, S, Barr, N, Beetles, U, Boggis, C, Bundred, S, Gadde, S, Lim, Y, Whiteside, S, Evans, DG, Howell, A, and Astley, SM
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- 2012
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10. Breast density measurement for personalised screening
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Sergeant, JC, Musa, S, Wilson, M, Evans, DG, Howell, A, and Astley, SM
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- 2012
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11. Modelling immune responses in sepsis
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Grealy, R, White, M, O'Dwyer, M, Stordeur, P, Doherty, DG, McManus, R, and Ryan, T
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- 2012
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12. Organizing the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): National Institutes of Health, Health Care Financing Administration, and industry funding
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Hobson, II, Robert W, Howard, Virginia J, Brott, Thomas G, Howard, George, Roubin, Gary S, and Ferguson, Robert DG
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- 2001
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13. The COMET Handbook: version 1.0
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Williamson, PR, Altman, DG, Bagley, H, Barnes, KL, Blazeby, JM, Brookes, ST, Clarke, M, Gargon, E, Gorst, S, Harman, N, Kirkham, JJ, McNair, A, Prinsen, CAC, Schmitt, J, Terwee, CB, and Young, B
- Abstract
The selection of appropriate outcomes is crucial when designing clinical trials in order to compare the effects of different interventions directly. For the findings to influence policy and practice, the outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. It is now widely acknowledged that insufficient attention has been paid to the choice of outcomes measured in clinical trials. Researchers are increasingly addressing this issue through the development and use of a core outcome set, an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.Accumulating work in this area has identified the need for guidance on the development, implementation, evaluation and updating of core outcome sets. This Handbook, developed by the COMET Initiative, brings together current thinking and methodological research regarding those issues. We recommend a four-step process to develop a core outcome set. The aim is to update the contents of the Handbook as further research is identified.
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- 2017
14. Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)
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Stivaros, S, Garg, S, Tziraki, M, Cai, Y, Thomas, O, Melloe, J, Morris, A, Jim, CS, Szumanska-Ryt, K, Parkes, L, Haroon, H, Montaldi, D, Webb, N, Keane, J, Castellanos, F, Silva, A, Huson, S, Williams, S, Evans, DG, Emsley, R, Green, J, Stivaros, S, Garg, S, Tziraki, M, Cai, Y, Thomas, O, Melloe, J, Morris, A, Jim, CS, Szumanska-Ryt, K, Parkes, L, Haroon, H, Montaldi, D, Webb, N, Keane, J, Castellanos, F, Silva, A, Huson, S, Williams, S, Evans, DG, Emsley, R, and Green, J
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Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/ behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = − 2.12, p = .055), GABA/Glx ratio (t(12) = − 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met ‘clinical responder’ criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network.
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- 2018
15. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing
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Jansen, IE, Ye, H, Heetveld, S, Lechler, MC, Michels, H, Seinstra, RI, Lubbe, SJ, Drouet, V, Lesage, S, Majounie, E, Gibbs, JR, Nalls, MA, Ryten, M, Botia, JA, Vandrovcova, J, Simon-Sanchez, J, Castillo-Lizardo, M, Rizzu, P, Blauwendraat, C, Chouhan, AK, Li, Y, Yogi, P, Amin, N, van Duijn, CM, Morris, HR, Brice, A, Singleton, AB, David, DC, Nollen, EA, Jain, S, Shulman, JM, Heutink, P, Hernandez, DG, Arepalli, S, Brooks, J, Price, R, Nicolas, A, Chong, S, Cookson, MR, Dillman, A, Moore, M, Traynor, BJ, Plagnol, V, Nicholas, WW, Sheerin, UM, Jose, MB, Charlesworth, G, Gardner, M, Guerreiro, R, Trabzuni, D, Hardy, J, Sharma, M, Saad, M, Javier, S-S, Schulte, C, Corvol, JC, Dürr, A, Vidailhet, M, Sveinbjörnsdóttir, S, Barker, R, Caroline, HW-G, Ben-Shlomo, Y, Berendse, HW, van Dijk, KD, Berg, D, Brockmann, K, Wurster, I, Mätzler, W, Gasser, T, Martinez, M, de Bie, RMA, Biffi, A, and Velseboer, D
- Abstract
Background: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Results: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. Conclusions: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.
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- 2017
16. Decatropis bicolor (Zucc.) Radlk essential oil induces apoptosis of the MDA-MB-231 breast cancer cell line
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M. C. Gómez García, A. Aquino Carreño, N. Pérez Hernández, J. Morales López, DG Pérez Ishiwara, E. San Martín Martínez, and C. C. Estanislao Gómez
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cytotoxic ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,Essential oil ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Western blot ,law ,Annexin ,Cell Line, Tumor ,Oils, Volatile ,Medicine ,Cytotoxic T cell ,Humans ,MTT assay ,Rutaceae ,Caspase ,biology ,medicine.diagnostic_test ,business.industry ,Plant Extracts ,General Medicine ,Molecular biology ,030104 developmental biology ,Complementary and alternative medicine ,030220 oncology & carcinogenesis ,biology.protein ,DNA fragmentation ,business ,Research Article - Abstract
Background Decatropis bicolor (Zucc.)Radlk is a plant that has been traditionally used for the treatment of breast cancer in some communities of Mexico. So, the aim of this study was to determine the cytotoxic and apoptotic effect of the essential oil of Decatropis bicolor against breast cancer cell line, MDA-MB-231. Methods The essential oil obtained from hydrodestillation of leaves of Decatropis bicolor was studied for its biological activity against breast cancer cells MDA-MB-231 by MTT assay, Hematoxylin-eosin stain, Annexin V-FITC, TUNEL and western blot assays and for its chemical composition by GC-MS. Results The results showed a relevant cytotoxic effect of the essential oil towards MDA-MB-231 cells in a dose- and time- dependent manner, with an IC50 of 53.81 ± 1.691 μg/ml but not in the epithelial mammary cell line MCF10A (207.51 ± 3.26 μg/ml). Morphological examination displayed apoptotic characteristics in the treated cells like cell size reduction, membrane blebbing and apoptotic bodies. In addition, the apoptotic rate significantly increased as well as DNA fragmentation and western blot analysis revealed that the essential oil induced apoptosis in the MDA-MB-231 cells via intrinsic pathways due to the activation of Bax, caspases 9 and 3. Phytochemical analysis of the Decatropis bicolor essential oil showed the presence of twenty-three compounds. Major components of the oil were 1,5-cyclooctadiene,3-(methyl-2)propenyl (18.38 %), β-terpineol (8.16 %) and 1-(3-methyl-cyclopent-2-enyl)-cyclohexene (6.12 %). Conclusions This study suggests that essential oil of Decatropis bicolor has a potential cytotoxic and antitumoral effect against breast cancer cells, with the presence of potential bioactive compounds. Our results contribute to the validation of the anticancer activity of the plant in Mexican traditional medicine. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1136-7) contains supplementary material, which is available to authorized users.
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- 2016
17. The COMET Initiative database: progress and activities from 2011 to 2013
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Gargon, E, Williamson, PR, Altman, DG, Blazeby, JM, and Clarke, M
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The Core Outcome Measures in Effectiveness Trials (COMET) Initiative database is an international repository of studies relevant to the development of core outcome sets. By the end of 2013, it included a unique collection of 306 studies. The website is increasingly being used, with more than 12,000 visits in 2013 (a 55% increase over 2012), 8,369 unique visitors (a 53% increase) and 6,844 new visitors (a 48% increase). There has been a rise in visits from outside the United Kingdom, with 2,405 such visits in 2013 (30% of all visits). By December 2013, a total of 4,205 searches had been completed, with 2,139 in 2013 alone.
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- 2016
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18. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer
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Eccles, SA, Aboagye, EO, Ali, S, Anderson, AS, Armes, J, Berditchevski, F, Blaydes, JP, Brennan, K, Brown, NJ, Bryant, HE, Bundred, NJ, Burchell, JM, Campbell, AM, Carroll, JS, Clarke, RB, Coles, CE, Cook, GJR, Cox, A, Curtin, NJ, Dekker, LV, Silva, IS, Duffy, SW, Easton, DF, Eccles, DM, Edwards, DR, Edwards, J, Evans, DG, Fenlon, DF, Flanagan, JM, Foster, C, Gallagher, WM, Garcia-Closas, M, Gee, JMW, Gescher, AJ, Goh, V, Groves, AM, Harvey, AJ, Harvie, M, Hennessy, BT, Hiscox, S, Holen, I, Howell, SJ, Howell, A, Hubbard, G, Hulbert-Williams, N, Hunter, MS, Jasani, B, Jones, LJ, Key, TJ, Kirwan, CC, Kong, A, Kunkler, IH, Langdon, SP, Leach, MO, Mann, DJ, Marshall, JF, Martin, LA, Martin, SG, Macdougall, JE, Miles, DW, Miller, WR, Morris, JR, Moss, SM, Mullan, P, Natrajan, R, O’Connor, JPB, O’Connor, R, Palmieri, C, Pharoah, PDP, Rakha, EA, Reed, E, Robinson, SP, Sahai, E, Saxton, JM, Schmid, P, Smalley, MJ, Speirs, V, Stein, R, Stingl, J, Streuli, CH, Tutt, ANJ, Velikova, G, Walker, RA, Watson, CJ, Williams, KJ, Young, LS, Thompson, AM, Carroll, Jason [0000-0003-3643-0080], Coles, Charlotte [0000-0003-4473-8552], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Watson, Christine [0000-0002-8548-5902], Apollo - University of Cambridge Repository, and Cancer Research UK
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Cancer Research ,medicine.medical_specialty ,ONCOLOGY DRUG DEVELOPMENT ,Breast Neoplasms ,Translational research ,ESTROGEN-RECEPTOR-BETA ,MAMMARY-GLAND DEVELOPMENT ,Metastasis ,Translational Research, Biomedical ,RC0254 ,chemistry.chemical_compound ,Breast cancer ,QUALITY-OF-LIFE ,ADJUVANT MULTINATIONAL TRIAL ,Epidemiology of cancer ,Animals ,Humans ,Medicine ,Oncology & Carcinogenesis ,Intensive care medicine ,Translational Medical Research ,Medicine(all) ,Gynecology ,Science & Technology ,TRANSGENIC MOUSE MODELS ,business.industry ,Research ,Cancer ,RANDOMIZED CONTROLLED-TRIAL ,Luminespib ,A300 ,ONCOLOGY ,medicine.disease ,EPITHELIAL-MESENCHYMAL TRANSITION ,CIRCULATING TUMOR-CELLS ,B900 ,Oncology ,RISK PREDICTION MODEL ,chemistry ,Hormonal therapy ,Female ,Personalized medicine ,business ,Life Sciences & Biomedicine ,1112 Oncology And Carcinogenesis - Abstract
IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
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- 2016
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19. Epidemiology, prehospital care and outcomes of patients arriving by ambulance with dyspnoea: An observational study
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Kelly, AM, Holdgate, A, Keijzers, G, Klim, S, Graham, CA, Craig, S, Kuan, WS, Jones, P, Lawoko, C, Laribi, S, McNulty, R, Cowell, DL, Jain, N, De Villecourt, T, Lee, K, Chalkley, D, Lozzi, L, Asha, SE, Duffy, M, Watkins, G, Rosengren, D, Thone, J, Martin, S, Orda, U, Thom, O, Kinnear, F, Watson, M, Eley, R, Ryan, A, Morel, DG, Furyk, Jeremy, Smith, RDB, Grummisch, M, Meek, R, Rosengarten, P, Chan, B, Haythorne, H, Archer, P, Wilson, K, Knott, J, Ritchie, P, Bryant, M, MacDonald, S, Mahlangu, M, Scott, M, Cheri, T, Nguyen, M, Chor, MSY, Wong, CP, Wong, TW, Leung, LP, Man, CK, Saiboon, IM, Rahman, NH, Lee, WY, Lee, FCY, Goh, SE, Russell, K, Kelly, AM, Holdgate, A, Keijzers, G, Klim, S, Graham, CA, Craig, S, Kuan, WS, Jones, P, Lawoko, C, Laribi, S, McNulty, R, Cowell, DL, Jain, N, De Villecourt, T, Lee, K, Chalkley, D, Lozzi, L, Asha, SE, Duffy, M, Watkins, G, Rosengren, D, Thone, J, Martin, S, Orda, U, Thom, O, Kinnear, F, Watson, M, Eley, R, Ryan, A, Morel, DG, Furyk, Jeremy, Smith, RDB, Grummisch, M, Meek, R, Rosengarten, P, Chan, B, Haythorne, H, Archer, P, Wilson, K, Knott, J, Ritchie, P, Bryant, M, MacDonald, S, Mahlangu, M, Scott, M, Cheri, T, Nguyen, M, Chor, MSY, Wong, CP, Wong, TW, Leung, LP, Man, CK, Saiboon, IM, Rahman, NH, Lee, WY, Lee, FCY, Goh, SE, and Russell, K
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- 2016
20. Regulation of ERK-MAPK signaling in human epidermis
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Cursons, J, Gao, J, Hurley, DG, Print, CG, Dunbar, PR, Jacobs, MD, Crampin, EJ, Cursons, J, Gao, J, Hurley, DG, Print, CG, Dunbar, PR, Jacobs, MD, and Crampin, EJ
- Abstract
The skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.
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- 2015
21. Management of a Serratia marcescens outbreak in a neonatal unit – improving hand hygiene does the job
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Riccardo Pfister, I Soulake, DG Pichoud, Angèle Gayet-Ageron, Walter Zingg, Gesuele Renzi, and Didier Pittet
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Microbiology (medical) ,medicine.medical_specialty ,biology ,business.industry ,Transmission (medicine) ,media_common.quotation_subject ,Public Health, Environmental and Occupational Health ,Outbreak ,biology.organism_classification ,Bioinformatics ,Infectious Diseases ,Hygiene ,Serratia marcescens ,Poster Presentation ,bacteria ,Medicine ,Pharmacology (medical) ,business ,Intensive care medicine ,media_common - Abstract
Many outbreaks due to Serratia marcescens among neonates have been described in the literature. While the source was rarely identified, the emphasis primarily was given to the role of the environment on the chain of transmission.
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- 2015
22. Tracking type specific prevalence of human Papillomavirus in cervical pre-cancer: a novel sampling strategy
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Waters, EK, Kaldor, JM, Hamilton, AJ, Smith, AMA, Philp, DJ, Donovan, B, Regan, DG, Waters, EK, Kaldor, JM, Hamilton, AJ, Smith, AMA, Philp, DJ, Donovan, B, and Regan, DG
- Abstract
Background: Surveillance designed to detect changes in the type-specific distribution of HPV in cervical intraepithelial neoplasia grade 3 (CIN-3) is necessary to evaluate the effectiveness of the Australian vaccination programme on cancer causing HPV types. This paper develops a protocol that eliminates the need to calculate required sample size; sample size is difficult to calculate in advance because HPV's true type-specific prevalence is imperfectly known. Method: A truncated sequential sampling plan that collects a variable sample size was designed to detect changes in the type-specific distribution of HPV in CIN-3. Computer simulation to evaluate the accuracy of the plan at classifying the prevalence of an HPV type as low ( 15%) and the average sample size collected was conducted and used to assess its appropriateness as a surveillance tool. Results: The plan classified the proportion of CIN-3 lesions positive for an HPV type very accurately, with >90% of simulations correctly classifying a simulated data-set with known prevalence. Misclassifying an HPV type of high prevalence as being of low prevalence, arguably the most serious kind of potential error, occurred
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- 2012
23. Identifying risk factors for readmission to the ICU: a qualitative approach
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A Lindhardt, K Tjelle, DG Strange, and K Jensen
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medicine.medical_specialty ,Risk groups ,Apache score ,business.industry ,Intensive care ,Emergency medicine ,Severity of illness ,Poster Presentation ,medicine ,Critical Care and Intensive Care Medicine ,Logistic regression ,High severity ,business - Abstract
Readmission to the ICU within 48 hours is an indicator of quality of intensive care and is associated with an increase in mortality. During the last years several groups have published data based on multivariate logistic regression analysis to describe characteristics of patients who needed readmission to the ICU. Older age, comorbid conditions and severity of illness (APACHE score) have been among the strongest predictors for readmission. In our ICU most patients are in the groups formerly identified as risk groups, which means that stratification and prediction of readmission is difficult. Because of the unusual high severity of acute and pre-existing illnesses we could not find a data match on comparable patient groups. To investigate whether we could reduce our rate of readmission we therefore decided to perform a qualitative investigation to identify risk factors related to readmission. After identification of the risk factors we will take actions to optimize care and perform ongoing control of the implemented actions to secure that they decreases the rate of readmission.
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- 2013
24. Breast density measurement for personalised screening
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Susan M. Astley, Anthony Howell, Mary E. Wilson, S Musa, Jamie C. Sergeant, and Dg. Evans
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Oncology ,Gynecology ,medicine.medical_specialty ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Population ,Cancer ,Early detection ,medicine.disease ,Breast cancer ,Internal medicine ,Poster Presentation ,medicine ,Mammography ,Breast density ,Risk factor ,skin and connective tissue diseases ,education ,business - Abstract
Breast density is both a modifiable risk factor for breast cancer and an indicator of the sensitivity of mammography. Reliable measurement in the screening population could enable personalised screening to maximise early detection of cancer. In the Predicting Risk of Cancer at Screening (PROCAS) study, we are investigating different approaches to measuring breast density, and we present comparative data from one subjective method and two automated volumetric methods.
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- 2012
25. Thrombocytopenia is associated with mortality in hospitalized patients with low risk of death
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F. G. Ribeiro, Octavio Messeder, A Camelier, José Mario Meira Teles, Rogério da Hora Passos, C Boaventura, M Oliveira, DG Flores, R Gomes, Augusto Manoel de Carvalho Farias, and Silva Ld
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medicine.medical_specialty ,business.industry ,Hospitalized patients ,hemic and lymphatic diseases ,Emergency medicine ,Poster Presentation ,medicine ,In patient ,Risk of death ,Critical Care and Intensive Care Medicine ,Intensive care medicine ,business - Abstract
Thrombocytopenia is inversely related to survival in critical care patients [1]. The objective of the present study was to evaluate the prevalence of thrombocytopenia in patients of an ICU and to determine whether it might be a significant predictor of outcome.
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- 2008
26. Conserved intron positions in ancient protein modules
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de Roos, Albert DG
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Research - Abstract
Background The timing of the origin of introns is of crucial importance for an understanding of early genome architecture. The Exon theory of genes proposed a role for introns in the formation of multi-exon proteins by exon shuffling and predicts the presence of conserved splice sites in ancient genes. In this study, large-scale analysis of potential conserved splice sites was performed using an intron-exon database (ExInt) derived from GenBank. Results A set of conserved intron positions was found by matching identical splice sites sequences from distantly-related eukaryotic kingdoms. Most amino acid sequences with conserved introns were homologous to consensus sequences of functional domains from conserved proteins including kinases, phosphatases, small GTPases, transporters and matrix proteins. These included ancient proteins that originated before the eukaryote-prokaryote split, for instance the catalytic domain of protein phosphatase 2A where a total of eleven conserved introns were found. Using an experimental setup in which the relation between a splice site and the ancientness of its surrounding sequence could be studied, it was found that the presence of an intron was positively correlated to the ancientness of its surrounding sequence. Intron phase conservation was linked to the conservation of the gene sequence and not to the splice site sequence itself. However, no apparent differences in phase distribution were found between introns in conserved versus non-conserved sequences. Conclusion The data confirm an origin of introns deep in the eukaryotic branch and is in concordance with the presence of introns in the first functional protein modules in an 'Exon theory of genes' scenario. A model is proposed in which shuffling of primordial short exonic sequences led to the formation of the first functional protein modules, in line with hypotheses that see the formation of introns integral to the origins of genome evolution. Reviewers This article was reviewed by Scott Roy (nominated by Anthony Poole), Sandro de Souza (nominated by Manyuan Long), and Gáspár Jékely.
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- 2007
27. Prognostic significance of serum creatinine in patients with acute coronary syndromes for prediction of inhospital mortality
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Mattos, MA, Toledo, DG, Mattos, CE, de Deus, FC, Assad, MHV, and Tura, BR
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Poster Presentation - Published
- 2005
28. Functional regulatory immune responses against human cartilage glycoprotein-39 in health versus proinflammatory responses in rheumatoid arthritis
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van Bilsen, JHM, van Dongen, H, Lard, LR, van der Voort, EIH, Elferink, DG, Bakker, AM, Miltenburg, AMM, Huizinga, TWJ, de Vries, RRP, and Toes, REM
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Poster Presentation - Published
- 2005
29. Primary angioplasty in a public hospital: initial results
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Mattos, MA, Toledo, DG, Mattos, CE, Abitbol, RA, Assad, MHV, Tura, BR, and Oliveira, OS
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Meeting Abstract - Published
- 2003
30. Hypoxaemia during tracheal suctioning; comparison of closed versus open techniques at varying PEEP
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Pogson, DG and Shirley, PJ
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Meeting Abstract - Published
- 2002
31. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial
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Sevene, E, Banda, CG, Mukaka, M, Maculuve, S, Macuacua, S, Vala, A, Piqueras, M, Kalilani-Phiri, L, Mallewa, J, Terlouw, DJ, Khoo, SH, Lalloo, DG, and Mwapasa, V
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Adult ,Cyclopropanes ,Male ,Drug–drug interactions ,Malawi ,lcsh:Arctic medicine. Tropical medicine ,Adolescent ,lcsh:RC955-962 ,Plasmodium falciparum ,Malària ,wa_395 ,wc_765 ,lcsh:Infectious and parasitic diseases ,Antimalarials ,Young Adult ,parasitic diseases ,qv_256 ,Humans ,lcsh:RC109-216 ,Nevirapine ,Malaria, Falciparum ,Mozambique ,wc_770 ,Human immunodeficiency virus ,Research ,Middle Aged ,Moçambic ,Artemisinins ,wc_750 ,Benzoxazines ,Malaria ,Drug Combinations ,Anti-Retroviral Agents ,Alkynes ,Antiretroviral drugs ,Quinolines ,Dihydroartemisinin–piperaquine ,Female - Abstract
Background HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Dihydroartemisinin–piperaquine (DPQ) is recommended for treatment of Plasmodium falciparum malaria, but its efficacy and safety has not been evaluated in HIV-infected individuals on ART, among whom drug–drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events were assessed in HIV-infected individuals on non-nucleoside reverse transcriptase inhibitor-based ART (efavirenz and nevirapine) with uncomplicated P. falciparum malaria treated with dihydroartemisinin–piperaquine. Methods An open label single arm clinical trial was conducted in Malawi (Blantyre and Chikhwawa districts) and Mozambique (Manhiça district) involving patients aged 15–65 years with uncomplicated P. falciparum malaria who were on efavirenz-based or nevirapine-based ART. They received a directly-observed 3-day standard treatment of DPQ and were followed up until day 63 for malaria infection and adverse events. Day-42 PCR-corrected-ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat (ITT) population. Results The study enrolled 160 and 61 patients on efavirenz and nevirapine-based ART, with a baseline geometric mean (95% CI) parasite density of 2681 (1964–3661) and 9819 (6606–14,593) parasites/µL, respectively. The day-42 PCR-corrected ACPR (95% CI) was 99.4% (95.6–99.9%) in the efavirenz group and 100% in the nevirapine group. Serious adverse events occurred in 5.0% (8/160) and 3.3% (2/61) of the participants in the efavirenz and nevirapine group, respectively, but none were definitively attributable to DPQ. Cases of prolonged QT interval (> 60 ms from baseline) occurred in 31.2% (48/154) and 13.3% (8/60) of the patients on the efavirenz and nevirapine ART groups, respectively. These were not clinically significant and resolved spontaneously over time. As this study was not designed to compare the efficacy and safety of DPQ in the two ART groups, no formal statistical comparisons were made between the two ART groups. Conclusions DPQ was highly efficacious and safe for the treatment of malaria in HIV-infected patients concurrently taking efavirenz- or nevirapine-based ART, despite known pharmacokinetic interactions between dihydroartemisinin–piperaquine and efavirenz- or nevirapine-based ART regimens. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013, https://pactr.samrc.ac.za/Search.aspx
32. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
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Rebbeck, TR, Friebel, TM, Mitra, N, Wan, F, Chen, S, Andrulis, IL, Apostolou, P, Arnold, N, Arun, BK, Barrowdale, D, Benitez, J, Berger, R, Berthet, P, Borg, A, Buys, SS, Caldes, T, Carter, J, Chiquette, J, Claes, KBM, Couch, FJ, Cybulski, C, Daly, MB, De La Hoya, M, Diez, O, Domchek, SM, Nathanson, KL, Durda, K, Ellis, S, EMBRACE, Evans, DG, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Hahnen, E, Hallberg, E, Hamann, U, Hansen, TVO, HEBON, Imyanitov, EN, Isaacs, C, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, John, EM, Karlan, BY, Kaufman, B, Investigators, K, Kwong, A, Laitman, Y, Lasset, C, Lazaro, C, Lester, J, Loman, N, Lubinski, J, Manoukian, S, Mitchell, G, Montagna, M, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Park, SK, Piedmonte, M, Radice, P, Rappaport-Fuerhauser, C, Rookus, MA, Seynaeve, C, Simard, J, Singer, CF, Soucy, P, Southey, M, Stoppa-Lyonnet, D, Sukiennicki, G, Szabo, CI, Tancredi, M, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Toloczko-Grabarek, A, Tung, N, Van Rensburg, EJ, Villano, D, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Zidan, J, Zorn, KK, McGuffog, L, Easton, D, Chenevix-Trench, G, Antoniou, AC, and Ramus, SJ
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skin and connective tissue diseases ,BRCA1 ,hereditary breast and ovarian cancer ,BRCA2 ,transheterozygosity ,3. Good health - Abstract
Background: Most $\textit{BRCA1}$ or $\textit{BRCA2}$ mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both $\textit{BRCA1}$ and $\textit{BRCA2}$ are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female $\textit{BRCA1/2}$ mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at $\textit{BRCA1}$ (SH1) or $\textit{BRCA2}$ (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; $p$ = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 ($p$ = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 ($p$ = 0.231), but was on average 4.5 years younger in TH than in SH2 ($p$ < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive ($p$ = 0.010) or progesterone receptor (PR) positive ($p$ = 0.013) than in SH1, but less likely to be ER positive ($p$ < 0.001) or PR positive ($p$ = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for $\textit{BRCA1}$ or $\textit{BRCA2}$ in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
33. The return-to-work process of individuals sick-listed because of whiplash-associated disorder: a three-year follow-up study in a Danish cohort of long-term sickness absentees.
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Biering-Sørensen, Sarah, Møller, Anne, Stoltenberg, Christian Dg, Holm, Jonas W, Skov, Peder G, and Stoltenberg, Christian D G
- Abstract
Background: The chronic course of whiplash-associated disorder (WAD) has implications for both the individual and society. It has been shown that up to 50% of patients have not yet returned to work six months after a whiplash injury. We wanted to study the return-to-work (RTW) process in individuals sick-listed for more than eight weeks in six Danish municipalities. RTW in individuals sick-listed due to WAD was compared to that in those sick-listed for other musculoskeletal disorders (MSD).Methods: Information about long-term sick-listed individuals in six Danish municipalities was retrieved from an existing database. Data on public transfer income were collected and the RTW process was followed on a weekly basis. Multivariate logistic regression analysis of RTW was done four times during the first three years after the start of sick-listing.Results: One hundred and four individuals were sick-listed due to WAD and 3,204 individuals were sick-listed due to other MSDs. After 6 months, the RTW was significantly lower in the WAD group. OR for RTW in the WAD group was 0.29 (0.18-0.49) compared to the MSD group. The RTW process for both groups stabilised after two years of follow-up; 44% returned to work in the WAD group as compared to 58% in the MSD group.Conclusion: Sick-listed individuals with whiplash-associated disorder are less likely to return to work than individuals who are sick-listed because of other musculoskeletal disorders. In both groups, RTW stabilised after two years of follow-up. [ABSTRACT FROM AUTHOR]- Published
- 2014
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34. Multifactorial intervention for children with asthma and overweight (Mikado): study design of a randomised controlled trial.
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Willeboordse, Maartje, van de Kant, Kim Dg, de Laat, Maroeska N, van Schayck, Onno Cp, Mulkens, Sandra, Dompeling, Edward, van de Kant, Kim D G, and van Schayck, Onno C P
- Abstract
Background: In children, the prevalence's of both obesity and asthma are disconcertingly high. Asthmatic children with obesity are characterised by less asthma control and a high need for asthma medication. As the obese asthmatic child is becoming more common in the clinical setting and the disease burden of the asthma-obesity phenotype is high, there is an increasing need for effective treatment in these children. In adults, weight reduction resulted in improved lung function, better asthma control and less need for asthma medication. In children this is hardly studied. The Mikado study aims to evaluate the effectiveness of a long term multifactorial weight reduction intervention, on asthma characteristics in children with asthma and a high body weight.Methods/design: The Mikado study is a two-armed, randomised controlled trial. In total, 104 participants will be recruited via online questionnaires, pulmonary paediatricians, the youth department of the Municipal Health Services and cohorts of existing studies. All participants will be aged 6-16 years, will have current asthma, a Body Mass Index in the overweight or obesity range, and no serious comorbidities (such as diabetes, heart diseases). Participants in the intervention arm will receive a multifactorial intervention of 18 months consisting of sessions concerning sports, parental involvement, individual counselling and lifestyle advices including dietary advices and cognitive behavioural therapy. The control group will receive usual care. The primary outcome variables will include Forced Expiratory Volume in one second and Body Mass Index - Standard Deviation Score. Secondary outcomes will include other lung function parameters (including dynamic and static lung function parameters), asthma control, asthma-specific quality of life, use of asthma medication and markers of systemic inflammation and airway inflammation.Discussion: In this randomised controlled trial we will study the potential of a multifactorial weight reduction intervention to improve asthma-related outcome measures in asthmatic children with overweight. Moreover, it will provide information about the underlying mechanisms in the relationship between asthma and a high body weight in children. These findings can contribute to optimal management programs and better clinical guidelines for children with asthma and overweight.Trial Registration: Clinicaltrial.gov NCT00998413. [ABSTRACT FROM AUTHOR]- Published
- 2013
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35. Decreased susceptibility of Neisseria gonorrhoeae isolates from Switzerland to Cefixime and Ceftriaxone: antimicrobial susceptibility data from 1990 and 2000 to 2012.
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Kovari, Helen, de Melo Oliveira, Maria Dg, Hauser, Paula, Läuchli, Severin, Meyer, Jürg, Weber, Rainer, and Zbinden, Reinhard
- Abstract
Background: Neisseria gonorrhoeae can rapidly develop resistance to antimicrobial agents. Over the last years, decreased gonococcal susceptibility to third-generation cephalosporins, especially cefixime, emerged worldwide. Therefore, current international guidelines recommend dual therapy for gonorrhoea with ceftriaxone plus either azithromycin or doxycycline. Gonococcal susceptibility data in Switzerland are sparse.Methods: We investigated the prevalence of antibiotic susceptibility of N. gonorrhoeae in specimens collected between 1990 and 2012 at the University of Zurich, Switzerland. Minimum inhibitory concentrations (MICs) for cefixime, ceftriaxone, ciprofloxacin, and penicillin were determined by Etests. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used to define reduced susceptibility.Results: A total of 320 isolates were tested. Between 1990 and 2006 all tested samples were susceptible to both cephalosporins. Subsequently, the prevalence of elevated MICs for cefixime increased to 10.4% (2007/2008), 11.5% (2009/2010), and 11.4% (2011/2012); and for ceftriaxone to 2.4% (2007/2008), 4.7% (2009/2010), and 0% (2011/2012), respectively. The prevalence of resistance to ciprofloxacin (72.7%) and penicillin (22.7%) was high in 2011/2012.Conclusions: Decreasing susceptibility of N. gonorrhoeae to third-generation cephalosporins in Switzerland supports treatment recommendations with ceftriaxone plus azithromycin or doxycycline. Health-care providers need to be aware of possible treatment failures with cephalosporins. Continued surveillance of gonococcal antimicrobial resistance is essential. [ABSTRACT FROM AUTHOR]- Published
- 2013
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36. Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review.
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van de Kant, Kim Dg, van der Sande, Linda Jtm, Jöbsis, Quirijn, van Schayck, Onno Cp, Dompeling, Edward, van de Kant, Kim D G, van der Sande, Linda J T M, and van Schayck, Onno C P
- Abstract
There is an increasing interest in the potential of exhaled biomarkers, such as volatile organic compounds (VOCs), to improve accurate diagnoses and management decisions in pulmonary diseases. The objective of this manuscript is to systematically review the current knowledge on exhaled VOCs with respect to their potential clinical use in asthma, lung cancer, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and respiratory tract infections. A systematic literature search was performed in PubMed, EMBASE, Cochrane database, and reference lists of retrieved studies. Controlled, clinical, English-language studies exploring the diagnostic and monitoring value of VOCs in asthma, COPD, CF, lung cancer and respiratory tract infections were included. Data on study design, setting, participant characteristics, VOCs techniques, and outcome measures were extracted. Seventy-three studies were included, counting in total 3,952 patients and 2,973 healthy controls. The collection and analysis of exhaled VOCs is non-invasive and could be easily applied in the broad range of patients, including subjects with severe disease and children. Various research groups demonstrated that VOCs profiles could accurately distinguish patients with a pulmonary disease from healthy controls. Pulmonary diseases seem to be characterized by a disease specific breath-print, as distinct profiles were found in patients with dissimilar diseases. The heterogeneity of studies challenged the inter-laboratory comparability. In conclusion, profiles of VOCs are potentially able to accurately diagnose various pulmonary diseases. Despite these promising findings, multiple challenges such as further standardization and validation of the diverse techniques need to be mastered before VOCs can be applied into clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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37. Rapid cell culture and pre-clinical screening of a transforming growth factor-beta (TGF-beta) inhibitor for orthopaedics.
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Schindeler A, Morse A, Peacock L, Mikulec K, Yu NY, Liu R, Kijumnuayporn S, McDonald MM, Baldock PA, Ruys AJ, Little DG, Schindeler, Aaron, Morse, Alyson, Peacock, Lauren, Mikulec, Kathy, Yu, Nicole Y C, Liu, Renjing, Kijumnuayporn, Sandy, McDonald, Michelle M, and Baldock, Paul A
- Abstract
Background: Transforming growth factor-beta (TGF-beta) and bone morphogenetic proteins (BMPs) utilize parallel and related signaling pathways, however the interaction between these pathways in bone remains unclear. TGF-beta inhibition has been previously reported to promote osteogenic differentiation in vitro, suggesting it may have a capacity to augment orthopaedic repair. We have explored this concept using an approach that represents a template for the testing of agents with prospective orthopaedic applications.Methods: The effects of BMP-2, TGF-beta1, and the TGF-beta receptor (ALK-4/5/7) inhibitor SB431542 on osteogenic differentiation were tested in the MC3T3-E1 murine pre-osteoblast cell line. Outcome measures included alkaline phosphatase staining, matrix mineralization, osteogenic gene expression (Runx2, Alp, Ocn) and phosphorylation of SMAD transcription factors. Next we examined the effects of SB431542 in two orthopaedic animal models. The first was a marrow ablation model where reaming of the femur leads to new intramedullary bone formation. In a second model, 20 microg rhBMP-2 in a polymer carrier was surgically introduced to the hind limb musculature to produce ectopic bone nodules.Results: BMP-2 and SB431542 increased the expression of osteogenic markers in vitro, while TGF-beta1 decreased their expression. Both BMP-2 and SB431542 were found to stimulate pSMAD1 and we also observed a non-canonical repression of pSMAD2. In contrast, neither in vivo system was able to provide evidence of improved bone formation or repair with SB431542 treatment. In the marrow ablation model, systemic dosing with up to 10 mg/kg/day SB431542 did not significantly increase reaming-induced bone formation compared to vehicle only controls. In the ectopic bone model, local co-administration of 38 microg or 192 microg SB431542 did not increase bone formation.Conclusions: ALK-4/5/7 inhibitors can promote osteogenic differentiation in vitro, but this may not readily translate to in vivo orthopaedic applications. [ABSTRACT FROM AUTHOR]- Published
- 2010
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38. Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease.
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Williams HR, Cox IJ, Walker DG, Cobbold JF, Taylor-Robinson SD, Marshall SE, Orchard TR, Williams, Horace R T, Cox, I Jane, Walker, David G, Cobbold, Jeremy F L, Taylor-Robinson, Simon D, Marshall, Sara E, and Orchard, Timothy R
- Abstract
Background: Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co-metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved.Methods: It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured.Results: Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007).Conclusions: Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD. [ABSTRACT FROM AUTHOR]- Published
- 2010
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39. Expression of the neuroprotective slow Wallerian degeneration (WldS) gene in non-neuronal tissues.
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Wishart TM, Brownstein DG, Thomson D, Tabakova AM, Boothe KM, Tsao JW, Gillingwater TH, Wishart, Thomas M, Brownstein, David G, Thomson, Derek, Tabakova, Anca M, Boothe, Katherine M, Tsao, Jack W, and Gillingwater, Thomas H
- Abstract
Background: The slow Wallerian Degeneration (Wld(S)) gene specifically protects axonal and synaptic compartments of neurons from a wide variety of degeneration-inducing stimuli, including; traumatic injury, Parkinson's disease, demyelinating neuropathies, some forms of motor neuron disease and global cerebral ischemia. The Wld(S) gene encodes a novel Ube4b-Nmnat1 chimeric protein (Wld(S) protein) that is responsible for conferring the neuroprotective phenotype. How the chimeric Wld(S) protein confers neuroprotection remains controversial, but several studies have shown that expression in neurons in vivo and in vitro modifies key cellular pathways, including; NAD biosynthesis, ubiquitination, the mitochondrial proteome, cell cycle status and cell stress. Whether similar changes are induced in non-neuronal tissue and organs at a basal level in vivo remains to be determined. This may be of particular importance for the development and application of neuroprotective therapeutic strategies based around Wld(S)-mediated pathways designed for use in human patients.Results: We have undertaken a detailed analysis of non-neuronal Wld(S) expression in Wld(S) mice, alongside gravimetric and histological analyses, to examine the influence of Wld(S) expression in non-neuronal tissues. We show that expression of Wld(S) RNA and protein are not restricted to neuronal tissue, but that the relative RNA and protein expression levels rarely correlate in these non-neuronal tissues. We show that Wld(S) mice have normal body weight and growth characteristics as well as gravimetrically and histologically normal organs, regardless of Wld(S) protein levels. Finally, we demonstrate that previously reported Wld(S)-induced changes in cell cycle and cell stress status are neuronal-specific, not recapitulated in non-neuronal tissues at a basal level.Conclusions: We conclude that expression of Wld(S) protein has no adverse effects on non-neuronal tissue at a basal level in vivo, supporting the possibility of its safe use in future therapeutic strategies targeting axonal and/or synaptic compartments in patients with neurodegenerative disease. Future experiments determining whether Wld(S) protein can modify responses to injury in non-neuronal tissue are now required. [ABSTRACT FROM AUTHOR]- Published
- 2009
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40. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency.
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Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA, Parr, David G, Dirksen, Asger, Piitulainen, Eeva, Deng, Chunqin, Wencker, Marion, and Stockley, Robert A
- Abstract
Background: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD).Methods: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment.Results: Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression.Conclusion: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.Trial Registration: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887. [ABSTRACT FROM AUTHOR]- Published
- 2009
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41. Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance.
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Dal-Bo M, Bertoni F, Forconi F, Zucchetto A, Bomben R, Marasca R, Deaglio S, Laurenti L, Efremov DG, Gaidano G, Del Poeta G, Gattei V, Dal-Bo, Michele, Bertoni, Francesco, Forconi, Francesco, Zucchetto, Antonella, Bomben, Riccardo, Marasca, Roberto, Deaglio, Silvia, and Laurenti, Luca
- Abstract
B-cell chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by extremely variable clinical courses with survivals ranging from 1 to more than 15 years. The pathogenetic factors playing a key role in defining the biological features of CLL cells, hence eventually influencing the clinical aggressiveness of the disease, are here divided into "intrinsic factors", mainly genomic alterations of CLL cells, and "extrinsic factors", responsible for direct microenvironmental interactions of CLL cells; the latter group includes interactions of CLL cells occurring via the surface B cell receptor (BCR) and dependent to specific molecular features of the BCR itself and/or to the presence of the BCR-associated molecule ZAP-70, or via other non-BCR-dependent interactions, e.g. specific receptor/ligand interactions, such as CD38/CD31 or CD49d/VCAM-1. A putative final model, discussing the pathogenesis and the clinicobiological features of CLL in relationship of these factors, is also provided. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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42. Evolutionary concepts in biobanking - the BC BioLibrary.
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Watson PH, Wilson-McManus JE, Barnes RO, Giesz SC, Png A, Hegele RG, Brinkman JN, Mackenzie IR, Huntsman DG, Junker A, Gilks B, Skarsgard E, Burgess M, Aparicio S, McManus BM, Watson, Peter H, Wilson-McManus, Janet E, Barnes, Rebecca O, Giesz, Sara C, and Png, Adrian
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Background: Medical research to improve health care faces a major problem in the relatively limited availability of adequately annotated and collected biospecimens. This limitation is creating a growing gap between the pace of scientific advances and successful exploitation of this knowledge. Biobanks are an important conduit for transfer of biospecimens (tissues, blood, body fluids) and related health data to research. They have evolved outside of the historical source of tissue biospecimens, clinical pathology archives. Research biobanks have developed advanced standards, protocols, databases, and mechanisms to interface with researchers seeking biospecimens. However, biobanks are often limited in their capacity and ability to ensure quality in the face of increasing demand. Our strategy to enhance both capacity and quality in research biobanking is to create a new framework that repatriates the activity of biospecimen accrual for biobanks to clinical pathology.Methods: The British Columbia (BC) BioLibrary is a framework to maximize the accrual of high-quality, annotated biospecimens into biobanks. The BC BioLibrary design primarily encompasses: 1) specialized biospecimen collection units embedded within clinical pathology and linked to a biospecimen distribution system that serves biobanks; 2) a systematic process to connect potential donors with biobanks, and to connect biobanks with consented biospecimens; and 3) interdisciplinary governance and oversight informed by public opinion.Results: The BC BioLibrary has been embraced by biobanking leaders and translational researchers throughout BC, across multiple health authorities, institutions, and disciplines. An initial pilot network of three Biospecimen Collection Units has been successfully established. In addition, two public deliberation events have been held to obtain input from the public on the BioLibrary and on issues including consent, collection of biospecimens and governance.Conclusion: The BC BioLibrary framework addresses common issues for clinical pathology, biobanking, and translational research across multiple institutions and clinical and research domains. We anticipate that our framework will lead to enhanced biospecimen accrual capacity and quality, reduced competition between biobanks, and a transparent process for donors that enhances public trust in biobanking. [ABSTRACT FROM AUTHOR]- Published
- 2009
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43. Trends in laboratory testing for diabetes in Ontario, Canada 1995-2005: a population-based study.
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Wilson SE, Lipscombe LL, Rosella LC, Manuel DG, Wilson, Sarah E, Lipscombe, Lorraine L, Rosella, Laura C, and Manuel, Douglas G
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Background: There are concerns that testing for type 2 diabetes is low and many people with diabetes are not diagnosed. We sought to describe the rates of diabetes-related lab testing in Ontario from 1995-2005, among adults without diabetes, and to explore the extent to which the Canadian clinical practice guidelines for screening are being followed.Methods: Descriptive counts of outpatient diabetes laboratory tests performed within Ontario's publicly funded, provincial health insurance program were recorded. The study population was Ontario residents, 20 years and older from 1995 to 2005 (9.3 million people in 2005). The Ontario Diabetes Database, a cumulative registry derived from administrative health records, was used to exclude people who had physician-diagnosed diabetes (n = 839,127 in 2005) from the primary analyses. Diabetes tests included serum blood glucose (SBG), hemoglobin A1c (HbA1c), and oral glucose tolerance tests (OGTT).Results: In 2005, 37% of Ontario adults without pre-existing diabetes were tested with an SBG test, a 28% increase from 1995. The age-adjusted proportion of adults without diabetes undergoing a HbA1c test increased from 1.7% in 1995 to 6.0% in 2005. In 2005, a similar number of HbA1c tests were performed for individuals with diabetes (483,746) and without diabetes (496,616) despite large differences in the two groups' denominators. Less than 1% of Ontarians underwent OGTT testing in any year between 1995-2005. Nearly two-thirds of adults age 40 years and over had an SBG test over a 3-year period (April 1, 2002-March 31, 2005), in accordance with the Canadian Diabetes Association recommendations.Conclusion: Diabetes testing is common and has increased over the last ten years. Despite its absence in Canada's diabetes screening recommendations, HbA1c testing among individuals without diabetes is increasing rapidly, and OGTT, which is recommended, is rarely performed. [ABSTRACT FROM AUTHOR]- Published
- 2009
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44. A controlled trial of value-based insurance design - the MHealthy: Focus on Diabetes (FOD) trial.
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Spaulding A, Fendrick AM, Herman WH, Stevenson JG, Smith DG, Chernew ME, Parsons DM, Bruhnsen K, Rosen AB, Spaulding, Alicen, Fendrick, A Mark, Herman, William H, Stevenson, James G, Smith, Dean G, Chernew, Michael E, Parsons, Dawn M, Bruhnsen, Keith, and Rosen, Allison B
- Abstract
Background: Diabetes affects over 20 million Americans, resulting in substantial morbidity, mortality, and costs. While medications are the cornerstone of secondary prevention, many evidence-based therapies are underutilized, and patients often cite out-of-pocket costs as the reason. Value-based insurance design (VBID) is a 'clinically sensitive' refinement to benefit design which links patient cost-sharing to therapy value; the more clinically beneficial (and valuable) a therapy is for a patient, the lower that patient's cost-sharing should be. We describe the design and implementation of MHealthy: Focus on Diabetes (FOD), a prospective, controlled trial of targeted co-payment reductions for high value, underutilized therapies for individuals with diabetes.Methods: The FOD trial includes 2,507 employees and dependents with diabetes insured by one large employer. Approximately 81% are enrolled in a single independent-practice association model health maintenance organization. The control group includes 8,637 patients with diabetes covered by other employers and enrolled in the same managed care organization. Both groups received written materials about the importance of adherence to secondary prevention therapies, while only the intervention group received targeted co-payment reductions for glycemic agents, antihypertensives, lipid-lowering agents, antidepressants, and diabetic eye exams. Primary outcomes include medication uptake and adherence. Secondary outcomes include health care utilization and expenditures. An interrupted time series, control group design will allow rigorous assessment of the intervention's impact, while controlling for unrelated temporal trends. Individual patient-level baseline data are presented.Discussion: To our knowledge, this is the first prospective controlled trial of co-payment reductions targeted to high-value services for high-risk patients. It will provide important information on feasibility of implementation and effectiveness of VBID in a real-world setting. This program has the potential for broad dissemination to other employers and insurers wishing to improve the value of their health care spending. [ABSTRACT FROM AUTHOR]- Published
- 2009
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45. Self-reported diabetes is associated with self-management behaviour: a cohort study.
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Shah BR, Manuel DG, Shah, Baiju R, and Manuel, Douglas G
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Background: The purposes of this cohort study were to establish how frequently people with physician-diagnosed diabetes self-reported the disease, to determine factors associated with self-reporting of diabetes, and to evaluate subsequent differences in self-management behaviour, health care utilisation and clinical outcomes between people who do and do not report their disease.Methods: We used a registry of physician-diagnosed diabetes as a reference standard. We studied respondents to a 2000/01 population-based health survey who were in the registry (n = 1,812), and we determined the proportion who reported having diabetes during the survey. Baseline factors associated with self-report and subsequent behavioural, utilisation and clinical differences between those who did and did not self-report were defined from the survey responses and from linkage with administrative data sources.Results: Only 75% of people with physician-diagnosed diabetes reported having the disease. People who did self-report were more likely to be male, to live in rural areas, to have longer disease duration and to have received specialist physician care. People who did not report having diabetes in the survey were markedly less likely to perform capillary blood glucose monitoring in the subsequent two years (OR 0.05, 95% CI 0.02 to 0.08). They were also less likely to receive specialist physician care (OR 0.55, 95% CI 0.37 to 0.86), and were less likely to require hospital care for hypo- or hyperglycaemia (OR 0.09, 95% CI 0.01 to 0.28).Conclusion: Many people with physician-diagnosed diabetes do not report having the disease, but most demographic and clinical features do not distinguish these individuals. These individuals are much less likely to perform capillary glucose monitoring, suggesting that their diabetes self-management is inadequate. Clinicians may be able to use the absence of glucose monitoring as a screening tool to identify people needing a detailed evaluation of their disease knowledge. [ABSTRACT FROM AUTHOR]- Published
- 2008
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46. Endorsement of the CONSORT Statement by high impact factor medical journals: a survey of journal editors and journal 'Instructions to Authors'.
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Hopewell S, Altman DG, Moher D, Schulz KF, Hopewell, Sally, Altman, Douglas G, Moher, David, and Schulz, Kenneth F
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Background: The CONSORT Statement provides recommendations for reporting randomized controlled trials. We assessed the extent to which leading medical journals that publish reports of randomized trials incorporate the CONSORT recommendations into their journal and editorial processes.Methods: This article reports on two observational studies. Study 1: We examined the online version of 'Instructions to Authors' for 165 high impact factor medical journals and extracted all text mentioning the CONSORT Statement or CONSORT extension papers. Any mention of the International Committee of Medical Journal Editors (ICMJE) or clinical trial registration were also sought and extracted. Study 2: We surveyed the editor-in-chief, or editorial office, for each of the 165 journals about their journal's endorsement of CONSORT recommendations and its incorporation into their editorial and peer-review processes.Results: Study 1: Thirty-eight percent (62/165) of journals mentioned the CONSORT Statement in their online 'Instructions to Authors'; of these 37% (23/62) stated this was a requirement, 63% (39/62) were less clear in their recommendations. Very few journals mentioned the CONSORT extension papers. Journals that referred to CONSORT were more likely to refer to ICMJE guidelines (RR 2.16; 95% CI 1.51 to 3.08) and clinical trial registration (RR 3.67; 95% CI 2.36 to 5.71) than those journals which did not.Study 2: Thirty-nine percent (64/165) of journals responded to the on-line survey, the majority were journal editors. Eighty-eight percent (50/57) of journals recommended authors comply with the CONSORT Statement; 62% (35/56) said they would require this. Forty-one percent (22/53) reported incorporating CONSORT into their peer-review process and 47% (25/53) into their editorial process. Eighty-one percent (47/58) reported including CONSORT in their 'Instructions to Authors' although there was some inconsistency when cross checking information on the journal's website. Sixty-nine percent (31/45) of journals recommended authors comply with the CONSORT extension for cluster trials, 60% (27/45) for harms and 42% (19/45) for non-inferiority and equivalence trials. Few journals mentioned these extensions in their 'Instructions to Authors'.Conclusion: Journals should be more explicit in their recommendations and expectations of authors regarding the CONSORT Statement and related CONSORT extensions papers. [ABSTRACT FROM AUTHOR]- Published
- 2008
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47. Self-care and adherence to medication: a survey in the hypertension outpatient clinic.
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Gohar F, Greenfield SM, Beevers DG, Lip GYH, and Jolly K
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- 2008
48. Activity of chemotherapy in mucinous ovarian cancer with a recurrence free interval of more than 6 months: results from the SOCRATES retrospective study.
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Pignata S, Ferrandina G, Scarfone G, Scollo P, Odicino F, Cormio G, Katsaros D, Villa A, Mereu L, Ghezzi F, Manzione L, Lauria R, Breda E, Alletti DG, Ballardini M, Lombardi AV, Sorio R, Mangili G, Priolo D, and Magni G
- Abstract
Background: Mucinous ovarian carcinoma have a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of chemotherapy in patients with platinum sensitive recurrent mucinous ovarian cancer.Methods: The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005. Patients with recurrent ovarian cancer with > 6 months of platinum free interval were considered eligible.Results: Twenty patients with mucinous histotype and 388 patients with other histotypes were analyzed. At baseline, mucinous tumours differed from the others for an higher number of patients with lower tumor grading (p = 0.0056) and less advanced FIGO stage (p = 0.025). At time of recurrence, a statistically significant difference was found in performance status (worse in mucinous, p = 0.024). About 20% of patients underwent secondary cytoreduction in both groups, but a lower number of patients were optimally debulked in the mucinous group (p = 0.03). Patients with mucinous cancer received more frequently single agent platinum than platinum based-combination therapy or other non-platinum schedules as second line therapy (p = 0.026), with a response rate lower than in non-mucinous group (36.4% vs 62.6%, respectively, p = 0.04). Median time to progression and overall survival were worse for mucinous ovarian cancer. Finally, mucinous cancer received a lower number of chemotherapy lines (p = 0.0023).Conclusion: This analysis shows that platinum sensitive mucinous ovarian cancer has a poor response to chemotherapy. Studies dedicated to this histological subgroup are needed. [ABSTRACT FROM AUTHOR]- Published
- 2008
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49. Role of carotid duplex imaging in carotid screening programmes - an overview.
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Saleem MA, Sadat U, Walsh SR, Young VE, Gillard JH, Cooper DG, Gaunt ME, Saleem, Muhammad A, Sadat, Umar, Walsh, Stewart R, Young, Victoria E, Gillard, Jonathan H, Cooper, David G, and Gaunt, Michael E
- Abstract
Background: Stroke is the third most common cause of death in the UK and the largest single cause of severe disability. Each year more than 110,000 people in England suffer from a stroke which costs the National Health Service (NHS) over GBP2.8 billion. Thus, it is imperative that patients at risk be screened for underlying carotid artery atherosclerosis.Aim: To assess the role of carotid ultrasound in different carotid screening programmes.Methods: A literature overview was carried out by using PubMed search engine, to identify different carotid screening programmes that had used ultrasound scan as a screening tool.Results: It appears that the carotid ultrasound is an effective method for screening carotid artery disease in community as it effectively predicts the presence of stenosis with high accuracy. There is a need for primary care to recommend high risk patients for regular screening, to reduce stroke and transient ischemic attack (TIA) related morbidity and mortality.Conclusion: Screening programmes using carotid ultrasonography contribute to public health awareness and promotion which in long term could potentially benefit in disease prevention and essentially promote better standards of healthcare. [ABSTRACT FROM AUTHOR]- Published
- 2008
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50. Low birthweight and preterm birth in young people with special educational needs: a magnetic resonance imaging analysis.
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Spencer MD, Moorhead TW, Gibson RJ, McIntosh AM, Sussmann JE, Owens DG, Lawrie SM, Johnstone EC, Spencer, Michael D, Moorhead, T William J, Gibson, Rod J, McIntosh, Andrew M, Sussmann, Jessika E D, Owens, David G C, Lawrie, Stephen M, and Johnstone, Eve C
- Abstract
Background: Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support.Methods: One hundred and thirty-seven participants aged 13-22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted.Results: A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (n = 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles.Conclusion: Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors. [ABSTRACT FROM AUTHOR]- Published
- 2008
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