77 results on '"Gath J"'
Search Results
2. Cancer, Fertility and Me : Developing and Testing a Novel Fertility Preservation Patient Decision Aid to Support Women at Risk of Losing Their Fertility Because of Cancer Treatment
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Jones, G.L., Moss, R.H., Darby, F., Mahmoodi, N., Phillips, B., Hughes, J., Vogt, K.S., Greenfield, D.M., Brauten-Smith, G., Gath, J., Campbell, T., Stark, D., Velikova, G., Snowden, J.A., Baskind, E., Mascerenhas, M., Yeomanson, D., Skull, J., Lane, S., Bekker, H.L., and Anderson, R.A.
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Cancer Research ,Oncology ,patient decision aid ,fertility preservation ,cancer ,women ,gonadotoxic treatment ,survivorship ,mixed-method study - Abstract
BackgroundWomen with a new cancer diagnosis face complex decisions about interventions aiming to preserve their fertility. Decision aids are more effective in supporting decision making than traditional information provision. We describe the development and field testing of a novel patient decision aid designed to support women to make fertility preservation treatment decisions around cancer diagnosis.MethodsA prospective, mixed-method, three stage study involving: 1) co-development of the resource in collaboration with a multi-disciplinary group of key stakeholders including oncology and fertility healthcare professionals and patient partners (n=24), 2) alpha testing with a group of cancer patients who had faced a fertility preservation treatment decision in the past (n=11), and oncology and fertility healthcare professionals and stakeholders (n=14) and, 3) beta testing with women in routine care who had received a recent diagnosis of cancer and were facing a fertility preservation treatment decision (n=41) and their oncology and fertility healthcare professionals (n=3). Ten service users recruited from a closed Breast Cancer Now Facebook group and the support group Cancer and Fertility UK also provided feedback on CFM via an online survey.ResultsA 60-page paper prototype of the Cancer, Fertility and Me patient decision aid was initially developed. Alpha testing of the resource found that overall, it was acceptable to cancer patients, healthcare professionals and key stakeholders and it was considered a useful resource to support fertility preservation treatment decision-making. However, the healthcare professionals felt that the length of the patient decision aid, and elements of its content may be a barrier to its use. Subsequently, the prototype was reduced to 40 pages. During beta testing of the shortened version in routine care, women who received the resource described its positive impact on their ability to make fertility preservation decisions and support them at a stressful time. However, practical difficulties emerged which impacted upon its wider dissemination in clinical practice and limited some elements of the evaluation planned.DiscussionWomen receiving the decision aid within the cancer treatment pathway found it helped them engage with decisions about fertility preservation, and make better informed, values-based care plans with oncology and fertility teams. More work is needed to address access and implementation of this resource as part of routine oncology care pathways.
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- 2022
3. Bridging the age gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer
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Ring, A., Battisti, N.M.L., Reed, M.W.R., Herbert, E., Morgan, J.L., Bradburn, M., Walters, S.J., Collins, K.A., Ward, S.E., Holmes, G.R., Burton, Maria, Lifford, K., Edwards, A., Robinson, T.G., Martin, C., Chater, T., Pemberton, K.J., Brennan, A., Cheung, K.L., Todd, A., Audisio, R.A., Wright, J., Simcock, R., Green, T., Revell, D., Gath, J., Horgan, K., Holcombe, C., Winter, M.C., Naik, J., Parmeshwar, R., Gosney, M.A., Hatton, M.Q., Thompson, A.M., Wyld, L., Collins, K., Ward, S., Holmes, G., Morgan, J., Walters, S., Burton, M., Brain, K., Robinson, T., Pemberton, K., Shrestha, A., Nettleship, A., Richards, P., Harder, H., Audisio, R., Murray, C., Thomson, A.M., Gosney, M., Hatton, M., Armitage, F., Patnick, J., Revill, D., and Winter, M.
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Oncology ,Bridged-Ring Compounds ,medicine.medical_specialty ,Cancer Research ,medicine.medical_treatment ,Breast Neoplasms ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Quality of life ,Drug Therapy ,Trastuzumab ,Internal medicine ,medicine ,Chemotherapy ,Humans ,Anthracyclines ,030212 general & internal medicine ,Prospective Studies ,Stage (cooking) ,Propensity Score ,Aged ,Aged, 80 and over ,business.industry ,Hazard ratio ,Cancer ,medicine.disease ,Survival Analysis ,Treatment Outcome ,Patient Satisfaction ,030220 oncology & carcinogenesis ,Quality of Life ,Observational study ,Female ,Taxoids ,business ,medicine.drug ,Cohort study - Abstract
Background Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy. Methods A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage. Results Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19–0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20–0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08–0.49];BCSS: HR 0.12 [95% CI 0.03–0.44]).Transient negative quality-of-life impacts were observed. Conclusions Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient. Trial Registration ISRCTN 46099296
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- 2021
4. Bridging the age gap in breast cancer: cluster randomized trial of the effects of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices
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Wyld, L., Reed, M.W.R., Collins, K., Burton, M., Lifford, K., Edwards, A., Ward, S., Holmes, G., Morgan, J., Bradburn, M., Walters, S.J., Ring, A., Robinson, T.G., Martin, C., Chater, T., Pemberton, K., Shrestha, A., Nettleship, A., Murray, C., Brown, M., Richards, P., Cheung, K.L., Todd, A., Harder, H., Brain, K., Audisio, R.A., Wright, J., Simcock, R., Armitage, F., Bursnall, M., Green, T., Revell, D., Gath, J., Horgan, K., Holcombe, C., Winter, M., Naik, J., Parmeshwar, R., Gosney, M., Hatton, M., and Thompson, A.M.
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Surgery - Abstract
Background\ud \ud Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice.\ud \ud \ud Methods\ud \ud A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice.\ud \ud \ud Results\ud \ud A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference –0.20, 95 per cent confidence interval (C.I.) –2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference –4.5 (C.I. –8.0 to 0) per cent; P = 0.013). Survival was similar in both arms.\ud \ud \ud Conclusion\ud \ud The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection.\ud \ud \ud Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).
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- 2021
5. Observational cohort study to determine the degree and causes of variation in the rate of surgery or primary endocrine therapy in older women with operable breast cancer
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Morgan, J.L., Holmes, G., Ward, S., Martin, C., Burton, M., Walters, S.J., Cheung, K.L., Audisio, R.A., Reed, M.W.R., Wyld, L., Collins, K., Lifford, K., Edwards, A., Brain, K., Ring, A., Robinson, T., Chater, T., Pemberton, K., Shrestha, A., Nettleship, A., Richards, P., Todd, A., Harder, H., Wright, J., Simcock, R., Murray, C., Green, T., Revill, D., Gath, J., Horgan, K., Holcombe, C., Naik, J., and Parmeshwar, R.
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Background\ud \ud In the UK there is variation in the treatment of older women with breast cancer, with up to 40% receiving primary endocrine therapy (PET), which is associated with inferior survival. Case mix and patient choice may explain some variation in practice but clinician preference may also be important.\ud \ud \ud \ud Methods\ud \ud A multicentre prospective cohort study of women aged >70 with operable breast cancer. Patient characteristics (health status, age, tumour characteristics, treatment allocation and decision-making preference) were analysed to identify whether treatment variation persisted following case-mix adjustment. Expected case-mix adjusted surgery rates were derived by logistic regression using the variables age, co-morbidity, tumour stage and grade. Concordance between patients’ preferred and actual decision-making style was assessed and associations between age, treatment and decision-making style calculated.\ud \ud \ud \ud Results\ud \ud Women (median age 77, range 70–102) were recruited from 56 UK breast units between 2013 and 2018. Of 2854/3369 eligible women with oestrogen receptor positive breast cancer, 2354 were treated with surgery and 500 with PET. Unadjusted surgery rates varied between hospitals, with 23/56 units falling outside the 95% confidence intervals on funnel plots. Adjusting for case mix reduced, but did not eliminate, this variation between hospitals (10/56 units had practice outside the 95% confidence intervals). Patients treated with PET had more patient-centred decisions compared to surgical patients (42.2% vs 28.4%, p
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- 2021
6. 716TiP DETERMINE: A pioneering UK precision medicine trial for rare cancers
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Middleton, G., Marshall, L., Billingham, L., Duffus, K.D., Greystoke, A., Carter, L., Forster, M.D., Cook, N., Hargrave, D., Danson, S., Roxburgh, P., Beggs, A.D., Chaturvedi, A., Chesler, L., Sarmiento-Castro, A., Dive, C., Rothwell, D., Gath, J., Halford, S., and Krebs, M.G.
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- 2023
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7. Cancer, fertility and me: a NEW fertility preservation patient decision aid to support YOUNG women with breast cancer
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Jones, G, Darby, F, Moss, R, Vogt, K, Skull, J, Velikova, G, Greenfield, D, Bekker, H, Mahmoodi, N, Snowden, J, Yeomanson, D, Gath, J, Phillips, B, Lane, S, and Anderson, R
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- 2020
8. Bio-NMR Amyloids seen by solid-state NMR: atomic-resolution structure, dynamics, and characterization of the pharmacophore: P00-2
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Meier, B., Böckmann, A., Ernst, M., Melki, R., Riek, R., Bousset, L., Gath, J., Habenstein, B., Huber, M., Lickgei, N., Ravotti, F., Schütz, A., Seuring, C., and Wasmer, C.
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- 2012
9. THE DEVELOPMENT OF A FERTILITY PRESERVATION DECISION AID TO SUPPORT TEENAGE AND ADULT WOMEN WITH CANCER
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Jones, G, Hughes, J, Mahmoodi, N, Greenfield, D, Brauten-Smith, G, Skull, J, Gath, J, Yeomanson D4, D, Lane, S, Phillips, B, Stark, D, Jacques, R, Baskind, E, Velikova, G, Collins, K, and Bekker, HL
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Introduction We describe the protocol for a recently funded three-year study (Yorkshire Cancer Research). Our aims are to develop a new evidence based fertility preservation (FP) decision aid (DA) and evaluate the impact of administering this resource at the point of cancer diagnosis/cancer treatment planning stage in oncology. While a few DAs exist to support the FP process, they are exclusively for breast cancer patients, and none have been developed for the UK female cancer population. Method A multi-centre prospective mixed-method observational study including teenage and adult women of reproductive age (16 years +) with a new diagnosis of any cancer attending cancer hospitals across two large Yorkshire cities. The study involves three stages: Stage 1 (Development of the DA), Stage 2 (Assessing the Learner Verification of the DA), Stage 3 (A quantitative and qualitative evaluation of the DA in routine clinical care). Results We are currently in Stage 1. NHS Research Ethics Committee approval has been granted. The content of the DA is being informed by a systematic literature review, an environmental scan of publically available literature, a previous three-year study carried out in Sheffield alongside clinical evidence from oncology and fertility guidelines and international patient decision aids standards. Discussion It is anticipated that our new DA will enable teenage and adult women to feel better supported and make more informed FP treatment decisions. It should also raise fertility awareness and improve the care of the women whilst they make FP choices and transition between oncology and fertility services.
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- 2016
10. The information and decision support needs of older women (>75 yrs) facing treatment choices for breast cancer : a qualitative study
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Burton, Maria, Collins, Karen, Lifford, K, Brain, K, Wyld, L, Caldon, L, Gath, J, Revell, D, and Reed, M
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Objective\ud \ud Primary Endocrine Therapy (PET) is a good alternative to surgery for breast cancer in older frailer women. Overall survival rates are equivalent although rates of local control are inferior. There is little research regarding the decision support needs of older patients faced with this choice. This qualitative study aimed to explore these among older breast cancer patients offered a choice of treatment, as the basis to develop an appropriate decision support tool.\ud \ud \ud Methods\ud \ud \ud Semi-structured interviews were undertaken with older women (>75 years) with breast cancer who had been offered a choice of PET or surgery at diagnosis. Women's involvement in their treatment decision and support for the process were explored and analysed using framework analysis.\ud \ud \ud Results\ud \ud \ud Thirty-three interviews were undertaken (median age 82, range 75–95 years, 22 PET, 11 surgery). Most women, regardless of treatment choice, wanted tailored information about the different treatment options, their impact on independence, the practicalities of treatment and the risk of recurrence and spread. Surgery was the treatment of choice in women wanting optimal disease control; those choosing PET felt that they were ‘too old’ for surgery and wanted minimal disruption.\ud \ud \ud Conclusions\ud \ud \ud Older women described making active treatment decisions. However, some knowledge was inaccurate. Women wanted information and decision support from their clinicians along with a specific tailored information booklet to support this process
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- 2014
11. Consistency in drift-ordered fluid equations.
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Gath, J. and Wiesenberger, M.
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NUMERICAL analysis , *EQUATIONS , *TERNARY system , *ISOTHERMAL flows , *QUANTITATIVE research - Abstract
We address several concerns related to the derivation of drift-ordered fluid equations. Starting from a fully Galilean invariant fluid system, we show how consistent sets of perturbative drift-fluid equations in the case of an isothermal collisionless fluid can be obtained. Treating all the dynamical fields on equal footing in the singular-drift expansion, we show under what conditions a set of perturbative equations can have a non-trivial quasi-neutral limit. We give a suitable perturbative setup where we provide the full set of perturbative equations for obtaining the first-order corrected fields and show that all the constants of motion are preserved at each order. With the dynamical field variables under perturbative control, we subsequently provide a quantitative analysis by means of numerical simulations. With direct access to first-order corrections, the convergence properties are addressed for different regimes of parameter space and the validity of the first-order approximation is discussed in the three settings: cold ions, hot ions, and finite charge density. [ABSTRACT FROM AUTHOR]
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- 2019
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12. 2LBA - Comparison of quality of life of older women treated with surgery or primary endocrine therapy for early breast cancer: propensity score matched analysis of a large prospective multicentre cohort study
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Shrestha, A., Martin, C., Burton, M., Collins, K., Holmes, G., Ward, S., Audisio, R., Chater, T., Pemberton, K., Robinson, T., Cheung, K.L., Ring, A., Walters, S., Reed, M., Gath, J., Green, T., Revell, D., and Wyld, L.
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- 2018
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13. Observational study of the development and evaluation of a fertility preservation patient decision aid for teenage and adult women diagnosed with cancer: the Cancer, Fertility and Me research protocol.
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Jones, G. L., Hughes, J., Mahmoodi, N., Greenfield, D., Brauten-Smith, G., Skull, J., Gath, J., Yeomanson, D., Baskind, E., Snowden, J. A., Jacques, R. M., Velikova, G., Collins, K., Stark, D., Phillips, R., Lane, S., and Bekker, H. L.
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Introduction: Women diagnosed with cancer and facing potentially sterilising cancer treatment have to make time-pressured decisions regarding fertility preservation with specialist fertility services while undergoing treatment of their cancer with oncology services. Oncologists identify a need for resources enabling them to support women's fertility preservation decisions more effectively; women report wanting more specialist information to make these decisions. The overall aim of the 'Cancer, Fertility and Me' study is to develop and evaluate a new evidence-based patient decision aid (PtDA) for women with any cancer considering fertility preservation to address this unmet need. Methods and analysis: This is a prospective mixedmethod observational study including women of reproductive age (16 years +) with a new diagnosis of any cancer across two regional cancer and fertility centres in Yorkshire, UK. The research involves three stages. In stage 1, the aim is to develop the PtDA using a systematic method of evidence synthesis and multidisciplinary expert review of current clinical practice and patient information. In stage 2, the aim is to assess the face validity of the PtDA. Feedback on its content and format will be ascertained using questionnaires and interviews with patients, user groups and key stakeholders. Finally, in stage 3 the acceptability of using this resource when integrated into usual cancer care pathways at the point of cancer diagnosis and treatment planning will be evaluated. This will involve a quantitative and qualitative evaluation of the PtDA in clinical practice. Measures chosen include using count data of the PtDAs administered in clinics and accessed online, decisional and patient-reported outcome measures and qualitative feedback. Quantitative data will be analysed using descriptive statistics, paired sample t-tests and CIs; interviews will be analysed using thematic analysis. Ethics and dissemination: Research Ethics Committee approval (Ref: 16/EM/0122) and Health Research Authority approval (Ref: 194751) has been granted. Findings will be published in open access peer-reviewed journals, presented at conferences for academic and health professional audiences, with feedback to health professionals and program managers. The Cancer, Fertility and Me patient decision aid (PtDA) will be disseminated via a diverse range of open-access media, study and charity websites, professional organisations and academic sources. External endorsement will be sought from the International Patient Decision Aid Standards (IPDAS) Collaboration inventory of PtDAs and other relevant professional organisations, for example, the British Fertility Society. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Mechanisms of excitation-contraction coupling studied using the principle of transient perturbation.
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Noble, M I M, Arlock, P, Gath, J, Grainger, N, Ravens, U, and Wohlfart, B
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- 1993
15. Pharmacokinetics and Bioavailability of Flucloxacillin in Elderly Hospitalized Patients.
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Gath, J., Charles, B., Sampson, J., and Smithurst, B.
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The pharmacokinetics and oral bioavailability of flucloxacillin were studied in five female and two male patients (age 68-87 yr) who had been hospitalized for orthopedic surgeries. A single dose of intravenous or oral flucloxacillin sodium (500 mg) was administered in random order on different occasions separated by at least 2 days. Blood and urine samples were taken up to 24 hours after drug administration and levels of flucloxacillin and 5-hydroxymethylflucloxacillin (5-HMF), a major metabolite, were measured by high-performance liquid chromatography. Flucloxacillin elimination, but not oral absorption, was reduced in the elderly, compared with data from young healthy subjects reported elsewhere. Total clearance, renal clearance, and volume of distribution were 0.083 ± 0.013 L/kg/hr, 0.038 ± 0.01 L/kg/hr, and 0.184 ± 0.034 L/kg, respectively. Regression of flucloxacillin renal clearance (CL
cr ) on estimated creatinine clearance (CLcr ) gave the relationship: Clr = 0.755 (CLcr + 10.6 (r = 0.91; P = 0.004). Terminal half-lives for flucloxacillin and 5-HMF were 2.21 ± 0.51 hr and 3.0 ± 0.75 hr, respectively, after intravenous administration. Flucloxacillin was absorbed rapidly after oral administration, with a mean absorption time of 0.95 ± 0.34 hr, and time to reach peak concentration of 1.20 ± 0.29 hr. The absolute bioavailability of flucloxacillin from capsules was 54.4 ± 18.8%. [ABSTRACT FROM AUTHOR]- Published
- 1995
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16. Cancer, Fertility and Me: developing and testing a novel fertility preservation patient decision aid to support women at risk of losing their fertility because of cancer treatment
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Jones, GL, Moss, RH, Darby, F, Phillips, B, Hughes, J, Vogt, K, Greenfield, D, Brauten-Smith, G, Gath, J, Campbell, T, Stark, DP, Velikova, G, Snowden, JA, Basskine, E, Mascerenhas, M, Yeomansen, D, Skull, J, Lane, S, Bekker, H, and Anderson, RA
17. The ACCURE-UK trial: The effect of appendectomy on the clinical course of ulcerative colitis – A feasibility study.
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Nepogodiev, D., Howard, R., Pathmakanthan, S., Iqbal, T., Singh, B., Oo, Y., Mathers, J., McMullan, C., Sahamai, S., Gath, J., Magill, L., Handley, K., Deeks, J., Bemelman, W., Morton, D., and Pinkney, T.
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- 2016
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18. Dependence on plasma shape and plasma fueling for small edge-localized mode regimes in TCV and ASDEX Upgrade
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V. Piergotti, F. Pesamosca, Bogdan Hnat, A. Sperduti, A. Krivska, J. Vicente, Panagiotis Tolias, Emanuele Poli, Matthias Hoelzl, Benedikt Geiger, A. Jardin, J. Ayllon-Guerola, G. Apruzzese, T. Lunt, J. Galdon-Quiroga, Riccardo Maggiora, M. Tardocchi, M. Koubiti, T. Jonsson, Bruce Lipschultz, P. Innocente, A. Gude, I Miron, M. G. Dunne, G. F. Harrer, A. Moro, A. Iantchenko, K. Galazka, P. Poloskei, K. Bogar, Roberto Ambrosino, G. Ferr, Vladimir E. Moiseenko, Istvan Cziegler, L. Guimarais, S. Vartanian, B. Erds, G. Pucella, V. Bobkov, James Buchanan, Raffaele Albanese, Harry M. Meyer, D. Boeyaert, G. F. Matthews, Eva Macusova, V. S. Marchenko, R. Zagórski, J. Buermans, A. Fil, W. Zhang, Giuseppe Gorini, B. Tal, D. Zaloga, Hugo Bufferand, A. Romano, L. Colas, J. Zebrowski, M. Weiland, L. Barrera-Orte, Matjaž Panjan, A.J. Thornton, E. Wolfrum, Miglena Dimitrova, R. M. McDermott, R. Lombroni, O. Tudisco, F. Reimold, E. R. Solano, X. Feng, Petra Bilkova, M. Groth, E. Alessi, D. S. Gahle, Olivier Février, I. Voitsekhovitch, Matthew Carr, A. Bock, O. Vasilovici, C. Ham, Lorenzo Figini, Guglielmo Rubinacci, Peter Lang, Pierre Manas, S. Costea, A. Kirk, F. Causa, J. Adamek, Vu N. M. T., M. Cavedon, O. Grover, Geert Verdoolaege, M. Spolaore, L. Sanchis-Sanchez, P. Bohm, P. V. Kazantzidis, Sarah Newton, M. Tomes, M.-L. Mayoral, J. R. Harrison, C. Mazzotta, H. Reimerdes, Jorge Morales, D. Brunetti, J. Gonzalez-Martin, Tomas Markovic, S. S. Henderson, D. Ricci, J. Juul Rasmussen, F. Janky, S. Saarelma, Z. Popovic, C. Tsironis, J. J. Rasmussen, S. K. Hansen, Sandra C. Chapman, Volker Naulin, H. Arnichand, Roberto Paccagnella, M. Faitsch, Anders Nielsen, M. Kong, V. Igochine, C. Piron, C. Bowman, Jorge Ferreira, D. Sytnykov, K. G. McClements, Olivier Sauter, Ondrej Ficker, Matthias Wiesenberger, T. Ravensbergen, C. Reux, Irena Ivanova-Stanik, Dirk Reiser, M. Bernert, M. Vallar, J-M Moret, M. Gruca, D. I. Refy, P. Cano Megias, Benoit Labit, M. Schubert, Giuliana Sias, O. Bogar, P. J. Mc Carthy, I. Faust, Gergely Papp, F. Matos, J. Garcia, C. Marini, E. L. Sorokovoy, Dimitri Voltolina, George Wilkie, J. M. Santos, R. R. Sheeba, Vladimir Weinzettl, Sergei Kasilov, J. Cerovsky, Matteo Agostini, G. Tardini, Laurie Porte, F. Dolizy, L. Gil, Matthias Komm, A. Dal Molin, B. Sieglin, Roch Kwiatkowski, M. C. C Messmer, Toke Koldborg Jensen, Vinodh Bandaru, Ben F. McMillan, Alessandra Fanni, Daniele Carnevale, Shimpei Futatani, D. P. Coster, V. Korovin, S. E. Sharapov, Patrik Ollus, J. Gath, A. Czarnecka, D. Gallart, M. Peterka, P. Vallejos Olivares, Jernej Kovacic, Nicolas Fedorczak, Silvio Ceccuzzi, L. Piron, J. Rosato, G. Kocsis, Stefan Kragh Nielsen, M. Garcia-Mu oz, Radomir Panek, S. F. Smith, Paolo Bettini, A. Mariani, R. Dejarnac, Lorenzo Frassinetti, D. Douai, L. Garzotti, H. J. Sun, C.K. Tsui, N. den Harder, John Elmerdahl Olsen, F. Bombarda, M. Francesco, Piero Martin, D. Hogeweij, P. Blanchard, F. Bouquey, Gabor Por, Luca Boncagni, Carlo Sozzi, Martin Hron, P. A. Schneider, V. P. Loschiavo, David Terranova, D. Aguiam, D. Choi, M. Gobbin, D. Iglesias, M. Reich, G. Avdeeva, A. Gallo, O. Biletskyi, M. Aradi, F. Liu, M. Griener, Antti Snicker, L. Kripner, Jérôme Bucalossi, L. Hesslow, Nick Walkden, M. Rodriguez-Ramos, T. C. Blanken, Cristian Galperti, F. Jaulmes, G. Calabr, G.A. Rattá, W. Bin, S. Garavaglia, V. Plyusnin, Andreas Frank Martitsch, A. Zisis, Rita Lorenzini, Duccio Testa, M. Passeri, Ola Embréus, N. Krawczyk, K. Särkimäki, Davide Galassi, D. Samaddar, M. Oberkofler, E. Seliunin, D. Brida, P. Buratti, F. Nabais, J. Ongena, J. Likonen, Yann Camenen, M. J. Mantsinen, F. Carpanese, S. Wiesen, P. Piovesan, Mirko Salewski, J. Hawke, Florian Laggner, R. Bilato, M. Wischmeier, L. Pigatto, G. I. Pokol, G. Giruzzi, Jens Madsen, D. Gadariya, L. Stipani, Christian Theiler, J. Stober, Michael Barnes, Timothy Goodman, R. D. Nem, J. J. Dominguez-Palacios Duran, F. Militello, Y. Kulyk, D. J. Cruz Zabala, A. Drenik, P. Manz, M. Scheffer, V. Pericoli Radolfini, B. Tilia, John Omotani, B. Vanovac, B. S. Schneider, E. Fable, Jakub Urban, T. Gyergyek, A. N. Karpushov, M. Farnik, Jakub Seidl, Christopher G. Albert, Antoine Merle, A. Cathey, D. A. Ryan, Sergio Galeani, R. Scannell, A. Havranek, G. de Carolis, C. Soria-Hoyo, S. Gibson, D. Carralero, D. Meshcheriakov, Morten Stejner, B. P. Duval, Francesco Cordella, Mitja Kelemen, Svetlana V. Ratynskaia, Stefano Coda, L. Calacci, C. Cianfarani, Faa Federico Felici, A. C. A. Figueiredo, L. Panaccione, E. Viezzer, Fabio Villone, Daniele Milanesio, Winfried Kernbichler, Mario Sassano, A. Teplukhina, S. Zoletnik, L. Laguardia, P. Molina Cabrera, Taina Kurki-Suonio, D. Micheletti, P. Zanca, Daniel Dunai, S. Feng, J. Decker, Stylianos Varoutis, Lorella Carraro, M. Wensing, Gustavo Granucci, Artur Palha, A. Kappatou, J. Garcia-Lopez, Felix I. Parra, Ye. O. Kazakov, S. Brezinsek, Didier Mazon, A. Lahtinen, I. Paradela Perez, P. Chmielewski, L. Giacomelli, Alessandro Pau, Gianluca Spizzo, R. Delogu, R. J. Akers, H. De Oliveira, Petr Vondracek, F. P. Orsitto, J. Hobirk, L. Xiang, A. Burckhart, B. Maljaars, V. Petrzilka, Ocleto D'Arcangelo, P. David, D. Grekov, Tamás Szepesi, Y. Andr be, P. Hacek, M. Toscano-Jimenez, T. Pütterich, L. Cordaro, V. Nikolaeva, F. Orain, M. Rabinski, C. Ionita-Schrittwieser, T. Tala, Maria Ester Puiatti, A. Casolari, T. Happel, Pär Strand, Benjamin Daniel Dudson, P. Mantica, Z. Huang, D. Colette, G. Ciraolo, Jan Mlynar, W. Suttrop, C. Meineri, J. Horacek, Seppo Sipilä, M. Gospodarczyk, S. Mastrostefano, Jesús Vega, Antti Hakola, Kevin Verhaegh, Roman Schrittwieser, C. Marchetto, M. Willensdorfer, Jari Varje, D. C. van Vugt, J. Faustin, Mathias Hoppe, M. Dreval, A. Perek, C. Angioni, Laure Vermare, U. A. Sheikh, J. F. Rivero-Rodriguez, G. Rubino, S.N. Reznik, Tsv K Popov, S. Nowak, A. S. Jacobsen, J. R. Martin Solis, David Moulton, Heinz Isliker, K. Wu, Anna Salmi, F. Nespoli, S. Elmore, O. Kudlacek, A. Kallenbach, Rok Zaplotnik, D. L. Keeling, L. Giannone, M. Maraschek, Carlos B. da Silva, F. Hitzler, M. Valovic, M. W. Jakubowski, L. Gabellieri, Jozef Varju, Marco Cecconello, M. Valisa, Vlado Menkovski, Gábor Cseh, E. Thoren, T. Eich, R. Coelho, F. Bagnato, Matteo Zuin, Alexander Kendl, G. Rocchi, G. Pautasso, D. Naydenkova, R. O. Pavlichenko, M. Fontana, Lionello Marrelli, Tommaso Bolzonella, Nicola Vianello, Pascale Hennequin, R. Ochoukov, Tom Wauters, Christian Hopf, Ch. Fuchs, E. Giovannozzi, Fulvio Auriemma, Roberto Maurizio, Stefan Buller, Massimo Nocente, K. Krieger, G. Grenfell, N. Rispoli, R. Dux, Barbara Cannas, Laboratoire de Physique des Plasmas (LPP), Université Paris-Saclay-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École polytechnique (X)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Labit, B., Eich, T., Harrer, G. F., Wolfrum, E., Bernert, M., Dunne, M. G., Frassinetti, L., Hennequin, P., Maurizio, R., Merle, A., Meyer, H., Saarelma, S., Sheikh, U., Adamek, J., Agostini, M., Aguiam, D., Akers, R., Albanese, R., Albert, C., Alessi, E., Ambrosino, R., Andr be, Y., Angioni, C., Apruzzese, G., Aradi, M., Arnichand, H., Auriemma, F., Avdeeva, G., Ayllon-Guerola, J. M., Bagnato, F., Bandaru, V. K., Barnes, M., Barrera-Orte, L., Bettini, P., Bilato, R., Biletskyi, O., Bilkova, P., Bin, W., Blanchard, P., Blanken, T., Bobkov, V., Bock, A., Boeyaert, D., Bogar, K., Bogar, O., Bohm, P., Bolzonella, T., Bombarda, F., Boncagni, L., Bouquey, F., Bowman, C., Brezinsek, S., Brida, D., Brunetti, D., Bucalossi, J., Buchanan, J., Buermans, J., Bufferand, H., Buller, S., Buratti, P., Burckhart, A., Calabr, G., Calacci, L., Camenen, Y., Cannas, B., Cano Megias, P., Carnevale, D., Carpanese, F., Carr, M., Carralero, D., Carraro, L., Casolari, A., Cathey, A., Causa, F., Cavedon, M., Cecconello, M., Ceccuzzi, S., Cerovsky, J., Chapman, S., Chmielewski, P., Choi, D., Cianfarani, C., Ciraolo, G., Coda, S., Coelho, R., Colas, L., Colette, D., Cordaro, L., Cordella, F., Costea, S., Coster, D., Cruz Zabala, D. J., Cseh, G., Czarnecka, A., Cziegler, I., D'Arcangelo, O., Dal Molin, A., David, P., De Carolis, G., De Oliveira, H., Decker, J., Dejarnac, R., Delogu, R., Den Harder, N., Dimitrova, M., Dolizy, F., Dominguez-Palacios Duran, J. J., Douai, D., Drenik, A., Dreval, M., Dudson, B., Dunai, D., Duval, B. P., Dux, R., Elmore, S., Embreus, O., Erds, B., Fable, E., Faitsch, M., Fanni, A., Farnik, M., Faust, I., Faustin, J., Fedorczak, N., Felici, F., Feng, S., Feng, X., Ferreira, J., Ferr, G., Fevrier, O., Ficker, O., Figini, L., Figueiredo, A., Fil, A., Fontana, M., Francesco, M., Fuchs, C., Futatani, S., Gabellieri, L., Gadariya, D., Gahle, D., Galassi, D., Galazka, K., Galdon-Quiroga, J., Galeani, S., Gallart, D., Gallo, A., Galperti, C., Garavaglia, S., Garcia, J., Garcia-Lopez, J., Garcia-Mu oz, M., Garzotti, L., Gath, J., Geiger, B., Giacomelli, L., Giannone, L., Gibson, S., Gil, L., Giovannozzi, E., Giruzzi, G., Gobbin, M., Gonzalez-Martin, J., Goodman, T. P., Gorini, G., Gospodarczyk, M., Granucci, G., Grekov, D., Grenfell, G., Griener, M., Groth, M., Grover, O., Gruca, M., Gude, A., Guimarais, L., Gyergyek, T., Hacek, P., Hakola, A., Ham, C., Happel, T., Harrison, J., Havranek, A., Hawke, J., Henderson, S., Hesslow, L., Hitzler, F., Hnat, B., Hobirk, J., Hoelzl, M., Hogeweij, D., Hopf, C., Hoppe, M., Horacek, J., Hron, M., Huang, Z., Iantchenko, A., Iglesias, D., Igochine, V., Innocente, P., Ionita-Schrittwieser, C., Isliker, H., Ivanova-Stanik, I., Jacobsen, A., Jakubowski, M., Janky, F., Jardin, A., Jaulmes, F., Jensen, T., Jonsson, T., Kallenbach, A., Kappatou, A., Karpushov, A., Kasilov, S., Kazakov, Y., Kazantzidis, P. V., Keeling, D., Kelemen, M., Kendl, A., Kernbichler, W., Kirk, A., Kocsis, G., Komm, M., Kong, M., Korovin, V., Koubiti, M., Kovacic, J., Krawczyk, N., Krieger, K., Kripner, L., Krivska, A., Kudlacek, O., Kulyk, Y., Kurki-Suonio, T., Kwiatkowski, R., Laggner, F., Laguardia, L., Lahtinen, A., Lang, P., Likonen, J., Lipschultz, B., Liu, F., Lombroni, R., Lorenzini, R., Loschiavo, V. P., Lunt, T., Macusova, E., Madsen, J., Maggiora, R., Maljaars, B., Manas, P., Mantica, P., Mantsinen, M. J., Manz, P., Maraschek, M., Marchenko, V., Marchetto, C., Mariani, A., Marini, C., Markovic, T., Marrelli, L., Martin, P., Martin Solis, J. R., Martitsch, A., Mastrostefano, S., Matos, F., Matthews, G., Mayoral, M. -L., Mazon, D., Mazzotta, C., Mc Carthy, P., Mcclements, K., Mcdermott, R., Mcmillan, B., Meineri, C., Menkovski, V., Meshcheriakov, D., Messmer, M., Micheletti, D., Milanesio, D., Militello, F., Miron, I. G., Mlynar, J., Moiseenko, V., Molina Cabrera, P. A., Morales, J., Moret, J. -M., Moro, A., Moulton, D., Nabais, F., Naulin, V., Naydenkova, D., Nem, R. D., Nespoli, F., Newton, S., Nielsen, A. H., Nielsen, S. K., Nikolaeva, V., Nocente, M., Nowak, S., Oberkofler, M., Ochoukov, R., Ollus, P., Olsen, J., Omotani, J., Ongena, J., Orain, F., Orsitto, F. P., Paccagnella, R., Palha, A., Panaccione, L., Panek, R., Panjan, M., Papp, G., Paradela Perez, I., Parra, F., Passeri, M., Pau, A., Pautasso, G., Pavlichenko, R., Perek, A., Pericoli Radolfini, V., Pesamosca, F., Peterka, M., Petrzilka, V., Piergotti, V., Pigatto, L., Piovesan, P., Piron, C., Piron, L., Plyusnin, V., Pokol, G., Poli, E., Poloskei, P., Popov, T., Popovic, Z., Por, G., Porte, L., Pucella, G., Puiatti, M. E., Putterich, T., Rabinski, M., Juul Rasmussen, J., Rasmussen, J., Ratta, G. A., Ratynskaia, S., Ravensbergen, T., Refy, D., Reich, M., Reimerdes, H., Reimold, F., Reiser, D., Reux, C., Reznik, S., Ricci, D., Rispoli, N., Rivero-Rodriguez, J. F., Rocchi, G., Rodriguez-Ramos, M., Romano, A., Rosato, J., Rubinacci, G., Rubino, G., Ryan, D. A., Salewski, M., Salmi, A., Samaddar, D., Sanchis-Sanchez, L., Santos, J., Sarkimaki, K., Sassano, M., Sauter, O., Scannell, R., Scheffer, M., Schneider, B. S., Schneider, P., Schrittwieser, R., Schubert, M., Seidl, J., Seliunin, E., Sharapov, S., Sheeba, R. R., Sias, G., Sieglin, B., Silva, C., Sipila, S., Smith, S., Snicker, A., Solano, E. R., Hansen, S. K., Soria-Hoyo, C., Sorokovoy, E., Sozzi, C., Sperduti, A., Spizzo, G., Spolaore, M., Stejner, M., Stipani, L., Stober, J., Strand, P., Sun, H., Suttrop, W., Sytnykov, D., Szepesi, T., Tal, B., Tala, T., Tardini, G., Tardocchi, M., Teplukhina, A., Terranova, D., Testa, D., Theiler, C., Thoren, E., Thornton, A., Tilia, B., Tolias, P., Tomes, M., Toscano-Jimenez, M., Tsironis, C., Tsui, C., Tudisco, O., Urban, J., Valisa, M., Vallar, M., Vallejos Olivares, P., Valovic, M., Van Vugt, D., Vanovac, B., Varje, J., Varju, J., Varoutis, S., Vartanian, S., Vasilovici, O., Vega, J., Verdoolaege, G., Verhaegh, K., Vermare, L., Vianello, N., Vicente, J., Viezzer, E., Villone, F., Voitsekhovitch, I., Voltolina, D., Vondracek, P., Vu, N. M. T., Walkden, N., Wauters, T., Weiland, M., Weinzettl, V., Wensing, M., Wiesen, S., Wiesenberger, M., Wilkie, G., Willensdorfer, M., Wischmeier, M., Wu, K., Xiang, L., Zagorski, R., Zaloga, D., Zanca, P., Zaplotnik, R., Zebrowski, J., Zhang, W., Zisis, A., Zoletnik, S., Zuin, M., Swiss Federal Institute of Technology Lausanne, Max-Planck-Institut für Plasmaphysik, Vienna University of Technology, KTH Royal Institute of Technology, Université Paris-Saclay, JET, Czech Academy of Sciences, National Research Council of Italy, University of Lisbon, University of Naples Federico II, Graz University of Technology, University of Naples Parthenope, Agenzia nazionale per le nuove tecnologie, l'energia e lo sviluppo economico sostenibile, Danmarks Tekniske Universitet, University of Seville, University of Oxford, EUROfusion Programme Management Unit, National Science Center Kharkov Institute of Physics and Technology, Eindhoven University of Technology, Forschungszentrum Jülich, CEA, University of York, Royal Military Academy, Chalmers University of Technology, Tuscia University, Università di Roma Tor Vergata, CNRS, University of Cagliari, CIEMAT, Uppsala University, University of Warwick, Soltan Institute for Nuclear Studies, University of Innsbruck, Hungarian Academy of Sciences, Budapest University of Technology and Economics, Durham University, BarcelonaTech, University of Strathclyde, Barcelona Supercomputing Center, University of Milan - Bicocca, Karlsruhe Institute of Technology, Fusion and Plasma Physics, J. Stefan Institute, VTT Technical Research Centre of Finland, Dutch Institute for Fundamental Energy Research, Aristotle University of Thessaloniki, National Technical University of Athens, National Centre for Nuclear Research, University of Helsinki, Université Côte d'Azur, Polytechnic University of Turin, NASU - Institute of Nuclear Research, University of Cassino and Southern Lazio, University College Cork, National Institute for Laser, Plasma and Radiation Physics, Department of Applied Physics, Sofia University St. Kliment Ohridski, Ghent University, Aalto-yliopisto, Aalto University, Labit, B, Eich, T, Harrer, G, Wolfrum, E, Bernert, M, Dunne, M, Frassinetti, L, Hennequin, P, Maurizio, R, Merle, A, Meyer, H, Saarelma, S, Sheikh, U, Adamek, J, Agostini, M, Aguiam, D, Akers, R, Albanese, R, Albert, C, Alessi, E, Ambrosino, R, Andr be, Y, Angioni, C, Apruzzese, G, Aradi, M, Arnichand, H, Auriemma, F, Avdeeva, G, Ayllon-Guerola, J, Bagnato, F, Bandaru, V, Barnes, M, Barrera-Orte, L, Bettini, P, Bilato, R, Biletskyi, O, Bilkova, P, Bin, W, Blanchard, P, Blanken, T, Bobkov, V, Bock, A, Boeyaert, D, Bogar, K, Bogar, O, Bohm, P, Bolzonella, T, Bombarda, F, Boncagni, L, Bouquey, F, Bowman, C, Brezinsek, S, Brida, D, Brunetti, D, Bucalossi, J, Buchanan, J, Buermans, J, Bufferand, H, Buller, S, Buratti, P, Burckhart, A, Calabr, G, Calacci, L, Camenen, Y, Cannas, B, Cano Megias, P, Carnevale, D, Carpanese, F, Carr, M, Carralero, D, Carraro, L, Casolari, A, Cathey, A, Causa, F, Cavedon, M, Cecconello, M, Ceccuzzi, S, Cerovsky, J, Chapman, S, Chmielewski, P, Choi, D, Cianfarani, C, Ciraolo, G, Coda, S, Coelho, R, Colas, L, Colette, D, Cordaro, L, Cordella, F, Costea, S, Coster, D, Cruz Zabala, D, Cseh, G, Czarnecka, A, Cziegler, I, D'Arcangelo, O, Dal Molin, A, David, P, De Carolis, G, De Oliveira, H, Decker, J, Dejarnac, R, Delogu, R, Den Harder, N, Dimitrova, M, Dolizy, F, Dominguez-Palacios Duran, J, Douai, D, Drenik, A, Dreval, M, Dudson, B, Dunai, D, Duval, B, Dux, R, Elmore, S, Embreus, O, Erds, B, Fable, E, Faitsch, M, Fanni, A, Farnik, M, Faust, I, Faustin, J, Fedorczak, N, Felici, F, Feng, S, Feng, X, Ferreira, J, Ferr, G, Fevrier, O, Ficker, O, Figini, L, Figueiredo, A, Fil, A, Fontana, M, Francesco, M, Fuchs, C, Futatani, S, Gabellieri, L, Gadariya, D, Gahle, D, Galassi, D, Galazka, K, Galdon-Quiroga, J, Galeani, S, Gallart, D, Gallo, A, Galperti, C, Garavaglia, S, Garcia, J, Garcia-Lopez, J, Garcia-Mu oz, M, Garzotti, L, Gath, J, Geiger, B, Giacomelli, L, Giannone, L, Gibson, S, Gil, L, Giovannozzi, E, Giruzzi, G, Gobbin, M, Gonzalez-Martin, J, Goodman, T, Gorini, G, Gospodarczyk, M, Granucci, G, Grekov, D, Grenfell, G, Griener, M, Groth, M, Grover, O, Gruca, M, Gude, A, Guimarais, L, Gyergyek, T, Hacek, P, Hakola, A, Ham, C, Happel, T, Harrison, J, Havranek, A, Hawke, J, Henderson, S, Hesslow, L, Hitzler, F, Hnat, B, Hobirk, J, Hoelzl, M, Hogeweij, D, Hopf, C, Hoppe, M, Horacek, J, Hron, M, Huang, Z, Iantchenko, A, Iglesias, D, Igochine, V, Innocente, P, Ionita-Schrittwieser, C, Isliker, H, Ivanova-Stanik, I, Jacobsen, A, Jakubowski, M, Janky, F, Jardin, A, Jaulmes, F, Jensen, T, Jonsson, T, Kallenbach, A, Kappatou, A, Karpushov, A, Kasilov, S, Kazakov, Y, Kazantzidis, P, Keeling, D, Kelemen, M, Kendl, A, Kernbichler, W, Kirk, A, Kocsis, G, Komm, M, Kong, M, Korovin, V, Koubiti, M, Kovacic, J, Krawczyk, N, Krieger, K, Kripner, L, Krivska, A, Kudlacek, O, Kulyk, Y, Kurki-Suonio, T, Kwiatkowski, R, Laggner, F, Laguardia, L, Lahtinen, A, Lang, P, Likonen, J, Lipschultz, B, Liu, F, Lombroni, R, Lorenzini, R, Loschiavo, V, Lunt, T, Macusova, E, Madsen, J, Maggiora, R, Maljaars, B, Manas, P, Mantica, P, Mantsinen, M, Manz, P, Maraschek, M, Marchenko, V, Marchetto, C, Mariani, A, Marini, C, Markovic, T, Marrelli, L, Martin, P, Martin Solis, J, Martitsch, A, Mastrostefano, S, Matos, F, Matthews, G, Mayoral, M, Mazon, D, Mazzotta, C, Mc Carthy, P, Mcclements, K, Mcdermott, R, Mcmillan, B, Meineri, C, Menkovski, V, Meshcheriakov, D, Messmer, M, Micheletti, D, Milanesio, D, Militello, F, Miron, I, Mlynar, J, Moiseenko, V, Molina Cabrera, P, Morales, J, Moret, J, Moro, A, Moulton, D, Nabais, F, Naulin, V, Naydenkova, D, Nem, R, Nespoli, F, Newton, S, Nielsen, A, Nielsen, S, Nikolaeva, V, Nocente, M, Nowak, S, Oberkofler, M, Ochoukov, R, Ollus, P, Olsen, J, Omotani, J, Ongena, J, Orain, F, Orsitto, F, Paccagnella, R, Palha, A, Panaccione, L, Panek, R, Panjan, M, Papp, G, Paradela Perez, I, Parra, F, Passeri, M, Pau, A, Pautasso, G, Pavlichenko, R, Perek, A, Pericoli Radolfini, V, Pesamosca, F, Peterka, M, Petrzilka, V, Piergotti, V, Pigatto, L, Piovesan, P, Piron, C, Piron, L, Plyusnin, V, Pokol, G, Poli, E, Poloskei, P, Popov, T, Popovic, Z, Por, G, Porte, L, Pucella, G, Puiatti, M, Putterich, T, Rabinski, M, Juul Rasmussen, J, Rasmussen, J, Ratta, G, Ratynskaia, S, Ravensbergen, T, Refy, D, Reich, M, Reimerdes, H, Reimold, F, Reiser, D, Reux, C, Reznik, S, Ricci, D, Rispoli, N, Rivero-Rodriguez, J, Rocchi, G, Rodriguez-Ramos, M, Romano, A, Rosato, J, Rubinacci, G, Rubino, G, Ryan, D, Salewski, M, Salmi, A, Samaddar, D, Sanchis-Sanchez, L, Santos, J, Sarkimaki, K, Sassano, M, Sauter, O, Scannell, R, Scheffer, M, Schneider, B, Schneider, P, Schrittwieser, R, Schubert, M, Seidl, J, Seliunin, E, Sharapov, S, Sheeba, R, Sias, G, Sieglin, B, Silva, C, Sipila, S, Smith, S, Snicker, A, Solano, E, Hansen, S, Soria-Hoyo, C, Sorokovoy, E, Sozzi, C, Sperduti, A, Spizzo, G, Spolaore, M, Stejner, M, Stipani, L, Stober, J, Strand, P, Sun, H, Suttrop, W, Sytnykov, D, Szepesi, T, Tal, B, Tala, T, Tardini, G, Tardocchi, M, Teplukhina, A, Terranova, D, Testa, D, Theiler, C, Thoren, E, Thornton, A, Tilia, B, Tolias, P, Tomes, M, Toscano-Jimenez, M, Tsironis, C, Tsui, C, Tudisco, O, Urban, J, Valisa, M, Vallar, M, Vallejos Olivares, P, Valovic, M, Van Vugt, D, Vanovac, B, Varje, J, Varju, J, Varoutis, S, Vartanian, S, Vasilovici, O, Vega, J, Verdoolaege, G, Verhaegh, K, Vermare, L, Vianello, N, Vicente, J, Viezzer, E, Villone, F, Voitsekhovitch, I, Voltolina, D, Vondracek, P, Vu, N, Walkden, N, Wauters, T, Weiland, M, Weinzettl, V, Wensing, M, Wiesen, S, Wiesenberger, M, Wilkie, G, Willensdorfer, M, Wischmeier, M, Wu, K, Xiang, L, Zagorski, R, Zaloga, D, Zanca, P, Zaplotnik, R, Zebrowski, J, Zhang, W, Zisis, A, Zoletnik, S, Zuin, M, Universitat Politècnica de Catalunya. Departament de Física, Universitat Politècnica de Catalunya. ANT - Advanced Nuclear Technologies Research Group, Control Systems Technology, Science and Technology of Nuclear Fusion, Data Mining, Sensorics for fusion reactors, and Magneto-Hydro-Dynamic Stability of Fusion Plasmas
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Nuclear and High Energy Physics ,Settore ING-INF/04 ,Work package ,grassy ELM ,ballooning modes ,Nuclear physics ,01 natural sciences ,Flattening ,Ballooning ,010305 fluids & plasmas ,grassy ELMs ,separatrix density ,ASDEX Upgrade ,[PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph] ,0103 physical sciences ,010306 general physics ,Edge-localized mode ,QC ,H-mode ,plasma triangularity ,type-II ELMs ,Physics ,Física [Àrees temàtiques de la UPC] ,type-II ELM ,Plasma ,Condensed Matter Physics ,Null (physics) ,Shear (sheet metal) ,Física nuclear ,Atomic physics ,ballooning mode - Abstract
Within the EUROfusion MST1 work package, a series of experiments has been conducted on AUG and TCV devices to disentangle the role of plasma fueling and plasma shape for the onset of small ELM regimes. On both devices, small ELM regimes with high confinement are achieved if and only if two conditions are fulfilled at the same time. Firstly, the plasma density at the separatrix must be large enough (), leading to a pressure profile flattening at the separatrix, which stabilizes type-I ELMs. Secondly, the magnetic configuration has to be close to a double null (DN), leading to a reduction of the magnetic shear in the extreme vicinity of the separatrix. As a consequence, its stabilizing effect on ballooning modes is weakened. Peer Reviewed Article escrit per 365 autors/autores: Labit, B.; Eich, T.; Harrer, G. F.; Wolfrum, E.; Bernert, M.; Dunne, M. G.; Frassinetti, L.; Hennequin, P.; Maurizio, R.; Merle, A.; Meyer, H.; Saarelma, S.; Sheikh, U.; Adamek, J.; Agostini, M.; Aguiam, D.; Akers, R.; Albanese, R.; Albert, C.; Alessi, E.; Ambrosino, R.; Andr be, Y.; Angioni, C.; Apruzzese, G.; Aradi, M.; Arnichand, H.; Auriemma, F.; Avdeeva, G.; Ayllon-Guerola, J. M.; Bagnato, F.; Bandaru, V. K.; Barnes, M.; Barrera-Orte, L.; Bettini, P.; Bilato, R.; Biletskyi, O.; Bilkova, P.; Bin, W.; Blanchard, P.; Blanken, T.; Bobkov, V.; Bock, A.; Boeyaert, D.; Bogar, K.; Bogar, O.; Bohm, P.; Bolzonella, T.; Bombarda, F.; Boncagni, L.; Bouquey, F.; Bowman, C.; Brezinsek, S.; Brida, D.; Brunetti, D.; Bucalossi, J.; Buchanan, J.; Buermans, J.; Bufferand, H.; Buller, S.; Buratti, P.; Burckhart, A.; Calabr, G.; Calacci, L.; Camenen, Y.; Cannas, B.; Cano Megías, P.; Carnevale, D.; Carpanese, F.; Carr, M.; Carralero, D.; Carraro, L.; Casolari, A.; Cathey, A.; Causa, F.; Cavedon, M.; Cecconello, M.; Ceccuzzi, S.; Cerovsky, J.; Chapman, S.; Chmielewski, P.; Choi, D.; Cianfarani, C.; Ciraolo, G.; Coda, S.; Coelho, R.; Colas, L.; Colette, D.; Cordaro, L.; Cordella, F.; Costea, S.; Coster, D.; Cruz Zabala, D. J.; Cseh, G.; Czarnecka, A.; Cziegler, I.; D’Arcangelo, O.; Dal Molin, A.; David, P.; De Carolis, G.; De Oliveira, H.; Decker, J.; Dejarnac, R.; Delogu, R.; Den Harder, N.; Dimitrova, M.; Dolizy, F.; Domínguez-Palacios Durán, J. J.; Douai, D.; Drenik, A.; Dreval, M.; Dudson, B.; Dunai, D.; Duval, B. P.; Dux, R.; Elmore, S.; Embréus, O.; Erds, B.; Fable, E.; Faitsch, M.; Fanni, A.; Farnik, M.; Faust, I.; Faustin, J.; Fedorczak, N.; Felici, F.; Feng, S.; Feng, X.; Ferreira, J.; Ferr, G.; Février, O.; Ficker, O.; Figini, L.; Figueiredo, A.; Fil, A.; Fontana, M.; Francesco, M.; Fuchs, C.; Futatani, S.; Gabellieri, L.; Gadariya, D.; Gahle, D.; Galassi, D.; Gałązka, K.; Galdon-Quiroga, J.; Galeani, S.; Gallart, D.; Gallo, A.; Galperti, C.; Garavaglia, S.; Garcia, J.; Garcia-Lopez, J.; Garcia-Mu oz, M.; Garzotti, L.; Gath, J.; Geiger, B.; Giacomelli, L.; Giannone, L.; Gibson, S.; Gil, L.; Giovannozzi, E.; Giruzzi, G.; Gobbin, M.; Gonzalez-Martin, J.; Goodman, T. P.; Gorini, G.; Gospodarczyk, M.; Granucci, G.; Grekov, D. 1; Grenfell, G.; Griener, M.; Groth, M.; Grover, O.; Gruca, M.; Gude, A.; Guimarais, L.; Gyergyek, T.; Hacek, P.; Hakola, A.; Ham, C.; Happel, T.; Harrison, J.; Havranek, A.; Hawke, J.; Henderson, S.; Hesslow, L.; Hitzler, F.; Hnat, B.; Hobirk, J.; Hoelzl, M.; Hogeweij, D.; Hopf, C.; Hoppe, M.; Horacek, J.; Hron, M.; Huang, Z.; Iantchenko, A.; Iglesias, D.; Igochine, V.; Innocente, P.; Ionita-Schrittwieser, C.; Isliker, H.; Ivanova-Stanik, I.; Jacobsen, A.; Jakubowski, M.; Janky, F.; Jardin, A.; Jaulmes, F.; Jensen, T.; Jonsson, T.; Kallenbach, A.; Kappatou, A.; Karpushov, A.; Kasilov, S.; Kazakov, Y.; Kazantzidis, P. V.; Keeling, D.; Kelemen, M.; Kendl, A.; Kernbichler, W.; Kirk, A.; Kocsis, G.; Komm, M.; Kong, M.; Korovin, V.; Koubiti, M.; Kovacic, J.; Krawczyk, N.; Krieger, K.; Kripner, L.; Křivská, A.; Kudlacek, O.; Kulyk, Y.; Kurki-Suonio, T.; Kwiatkowski, R.; Laggner, F.; Laguardia, L.; Lahtinen, A.; Lang, P.; Likonen, J.; Lipschultz, B.; Liu, F.; Lombroni, R.; Lorenzini, R.; Loschiavo, V. P.; Lunt, T.; MacUsova, E.; Madsen, J.; Maggiora, R.; Maljaars, B.; Manas, P.; Mantica, P.; Mantsinen, M. J.; Manz, P.; Maraschek, M.; Marchenko, V.; Marchetto, C.; Mariani, A.; Marini, C.; Markovic, T.; Marrelli, L.; Martin, P.; Martín Solís, J. R.; Martitsch, A.; Mastrostefano, S.; Matos, F.; Matthews, G.; Mayoral, M.-L.; Mazon, D.; Mazzotta, C.; Mc Carthy, P.; McClements, K.; McDermott, R.; McMillan, B.; Meineri, C.; Menkovski, V.; Meshcheriakov, D.; Messmer, M.; Micheletti, D.; Milanesio, D.; Militello, F.; Miron, I. G.; Mlynar, J.; Moiseenko, V.; Molina Cabrera, P. A.; Morales, J.; Moret, J.-M.; Moro, A.; Moulton, D.; Nabais, F.; Naulin, V.; Naydenkova, D.; Nem, R. D.; Nespoli, F.; Newton, S.; Nielsen, A. H.; Nielsen, S. K.; Nikolaeva, V.; Nocente, M.; Nowak, S.; Oberkofler, M.; Ochoukov, R.; Ollus, P.; Olsen, J.; Omotani, J.; Ongena, J.; Orain, F.; Orsitto, F. P.; Paccagnella, R.; Palha, A.; Panaccione, L.; Panek, R.; Panjan, M.; Papp, G.; Paradela Perez, I.; Parra, F.; Passeri, M.; Pau, A.; Pautasso, G.; Pavlichenko, R.; Perek, A.; Pericoli Radolfini, V.; Pesamosca, F.; Peterka, M.; Petrzilka, V.; Piergotti, V.; Pigatto, L.; Piovesan, P.; Piron, C.; Piron, L.; Plyusnin, V.; Pokol, G.; Poli, E.; Pölöskei, P.; Popov, T.; Popovic, Z.; Pór, G.; Porte, L.; Pucella, G.; Puiatti, M. E.; Pütterich, T.; Rabinski, M.; Juul Rasmussen, J.; Rasmussen, J.; Rattá, G. A.; Ratynskaia, S.; Ravensbergen, T.; Réfy, D.; Reich, M.; Reimerdes, H.; Reimold, F.; Reiser, D.; Reux, C.; Reznik, S.; Ricci, D.; Rispoli, N.; Rivero-Rodriguez, J. F.; Rocchi, G.; Rodriguez-Ramos, M.; Romano, A.; Rosato, J.; Rubinacci, G.; Rubino, G.; Ryan, D. A.; Salewski, M.; Salmi, A.; Samaddar, D.; Sanchis-Sanchez, L.; Santos, J.; Särkimäki, K.; Sassano, M.; Sauter, O.; Scannell, R.; Scheffer, M.; Schneider, B. S.; Schneider, P.; Schrittwieser, R.; Schubert, M.; Seidl, J.; Seliunin, E.; Sharapov, S.; Sheeba, R. R.; Sias, G.; Sieglin, B.; Silva, C.; Sipilä, S.; Smith, S.; Snicker, A.; Solano, E. R.; Hansen, S. K.; Soria-Hoyo, C.; Sorokovoy, E.; Sozzi, C.; Sperduti, A.; Spizzo, G.; Spolaore, M.; Stejner, M.; Stipani, L.; Stober, J.; Strand, P.; Sun, H.; Suttrop, W.; Sytnykov, D.; Szepesi, T.; Tál, B.; Tala, T.; Tardini, G.; Tardocchi, M.; Teplukhina, A.; Terranova, D.; Testa, D.; Theiler, C.; Thorén, E.; Thornton, A.; Tilia, B.; Tolias, P.; Tomes, M.; Toscano-Jimenez, M.; Tsironis, C.; Tsui, C.; Tudisco, O.; Urban, J.; Valisa, M.; Vallar, M.; Vallejos Olivares, P.; Valovic, M.; Van Vugt, D.; Vanovac, B.; Varje, J.; Varju, J.; Varoutis, S. 1; Vartanian, S.; Vasilovici, O.; Vega, J.; Verdoolaege, G.; Verhaegh, K.; Vermare, L.; Vianello, N.; Vicente, J.; Viezzer, E.; Villone, F.; Voitsekhovitch, I.; Voltolina, D.; Vondracek, P.; Vu, N. M. T.; Walkden, N.; Wauters, T.; Weiland, M.; Weinzettl, V.; Wensing, M.; Wiesen, S.; Wiesenberger, M.; Wilkie, G.; Willensdorfer, M.; Wischmeier, M.; Wu, K.; Xiang, L.; Zagorski, R.; Zaloga, D.; Zanca, P.; Zaplotnik, R.; Zebrowski, J.; Zhang, W.; Zisis, A.; Zoletnik, S.; Zuin, M.
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- 2019
19. 91 (PB-091) Poster - Understanding patient experiences of early breast cancer treatment: informing future studies to reduce treatment burden.
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Potter, S., Mactier, M., Fairhurst, K., Stobart, H., Gath, J., and McIntosh, S.
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BREAST tumor treatment , *EARLY detection of cancer , *CONFERENCES & conventions , *PATIENTS' attitudes - Published
- 2024
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20. The transient outward current in cardiac myocytes from patients with terminal heart failure and from rats
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Wettwer, E., Flüß, M., Gath, J., Mewes, Th., Hoey, A., Grundke, M., Hauser, G., Zerkowski, H.-R., Reidemeister, J.Ch., and Ravens, U.
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- 1992
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21. l-type calcium current in cardiac myocytes from patients with terminal cardiac failure or ischemic heart disease and from guinea pigs
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Mewes, Th., Wettwer, E., Gath, J., Hoey, A., Grundke, M., Hauser, G., Zerkowski, H.-R., Reidemeister, J.Ch., and Ravens, U.
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- 1992
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22. 185: The SPECIAL trial: exploring the place of early specialist palliative care in UK lung cancer management.
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Ahmedzai, S.H., Milroy, R., Billingham, C., Ryan, T., Young, T., Gath, J., Stubbs, C., and Pope, A.
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PALLIATIVE treatment , *LUNG cancer treatment , *CLINICAL trials , *PUBLIC health , *CANCER periodicals - Published
- 2015
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23. Understanding Patient Experiences to Inform Future Studies to Optimize Personalization of Treatment for Early Breast Cancer.
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McIntosh SA, Mactier M, Fairhurst K, Gath J, Stobart H, and Potter S
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- Humans, Female, Middle Aged, Surveys and Questionnaires, Adult, Aged, Prognosis, Follow-Up Studies, Combined Modality Therapy, Survival Rate, Aged, 80 and over, Breast Neoplasms therapy, Breast Neoplasms pathology, Quality of Life, Precision Medicine
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Background: Breast cancer treatment is multimodal, but not all patients benefit from each treatment, and many experience morbidities significantly impacting quality of life. There is increasing interest in tailoring breast cancer treatments to optimize oncological outcomes and reduce treatment burden, but it is vital that future trials focus on treatments that most impact patients. This study was designed to explore patient experiences of treatment to inform future research., Methods: An online survey was co-developed with patient advocates to explore respondents' experiences of breast cancer treatment. Questions included simple demographics, treatments received, and views regarding omitting treatments if that is deemed safe. The survey was circulated via social media and patient advocacy groups. Responses were summarized by using simple statistics; free text was analyzed thematically., Results: Of the 235 participants completing the survey, 194 (82.6%) would choose to omit a specific treatment if safe to do so. The most commonly selected treatments were chemotherapy (n = 69, 35.6%) and endocrine therapy (n = 61, 31.4%) mainly due to side effects. Fewer respondents would choose to omit surgery (n = 40, 20.6%) or radiotherapy (n = 20, 10.3%). Several women commented that survival was their "absolute priority" and that high-quality evidence to support the safety of reducing treatment would be essential., Conclusions: Patients with breast cancer are individuals who may wish to optimize different components of their treatment. A portfolio of studies co-designed with patients is needed to establish an evidence base for greater treatment personalization with studies focused on reducing avoidable chemotherapy and endocrine therapy a priority., (© 2024. The Author(s).)
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- 2024
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24. The feasibility and acceptability of an app-based intervention with brief behavioural support (APPROACH) to promote brisk walking in people diagnosed with breast, prostate and colorectal cancer in the UK.
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Lally P, Kennedy F, Smith S, Beeken RJ, Buck C, Thomas C, Counsell N, Wyld L, Martin C, Williams S, Roberts A, Greenfield DM, Gath J, Potts HWW, Latimer N, Smith L, and Fisher A
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- Male, Humans, Prostate, Feasibility Studies, Walking, United Kingdom, Mobile Applications, Colorectal Neoplasms therapy
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Introduction: Increased moderate to vigorous physical activity (MVPA) can improve clinical and psychosocial outcomes for people living with and beyond cancer (LWBC). This study aimed to assess the feasibility and acceptability of trial procedures in a pilot randomised controlled trial (RCT) of a theory-driven app-based intervention with behavioural support focused on promoting brisk walking (a form of MVPA) in people LWBC (APPROACH)., Methods: Participants diagnosed with breast, prostate or colorectal cancer were recruited from a single UK hospital site. Assessments at baseline and 3 months included online questionnaires, device-measured brisk walking (activPAL accelerometer) and self-reported weight and height. Participants were randomised to intervention or control (care as usual). The intervention comprised a non-cancer-specific app to promote brisk walking (National Health Service 'Active 10') augmented with print information about habit formation, a walking planner and two behavioural support telephone calls. Feasibility and acceptability of trial procedures were explored. Initial estimates for physical activity informed a power calculation for a phase III RCT. A preliminary health economics analysis was conducted., Results: Of those medically eligible, 369/577 (64%) were willing to answer further eligibility questions and 90/148 (61%) of those eligible were enrolled. Feasibility outcomes, including retention (97%), assessment completion rates (>86%) and app download rates in the intervention group (96%), suggest that the trial procedures are acceptable and that the intervention is feasible. The phase III RCT will require 472 participants to be randomised. As expected, the preliminary health economic analyses indicate a high level of uncertainty around the cost-effectiveness of the intervention., Conclusions: This pilot study demonstrates that a large trial of the brisk walking intervention with behavioural support is both feasible and acceptable to people LWBC. The results support progression onto a confirmatory phase III trial to determine the efficacy and cost-effectiveness of the intervention., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2024
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25. British Society of Gastroenterology guidelines on sedation in gastrointestinal endoscopy.
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Sidhu R, Turnbull D, Haboubi H, Leeds JS, Healey C, Hebbar S, Collins P, Jones W, Peerally MF, Brogden S, Neilson LJ, Nayar M, Gath J, Foulkes G, Trudgill NJ, and Penman I
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- Humans, Conscious Sedation, Endoscopy, Gastrointestinal adverse effects, Endoscopy, Gastrointestinal methods, Benzodiazepines, Gastroenterology, Propofol
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Over 2.5 million gastrointestinal endoscopic procedures are carried out in the United Kingdom (UK) every year. Procedures are carried out with local anaesthetic r with sedation. Sedation is commonly used for gastrointestinal endoscopy, but the type and amount of sedation administered is influenced by the complexity and nature of the procedure and patient factors. The elective and emergency nature of endoscopy procedures and local resources also have a significant impact on the delivery of sedation. In the UK, the vast majority of sedated procedures are carried out using benzodiazepines, with or without opiates, whereas deeper sedation using propofol or general anaesthetic requires the involvement of an anaesthetic team. Patients undergoing gastrointestinal endoscopy need to have good understanding of the options for sedation, including the option for no sedation and alternatives, balancing the intended aims of the procedure and reducing the risk of complications. These guidelines were commissioned by the British Society of Gastroenterology (BSG) Endoscopy Committee with input from major stakeholders, to provide a detailed update, incorporating recent advances in sedation for gastrointestinal endoscopy.This guideline covers aspects from pre-assessment of the elective 'well' patient to patients with significant comorbidity requiring emergency procedures. Types of sedation are discussed, procedure and room requirements and the recovery period, providing guidance to enhance safety and minimise complications. These guidelines are intended to inform practising clinicians and all staff involved in the delivery of gastrointestinal endoscopy with an expectation that this guideline will be revised in 5-years' time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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26. Outcomes of complex oncoplastic breast surgery in older women. Analysis of data from the Age Gap cohort study.
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Quddus R, Banks J, Morgan JL, Martin C, Reed MW, Walters S, Cheung KL, Todd A, Audisio R, Green T, Revell D, Gath J, Horgan K, Holcombe C, Parmeshwar R, Thompson A, and Wyld L
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- Female, Humans, Aged, Mastectomy, Cohort Studies, Quality of Life, Mastectomy, Segmental, Breast Neoplasms surgery, Mammaplasty
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Key Words: Breast cancer, mastectomy, breast conserving surgery, post-mastectomy reconstruction, older women, quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Ltd.)
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- 2023
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27. The value of standards for health datasets in artificial intelligence-based applications.
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Arora A, Alderman JE, Palmer J, Ganapathi S, Laws E, McCradden MD, Oakden-Rayner L, Pfohl SR, Ghassemi M, McKay F, Treanor D, Rostamzadeh N, Mateen B, Gath J, Adebajo AO, Kuku S, Matin R, Heller K, Sapey E, Sebire NJ, Cole-Lewis H, Calvert M, Denniston A, and Liu X
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- Humans, Consensus, Systematic Reviews as Topic, Artificial Intelligence, Delivery of Health Care
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Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative)., (© 2023. The Author(s).)
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- 2023
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28. Study within a trial of electronic versus paper-based Patient-Reported oUtcomes CollEction (SPRUCE): study protocol for a partially randomised patient preference study.
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Philipps L, Foster S, Gardiner D, Gath J, Gillman A, Haviland J, Hill E, King D, Manning G, Stiles M, Hall E, and Lewis R
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- Humans, Data Collection, Electronics, Patient Reported Outcome Measures, Patient Preference, Academies and Institutes
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Introduction: Patient-reported outcomes (PRO) are currently collected from trial participants using paper questionnaires by the Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU). Streamlining PRO collection using electronic questionnaires (ePRO) may improve data collection and patient experience. Here, we outline our protocol for a Study within a trial of electronic versus paper-based Patient-Reported oUtcomes CollEction (SPRUCE), which investigates the acceptability of ePRO in oncology clinical trials., Methods and Analysis: SPRUCE was developed alongside patient and public contributors. SPRUCE runs in multiple host trials with a partially randomised patient preference design, allowing participants to be randomised or choose their preference of electronic or paper questionnaires. Questionnaires are scheduled in accordance with host trial follow-up. The primary objective will assess differences in return rates (compliance) between ePRO and paper PROs at the first timepoint post-host trial intervention in the randomised group. Paper PRO compliance is expected to be 90%. 244 randomised participants are required to exclude ≤80% compliance rates with ePRO (10% non-inferiority margin, with 80% power and one-sided alpha=0.05). SPRUCE aims to assess acceptability of ePRO in oncology clinical trials, establish whether ePRO is acceptable to ICR-CTSU trial participants and can capture complete PRO data, consistent with paper PROs., Ethics and Dissemination: The SPRUCE protocol (ICR-CTSU/2021/10074) was approved by the Coventry and Warwick Central Research Ethics Committee (21/WM/0223) on 21 October 2021. Results will be disseminated via presentations, publications and lay summaries. No participant identifiable data will be included., Trial Registration: SWAT169., Competing Interests: Competing interests: EH receives support from a Cancer Research UK (CRUK) core grant (C1491/A25351) and LP receives support from her PhD by a CRUK clinical trials fellowship (A30384); no other authors have any potential conflicts of interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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29. Tackling bias in AI health datasets through the STANDING Together initiative.
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Ganapathi S, Palmer J, Alderman JE, Calvert M, Espinoza C, Gath J, Ghassemi M, Heller K, Mckay F, Karthikesalingam A, Kuku S, Mackintosh M, Manohar S, Mateen BA, Matin R, McCradden M, Oakden-Rayner L, Ordish J, Pearson R, Pfohl SR, Rostamzadeh N, Sapey E, Sebire N, Sounderajah V, Summers C, Treanor D, Denniston AK, and Liu X
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- Bias, Artificial Intelligence
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- 2022
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30. Margin status and survival outcomes after breast cancer conservation surgery: prospectively registered systematic review and meta-analysis.
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Bundred JR, Michael S, Stuart B, Cutress RI, Beckmann K, Holleczek B, Dahlstrom JE, Gath J, Dodwell D, and Bundred NJ
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- Breast pathology, Female, Humans, Margins of Excision, Mastectomy, Mastectomy, Segmental, Neoplasm Recurrence, Local, Breast Neoplasms
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Objective: To determine if margin involvement is associated with distant recurrence and to determine the required margin to minimise both local recurrence and distant recurrence in early stage invasive breast cancer., Design: Prospectively registered systematic review and meta-analysis of literature., Data Sources: Medline (PubMed), Embase, and Proquest online databases. Unpublished data were sought from study authors., Eligibility Criteria: Eligible studies reported on patients undergoing breast conserving surgery (for stages I-III breast cancer), allowed an estimation of outcomes in relation to margin status, and followed up patients for a minimum of 60 months. Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or by mastectomy were excluded. Where applicable, margins were categorised as tumour on ink (involved), close margins (no tumour on ink but <2 mm), and negative margins (≥2 mm)., Results: 68 studies from 1 January 1980 to 31 December 2021, comprising 112 140 patients with breast cancer, were included. Across all studies, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had involved (tumour on ink) margins and 17.8% (13.0% to 23.9%) had tumour on ink or a close margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour on ink, 8.4% (4.4% to 15.5%) in patients with tumour on ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumour on ink margins were associated with increased distant recurrence (hazard ratio 2.10, 95% confidence interval 1.65 to 2.69, P<0.001) and local recurrence (1.98, 1.66 to 2.36, P<0.001). Close margins were associated with increased distant recurrence (1.38, 1.13 to 1.69, P<0.001) and local recurrence (2.09, 1.39 to 3.13, P<0.001) compared with negative margins, after adjusting for receipt of adjuvant chemotherapy and radiotherapy. In five studies published since 2010, tumour on ink margins were associated with increased distant recurrence (2.41, 1.81 to 3.21, P<0.001) as were tumour on ink and close margins (1.44, 1.22 to 1.71, P<0.001) compared with negative margins., Conclusions: Involved or close pathological margins after breast conserving surgery for early stage, invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. On the basis of current evidence, international guidelines should be revised., Systematic Review Registration: CRD42021232115., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; NJB received a National Institute for Health and Care Research, Research for Patient Benefit grant investigating a margin device. The authors declare no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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31. Cancer, Fertility and Me: Developing and Testing a Novel Fertility Preservation Patient Decision Aid to Support Women at Risk of Losing Their Fertility Because of Cancer Treatment.
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Jones GL, Moss RH, Darby F, Mahmoodi N, Phillips B, Hughes J, Vogt KS, Greenfield DM, Brauten-Smith G, Gath J, Campbell T, Stark D, Velikova G, Snowden JA, Baskind E, Mascerenhas M, Yeomanson D, Skull J, Lane S, Bekker HL, and Anderson RA
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Background: Women with a new cancer diagnosis face complex decisions about interventions aiming to preserve their fertility. Decision aids are more effective in supporting decision making than traditional information provision. We describe the development and field testing of a novel patient decision aid designed to support women to make fertility preservation treatment decisions around cancer diagnosis., Methods: A prospective, mixed-method, three stage study involving: 1) co-development of the resource in collaboration with a multi-disciplinary group of key stakeholders including oncology and fertility healthcare professionals and patient partners (n=24), 2) alpha testing with a group of cancer patients who had faced a fertility preservation treatment decision in the past (n=11), and oncology and fertility healthcare professionals and stakeholders (n=14) and, 3) beta testing with women in routine care who had received a recent diagnosis of cancer and were facing a fertility preservation treatment decision (n=41) and their oncology and fertility healthcare professionals (n=3). Ten service users recruited from a closed Breast Cancer Now Facebook group and the support group Cancer and Fertility UK also provided feedback on CFM via an online survey., Results: A 60-page paper prototype of the Cancer, Fertility and Me patient decision aid was initially developed. Alpha testing of the resource found that overall, it was acceptable to cancer patients, healthcare professionals and key stakeholders and it was considered a useful resource to support fertility preservation treatment decision-making. However, the healthcare professionals felt that the length of the patient decision aid, and elements of its content may be a barrier to its use. Subsequently, the prototype was reduced to 40 pages. During beta testing of the shortened version in routine care, women who received the resource described its positive impact on their ability to make fertility preservation decisions and support them at a stressful time. However, practical difficulties emerged which impacted upon its wider dissemination in clinical practice and limited some elements of the evaluation planned., Discussion: Women receiving the decision aid within the cancer treatment pathway found it helped them engage with decisions about fertility preservation, and make better informed, values-based care plans with oncology and fertility teams. More work is needed to address access and implementation of this resource as part of routine oncology care pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jones, Moss, Darby, Mahmoodi, Phillips, Hughes, Vogt, Greenfield, Brauten-Smith, Gath, Campbell, Stark, Velikova, Snowden, Baskind, Mascerenhas, Yeomanson, Skull, Lane, Bekker and Anderson.)
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- 2022
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32. A phase IB and randomised phase IIA trial of CApecitabine plus Radium-223 (Xofigo™) in breast cancer patients with BONe metastases: CARBON trial results.
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Winter M, Coleman R, Kendall J, Palmieri C, Twelves C, Howell S, MacPherson I, Wilson C, Purohit K, Gath J, Taylor C, Eastell R, Murden G, Brown SR, Rathbone E, and Brown J
- Abstract
Background: Approximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra
223 ) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra223 with capecitabine chemotherapy in patients with MBC with bone involvement., Methods: CARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m2 bd days 4-17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0-2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra223 . Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra223 or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease., Results: In addition to bone metastases, 10/23 [44%] and 13/23 [57%] capecitabine + Ra223 and 2/11 [18%] and 9/11 [82%] capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra223 patients had received prior chemotherapy for MBC: 11/23 [48%] vs 2/11 [18%]. The analysis populations comprise 34 patients (23 capecitabine + Ra223 , 11 capecitabine); 2 patients randomised to capecitabine + Ra223 received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra223 (range 3-12) and 12 in the capecitabine arm (range 1-12). 94/95 prescribed Ra223 cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms., Conclusion: Capecitabine + Ra223 at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically., Competing Interests: Janet Brown declared research grants (to her institution) from Amgen, AstraZeneca and Bayer and personal fees from Amgen, Novartis, BMS, Ipsen, Sandoz, MSD and Bayer and support for attending meetings from Ipsen. Matthew Winter declared consulting fees from Gilead, Novartis and Eli Lilly, payment for lectures/presentations/speakers bureaus from Eli Lilly, Pfizer, Novartis and Easai and support for attending meetings and/or travel from Eli Lilly, Gilead, Novartis and Easai. Robert Coleman declared consulting fees from AstraZeneca, Boehringer Ingelheim, ITM and Sanofi; speaker fees from Amgen, ITM, Novartis and Pierre Fabre; and has a patent pending and share options with Inbiomotion. Caroline Wilson declared consultancy fees from Pfizer, Novartis, Amgen and Roche Iain MacPherson declared consultancy fees from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, In3Bio, MSD, Novartis, Pfizer and Roche and travel support from Eisai and Roche. Richard Eastell declared consultancy funding from IDS, Sandoz, Samsung, Haoma Medica, CL Bio, Biocon, Takeda, meeting presentations from Pharmacosmos, Alexion and Amgen and grant funding from Amgen, Roche, Pharmacosmos and Alexion. Chris Twelves declared fees from AstraZenenca, Pfizer, Novartis, MSD and Eisai. Sacha Howell declared speaker fees and advisory board fees from Pfizer. Carlo Palmieri declared grant funding from Daiichi Sankyo, Pfizer and Seagen, travel support from Gilead and Roche and honoraria from Astrazeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, Novartis, Pfizer and Roche. All other authors declared no conflicts of interests., (© 2022 Published by Elsevier GmbH.)- Published
- 2022
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33. Improving outcomes for women aged 70 years or above with early breast cancer: research programme including a cluster RCT
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Wyld L, Reed MWR, Collins K, Ward S, Holmes G, Morgan J, Bradburn M, Walters S, Burton M, Lifford K, Edwards A, Brain K, Ring A, Herbert E, Robinson TG, Martin C, Chater T, Pemberton K, Shrestha A, Nettleship A, Richards P, Brennan A, Cheung KL, Todd A, Harder H, Audisio R, Battisti NML, Wright J, Simcock R, Murray C, Thompson AM, Gosney M, Hatton M, Armitage F, Patnick J, Green T, Revill D, Gath J, Horgan K, Holcombe C, Winter M, Naik J, and Parmeshwar R
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Background: In breast cancer management, age-related practice variation is widespread, with older women having lower rates of surgery and chemotherapy than younger women, based on the premise of reduced treatment tolerance and benefit. This may contribute to inferior outcomes. There are currently no age- and fitness-stratified guidelines on which to base treatment recommendations., Aim: We aimed to optimise treatment choice and outcomes for older women (aged ≥ 70 years) with operable breast cancer., Objectives: Our objectives were to (1) determine the age, comorbidity, frailty, disease stage and biology thresholds for endocrine therapy alone versus surgery plus adjuvant endocrine therapy, or adjuvant chemotherapy versus no chemotherapy, for older women with breast cancer; (2) optimise survival outcomes for older women by improving the quality of treatment decision-making; (3) develop and evaluate a decision support intervention to enhance shared decision-making; and (4) determine the degree and causes of treatment variation between UK breast units., Design: A prospective cohort study was used to determine age and fitness thresholds for treatment allocation. Mixed-methods research was used to determine the information needs of older women to develop a decision support intervention. A cluster-randomised trial was used to evaluate the impact of this decision support intervention on treatment choices and outcomes. Health economic analysis was used to evaluate the cost–benefit ratio of different treatment strategies according to age and fitness criteria. A mixed-methods study was used to determine the degree and causes of variation in treatment allocation., Main Outcome Measures: The main outcome measures were enhanced age- and fitness-specific decision support leading to improved quality-of-life outcomes in older women (aged ≥ 70 years) with early breast cancer., Results: (1) Cohort study: the study recruited 3416 UK women aged ≥ 70 years (median age 77 years). Follow-up was 52 months. (a) The surgery plus adjuvant endocrine therapy versus endocrine therapy alone comparison: 2854 out of 3416 (88%) women had oestrogen-receptor-positive breast cancer, 2354 of whom received surgery plus adjuvant endocrine therapy and 500 received endocrine therapy alone. Patients treated with endocrine therapy alone were older and frailer than patients treated with surgery plus adjuvant endocrine therapy. Unmatched overall survival and breast-cancer-specific survival were higher in the surgery plus adjuvant endocrine therapy group (overall survival: hazard ratio 0.27, 95% confidence interval 0.23 to 0.33; p < 0.001; breast-cancer-specific survival: hazard ratio 0.41, 95% confidence interval 0.29 to 0.58; p < 0.001) than in the endocrine therapy alone group. In matched analysis, surgery plus adjuvant endocrine therapy was still associated with better overall survival (hazard ratio 0.72, 95% confidence interval 0.53 to 0.98; p = 0.04) than endocrine therapy alone, but not with better breast-cancer-specific survival (hazard ratio 0.74, 95% confidence interval 0.40 to 1.37; p = 0.34) or progression-free-survival (hazard ratio 1.11, 95% confidence interval 0.55 to 2.26; p = 0.78). (b) The adjuvant chemotherapy versus no chemotherapy comparison: 2811 out of 3416 (82%) women received surgery plus adjuvant endocrine therapy, of whom 1520 (54%) had high-recurrence-risk breast cancer [grade 3, node positive, oestrogen receptor negative or human epidermal growth factor receptor-2 positive, or a high Oncotype DX
® (Genomic Health, Inc., Redwood City, CA, USA) score of > 25]. In this high-risk population, there were no differences according to adjuvant chemotherapy use in overall survival or breast-cancer-specific survival after propensity matching. Adjuvant chemotherapy was associated with a lower risk of metastatic recurrence than no chemotherapy in the unmatched (adjusted hazard ratio 0.36, 95% confidence interval 0.19 to 0.68; p = 0.002) and propensity-matched patients (adjusted hazard ratio 0.43, 95% confidence interval 0.20 to 0.92; p = 0.03). Adjuvant chemotherapy improved the overall survival and breast-cancer-specific survival of patients with oestrogen-receptor-negative disease. (2) Mixed-methods research to develop a decision support intervention: an iterative process was used to develop two decision support interventions (each comprising a brief decision aid, a booklet and an online tool) specifically for older women facing treatment choices (endocrine therapy alone or surgery plus adjuvant endocrine therapy, and adjuvant chemotherapy or no chemotherapy) using several evidence sources (expert opinion, literature and patient interviews). The online tool was based on models developed using registry data from 23,842 patients and validated on an external data set of 14,526 patients. Mortality rates at 2 and 5 years differed by < 1% between predicted and observed values. (3) Cluster-randomised clinical trial of decision support tools: 46 UK breast units were randomised (intervention, n = 21; usual care, n = 25), recruiting 1339 women (intervention, n = 670; usual care, n = 669). There was no significant difference in global quality of life at 6 months post baseline (difference –0.20, 95% confidence interval –2.7 to 2.3; p = 0.90). In women offered a choice of endocrine therapy alone or surgery plus adjuvant endocrine therapy, knowledge about treatments was greater in the intervention arm than the usual care arm (94% vs. 74%; p = 0.003). Treatment choice was altered, with higher rates of endocrine therapy alone than of surgery in the intervention arm. Similarly, chemotherapy rates were lower in the intervention arm (endocrine therapy alone rate: intervention sites 21% vs. usual-care sites 15%, difference 5.5%, 95% confidence interval 1.1% to 10.0%; p = 0.02; adjuvant chemotherapy rate: intervention sites 10% vs. usual-care site 15%, difference 4.5%, 95% confidence interval 0.0% to 8.0%; p = 0.013). Survival was similar in both arms. (4) Health economic analysis: a probabilistic economic model was developed using registry and cohort study data. For most health and fitness strata, surgery plus adjuvant endocrine therapy had lower costs and returned more quality-adjusted life-years than endocrine therapy alone. However, for some women aged > 90 years, surgery plus adjuvant endocrine therapy was no longer cost-effective and generated fewer quality-adjusted life-years than endocrine therapy alone. The incremental benefit of surgery plus adjuvant endocrine therapy reduced with age and comorbidities. (5) Variation in practice: analysis of rates of surgery plus adjuvant endocrine therapy or endocrine therapy alone between the 56 breast units in the cohort study demonstrated significant variation in rates of endocrine therapy alone that persisted after adjustment for age, fitness and stage. Clinician preference was an important determinant of treatment choice., Conclusions: This study demonstrates that, for older women with oestrogen-receptor-positive breast cancer, there is a cohort of women with a life expectancy of < 4 years for whom surgery plus adjuvant endocrine therapy may offer little benefit and simply have a negative impact on quality of life. The Age Gap decision tool may help make this shared decision. Similarly, although adjuvant chemotherapy offers little benefit and has a negative impact on quality of life for the majority of older women with oestrogen-receptor-positive breast cancer, for women with oestrogen-receptor-negative breast cancer, adjuvant chemotherapy is beneficial. The negative impacts of adjuvant chemotherapy on quality of life, although significant, are transient. This implies that, for the majority of fitter women aged ≥ 70 years, standard care should be offered., Limitations: As with any observational study, despite detailed propensity score matching, residual bias cannot be excluded. Follow-up was at median 52 months for the cohort analysis. Longer-term follow-up will be required to validate these findings owing to the slow time course of oestrogen-receptor-positive breast cancer., Future Work: The online algorithm is now available (URL: https://agegap.shef.ac.uk/; accessed May 2022). There are plans to validate the tool and incorprate quality-of-life and 10-year survival outcomes., Trial Registration: This trial is registered as ISRCTN46099296., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research ; Vol. 10, No. 6. See the NIHR Journals Library website for further project information., (Copyright © 2022 Wyld et al. This work was produced by Wyld et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.)- Published
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34. Usability of myfood24 Healthcare and Mathematical Diet Optimisation in Clinical Populations: A Pilot Feasibility Randomised Controlled Trial.
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Threapleton DE, Beer SL, Foley DJ, Gibson LE, Trevillion S, Burke D, Wheatstone P, Gath J, Hex N, Setters J, Greenwood DC, and Cade JE
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- Diet Records, Feasibility Studies, Humans, Surveys and Questionnaires, Diet, Patient Compliance
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Monitoring nutritional intake is of clinical value, but few existing tools offer electronic dietary recording, instant nutritional analysis, and a platform connecting healthcare teams with patients that provides timely, personalised support. This feasibility randomised controlled trial tests the usability of 'myfood24 Healthcare', a dietary assessment app and healthcare professional website, in two clinical populations. Patients were recruited from a weight management programme (n21) and from a group of gastroenterology surgery outpatients ( n = 27). They were randomised into three groups: standard care, myfood24, or myfood24 + diet optimisation (automated suggestions for dietary improvement). The participants were asked to record their diet at least four times over eight weeks. During the study, healthcare professionals viewed recorded dietary information to facilitate discussions about diet and nutritional targets. The participants provided feedback on usability and acceptability. A total of 48 patients were recruited, and 16 were randomised to each of the three groups. Compliance among app users ( n = 32) was reasonable, with 25 (78%) using it at least once and 16 (50%) recording intake for four days or more. Among users, the mean (standard deviation) number of days used was 14.0 (17.5), and the median (interquartile range) was six (2.5-17.0) over 2 months. Feedback questionnaires were completed by only 23 of 46 participants (50%). The mean System Usability Score ( n = 16) was 59 (95% confidence interval, 48-70). Patient and healthcare professional feedback indicates a need for more user training and the improvement of some key app features such as the food search function. This feasibility study shows that myfood24 Healthcare is acceptable for patients and healthcare professionals. These data will inform app refinements and its application in a larger clinical effectiveness trial.
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- 2022
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35. Observational cohort study in older women with early breast cancer: Use of radiation therapy and impact on health-related quality of life and mortality.
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Battisti NML, Hatton MQ, Reed MWR, Herbert E, Morgan JL, Bradburn M, Simcock R, Walters SJ, Collins KA, Ward SE, Holmes GR, Burton M, Lifford KJ, Edwards A, Robinson TG, Martin C, Chater T, Pemberton KJ, Brennan A, Leung Cheung K, Todd A, Audisio RA, Wright J, Green T, Revell D, Gath J, Horgan K, Holcombe C, Winter MC, Naik J, Parmeshwar R, Gosney MA, Thompson AM, Wyld L, and Ring A
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- Aged, Cohort Studies, Female, Humans, Mastectomy, Mastectomy, Segmental, Quality of Life, Radiotherapy, Adjuvant, Breast Neoplasms radiotherapy, Breast Neoplasms surgery
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Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL)., Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires., Results: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months., Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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36. Process evaluation of the Bridging the Age Gap in Breast Cancer decision support intervention cluster randomised trial.
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Burton M, Lifford KJ, Wyld L, Armitage F, Ring A, Nettleship A, Collins K, Morgan J, Reed MWR, Holmes GR, Bradburn M, Gath J, Green T, Revell D, Brain K, and Edwards A
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- Aged, Decision Making, Shared, Female, Humans, Breast Neoplasms therapy
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Background: The Bridging the Age Gap in Breast Cancer research programme sought to improve treatment decision-making for older women with breast cancer by developing and testing, in a cluster randomised trial (n = 1339 patients), two decision support interventions (DESIs). Both DESIs were used in the intervention arm and each comprised an online risk prediction model, brief decision aid and information booklet. One DESI supported the decision to have either primary endocrine therapy (PET) or surgery with adjuvant therapies and the second supported the decision to have adjuvant chemotherapy after surgery or not., Methods: Sixteen sites were randomly selected to take part in the process evaluation. Multiple methods of data collection were used. Medical Research Council (MRC) guidelines for the evaluation of complex interventions were used., Results: Eighty-two patients, mean age 75.5 (range 70-93), provided data for the process evaluation. Seventy-three interviews were completed with patients. Ten clinicians from six intervention sites took part in telephone interviews. Dose: Ninety-one members of staff in the intervention arm received intervention training. Reach: The online tool was accessed on 324 occasions by 27 clinicians. Reasons for non-use of the online tool were commonly that the patient had already made a decision or that there was no online access in the clinic. Of the 32 women for whom there were data available, fifteen from the intervention arm and six from the usual care arm were offered a choice of treatment. Fidelity: Clinicians used the online tool in different ways, with some using it during the consultation and others checking the online survival estimates before the consultation. Adaptation: There was evidence of adaptation when using the DESIs. A lack of infrastructure, e.g. internet access, was a barrier to the use of the online tool. The brief decision aid was rarely used. Mediators: Shared decision-making: Most patients felt able to contribute to decision-making and expressed high levels of satisfaction with the process. Participants' responses to intervention: Six patients reported the DESIs to be very useful, one somewhat useful and two moderately useful., Conclusions: Clinicians who participated were mainly supportive of the interventions and had attempted some adaptations to make the interventions applicable, but there were practical and engagement barriers that led to sub-optimal adoption in routine practice., Trial Registration: ISRCTN46099296 . Registered on 11 August 2016-retrospectively registered., (© 2021. The Author(s).)
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- 2021
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37. Bridging The Age Gap: observational cohort study of effects of chemotherapy and trastuzumab on recurrence, survival and quality of life in older women with early breast cancer.
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Ring A, Battisti NML, Reed MWR, Herbert E, Morgan JL, Bradburn M, Walters SJ, Collins KA, Ward SE, Holmes GR, Burton M, Lifford K, Edwards A, Robinson TG, Martin C, Chater T, Pemberton KJ, Brennan A, Cheung KL, Todd A, Audisio RA, Wright J, Simcock R, Green T, Revell D, Gath J, Horgan K, Holcombe C, Winter MC, Naik J, Parmeshwar R, Gosney MA, Hatton MQ, Thompson AM, and Wyld L
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- Aged, Aged, 80 and over, Anthracyclines adverse effects, Breast Neoplasms psychology, Bridged-Ring Compounds adverse effects, Drug Therapy, Female, Humans, Patient Satisfaction statistics & numerical data, Propensity Score, Prospective Studies, Survival Analysis, Taxoids adverse effects, Trastuzumab adverse effects, Treatment Outcome, Anthracyclines therapeutic use, Breast Neoplasms drug therapy, Bridged-Ring Compounds therapeutic use, Quality of Life psychology, Taxoids therapeutic use, Trastuzumab therapeutic use
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Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy., Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage., Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed., Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient., Trial Registration: ISRCTN 46099296., (© 2021. The Author(s).)
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- 2021
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38. Formalising the induction of patient and public involvement contributors on trial oversight committees.
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Pickering EC, Hanley B, Bell P, Gath J, Hanlon P, Oldroyd R, Stephens R, and Tweed CD
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Background: Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, running and oversight. This research explored the induction and training of PPI Contributors joining trial oversight committees and was used to update the Medical Research Council Clinical Trials Unit at University College London's (MRC CTU at UCL) induction pack for new PPI Contributors., Methods: Published and unpublished materials provided by other CTUs and research organisations on training for PPI Contributors on oversight committees were reviewed, with themes then triangulated to identify the most common topics covered in induction training. A face-to-face workshop with PPI Contributors from the MRC CTU at UCL reviewed a draft updated Induction Pack. Findings from these discussions were incorporated into a revised induction pack which was then re-reviewed by the workshop attendees., Results: No published literature on this subject was found. However, several common themes were identified from unpublished materials. Workshop attendees agreed with most of the themes suggested in the initial draft pack based on the literature search and also provided a number of additional topics for discussion., Conclusions: There is very little consistency in the induction of PPI Contributors on oversight committees. Whilst most local guidance explains the general role of a PPI Contributor, more context and background of the particular trial needs to be provided to allow for adequate induction of new committee members. The Induction Pack created provides a framework upon which trial managers can build a full picture of their study.
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- 2021
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39. Age specific recruitment and retention to a large multicentre observational breast cancer trial in older women: The Age Gap Trial.
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Todd A, Martin C, Morgan J, Herbert E, Bradburn M, Burton M, Reed MWR, Chater T, Pemberton K, Walters S, Cheung KL, Audisio RA, Ring A, Robinson T, Green T, Gath J, and Wyld L
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- Activities of Daily Living, Aged, Female, Humans, Logistic Models, Research Design, United Kingdom, Breast Neoplasms therapy
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Introduction: Recruitment and retention are two of the most important factors in successfully running clinical trials. Many trials encounter problems with both, causing delays or preventing study progress. These issues are greater in older adults and patients with cancer., Materials and Methods: We assessed recruitment and retention in a large, multicentre, observational breast cancer study in older female patients (>70 years, N = 3440). Data collected by the Age Gap study were used to assess rates of, and reasons for, patients not being recruited or retained. Statistical analysis assessed the impact of age as a predictor of recruitment and retention., Results: Between February 2013 and June 2018, 6876 patients were screened and 3456 were consented across 56 United Kingdom (UK) breast units. Reasons for non-recruitment included ineligibility, clinician issues, staffing resource issues, patients' lack of interest or time and trial burden. In comparison with the age demographics of patients with breast cancer in the UK, women aged 70-75 years were over-represented compared to older age groups. Logistic regression demonstrated that older age significantly reduced the odds of consent (OR = 0.96, CI: 0.938-0.982; p < 0.001). Multivariate analysis showed that age (p < 0.001), markers of poor functional ability (Eastern Cooperative Oncology Group Performance Status (p = 0.011)) and instrumental activities of daily living (p = 0.026) were significant predictors of withdrawal., Discussion: This study has demonstrated that selection and attrition bias for age are apparent despite a range of 'age friendly' study design measures. Exploration of the underlying reasons for this and development of measures to address this should be the focus of further research., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. Jenna Morgan, Stephen Walters and Thompson Robinson are all funded or part funded by the NIHR., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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40. Treatment choices for older women with primary operable breast cancer and cognitive impairment: Results from a prospective, multicentre cohort study.
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Martin C, Shrestha A, Morgan J, Bradburn M, Herbert E, Burton M, Todd A, Walters S, Ward S, Holmes G, Reed M, Collins K, Robinson TG, Ring A, Cheung KL, Audisio R, Gath J, Revell D, Green T, Lifford K, Edwards A, Chater T, Pemberton K, and Wyld L
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- Aged, Cohort Studies, Female, Humans, Neoplasm Recurrence, Local, Prospective Studies, Breast Neoplasms complications, Breast Neoplasms therapy, Cognitive Dysfunction etiology
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Objectives: The presence of dementia co-existing with a diagnosis of breast cancer may render management more challenging and have a substantial impact on oncological outcomes. The aim of this study was to examine the treatment and outcomes of older women with co-existing cognitive impairment and primary breast cancer., Materials and Methods: A prospective, multicentre UK cohort study of women aged 70 years or over with primary operable breast cancer. Patients with and without cognitive impairment were compared to assess differences in treatment and survival outcomes., Results: In total, 3416 women were recruited between 2013 and 2018. Of these, 478 (14%) had a diagnosis of dementia or cognitive impairment, subcategorised as mild, moderate and severely impaired. Up to 85% of women with normal cognition underwent surgery compared to 74%, 61% and 40% with mild, moderate, and severe impairment (p = 0.001). Among women at higher risk of recurrence, the uptake of chemotherapy was 25% for cognitively normal women compared to 20%, 22% and 12% for mild, moderate and severe impairment groups (p = 0.222). Radiotherapy use was similar in the subgroups. Although patients with cognitive impairment had shorter overall survival (HR: 2.10, 95% CI: 1.77-2.50, p < 0.001), there were no statistically significant differences in breast cancer specific or progression-free survival., Conclusion: Cognitive impairment appears to play a significant part in deciding how to treat older women with breast cancer. Standard treatment may be over-treatment for some women with severe dementia and careful consideration must be given to a more tailored approach in these women., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. Professors Thompson Robinson and Stephen Walters are National Institute for Health Research (NIHR) Senior Investigators and Jenna Morgan is a NIHR Clinical Lecturer., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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41. Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.
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Wyld L, Reed MWR, Collins K, Burton M, Lifford K, Edwards A, Ward S, Holmes G, Morgan J, Bradburn M, Walters SJ, Ring A, Robinson TG, Martin C, Chater T, Pemberton K, Shrestha A, Nettleship A, Murray C, Brown M, Richards P, Cheung KL, Todd A, Harder H, Brain K, Audisio RA, Wright J, Simcock R, Armitage F, Bursnall M, Green T, Revell D, Gath J, Horgan K, Holcombe C, Winter M, Naik J, Parmeshwar R, Gosney M, Hatton M, and Thompson AM
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- Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms mortality, Chemotherapy, Adjuvant, Female, Health Knowledge, Attitudes, Practice, Humans, Quality of Life, Breast Neoplasms therapy, Decision Making, Decision Support Techniques
- Abstract
Background: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice., Methods: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice., Results: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms., Conclusion: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com)., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)
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- 2021
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42. Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.
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Morgan JL, Shrestha A, Reed MWR, Herbert E, Bradburn M, Walters SJ, Martin C, Collins K, Ward S, Holmes G, Burton M, Lifford K, Edwards A, Ring A, Robinson T, Chater T, Pemberton K, Brennan A, Cheung KL, Todd A, Audisio R, Wright J, Simcock R, Thomson AM, Gosney M, Hatton M, Green T, Revill D, Gath J, Horgan K, Holcombe C, Winter MC, Naik J, Parmeschwar R, and Wyld L
- Subjects
- Aged, Aged, 80 and over, Breast Neoplasms metabolism, Breast Neoplasms psychology, Female, Humans, Longitudinal Studies, Mastectomy, Prospective Studies, Receptors, Estrogen metabolism, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms therapy, Quality of Life
- Abstract
Background: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy., Methods: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage., Results: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains., Conclusion: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)
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- 2021
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43. Bridging the Age Gap in breast cancer: Impact of chemotherapy on quality of life in older women with early breast cancer.
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Battisti NML, Reed MWR, Herbert E, Morgan JL, Collins KA, Ward SE, Holmes GR, Bradburn M, Walters SJ, Burton M, Lifford K, Edwards A, Robinson TG, Martin C, Chater T, Pemberton KJ, Shrestha A, Brennan A, Cheung KL, Todd A, Audisio RA, Wright J, Simcock R, Green T, Revell D, Gath J, Horgan K, Holcombe C, Winter MC, Naik J, Parmeshwar R, Gosney MA, Hatton MQ, Thompson AM, Wyld L, and Ring A
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- Aged, Aged, 80 and over, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular drug therapy, Carcinoma, Lobular pathology, Female, Follow-Up Studies, Humans, Prognosis, Prospective Studies, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms psychology, Carcinoma, Ductal, Breast psychology, Carcinoma, Lobular psychology, Quality of Life
- Abstract
Introduction: Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study., Materials and Methods: A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013-2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching., Results: Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18-24 months in unmatched and matched cohorts., Conclusions: The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy., Trial Registration Number Isrctn: 46099296., Competing Interests: Conflict of interest statement The authors declare no conflict of interest. Professors Stephen Walters and Thompson Robinson are National Institute for Health Research (NIHR) Senior Investigators; Jenna Morgan is a NIHR Clinical Lecturer; and Kate Lifford is funded by the NIHR as part of this project. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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44. Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life.
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Wyld L, Reed MWR, Morgan J, Collins K, Ward S, Holmes GR, Bradburn M, Walters S, Burton M, Herbert E, Lifford K, Edwards A, Ring A, Robinson T, Martin C, Chater T, Pemberton K, Shrestha A, Brennan A, Cheung KL, Todd A, Audisio R, Wright J, Simcock R, Green T, Revell D, Gath J, Horgan K, Holcombe C, Winter M, Naik J, Parmeshwar R, Patnick J, Gosney M, Hatton M, and Thomson AM
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- Aged, Aged, 80 and over, Breast Neoplasms mortality, Female, Humans, Propensity Score, Prospective Studies, Risk Factors, Survival Analysis, Breast Neoplasms surgery, Quality of Life psychology
- Abstract
Background: Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET., Methods: Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET., Findings: A total of 3416 women (median age 77, range 69-102) were recruited from 56 breast units-2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23-0.33, P < 0.001). Unmatched breast cancer-specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29-0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53-0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40-1.37, P = 0.34) although at 4-5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance., Interpretation: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4-5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/)., Trial Registration Number: ISRCTN: 46099296., Competing Interests: Conflict of interest statement None declared., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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45. The three-dimensional structure of human β-endorphin amyloid fibrils.
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Seuring C, Verasdonck J, Gath J, Ghosh D, Nespovitaya N, Wälti MA, Maji SK, Cadalbert R, Güntert P, Meier BH, and Riek R
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- Amino Acid Sequence, Amyloid genetics, Amyloid metabolism, Cloning, Molecular, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Glutamic Acid metabolism, Humans, Hydrogen Bonding, Hydrogen-Ion Concentration, Models, Molecular, Mutation, Neurotransmitter Agents genetics, Neurotransmitter Agents metabolism, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Sequence Alignment, Sequence Homology, Amino Acid, beta-Endorphin genetics, beta-Endorphin metabolism, Amyloid chemistry, Glutamic Acid chemistry, Neurotransmitter Agents chemistry, Protons, beta-Endorphin chemistry
- Abstract
In the pituitary gland, hormones are stored in a functional amyloid state within acidic secretory granules before they are released into the blood. To gain a detailed understanding of the structure-function relationship of amyloids in hormone secretion, the three-dimensional (3D) structure of the amyloid fibril of the human hormone β-endorphin was determined by solid-state NMR. We find that β-endorphin fibrils are in a β-solenoid conformation with a protonated glutamate residue in their fibrillar core. During exocytosis of the hormone amyloid the pH increases from acidic in the secretory granule to neutral level in the blood, thus it is suggested-and supported with mutagenesis data-that the pH change in the cellular milieu acts through the deprotonation of glutamate 8 to release the hormone from the amyloid. For amyloid disassembly in the blood, it is proposed that the pH change acts together with a buffer composition change and hormone dilution. In the pituitary gland, peptide hormones can be stored as amyloid fibrils within acidic secretory granules before release into the blood stream. Here, we use solid-state NMR to determine the 3D structure of the amyloid fiber formed by the human hormone β-endorphin. We find that β-endorphin fibrils are in a β-solenoid conformation that is generally reminiscent of other functional amyloids. In the β-endorphin amyloid, every layer of the β-solenoid is composed of a single peptide and protonated Glu8 is located in the fibrillar core. The secretory granule has an acidic pH but, on exocytosis, the β-endorphin fibril would encounter neutral pH conditions (pH 7.4) in the blood; this pH change would result in deprotonation of Glu8 to release the hormone peptide from the amyloid. Analyses of β-endorphin variants carrying mutations in Glu8 support the role of the protonation state of this residue in fibril disassembly, among other environmental changes.
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- 2020
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46. Bridging the age gap in breast cancer: evaluation of decision support interventions for older women with operable breast cancer: protocol for a cluster randomised controlled trial.
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Collins K, Reed M, Lifford K, Burton M, Edwards A, Ring A, Brain K, Harder H, Robinson T, Cheung KL, Morgan J, Audisio R, Ward S, Richards P, Martin C, Chater T, Pemberton K, Nettleship A, Murray C, Walters S, Bortolami O, Armitage F, Leonard R, Gath J, Revell D, Green T, and Wyld L
- Subjects
- Aged, Aged, 80 and over, Algorithms, Antineoplastic Agents, Hormonal therapeutic use, Cluster Analysis, Estrogen Receptor Modulators therapeutic use, Female, Health Status, Humans, Patient Participation, Quality of Life, Breast Neoplasms drug therapy, Breast Neoplasms surgery, Decision Making, Decision Support Techniques
- Abstract
Introduction: While breast cancer outcomes are improving steadily in younger women due to advances in screening and improved therapies, there has been little change in outcomes among the older age group. It is inevitable that comorbidities/frailty rates are higher, which may increase the risks of some breast cancer treatments such as surgery and chemotherapy, many older women are healthy and may benefit from their use. Adjusting treatment regimens appropriately for age/comorbidity/frailty is variable and largely non-evidence based, specifically with regard to rates of surgery for operable oestrogen receptor-positive disease and rates of chemotherapy for high-risk disease., Methods and Analysis: This multicentre, parallel group, pragmatic cluster randomised controlled trial (RCT) (2015-18) reported here is nested within a larger ongoing 'Age Gap Cohort Study' (2012-18RP-PG-1209-10071), aims to evaluate the effectiveness of a complex intervention of decision support interventions to assist in the treatment decision making for early breast cancer in older women. The interventions include two patient decision aids (primary endocrine therapy vs surgery/antioestrogen therapy and chemotherapy vs no chemotherapy) and a clinical treatment outcomes algorithm for clinicians., Ethics and Dissemination: National and local ethics committee approval was obtained for all UK participating sites. Results from the trial will be submitted for publication in international peer-reviewed scientific journals., Iras Reference: 115550., Trial Registration Number: European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2015-004220-61;Pre-results. Sponsor's Protocol Code Number Sheffield Teaching Hospitals STH17086. ISRCTN 32447*., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2017
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47. Line-Broadening in Low-Temperature Solid-State NMR Spectra of Fibrils.
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Bauer T, Dotta C, Balacescu L, Gath J, Hunkeler A, Böckmann A, and Meier BH
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- Amino Acid Sequence, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Protein Conformation, Amyloid chemistry, Magnetic Resonance Spectroscopy methods, Temperature
- Abstract
The temperature-dependent resonance-line broadening of HET-s(218-289) in its amyloid form is investigated in the range between 110 K and 280 K. Significant differences are observed between residues in the structured hydrophobic triangular core, which are broadened the least and can be detected down to 100 K, and in the solvent-exposed parts, which are broadened the most and often disappear from the observed spectrum around 200 K. Below the freezing of the bulk water, around 273 K, the protein fibrils are still surrounded by a layer of mobile water whose thickness decreases with temperature, leading to drying out of the fibrils.
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- 2017
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48. Hexagonal ice in pure water and biological NMR samples.
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Bauer T, Gath J, Hunkeler A, Ernst M, Böckmann A, and Meier BH
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- Algorithms, Models, Chemical, Models, Molecular, Molecular Conformation, Ice analysis, Magnetic Resonance Spectroscopy methods, Water chemistry
- Abstract
Ice, in addition to "liquid" water and protein, is an important component of protein samples for NMR spectroscopy at subfreezing temperatures but it has rarely been observed spectroscopically in this context. We characterize its spectroscopic behavior in the temperature range from 100 to 273 K, and find that it behaves like pure water ice. The interference of magic-angle spinning (MAS) as well as rf multiple-pulse sequences with Bjerrum-defect motion greatly influences the ice spectra.
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- 2017
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49. Solid-state NMR sequential assignment of the β-endorphin peptide in its amyloid form.
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Seuring C, Gath J, Verasdonck J, Cadalbert R, Rivier J, Böckmann A, Meier BH, and Riek R
- Subjects
- Amino Acid Sequence, Protein Conformation, beta-Strand, Sequence Alignment, Amyloid chemistry, Nuclear Magnetic Resonance, Biomolecular, Protein Multimerization, beta-Endorphin chemistry
- Abstract
Insights into the three-dimensional structure of hormone fibrils are crucial for a detailed understanding of how an amyloid structure allows the storage of hormones in secretory vesicles prior to hormone secretion into the blood stream. As an example for various hormone amyloids, we have studied the endogenous opioid neuropeptide β-endorphin in one of its fibril forms. We have achieved the sequential assignment of the chemical shifts of the backbone and side-chain heavy atoms of the fibril. The secondary chemical shift analysis revealed that the β-endorphin peptide adopts three β-strands in its fibril state. This finding fosters the amyloid nature of a hormone at the atomic level.
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- 2016
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50. Further exploration of the conformational space of α-synuclein fibrils: solid-state NMR assignment of a high-pH polymorph.
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Verasdonck J, Bousset L, Gath J, Melki R, Böckmann A, and Meier BH
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- Amino Acid Sequence, Animals, Hydrogen-Ion Concentration, Mice, Protein Isoforms chemistry, Protein Structure, Secondary, Nuclear Magnetic Resonance, Biomolecular, alpha-Synuclein chemistry
- Abstract
Polymorphism is a common and important phenomenon for protein fibrils which has been linked to the appearance of strains in prion and other neurodegenerative diseases. Parkinson disease is a frequently occurring neurodegenerative pathology, tightly associated with the formation of Lewy bodies. These deposits mainly consist of α-synuclein in fibrillar, β-sheet-rich form. α-synuclein is known to form numerous different polymorphs, which show distinct structural features. Here, we describe the chemical shift assignments, and derive the secondary structure, of a polymorph that was fibrillized at higher-than-physiological pH conditions. The fibrillar core contains residues 40-95, with both the C- and N-terminus not showing any ordered, rigid parts. The chemical shifts are similar to those recorded previously for an assigned polymorph that was fibrillized at neutral pH.
- Published
- 2016
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