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2. Biological phosphate removal from municipal wastewater

Author

Chalmers, E.

Subjects
628
Abstract

Phosphate removal from wastewater during treatment is a legal requirement to prevent environmental damage caused by releasing large amounts of nutrients into water courses. The most commonly applied removal methods, due to their ease of use, are based upon precipitation of the phosphate by chemical addition. An alternative method has been developed involving specialised micro-organisms, termed phosphate accumulating organisms (PAO), which take up and store greater than required amounts of phosphate. This process, designated enhanced biological phosphate removal (EBPR), has developed empirically since the observation that cycling the wastewater through anaerobic/aerobic phases selects for these PAO and the phosphate is removed from the liquid. There are still many aspects of the EBPR process that are far from fully understood; these include the identity of the organisms that are responsible for the phosphate uptake and the reasons why plants will occasionally stop removing phosphate. This project addresses these points, firstly by determining the effect of knockout and over-expression of ppk and ppx - genes known to be important in cellular polyphosphate metabolism in Pseudomonas putida, an organism found in sludge, which can accumulate polyphosphate. Previous mutational studies have mostly focused on Escherichia coli and Pseudomonas aeruginosa, which do not proliferate in sewage plants. The effect of the mutations upon growth, polyphosphate production and stress responses were ascertained. It appeared that two separate populations of polyphosphate were present, one being synthesized by polyphosphate kinase, the other by some as yet unidentified pathway. Further investigation of this 'large polyphosphate' established it was not polyphosphate but an unknown contaminating material that co-separated during the extraction procedure. Analysis of this compound suggested it was an exopolysaccharide, similar in character to alginate. The second aspect of the project focussed on the isolation of micro-organisms from a local EBPR plant followed by the selection, identification and characterization of potential PAOs. The development of a fully defined phosphate removing sludge community was attempted, in order to facilitate the study of the process. This was undertaken by operating a two litre bioreactor under EBPR conditions and allowing a self-selected community to develop from the inoculated isolates.

Published
2005

6. Assumptions and Expectations in Higher Education. Resource Allocation Management in Higher Education. Techniques: Use of Systems and Budgeting Methodology.

Author

National Association of College and University Business Officers, Washington, DC. and Chalmers, E. Laurence

Abstract

The assumptions and the expectations of the budgeting systems in higher education are presented in an attempt to clarify the magnitude of the task of setting up a budgetary methodology. The assumptions of effective budgeting should be identical to the purposes of the institutions that are served. Developing a system around the acquisition, storage, and transmission of knowledge, however, involves translating qualitative variables into quantitative ones such as credit hours or learning opportunities, support of faculty research, and public service functions. Even more controversial are the expectations people have about college and university systems and budgeting methodologies. There are three categories of people involved: the users, the distributors, and the providers of education. Each has varying perspectives and conflicting expectations. Users expect sensitivity and flexibility; distributors expect equity and efficiency; providers expect austerity and accountability. The financial officer must set up systems that attempt to satisfy all of these. (JMF)

Published
1972

17. International pediatric thrombosis network to advance pediatric thrombosis research: Communication from the ISTH SSC subcommittee on pediatric and neonatal thrombosis and hemostasis

Author

van Ommen, CH, Albisetti, M, Bhatt, M, Bonduel, M, Branchford, B, Chalmers, E, Chan, A, Goldenberg, NA, Holzhauer, S, Monagle, P, Nowak-Goettl, U, Revel-Vilk, S, Sciuccatie, G, Sirachainan, N, Male, C, van Ommen, CH, Albisetti, M, Bhatt, M, Bonduel, M, Branchford, B, Chalmers, E, Chan, A, Goldenberg, NA, Holzhauer, S, Monagle, P, Nowak-Goettl, U, Revel-Vilk, S, Sciuccatie, G, Sirachainan, N, and Male, C

Abstract

Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm-PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high-quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.

Published
2021

19. Long-term follow-up of neonatal intracranial haemorrhage in children with severe haemophilia

Author

Andersson, Nadine G., Wu, Runhui, Carcao, Manuel, Claeyssens-Donadel, S. golène, Kobelt, Rainer, Liesner, Ri, Mäkipernaa, Anne, Ranta, Susanna, Ljung, Rolf, Auerswald, G., Barnes, C., Chalmers, E., Chambost, H., Clausen, N., Dunn, A. L., Escuriola Ettinghausen, C., Fischer, K., Fijnvandraat, K., van Geet, C., Hoffmann, M., Kavakli, K., Kenet, G., Königs, C., Kurnik, K., Manco-Johnson, M., Mancuso, M. E., Molinari, C., Muntean, W., Nolan, B., Perez Garrido, R., Platokouki, E., Rafowicz, A., Santagostino, E., Shapiro, A., Thomas, A., Williams, M., Paediatric Haematology, and ARD - Amsterdam Reproduction and Development

Subjects
neonatal haematology, medicine.medical_specialty, Pediatrics, Hematology, Long term follow up, business.industry, Intracranial haemorrhage, MEDLINE, haemophilia, 030204 cardiovascular system & hematology, Haemophilia, medicine.disease, \sequelae, 03 medical and health sciences, 0302 clinical medicine, children, Internal medicine, medicine, business, 030215 immunology, intracranial haemorrhage
Published
2020

20. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

Author

Male, C., Lensing, A.W.A., Palumbo, J.S., Kumar, R., Nurmeev, I., Hege, K., Bonnet, D., Connor, P., Hooimeijer, H.L., Torres, M., Chan, A.K., Kenet, G., Holzhauer, S., Santamaria, A., Amedro, P., Chalmers, E., Simioni, P., Bhat, R.V., Yee, D.L., Lvova, O., Beyer-Westendorf, J., Biss, T.T., Martinelli, I., Saracco, P., Peters, M., Kallay, K., Gauger, C.A., Massicotte, M.P., Young, G., Pap, A.F., Majumder, M., Smith, W.T., Heubach, J.F., Berkowitz, S.D., Thelen, K., Kubitza, D., Crowther, M., Loo, D.M.W.M. te, Prins, M.H, Monagle, P., Male, C., Lensing, A.W.A., Palumbo, J.S., Kumar, R., Nurmeev, I., Hege, K., Bonnet, D., Connor, P., Hooimeijer, H.L., Torres, M., Chan, A.K., Kenet, G., Holzhauer, S., Santamaria, A., Amedro, P., Chalmers, E., Simioni, P., Bhat, R.V., Yee, D.L., Lvova, O., Beyer-Westendorf, J., Biss, T.T., Martinelli, I., Saracco, P., Peters, M., Kallay, K., Gauger, C.A., Massicotte, M.P., Young, G., Pap, A.F., Majumder, M., Smith, W.T., Heubach, J.F., Berkowitz, S.D., Thelen, K., Kubitza, D., Crowther, M., Loo, D.M.W.M. te, Prins, M.H, and Monagle, P.

Abstract

1 januari 2020, Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access), BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received >/=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved e

Published
2020

21. Rationale and design of a randomised controlled trial testing the effect of personalised diet in individuals with pre-diabetes or type 2 diabetes mellitus treated with metformin

Author

Htet, TD, Godneva, A, Liu, Z, Chalmers, E, Kolobkov, D, Snaith, JR, Richens, R, Toth, K, Danta, M, Hng, TM, Elinav, E, Segal, E, Greenfield, JR, Samocha-Bonet, D, Htet, TD, Godneva, A, Liu, Z, Chalmers, E, Kolobkov, D, Snaith, JR, Richens, R, Toth, K, Danta, M, Hng, TM, Elinav, E, Segal, E, Greenfield, JR, and Samocha-Bonet, D

Abstract

Introduction Metformin and diets aimed at promoting healthy body weight are the first line in treating type 2 diabetes mellitus (T2DM). Clinical practice, backed by clinical trials, suggests that many individuals do not reach glycaemic targets using this approach alone. The primary aim of the Personalised Medicine in Pre-diabetes-Towards Preventing Diabetes in Individuals at Risk (PREDICT) Study is to test the efficacy of personalised diet as adjuvant to metformin in improving glycaemic control in individuals with dysglycaemia. Methods and analysis PREDICT is a two-Arm, parallel group, single-masked randomised controlled trial in adults with pre-diabetes or early-stage T2DM (with glycated haemoglobin (HbA1c) up to 8.0% (64 mmol/mol)), not treated with glucose-lowering medication. PREDICT is conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney). Enrolment of participants commenced in December 2018 and expected to complete in December 2021. Participants are commenced on metformin (Extended Release, titrated to a target dose of 1500 mg/day) and randomised with equal allocation to either (1) the Personalised Nutrition Project algorithm-based diet or (2) low-fat high-dietary fibre diet, designed to provide caloric restriction (75%) in individuals with body mass index >25 kg/m 2. Treatment duration is 6 months and participants visit the Clinical Research Facility five times over approximately 7 months. The primary outcome measure is HbA1c. The secondary outcomes are (1) time of interstitial glucose <7.8 mmol/L and (2) glycaemic variability (continuous glucose monitoring), (3) body weight, (4) fat mass and (5) abdominal visceral fat volume (dual-energy X-ray absorptiometry), serum (6) low-density lipoprotein cholesterol (7) high-density lipoprotein cholesterol and (8) triglycerides concentrations, (9) blood pressure, and (10) liver fat (Fibroscan). Ethics and dissemination The study has been approved by the St Vincent's Hospital H

Published
2020

22. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT)

Author

Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, Coutinho, JM, Connor, P, van Kammen, MS, Lensing, AWA, Chalmers, E, Kallay, K, Hege, K, Simioni, P, Biss, T, Bajolle, F, Bonnet, D, Grunt, S, Kumar, R, Lvova, O, Bhat, R, Van Damme, A, Palumbo, J, Santamaria, A, Saracco, P, Payne, J, Baird, S, Godder, K, Labarque, V, Male, C, Martinelli, I, Soto, MM, Motwani, J, Shah, S, Hooimeijer, HL, Prins, MH, Kubitza, D, Smith, WT, Berkowitz, SD, Pap, AF, Majumder, M, Monagle, P, and Coutinho, JM

Abstract

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

Published
2020

23. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (Einstein-Jr CVT)

Author

Connor, P., van Kammen, M. S., Lensing, A. W. A., Chalmers, E., Kállay, K., Hege, K., Simioni, P., Biss, T., Bajolle, F., Bonnet, D., Grunt, S., Kumar, R., Lvova, O., Bhat, R., van Damme, A., Palumbo, J., Santamaria, A., Saracco, P., Payne, J., Baird, S., Godder, K., Labarque, V., Male, C., Martinelli, I., Soto, M. M., Motwani, J., Shah, S., Hooimeijer, H. L., Prins, M. H., Kubitza, D., Smith, W. T., Berkowitz, S. D., Pap, A. F., Majumder, M., Monagle, P., Coutinho, J. M., EINSTEIN-Jr, Cerebral, Venous, Thrombosis, trial, investigators, Connor, P., van Kammen, M. S., Lensing, A. W. A., Chalmers, E., Kállay, K., Hege, K., Simioni, P., Biss, T., Bajolle, F., Bonnet, D., Grunt, S., Kumar, R., Lvova, O., Bhat, R., van Damme, A., Palumbo, J., Santamaria, A., Saracco, P., Payne, J., Baird, S., Godder, K., Labarque, V., Male, C., Martinelli, I., Soto, M. M., Motwani, J., Shah, S., Hooimeijer, H. L., Prins, M. H., Kubitza, D., Smith, W. T., Berkowitz, S. D., Pap, A. F., Majumder, M., Monagle, P., Coutinho, J. M., and EINSTEIN-Jr, Cerebral, Venous, Thrombosis, trial, investigators

Abstract

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], 22.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, 26.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843. © 2020 by The American Society of Hematology

Published
2020

24. Long-term follow-up of neonatal intracranial haemorrhage in children with severe haemophilia

Author

Poli Van Creveldkliniek Medisch, Child Health, Circulatory Health, Andersson, Nadine G., Wu, Runhui, Carcao, Manuel, Claeyssens-Donadel, Ségolène, Kobelt, Rainer, Liesner, Ri, Mäkipernaa, Anne, Ranta, Susanna, Ljung, Rolf, Auerswald, G., Barnes, C., Chalmers, E., Chambost, H., Clausen, N., Dunn, A. L., Escuriola Ettinghausen, C., Fischer, K., Fijnvandraat, K., van Geet, C., Hoffmann, M., Kavakli, K., Kenet, G., Königs, C., Kurnik, K., Manco-Johnson, M., Mancuso, M. E., Molinari, C., Muntean, W., Nolan, B., Perez Garrido, R., Platokouki, E., Rafowicz, A., Santagostino, E., Shapiro, A., Thomas, A., Williams, M., Poli Van Creveldkliniek Medisch, Child Health, Circulatory Health, Andersson, Nadine G., Wu, Runhui, Carcao, Manuel, Claeyssens-Donadel, Ségolène, Kobelt, Rainer, Liesner, Ri, Mäkipernaa, Anne, Ranta, Susanna, Ljung, Rolf, Auerswald, G., Barnes, C., Chalmers, E., Chambost, H., Clausen, N., Dunn, A. L., Escuriola Ettinghausen, C., Fischer, K., Fijnvandraat, K., van Geet, C., Hoffmann, M., Kavakli, K., Kenet, G., Königs, C., Kurnik, K., Manco-Johnson, M., Mancuso, M. E., Molinari, C., Muntean, W., Nolan, B., Perez Garrido, R., Platokouki, E., Rafowicz, A., Santagostino, E., Shapiro, A., Thomas, A., and Williams, M.

Published
2020

27. Management of Inherited Bleeding Disorders in Pregnancy (Green-top Guideline No. 71)

Author

Pavord, S., Rayment, R., Madan, B., Cumming, A., Lester, W., Chalmers, E., Myers, B., Maybury, H., Tower, C., and Kadir, R. A.

Subjects
lcsh:R, lcsh:Medicine
Abstract

Это руководство предназначено как для специалистов-гематологов, так и для акушеров, которые имеют опыт ведения беременных с нарушениями свертываемости крови. Кроме того, эти рекомендации могут быть полезными для анестезиологов в акушерстве и неонатологов. Женщины, унаследовавшие нарушения свертываемости крови, могут подвергаться значительному риску кровотечения после выкидышей, абортов, дородовых процедур и родов. Они требуют индивидуального мультидисциплинарного специализированного ухода с перекрестной коммуникацией специалистов, в том числе анестезиологов и неонатологов при необходимости. Был достигнут прогресс в выявлении акушерских проблем у этих женщин и повышении уровня осведомленности об оказании медицинской помощи среди работников здравоохранения. Конкретные аспекты их ведения в акушерстве включают консультирование на этапе преконцепционной подготовки, пренатальную диагностику (ПНД), антенатальный, внутриутробный и послеродовой уход и немедленную помощь новорожденному.

Published
2017

31. Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds

Author

Andersson, NG, Chalmers, EA, Kenet, G, Ljung, R, Makipernaa, A, Chambost, H, Roca, CA, Roman, MTA, Buhrlen, M, van den Berg, HM, Chalmers, E, Cid, AR, Claeyssens, S, Escuriola, C, Fischer, K, Van Geet, C, Kobelt, R, Konigs, C, Kurnik, K, Liesner, R, Molinari, A, Muntean, W, Nolan, B, Oldenburg, J, Garrido, RP, Platokouki, H, Rafowicz, A, Ranta, S, Santagostino, E, Mancuso, ME, Bonomi, AB, Mikkelsen, TS, Thomas, A, Williams, M, Carcao, M, Rivard, G, and PedNet Haemophilia Res Fdn

Abstract

The optimal mode of delivery for a pregnant hemophilia carrier is still a matter of debate. The aim of the study was to determine the incidence of intracranial hemorrhage and other major bleeds in neonates with moderate and severe hemophilia in relationship to mode of delivery and known family history. A total of 926 neonates, 786 with severe and 140 with moderate hemophilia were included in this PedNet multicenter study. Vaginal delivery was performed in 68.3% (n=633) and Cesarean section in 31.6% (n=293). Twenty intracranial hemorrhages (2.2%) and 44 other major bleeds (4.8%) occurred. Intracranial hemorrhages occurred in 2.4% of neonates following vaginal delivery compared to 1.7% after Cesarean section (P=not significant); other major bleeds occurred in 4.2% born by vaginal delivery and in 5.8% after Cesarean section (P=not significant). Further analysis of subgroups (n=813) identified vaginal delivery with instruments being a significant risk factor for both intracranial hemorrhages and major bleeds (Relative Risk: 4.78-7.39; P

Published
2019

45. Comprehensive cancer-predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

Author

Whitworth, J, Smith, PS, Martin, J-E, West, H, Luchetti, A, Rodger, F, Clark, G, Carss, K, Stephens, J, Stirrups, K, Penkett, C, Mapeta, R, Ashford, S, Megy, K, Shakeel, H, Ahmed, M, Adlard, J, Barwell, J, Brewer, C, Casey, RT, Armstrong, R, Cole, T, Evans, DG, Fostira, F, Greenhalgh, L, Hanson, H, Henderson, A, Hoffman, J, Izatt, L, Kumar, A, Kwong, A, Lalloo, F, Ong, KR, Paterson, J, Park, S-M, Chen-Shtoyerman, R, Searle, C, Side, L, Skytte, A-B, Snape, K, Woodward, ER, Tischkowitz, MD, Maher, ER, Aitman, T, Alachkar, H, Ali, S, Allen, L, Allsup, D, Ambegaonkar, G, Anderson, J, Antrobus, R, Arno, G, Arumugakani, G, Astle, W, Attwood, A, Austin, S, Bacchelli, C, Bakchoul, T, Bariana, TK, Baxendale, H, Bennett, D, Bethune, C, Bibi, S, Bitner-Glindzicz, M, Bleda, M, Boggard, H, Bolton-Maggs, P, Booth, C, Bradley, JR, Brady, A, Brown, M, Browning, M, Bryson, C, Burns, S, Calleja, P, Canham, N, Carmichael, J, Caulfield, M, Chalmers, E, Chandra, A, Chinnery, P, Chitre, M, Church, C, Clement, E, Clements-Brod, N, Clowes, V, Coghlan, G, Collins, P, Cookson, V, Cooper, N, Corris, P, Creaser-Myers, A, Dacosta, R, Daugherty, L, Davies, S, Davis, J, De Vries, M, Deegan, P, Deevi, SVV, Deshpande, C, Devlin, L, Dewhurst, E, Dixon, P, Doffinger, R, Dormand, N, Drewe, E, Edgar, D, Egner, W, Erber, WN, Erwood, M, Everington, T, Favier, R, Firth, H, Fletcher, D, Flinter, F, Frary, A, Freson, K, Furie, B, Furnell, A, Gale, D, Gardham, A, Gattens, M, Ghali, N, Ghataorhe, PK, Ghurye, R, Gibbs, S, Gilmour, K, Gissen, P, Goddard, S, Gomez, K, Gordins, P, Graf, S, Gräf, S, Greene, D, Greenhalgh, A, Greinacher, A, Grigoriadou, S, Grozeva, D, Hackett, S, Hadinnapola, C, Hague, R, Haimel, M, Halmagyi, C, Hammerton, T, Hart, D, Hayman, G, Heemskerk, JWM, Henderson, R, Hensiek, A, Henskens, Y, Herwadkar, A, Holden, S, Holder, M, Holder, S, Hu, F, Veld, A, Huissoon, A, Humbert, M, Hurst, J, James, R, Jolles, S, Josifova, D, Kazmi, R, Keeling, D, Kelleher, P, Kelly, AM, Kennedy, F, Kiely, D, Kingston, N, Koziell, A, Krishnakumar, D, Kuijpers, TW, Kuijpers, T, Kumararatne, D, Kurian, M, Laffan, MA, Lambert, MP, Allen, HL, Lango-Allen, H, Lawrie, A, Lear, S, Lees, M, Lentaigne, C, Liesner, R, Linger, R, Longhurst, H, Lorenzo, L, Louka, E, Machado, R, Ross, RM, Maclaren, R, Maher, E, Maimaris, J, Mangles, S, Manson, A, Markus, HS, Martin, J, Masati, L, Mathias, M, Matser, V, Maw, A, McDermott, E, McJannet, C, Meacham, S, Meehan, S, Mehta, S, Michaelides, M, Millar, CM, Moledina, S, Moore, A, Morrell, N, Mumford, A, Murng, S, Murphy, E, Nejentsev, S, Noorani, S, Nurden, P, Oksenhendler, E, Othman, S, Ouwehand, WH, Papadia, S, Parker, A, Pasi, J, Patch, C, Payne, J, Peacock, A, Peerlinck, K, Penkett, CJ, Pepke-Zaba, J, Perry, D, Perry, DJ, Pollock, V, Polwarth, G, Ponsford, M, Qasim, W, Quinti, I, Rankin, S, Rankin, J, Raymond, FL, Rayner-Matthews, P, Rehnstrom, K, Reid, E, Rhodes, CJ, Richards, M, Richardson, S, Richter, A, Roberts, I, Rondina, M, Rosser, E, Roughley, C, Roy, N, Rue-Albrecht, K, Samarghitean, C, Sanchis-Juan, A, Sandford, R, Santra, S, Sargur, R, Savic, S, Schotte, G, Schulman, S, Schulze, H, Scott, R, Scully, M, Seneviratne, S, Sewell, C, Shamardina, O, Shipley, D, Simeoni, I, Sivapalaratnam, S, Smith, KGC, Sohal, A, Southgate, L, Staines, S, Staples, E, Stark, H, Stauss, H, Stein, P, Stock, S, Suntharalingam, J, Talks, K, Tan, Y, Thachil, J, Thaventhiran, J, Thomas, E, Thomas, M, Thompson, D, Thrasher, A, Tischkowitz, M, Titterton, C, Toh, C-H, Toshner, M, Treacy, C, Trembath, R, Tuna, S, Turek, W, Turro, E, Van Geet, C, Veltman, M, Vogt, J, Von Ziegenweldt, J, Noordegraaf, AV, Wakeling, E, Wanjiku, I, Warner, TQ, Wassmer, E, Watkins, H, Watt, C, Webster, N, Welch, S, Westbury, S, Wharton, J, Whitehorn, D, Wilkins, M, Willcocks, L, Williamson, C, Woods, G, Wort, J, Yeatman, N, Yong, P, Young, T, and Yu, P

Abstract

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Published
2018
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46. Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data

Author

Farmery, JHR, Smith, ML, Lynch, AG, Huissoon, A, Furnell, A, Mead, A, Levine, AP, Manzur, A, Thrasher, A, Greenhalgh, A, Parker, A, Sanchis-Juan, A, Richter, A, Gardham, A, Lawrie, A, Sohal, A, Creaser-Myers, A, Frary, A, Greinacher, A, Themistocleous, A, Peacock, AJ, Marshall, A, Mumford, A, Rice, A, Webster, A, Brady, A, Koziell, A, Manson, A, Chandra, A, Hensiek, A, In't Veld, AH, Maw, A, Kelly, AM, Moore, A, Noordegraaf, AV, Attwood, A, Herwadkar, A, Ghofrani, A, Houweling, AC, Girerd, B, Furie, B, Treacy, CM, Millar, CM, Sewell, C, Roughley, C, Titterton, C, Williamson, C, Hadinnapola, C, Deshpande, C, Toh, C-H, Bacchelli, C, Patch, C, Van Geet, C, Babbs, C, Bryson, C, Penkett, CJ, Rhodes, CJ, Watt, C, Bethune, C, Booth, C, Lentaigne, C, McJannet, C, Church, C, French, C, Samarghitean, C, Halmagyi, C, Gale, D, Greene, D, Hart, D, Allsup, D, Bennett, D, Edgar, D, Kiely, DG, Gosal, D, Perry, DJ, Keeling, D, Montani, D, Shipley, D, Whitehorn, D, Fletcher, D, Krishnakumar, D, Grozeva, D, Kumararatne, D, Thompson, D, Josifova, D, Maher, E, Wong, EKS, Murphy, E, Dewhurst, E, Louka, E, Rosser, E, Chalmers, E, Colby, E, Drewe, E, McDermott, E, Thomas, E, Staples, E, Clement, E, Matthews, E, Wakeling, E, Oksenhendler, E, Turro, E, Reid, E, Wassmer, E, Raymond, FL, Hu, F, Kennedy, F, Soubrier, F, Flinter, F, Kovacs, G, Polwarth, G, Ambegaonkar, G, Arno, G, Hudson, G, Woods, G, Coghlan, G, Hayman, G, Arumugakani, G, Schotte, G, Cook, HT, Alachkar, H, Allen, HL, Lango-Allen, H, Stark, H, Stauss, H, Schulze, H, Boggard, HJ, Baxendale, H, Dolling, H, Firth, H, Gall, H, Watson, H, Longhurst, H, Markus, HS, Watkins, H, Simeoni, I, Emmerson, I, Roberts, I, Quinti, I, Wanjiku, I, Gibbs, JSR, Thaventhiran, J, Whitworth, J, Hurst, J, Collins, J, Suntharalingam, J, Payne, J, Thachil, J, Martin, JM, Martin, J, Carmichael, J, Maimaris, J, Paterson, J, Pepke-Zaba, J, Heemskerk, JWM, Gebhart, J, Davis, J, Pasi, J, Bradley, JR, Wharton, J, Stephens, J, Rankin, J, Anderson, J, Vogt, J, Von Ziegenweldt, J, Rehnstrom, K, Megy, K, Talks, K, Peerlinck, K, Yates, K, Freson, K, Stirrups, K, Gomez, K, Smith, KGC, Carss, K, Rue-Albrecht, K, Gilmour, K, Masati, L, Scelsi, L, Southgate, L, Ranganathan, L, Ginsberg, L, Devlin, L, Willcocks, L, Ormondroyd, L, Lorenzo, L, Harper, L, Allen, L, Daugherty, L, Chitre, M, Kurian, M, Humbert, M, Tischkowitz, M, Bitner-Glindzicz, M, Erwood, M, Scully, M, Veltman, M, Caulfield, M, Layton, M, McCarthy, M, Ponsford, M, Toshner, M, Bleda, M, Wilkins, M, Mathias, M, Reilly, M, Afzal, M, Brown, M, Rondina, M, Stubbs, M, Haimel, M, Lees, M, Laffan, MA, Browning, M, Gattens, M, Richards, M, Michaelides, M, Lambert, MP, Makris, M, De Vries, M, Mahdi-Rogers, M, Saleem, M, Thomas, M, Holder, M, Eyries, M, Clements-Brod, N, Canham, N, Dormand, N, Van Zuydam, N, Kingston, N, Ghali, N, Cooper, N, Morrell, NW, Yeatman, N, Roy, N, Shamardina, O, Alavijeh, OS, Gresele, P, Nurden, P, Chinnery, P, Deegan, P, Yong, P, Yu-Wai-Man, P, Corris, PA, Calleja, P, Gissen, P, Bolton-Maggs, P, Rayner-Matthews, P, Ghataorhe, PK, Gordins, P, Stein, P, Collins, P, Dixon, P, Kelleher, P, Ancliff, P, Yu, P, Tait, RC, Linger, R, Doffinger, R, Machado, R, Kazmi, R, Sargur, R, Favier, R, Tan, R, Liesner, R, Antrobus, R, Sandford, R, Scott, R, Trembath, R, Horvath, R, Hadden, R, MackenzieRoss, RV, Henderson, R, MacLaren, R, James, R, Ghurye, R, DaCosta, R, Hague, R, Mapeta, R, Armstrong, R, Noorani, S, Murng, S, Santra, S, Tuna, S, Johnson, S, Chong, S, Lear, S, Walker, S, Goddard, S, Mangles, S, Westbury, S, Mehta, S, Hackett, S, Nejentsev, S, Moledina, S, Bibi, S, Meehan, S, Othman, S, Revel-Vilk, S, Holden, S, McGowan, S, Staines, S, Savic, S, Burns, S, Grigoriadou, S, Papadia, S, Ashford, S, Schulman, S, Ali, S, Park, S-M, Davies, S, Stock, S, Deevi, SVV, Graf, S, Ghio, S, Wort, SJ, Jolles, S, Austin, S, Welch, S, Meacham, S, Rankin, S, Seneviratne, S, Holder, S, Sivapalaratnam, S, Richardson, S, Kuijpers, T, Kuijpers, TW, Bariana, TK, Bakchoul, T, Everington, T, Renton, T, Young, T, Aitman, T, Warner, TQ, Vale, T, Hammerton, T, Pollock, V, Matser, V, Cookson, V, Clowes, V, Qasim, W, Wei, W, Erber, WN, Ouwehand, WH, Astle, W, Egner, W, Turek, W, Henskens, Y, Tan, Y, Lynch, Andy G [0000-0002-7876-7338], Apollo - University of Cambridge Repository, Medical Research Council (MRC), and British Heart Foundation

Subjects
Whole genome sequencing, 0303 health sciences, Multidisciplinary, Science & Technology, lcsh:R, lcsh:Medicine, Computational biology, Biology, Telomere, Multidisciplinary Sciences, 03 medical and health sciences, 0302 clinical medicine, NIHR BioResource - Rare Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, lcsh:Q, Ploidy, lcsh:Science, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018 The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man. In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article. These errors have now been corrected in the HTML and PDF versions of the Article.

Published
2018

47. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee

Author

Collins, P., Liesner, R., Makris, M., Talks, K., Chowdary, P., Chalmers, E., Hall, G., Percy, C., Hay, C., and Hart, D.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, hemic and lymphatic diseases
Abstract

Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co‐administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors’ Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018.

Published
2018

48. PRO146 HEALTH-RELATED QUALITY OF LIFE AND PRODUCTIVITY/ACTIVITY IMPAIRMENT IN PATIENTS WITH TRANSFUSION DEPENDENT B-THALASSAEMIA IN THE UK NHS: DATA FROM A UK MULTICENTRE OBSERVATIONAL STUDY

Author

Ryan, K., primary, Pancham, S., additional, Telfer, P., additional, Shah, F., additional, Kell, J., additional, Pollard, S., additional, Wynn, R., additional, Velangi, M., additional, Chalmers, E., additional, Hickey, J., additional, Paramore, C., additional, and Jobanputra, M., additional

Published
2019
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