49 results on '"McIlroy G"'
Search Results
2. Factors predicting survival in adult acute myeloid leukaemia: The experience of a district general hospital: 313
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McIlroy, G, Hasan, S Y, Murrin, R, Gilson, J, Craddock, C, and Wandroo, F
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- 2016
3. Plasma cell dyscrasia and an increased risk of fracture: Evidence from hospital episodes statistics: 213
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McIlroy, G, Cook, M, Pratt, G, Drayson, M, Cockwell, P, Yadav, P, Evison, F, Mytton, J, and Pinney, J
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- 2016
4. Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein
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Mody, N., Agouni, A., Mcilroy, G. D., Platt, B., and Delibegovic, M.
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- 2011
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5. MODULATION OF RETINOIC ACID-REGULATED GENE EXPRESSION BY FENRETINIDE PREVENTS DIET-INDUCED OBESITY IN C57BL/6 MICE AND TRIGLYCERIDE ACCUMULATION IN 3T3-L1 ADIPOCYTES.: 548 accepted poster
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Mody, N., Mcilroy, G., McCaffery, P., and Delibegovic, M.
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- 2012
6. PF795 EXPLORING THE REAL-LIFE CLINICAL VALUE OF LOW DOSE DIRECT ANTICOAGULANTS FOR SECONDARY PREVENTION OF THROMBOEMBOLISM
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Saul, S., primary, McIlroy, G., additional, Smith, N., additional, Perrin, D., additional, Fair, S., additional, and Kartsios, C., additional
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- 2019
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7. Some data on assisted dying from Oregon are worrying
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McIlroy, G. E., primary
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- 2014
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8. Development of Deaf Identity: An Ethnographic Study
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McIlroy, G., primary and Storbeck, C., additional
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- 2011
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9. Susceptibility to diet-induced obesity and glucose intolerance in the APP/ PSEN1 mouse model of Alzheimer's disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein
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Mody, N., Agouni, A., Mcilroy, G., Platt, B., and Delibegovic, M.
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ims/hypothesis: Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer's disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein ( APP) and presenilin 1 ( PSEN1) ( APP/ PSEN1), or PSEN1 alone, which are well-characterised animal models of Alzheimer's disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent. Methods: We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/ PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. Results: While there were no body weight differences between 16-17- and 20-21-month-old PSEN1 mice, APP/ PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/ PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/ PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/ PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/ PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/ PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/ PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. Conclusions/interpretation: Our results indicate that Alzheimer's disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance. [ABSTRACT FROM AUTHOR]
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- 2011
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10. Should you toss Medicaid when it's losing money?
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Hudson T, McIlroy G, and Laszewski R
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- 1999
11. Ibrutinib as part of risk-stratified treatment for posttransplant lymphoproliferative disorder: the phase 2 TIDaL trial.
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Chaganti S, Maycock S, McIlroy G, Jackson A, Bishop R, Johnson S, Kanfer E, Kassam S, Cwynarski K, Wrench D, Arumainathan A, Fox CP, Johnson R, McKay P, Paneesha S, Rowntree C, Balotis C, Collins GP, Davies A, Wright J, Burns S, Laurence A, Wheatley K, and Menne T
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- Humans, Middle Aged, Female, Male, Aged, Adult, Organ Transplantation adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide therapeutic use, Cyclophosphamide adverse effects, Vincristine administration & dosage, Vincristine adverse effects, Vincristine therapeutic use, Doxorubicin adverse effects, Doxorubicin therapeutic use, Doxorubicin administration & dosage, Prednisone administration & dosage, Prednisone adverse effects, Prednisone therapeutic use, Prospective Studies, Pyrazoles therapeutic use, Pyrazoles adverse effects, Pyrazoles administration & dosage, Piperidines therapeutic use, Piperidines adverse effects, Piperidines administration & dosage, Adenine analogs & derivatives, Adenine therapeutic use, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders etiology, Rituximab adverse effects, Rituximab administration & dosage, Rituximab therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects
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Abstract: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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12. Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.
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Goodyear CS, Patel A, Barnes E, Willicombe M, Siebert S, de Silva TI, Snowden JA, Lim SH, Bowden SJ, Billingham L, Richter A, Carroll M, Carr EJ, Beale R, Rea D, Parry H, Pirrie S, Lim Z, Satsangi J, Dunachie SJ, Cook G, Miller P, Basu N, Gilmour A, Hodgkins AM, Evans L, Hughes A, Longet S, Meacham G, Yong KL, A'Hearne MJ, Koh MBC, Burns SO, Orchard K, Paterson C, McIlroy G, Murray SM, Thomson T, Dimitriadis S, Goulston L, Miller S, Keillor V, Prendecki M, Thomas D, Kirkham A, McInnes IB, and Kearns P
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- Humans, Female, Male, Middle Aged, Aged, Antibodies, Viral blood, Prospective Studies, Immunization, Secondary, 2019-nCoV Vaccine mRNA-1273 immunology, Adult, T-Lymphocytes immunology, United Kingdom, ChAdOx1 nCoV-19 immunology, COVID-19 prevention & control, COVID-19 immunology, Immunocompromised Host immunology, SARS-CoV-2 immunology, COVID-19 Vaccines immunology, COVID-19 Vaccines administration & dosage, Immunogenicity, Vaccine, BNT162 Vaccine immunology, BNT162 Vaccine administration & dosage
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Background: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies., Methods: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete., Findings: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related., Interpretation: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose., Funding: Medical Research Council, Blood Cancer UK., Competing Interests: Declaration of interests DR reports research funding from Roche, Biotheranostics, RNA diagnostics, and Celgene; and honoraria or consultancy fees from Novartis, Pfizer, Lily, Roche, and AstraZeneca–Diiachi Sankyo. EB reports research funding from Vaccitech; consultancy fees from Roche, Vaccitech, and AstraZeneca; and holds patents in ChAdOx1 hepatitis B virus and hepatitis C virus vaccines. HP reports honoraria from AstraZeneca. IBM reports research funding or consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb (BMS), Causeway Therapeutics Cabaletta, Eli Lilly, Evelo Biosciences, Gilead, GSK, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; consultancy fees from AbbVie, Amgen, BMS, Causeway Therapeutics Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; and is on the board of directors of Evelo Biosciences. KO reports royalties to his institution from Telix Pharmaceuticals for Radiolabelled anti-CD66 antibody; consulting fees from Sanofi and Takeda; and stocks in GSK. KLY reports honoraria from Sanofi Genzyme, Takeda, and Amgen; support for meeting attendance from Takeda; and participation on a trial steering committee for Sanofi and an advisory board for Janssen. MJA reports research funding from Pfizer. MW reports research funding from Oxford Immunotech. MBCK reports honoraria from Gilead. MC reports consultancy fees from VacciTech. PK reports research funding from Bayer; and consultancy fees from AstraZeneca, Merck, and BMS. SM reports stock options in TCB BioPharm. SHL reports honoraria from AstraZeneca. SS reports research funding from Amgen, Boehringer-Ingelheim, BMS, GSK, Janssen, and UCB; and consultancy fees or honoraria from AbbVie, Eli Lilly, GSK, Janssen, and UCB. SOB reports research funding from CSL Behring; and consultancy fees, honoraria, or support for attending meetings from GSK, Baxalta US, and Biotest. JAS reports honoraria from Novartis and Gilead; advisory board fees from the Kiadis clinical trial, Medac, and NHS England National Specialised Commissioning Clinical Reference Group for Blood and Marrow Transplantation; and unpaid roles as President of British Society of Blood and Marrow Transplantation and Cellular Therapy, secretary of the European Society for Blood and Marrow Transplantation and as a board member of the British Society of Haematology. SJD is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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13. The management of newly diagnosed large B-cell lymphoma: A British Society for Haematology Guideline.
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Fox CP, Chaganti S, McIlroy G, Barrington SF, Burton C, Cwynarski K, Eyre TA, Illidge T, Kalakonda N, Kuhnl A, McKay P, and Davies AJ
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- Humans, Rituximab, Lymphoma, Large B-Cell, Diffuse diagnosis, Hematology
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- 2024
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14. Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial.
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McIlroy G, Lax S, Gaskell C, Jackson A, Rhodes M, Seale T, Fox S, Hopkins L, Okosun J, Barrington SF, Ringshausen I, Ramsay AG, Calaminici M, Linton K, and Bishton M
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- Humans, Positron Emission Tomography Computed Tomography, Arm pathology, Bayes Theorem, Quality of Life, Treatment Outcome, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Clinical Trials, Phase II as Topic, Lymphoma, Follicular drug therapy
- Abstract
Background: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined., Methods: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms., Discussion: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery., Trial Registration: ClinicalTrials.gov: NCT05848765; 08-May-2023., Eudract: 2022-000677-75; 10-Feb-2022., (© 2024. The Author(s).)
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- 2024
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15. Enhancement of Omicron-specific immune responses following bivalent COVID-19 booster vaccination in patients with chronic lymphocytic leukaemia.
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Roberts T, Uwenedi G, Bruton R, McIlroy G, Damery S, Sylla P, Logan N, Scott S, Lau M, Elzaidi A, Plass S, Mallick S, Spencer K, Stephens C, Bentley C, Pratt G, Zuo J, Paneesha S, Willett B, Moss P, and Parry H
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- Humans, Leukemia, Lymphocytic, Chronic, B-Cell, COVID-19 prevention & control
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- 2024
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16. Robust generation of neutralising antibodies against Omicron variants following bivalent mRNA booster vaccine in elderly people aged >80 years.
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Parry H, Bruton R, Uwenedi G, Roberts T, Sylla P, Cook J, Elzaidi A, Lau M, Drury T, Bray A, Mallick S, Spencer K, Bentley C, McIlroy G, Scott S, Logan N, Zuo J, Willett B, and Moss P
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- Aged, Humans, Antibodies, Viral, Antibodies, Neutralizing, Vaccines
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Competing Interests: Declaration of Competing Interest P.M. declares renumeration for educational meeting and advisory board work at Astra Zeneca and for educational meetings with Moderna. H.P. declares renumeration for educational meeting and advisory board work at Astra Zeneca. Other authors declare no competing interests.
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- 2024
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17. Delayed diagnosis resulting in increased disease burden in multiple myeloma: the legacy of the COVID-19 pandemic.
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Carmichael J, Seymour F, McIlroy G, Tayabali S, Amerikanou R, Feyler S, Popat R, Pratt G, Parrish C, Ashcroft AJ, Jackson GH, and Cook G
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- Humans, SARS-CoV-2, Pandemics, Delayed Diagnosis, Transplantation, Autologous, COVID-19 Testing, COVID-19 epidemiology, Multiple Myeloma diagnosis, Multiple Myeloma epidemiology, Multiple Myeloma therapy, Hematopoietic Stem Cell Transplantation
- Abstract
The COVID-19 pandemic has had global healthcare impacts, including high mortality from SARS-CoV-2 infection in cancer patients; individuals with multiple myeloma (MM) are especially susceptible to poor outcomes. However, even for MM patients who avoided severe infection, the ramifications of the pandemic have been considerable. The consequences of necessary socio-geographical behavior adaptation, including prolonged shielding and interruptions in delivery of non-pandemic medical services are yet to be fully understood. Using a real-world dataset of 323 consecutive newly diagnosed MM patients in England, we investigated the impact of the COVID-19 pandemic on routes to myeloma diagnosis, disease stage at presentation and relevant clinical outcomes. We demonstrate increasing MM presentations via emergency services and increased rates of bony and extra-medullary disease. Differences were seen in choice of induction therapy and the proportion of eligible patients undertaking autologous stem cell transplantation. Whilst survival was statistically inferior for emergency presentations, significant survival differences have yet to be demonstrated for the entire cohort diagnosed during the pandemic, making extended follow-up critical in this group. This dataset highlights wide-ranging issues facing MM patients consequent of the COVID-19 pandemic, with full impacts for clinicians and policy-makers yet to be elucidated., (© 2023. The Author(s).)
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- 2023
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18. Vaccine subtype and dose interval determine immunogenicity of primary series COVID-19 vaccines in older people.
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Parry H, Bruton R, Ayodele R, Sylla P, McIlroy G, Logan N, Scott S, Nicol S, Verma K, Stephens C, Willett B, Zuo J, and Moss P
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- Aged, BNT162 Vaccine, Humans, Immunogenicity, Vaccine, RNA, Messenger, COVID-19 prevention & control, COVID-19 Vaccines
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Age is the strongest determinant of COVID-19 mortality, and over 2 billion people have received primary series vaccination with BNT162b2 (mRNA) or ChAdOx1 (adenoviral vector). However, the profile of sustained vaccine immunogenicity in older people is unknown. Here, we determine spike-specific humoral and cellular immunity to 8 months following BNT162b2 or ChAdOx1 in 245 people aged 80-98 years. Vaccines are strongly immunogenic, with antibodies retained in every donor, while titers fall to 23%-26% from peak. Peak immunity develops rapidly with standard interval BNT162b2, although antibody titers are enhanced 3.7-fold with extended interval. Neutralization of ancestral variants is superior following BNT162b2, while neutralization of Omicron is broadly negative. Conversely, cellular responses are stronger following ChAdOx1 and are retained to 33%-60% of peak with all vaccines. BNT162b2 and ChAdOx1 elicit strong, but differential, sustained immunogenicity in older people. These data provide a baseline to assess optimal booster regimen in this vulnerable age group., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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19. COVID-19 vaccines elicit robust cellular immunity and clinical protection in chronic lymphocytic leukemia.
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Parry H, Bruton R, Roberts T, McIlroy G, Damery S, Sylla P, Dowell AC, Tut G, Lancaster T, Bone D, Willett B, Logan N, Scott S, Hulme S, Jadir A, Amin U, Nicol S, Stephens C, Faustini S, Al-Taei S, Richter A, Blakeway D, Verma K, Margielewska-Davies S, Pearce H, Pratt G, Zuo J, Paneesha S, and Moss P
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- COVID-19 Vaccines, Humans, Immunity, Cellular, COVID-19 prevention & control, Leukemia, Lymphocytic, Chronic, B-Cell
- Abstract
Competing Interests: Declaration of interests The authors declare no conflicts of interest.
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- 2022
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20. Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.
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Wilson MR, Eyre TA, Kirkwood AA, Wong Doo N, Soussain C, Choquet S, Martinez-Calle N, Preston G, Ahearne M, Schorb E, Moles-Moreau MP, Ku M, Rusconi C, Khwaja J, Narkhede M, Lewis KL, Calimeri T, Durot E, Renaud L, Øvlisen AK, McIlroy G, Ebsworth TJ, Elliot J, Santarsieri A, Ricard L, Shah N, Liu Q, Zayac AS, Vassallo F, Lebras L, Roulin L, Lombion N, Manos K, Fernandez R, Hamad N, Lopez-Garcia A, O'Mahony D, Gounder P, Forgeard N, Lees C, Agbetiafa K, Strüßmann T, Htut TW, Clavert A, Scott H, Guidetti A, Barlow BR, Tchernonog E, Smith J, Miall F, Fox CP, Cheah CY, El Galaly TC, Ferreri AJM, Cwynarski K, and McKay P
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- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide, Doxorubicin, Humans, Methotrexate, Neoplasm Recurrence, Local drug therapy, Prednisone, Retrospective Studies, Rituximab therapeutic use, Vincristine, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms prevention & control, Lymphoma, Large B-Cell, Diffuse pathology
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Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion., (© 2022 by The American Society of Hematology.)
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- 2022
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21. Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.
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Copland M, Slade D, McIlroy G, Horne G, Byrne JL, Rothwell K, Brock K, De Lavallade H, Craddock C, Clark RE, Smith ML, Fletcher R, Bishop R, Milojkovic D, and Yap C
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- Adolescent, Adult, Cytarabine adverse effects, Female, Granulocyte Colony-Stimulating Factor adverse effects, Humans, Idarubicin adverse effects, Imidazoles adverse effects, Male, Pyridazines adverse effects, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Background: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability., Methods: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m
2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented., Findings: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia)., Interpretation: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers., Funding: Blood Cancer UK and Incyte., Competing Interests: Declaration of interests MC has received research funding from Novartis, Bristol Myers Squibb, Cyclacel, and Takeda/Incyte; is an advisory board member for Bristol Myers Squibb, Novartis, Incyte, Daiichi Sankyo, and Pfizer; has received honoraria from Astellas, Bristol Myers Squibb, Novartis, Incyte, Pfizer, and Gilead. JLB is on the advisory board for and has received honoraria from Incyte. KR is on the advisory board for Novartis; and has received honoraria from Novartis, Incyte, Pfizer, and Daiichi Sankyo. KB is employed by UCB; has received personal fees from Eli Lilly and Invex Therapeutics; has received reimbursement from Merck and Roche; and holds shares in AstraZeneca and GlaxoSmithKline. HDL has received research funding from Incyte and Bristol Myers Squibb; and has received speaker fees from Incyte, Bristol Myers Squibb, and Pfizer. REC has received research support and honoraria from Novartis and Bristol Myers Squibb; and has received honoraria from Pfizer in the past 3 years. MLS is on the advisory board for Daiichi Sankyo and Pfizer; and has received honoraria from ARIAD. DM has received honoraria and been part of the speakers bureau for Novartis, Incyte, Bristol Myers Squibb, and Pfizer. CY has received personal fees from Celgene and Faron Pharmaceuticals, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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22. Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia.
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Parry H, McIlroy G, Bruton R, Damery S, Tyson G, Logan N, Davis C, Willett B, Zuo J, Ali M, Kaur M, Stephens C, Brant D, Otter A, McSkeane T, Rolfe H, Faustini S, Richter A, Lee S, Wandroo F, Shafeek S, Pratt G, Paneesha S, and Moss P
- Subjects
- Adult, Aged, Aged, 80 and over, Antibody Formation, COVID-19 complications, COVID-19 immunology, COVID-19 Vaccines immunology, Female, HEK293 Cells, Humans, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Male, Middle Aged, Antibodies, Neutralizing immunology, COVID-19 prevention & control, COVID-19 Vaccines therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell complications, SARS-CoV-2 immunology
- Abstract
Background: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses., Method: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms., Results: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination., Conclusions: These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort., (© 2021. The Author(s).)
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- 2022
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23. Azacitidine for the treatment of steroid-refractory chronic graft-versus-host disease: the results of the phase II AZTEC clinical trial.
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Malladi R, Ahmed I, McIlroy G, Dignan FL, Protheroe R, Jackson A, Moss P, Nunnick J, Siddique S, Bishop R, Elhaneid M, Hodgkinson A, and Craddock C
- Subjects
- Azacitidine pharmacology, Azacitidine therapeutic use, Chronic Disease, Humans, Prospective Studies, Quality of Life, Steroids therapeutic use, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m
2 days 1-5 per 28-day cycle. Azacitidine was tolerated by 13/14 patients, and 7/14 showed an objective response. Clinical responses were mirrored by improvements in patient-reported cGvHD symptoms and quality of life. AZTEC demonstrates that azacitidine is a safe and promising option for the treatment of cGvHD, and continued evaluation in the second stage of this phase II efficacy study is supported., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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24. A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.
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Fox CP, Ali AS, McIlroy G, Thust S, Martinez-Calle N, Jackson AE, Hopkins LM, Thomas CM, Kassam S, Wright J, Chaganti S, Smith J, Chau I, Culligan D, Linton KM, Collins GP, Ferreri AJM, Lewis D, Davies AJ, Johnson R, Auer DP, and Cwynarski K
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Combined Modality Therapy, Humans, Prospective Studies, Thiotepa therapeutic use, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2021
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25. Progress towards inclusive blood donation.
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McIlroy G
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- Bisexuality, Homosexuality, Male, Humans, Male, United Kingdom, Blood Donors, Health Policy, Risk Assessment, Sexual and Gender Minorities
- Published
- 2021
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26. Improved outcomes with allogeneic compared with autologous stem cell transplantation in aggressive T-cell lymphoma.
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McIlroy G, Barmayehvar B, Kamarajah SK, George L, Gondal AZ, Malladi R, and Chaganti S
- Subjects
- Disease Management, Humans, Lymphoma, T-Cell diagnosis, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Lymphoma, T-Cell therapy
- Published
- 2020
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27. Management of venous thromboembolism in patients experiencing direct oral anticoagulant treatment failure: a single-center review of practice and outcomes.
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McIlroy G, Smith N, Lokare A, Beale K, and Kartsios C
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- Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Male, Middle Aged, Retrospective Studies, Anticoagulants administration & dosage, Anticoagulants adverse effects, Heparin, Low-Molecular-Weight administration & dosage, Heparin, Low-Molecular-Weight adverse effects, Treatment Failure, Venous Thromboembolism therapy
- Abstract
Direct oral anticoagulants (DOACs) have gained in popularity over vitamin K antagonists for the treatment of venous thromboembolism, however their efficacy is not routinely monitored. It is therefore a clinical challenge to know how to respond when treatment with DOACs fails, and there is little formal guidance on how to manage these patients. We sought to characterize VTE patients who experienced DOAC failure at our institution, and rationalize subsequent treatment strategies. We collated the details of 54 consecutive patients with suboptimal response or breakthrough thrombosis on a DOAC, from our large specialist-led thrombosis clinic. Initial treatment changes were recorded, as well as long-term anticoagulation therapy and treatment outcomes. On first recognition of DOAC failure, 69% of patients were temporarily switched to therapeutic-dose low molecular weight heparin; most of the remaining patients were treated with an alternative DOAC regimen. After a limited period of parenteral treatment, 84% of patients returned to oral anticoagulation, the majority of whom experienced no further treatment failures. By the end of follow-up, 72% of patients were either on long-term DOAC therapy or had completed treatment altogether. In the absence of evidence or guidelines, brief rescue of anticoagulation with parenteral therapy can be an effective strategy when treatment with a DOAC fails.
- Published
- 2020
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28. Mixed T-cell chimerism at 3 months followed by donor lymphocyte infusion is independently associated with favorable outcomes in alemtuzumab-based reduced-intensity allogeneic hematopoietic stem cell transplantation.
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McIlroy G, Nikolousis E, Abou-Zeid N, Shankara P, Kishore B, Kaparou M, Lovell R, Elmoamly S, Davies D, Horgan C, Shenouda A, and Kanellopoulos A
- Subjects
- Alemtuzumab therapeutic use, Chimerism, Humans, T-Lymphocytes, Transplantation Chimera, Transplantation Conditioning, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation
- Published
- 2020
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29. Autoimmune Cytopenias Developing Late Post Alemtuzumab-Based Allogeneic Stem Cell Transplantation: Presentation of Short Case Series from a Transplant Center.
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Lloyd R, Nikolousis E, Kishore B, Lovell R, Shankara P, Zeid NA, Horgan C, Panteliadou AK, McIlroy G, Xenou E, Kaparou M, Holder K, Murthy V, and Kanellopoulos A
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Transplantation, Homologous, Alemtuzumab adverse effects, Autoimmune Diseases etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Stem cell transplantation remains the curative option for many patients with hematological malignancies. The long-term effects of these treatments on the patients and their immune systems have been extensively investigated, but there remains a paucity of data regarding autoimmune manifestations post-transplant, although these effects are well recognized.Herein we present the clinical picture and therapeutic approach in three patients (cases 1-3), with varied presentations of autoimmune disease post-transplant. Case 1 exhibited autoimmune hemolytic anemia and other autoimmune manifestations (serositis, thyroiditis), that were probably linked to graft versus relapsed leukemia effect. Cases 2 and 3 had pure red white cell aplasia and pure red cell aplasia, respectively, which were associated with hyperglobulinemia and a clonal T cell expansion.
- Published
- 2020
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30. Reduced intensity alemtuzumab-containing allogeneic stem cell transplantation for relapsed/refractory low grade lymphoma: reflections on a single center experience.
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Horgan C, Elmoamly S, McIlroy G, Davies D, Kaparou M, Giles H, Xenou E, Kishore B, Lovell R, Nikolousis E, Shankara P, and Kanellopoulos A
- Subjects
- Cause of Death, Drug Resistance, Neoplasm, Female, Humans, Lymphoma mortality, Male, Prognosis, Recurrence, Retreatment, Transplantation, Homologous, Treatment Outcome, Alemtuzumab administration & dosage, Antineoplastic Agents, Immunological administration & dosage, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Lymphoma pathology, Lymphoma therapy, Transplantation Conditioning adverse effects, Transplantation Conditioning methods
- Published
- 2019
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31. Very early lineage-specific chimerism after reduced intensity stem cell transplantation is highly predictive of clinical outcome for patients with myeloid disease.
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Kinsella FAM, Inman CF, Gudger A, Chan YT, Murray DJ, Zuo J, McIlroy G, Nagra S, Nunnick J, Holder K, Wall K, Griffiths M, Craddock C, Nikolousis E, Moss P, and Malladi R
- Subjects
- Adult, Aged, Allografts, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Rate, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Lymphoma blood, Lymphoma mortality, Lymphoma therapy, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, T-Lymphocytes metabolism, Transplantation Chimera blood
- Abstract
Background: The importance of chimerism status in the very early period after hematopoietic stem cell transplantation is unclear. We determined PBMC and T-cell donor chimerism 50 days after transplantation and related this to disease relapse and overall survival., Methods: 144 sequential patients underwent transplantation of which 90 had AML/MDS and 54 had lymphoma. 'Full donor chimerism' was defined as ≥99% donor cells and three patient groups were defined: 40% with full donor chimerism (FC) in both PBMC and T-cells; 25% with mixed chimerism (MC) within both compartments and 35% with 'split' chimerism (SC) characterised by full donor chimerism within PBMC and mixed chimerism within T-cells., Results: In patients with myeloid disease a pattern of mixed chimerism (MC) was associated with a one year relapse rate of 45% and a five year overall survival of 40% compared to values of 8% and 75%, and 17% and 60%, for those with SC or FC respectively. The pattern of chimerism had no impact on clinical outcome for lymphoma., Conclusion: The pattern of lineage-specific chimerism at 50 days after transplantation is highly predictive of clinical outcome for patients with myeloid malignancy and may help to guide subsequent clinical management., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
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32. Understanding communities is essential for good care.
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McIlroy G, Taibjee R, and Morrison C
- Subjects
- Adolescent, Humans, Sexual and Gender Minorities
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2019
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33. Increased fracture risk in plasma cell dyscrasias is associated with poorer overall survival.
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McIlroy G, Mytton J, Evison F, Yadav P, Drayson MT, Cook M, Pratt G, Cockwell P, and Pinney JH
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Fractures, Bone epidemiology, Fractures, Spontaneous epidemiology, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Male, Paraproteinemias epidemiology, Population Surveillance, Proportional Hazards Models, Risk, Survival Analysis, Young Adult, Fractures, Bone etiology, Fractures, Spontaneous etiology, Paraproteinemias complications, Paraproteinemias mortality
- Abstract
Pathological fractures are a common complication of plasma cell dyscrasias (PCD) and are associated with significant morbidity. Routine use of bisphosphonates over the past decade has aimed to reduce the risk of fractures in patients with multiple myeloma, but despite this, fractures continue to represent a significant burden of disease. In this study we report the fracture rate of hospital in-patients with PCD in England. Data from the national registry Hospital Episode Statistics between 2001 and 2015 were used to determine fracture rate and its effect on overall survival. Fracture rates were 17·8 times higher than the general population in the first year after admission with PCD, and remained elevated for up to 10 years after first admission. The increased fracture risk preceded the first admission with PCD and, conversely, the incidence of PCD increased after admission with one or more fractures. Overall survival is improving with PCD, however poorer survival is found in patients with a preceding fracture (Hazard ratio 1·20). Despite widespread bisphosphonate use, fractures remain common in PCD, and are associated with poorer outcomes., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2017
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34. Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity.
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Ulian-Benitez S, Bishop S, Foldi I, Wentzell J, Okenwa C, Forero MG, Zhu B, Moreira M, Phizacklea M, McIlroy G, Li G, Gay NJ, and Hidalgo A
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Carrier Proteins genetics, Central Nervous System growth & development, Central Nervous System metabolism, Drosophila genetics, Drosophila physiology, Humans, Larva metabolism, Motor Neurons metabolism, Nerve Growth Factors genetics, Neuromuscular Junction, Protein Binding, Signal Transduction, Synaptic Transmission, Drosophila Proteins genetics, Membrane Proteins genetics, Nerve Growth Factors metabolism, Neuronal Plasticity genetics, Receptor Protein-Tyrosine Kinases genetics
- Abstract
Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signaling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). We tested the eleven LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 is expressed in the CNS, interacts genetically with DNTs and can bind DNT2 in signaling assays and co-immunoprecipitations. Ligand binding is promiscuous, as Kek-6 can also bind DNT1, and Kek-2 and Kek-5 can also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and DNT2 is produced by the muscle to function as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth and synaptic structure. Evidence indicates that Kek-6 does not antagonise the alternative DNT2 receptor Toll-6. Instead, Kek-6 and Toll-6 interact physically, and together regulate structural synaptic plasticity and homeostasis. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that they regulate NMJ growth and active zone formation downstream of DNT2 and Kek-6. The synaptic functions of Kek-6 could be evolutionarily conserved. This raises the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain.
- Published
- 2017
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35. Are online symptoms checkers useful for patients with inflammatory arthritis?
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Powley L, McIlroy G, Simons G, and Raza K
- Subjects
- Adult, Aged, Diagnosis, Differential, Female, Gout diagnosis, Health Care Surveys, Humans, Internet, Joint Dislocations diagnosis, Male, Middle Aged, Osteoarthritis diagnosis, Referral and Consultation, State Medicine, Arthralgia diagnosis, Arthritis, Psoriatic diagnosis, Arthritis, Rheumatoid diagnosis, Patient Acceptance of Health Care statistics & numerical data
- Abstract
Background: Online symptom checkers are increasingly used by patients however there is little published evidence of their effectiveness in real patients. The aim of this study was to evaluate how patients with inflammatory arthritis and inflammatory arthralgia use the internet to look for health information and to assess the advice given and diagnoses suggested by the NHS and WebMD symptom checkers in relation to the patients' actual diagnoses., Methods: Thirty-four patients with inflammatory arthritis (rheumatoid arthritis (n = 13), psoriatic arthritis (n = 4), unclassified arthritis (n = 4)) and inflammatory arthralgia (n = 13) newly presenting to a secondary care based clinic were identified using a consecutive sampling approach. Consenting patients were asked questions about their internet use in relation to their presenting symptoms. They then completed the NHS and the WebMD symptom checkers and their answers and the outcomes were recorded., Results: Sixteen patients had previously consulted the internet regarding their symptoms. Neither age nor gender significantly influenced internet usage. Actions advised via the NHS symptom checker were: call an ambulance (n = 11), attend A&E (n = 4), contact your GP straight away (n = 2), see your GP today (n = 6), or see your GP within 36 h (n = 11). The 5 most common differential diagnoses given by Web MD were gout (n = 28), rheumatoid arthritis (n = 24), psoriatic arthritis (n = 22), osteoarthritis (n = 18) and finger dislocation (n = 10). The most common first differential diagnosis was osteoarthritis (n = 12). Only 4 out of 21 patients with inflammatory arthritis were given a first diagnosis of rheumatoid arthritis or psoriatic arthritis., Conclusions: Our data highlight that help seeking advice given online is often inappropriate and that the diagnoses suggested are frequently inaccurate. Recommendations to seek emergency advice may cause inappropriate healthcare utilization.
- Published
- 2016
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36. Acute myocardial infarction, associated with the use of a synthetic adamantyl-cannabinoid: a case report.
- Author
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McIlroy G, Ford L, and Khan JM
- Subjects
- Adamantane administration & dosage, Adamantane urine, Administration, Inhalation, Adult, Cannabinoids administration & dosage, Cannabinoids urine, Designer Drugs administration & dosage, Designer Drugs analysis, Diagnosis, Differential, Emergency Medical Services, England, Humans, Inhalant Abuse diagnosis, Inhalant Abuse urine, Male, Myocardial Infarction therapy, Psychotropic Drugs administration & dosage, Psychotropic Drugs urine, Toxicokinetics, Treatment Outcome, Adamantane toxicity, Cannabinoids toxicity, Designer Drugs toxicity, Inhalant Abuse physiopathology, Myocardial Infarction etiology, Psychotropic Drugs toxicity
- Abstract
Background: "Legal highs" are novel psychoactive substances that have evaded statutory control. Synthetic cannabinoid compounds with adamantane moieties have recently been identified, which have high potency at target receptors and are undetectable on conventional toxicology testing. However, little is known about any harmful effects, and their potential to cause serious ill health. We describe a case of myocardial infarction following the use of this class of drug., Case Presentation: We report the case of a 39-year-old man admitted after an out-of-hospital cardiac arrest, in whom ECG and elevated cardiac enzymes confirmed ST-elevation myocardial infarction. Normal coronary perfusion was restored after thrombectomy and coronary artery stenting. In the hours preceding his admission, the patient is known to have consumed the legal high product "Black Mamba". Subsequent urine testing confirmed the presence of an adamantyl-group synthetic cannabinoid, whilst cannabis, cocaine, amphetamines and other drugs of abuse were not detected., Conclusion: The use of legal highs is being increasingly recognised, but the chemical compositions and physiological effects of these drugs are poorly characterised and are continually changing. Synthetic cannabinoids, rarely identified on toxicological testing, can be linked to serious adverse cardiovascular events. This case highlights the importance of testing for novel psychoactive compounds, and recognising their potential to cause life-threatening conditions.
- Published
- 2016
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37. Second-generation antipsychotic drug use in hospital inpatients with dementia: the impact of a safety warning on rates of prescribing.
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McIlroy G, Thomas SK, and Coleman JJ
- Subjects
- England, Female, Humans, Male, Antipsychotic Agents therapeutic use, Dementia drug therapy, Inpatients, Practice Patterns, Physicians' statistics & numerical data, Risperidone therapeutic use
- Abstract
Background: Behavioural and psychological symptoms of dementia are distressing for patients and are frequently treated with second-generation antipsychotics. Concerns about the drugs' safety resulted in a Medicines and Healthcare Products Regulatory Agency (MHRA) warning against their use in March 2009., Methods: Second-generation antipsychotic drug use was determined amongst patients with dementia admitted to the University Hospitals Birmingham National Health Service Foundation Trust, between July 2005 and December 2011. An interrupted time series analysis was carried out to investigate changes in rates of prescribing following the safety warning. Risperidone was analysed separately, in accordance with its limited licence for use in older adults with dementia, granted in October 2008., Results: Before the safety warning, second-generation antipsychotic use was increasing in patients with dementia. After the MHRA warning, their use fell by 1.9% per month compared with that before. Use of risperidone continued to rise over the same period, often against the terms of its licence., Conclusions: Drug safety warnings may influence prescribing practice, although continued use of antipsychotics in dementia could reflect a lack of alternative treatment options., (© The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
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38. Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS.
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McIlroy G, Foldi I, Aurikko J, Wentzell JS, Lim MA, Fenton JC, Gay NJ, and Hidalgo A
- Subjects
- Animals, Animals, Genetically Modified, Cells, Cultured, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster, Embryo, Nonmammalian, Green Fluorescent Proteins genetics, Larva, Locomotion genetics, Nerve Tissue Proteins metabolism, Neurons metabolism, Protein Binding genetics, RNA, Messenger metabolism, Receptors, Nerve Growth Factor genetics, Toll-Like Receptor 6 genetics, Toll-Like Receptor 7 genetics, Transfection, Central Nervous System embryology, Central Nervous System growth & development, Central Nervous System metabolism, Gene Expression Regulation, Developmental genetics, Receptors, Nerve Growth Factor metabolism, Toll-Like Receptor 6 metabolism, Toll-Like Receptor 7 metabolism
- Abstract
Neurotrophin receptors corresponding to vertebrate Trk, p75(NTR) or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2, have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. DNT1 (also known as NT1 and spz2) and DNT2 (also known as NT2 and spz5) interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously and are distributed in vivo in domains complementary to or overlapping with those of Toll-6 and Toll-7. We conclude that in fruit flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families.
- Published
- 2013
- Full Text
- View/download PDF
39. The impact of direct healthcare professional communication on prescribing practice in the UK hospital setting: an interrupted time series analysis.
- Author
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Thomas SK, Hodson J, McIlroy G, Dhami A, and Coleman JJ
- Subjects
- Antipsychotic Agents adverse effects, Antipsychotic Agents therapeutic use, Clopidogrel, Dementia drug therapy, Drug Interactions, Hospitals, Humans, Omeprazole adverse effects, Omeprazole therapeutic use, Practice Patterns, Physicians', Proton Pump Inhibitors adverse effects, Proton Pump Inhibitors therapeutic use, Ticlopidine adverse effects, Ticlopidine analogs & derivatives, Ticlopidine therapeutic use, United Kingdom, Adverse Drug Reaction Reporting Systems, Communication, Drug Prescriptions, Health Personnel
- Abstract
Background: Direct Healthcare Professional Communications (DHPCs) aim to quickly disseminate information to key healthcare professionals to inform practice and minimize patient harm. The Medicines and Healthcare products Regulatory Agency (MHRA) issues warnings and alerts to communicate safety information effectively in the UK., Objective: To investigate the impact of MHRA DHPCs on prescribing practice in the secondary-care setting, looking specifically at a drug-drug interaction-the concomitant use of clopidogrel and proton pump inhibitors (PPIs) [as omeprazole]-and a drug-disease contraindication-the use of conventional (typical) antipsychotics in dementia., Methods: The effects of the MHRA DHPCs were analysed using segmented binary logistic regression of interrupted time series. This allowed for the detection of any significant changes in prescribing practice occurring after the MHRA warnings were issued, whilst controlling for the baseline period., Results: Of the patients concomitantly prescribed clopidogrel and omeprazole on admission, the rate at which omeprazole was substituted for either another PPI (with the exception of esomeprazole), or for a histamine H2-antagonist showed a significant step-change increase after the DHPC was issued. The modelled rate increased from 5.1 % in the month directly before the intervention to 25.1 % in the following month (odds ratio [OR] 6.18; p < 0.001). However, the action taken in the switching of therapy was not always consistent with the advice from the current MHRA warning. The rate of typical antipsychotic prescribing in patients with dementia was declining significantly by 3.9 % per quarter prior to the DHPC being issued (OR 0.970; p = 0.035). No significant step-change was detected immediately after the DHPC (p = 0.962). However, the rate of decline increased significantly in the post-warning period to 12.3 % per quarter (OR 0.938; p = 0.006)., Conclusion: This study has shown that DHPCs issued by the MHRA as warnings are associated with changes in prescribing practices in secondary care. However, their impact is variable depending on the intervention described by the warning. A national initiative to ensure patient safety information is effectively translated into practice and the effect of the warning continues beyond the period of the issue would be beneficial.
- Published
- 2013
- Full Text
- View/download PDF
40. Trophic neuron-glia interactions and cell number adjustments in the fruit fly.
- Author
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Hidalgo A, Kato K, Sutcliffe B, McIlroy G, Bishop S, and Alahmed S
- Subjects
- Animals, Cell Count, Cell Death physiology, Drosophila cytology, Humans, Nerve Growth Factors physiology, Neuronal Plasticity physiology, Stochastic Processes, Drosophila physiology, Neuroglia physiology, Neurons physiology
- Abstract
Trophic interactions between neurons and enwrapping glia, and between neurons and target cells, provide plasticity to the mammalian nervous system. Here, we review evidence that analogous cell interactions operate in the development of the nervous system of the fruit-fly Drosophila. Homologues of the canonical mammalian trophic factors also maintain neuronal and glial survival in Drosophila, adjusting cell populations to enable appropriate function, and revealing commonalities in nervous system development across the animals. There are also differences between neuron-glia interactions in flies and humans, not surprisingly, because we are only related to flies through a remote common ancestor. Nevertheless, the shared cellular and molecular mechanisms underlying developmental plasticity and enwrapping glial functions, strengthen the opportunity to use Drosophila to understand the brain, to model brain diseases and to understand the involvement of glial cells in nervous system regeneration., (Copyright © 2010 Wiley-Liss, Inc.)
- Published
- 2011
- Full Text
- View/download PDF
41. South African Deaf education and the Deaf community.
- Author
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Storbeck C, Martin D, Parkin I, Magongwa L, Druchen BP, Batchelor M, McIlroy G, De Villiers D, Captieux-Bhana N, Rasebopye L, Rasebopye D, Krige-Henderson S, Krige F, Louw A, Surtees T, Smit AL, Cox R, and Henderson M
- Subjects
- Adolescent, Adult, Art, Child, Child, Preschool, Cultural Characteristics, Education, Professional, Employment, Faculty, Female, History, 19th Century, History, 20th Century, Humans, Jehovah's Witnesses psychology, Male, Mental Health, Parents psychology, Persons With Hearing Impairments history, Persons With Hearing Impairments psychology, Professional Role, Sign Language, South Africa, Spirituality, Sports, Teaching methods, Vocational Education, Young Adult, Education of Hearing Disabled, Education, Special history, Mainstreaming, Education history
- Abstract
In a special section of the american Annals of the Deaf, Deaf education and the Deaf community in South Africa are discussed. The special section is organized into 7 segments: a historical overview to establish context, the educational context, educators and learners, postgraduate education and employment, perspectives of Deaf children and their parents, sport and the arts, and spiritual lives and mental health. Throughout the entire section, however, the central focus is on the overall foundation (or lack thereof) of education for Deaf learners in South Africa.
- Published
- 2010
- Full Text
- View/download PDF
42. Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction.
- Author
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Sanz A, Soikkeli M, Portero-Otín M, Wilson A, Kemppainen E, McIlroy G, Ellilä S, Kemppainen KK, Tuomela T, Lakanmaa M, Kiviranta E, Stefanatos R, Dufour E, Hutz B, Naudí A, Jové M, Zeb A, Vartiainen S, Matsuno-Yagi A, Yagi T, Rustin P, Pamplona R, and Jacobs HT
- Subjects
- Animals, Blotting, Western, Caloric Restriction, Drosophila melanogaster enzymology, Electron Transport Complex I genetics, Histocytochemistry, Longevity genetics, Mitochondria metabolism, Oxidative Stress genetics, Oxidative Stress physiology, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Aging metabolism, Drosophila melanogaster physiology, Electron Transport Complex I metabolism, Longevity physiology, Reactive Oxygen Species metabolism, Saccharomyces cerevisiae Proteins metabolism
- Abstract
Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously. Mitochondrial extracts from NDI1-expressing flies displayed a rotenone-insensitive NADH dehydrogenase activity, and functionality of the enzyme in vivo was confirmed by the rescue of lethality resulting from RNAi knockdown of complex I. NDI1 expression increased median, mean, and maximum lifespan independently of dietary restriction, and with no change in sirtuin activity. NDI1 expression mitigated the aging associated decline in respiratory capacity and the accompanying increase in mitochondrial reactive oxygen species production, and resulted in decreased accumulation of markers of oxidative damage in aged flies. Our results support a central role of mitochondrial oxidative phosphorylation complex I in influencing longevity via oxidative stress, independently of pathways connected to nutrition and growth signaling.
- Published
- 2010
- Full Text
- View/download PDF
43. Production of reactive oxygen species by the mitochondrial electron transport chain in Drosophila melanogaster.
- Author
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Sanz A, Stefanatos R, and McIlroy G
- Subjects
- Analysis of Variance, Animals, Electron Transport drug effects, Male, Rotenone toxicity, Drosophila melanogaster metabolism, Electron Transport Chain Complex Proteins metabolism, Mitochondria metabolism, Models, Animal, Reactive Oxygen Species metabolism
- Abstract
Mitochondrial free radicals and in particular mitochondrial Reactive Oxygen Species (mtROS) are considered to be totally or partially responsible for several different diseases including Parkinson, diabetes or cancer. Even more importantly, mtROS have also been proposed as the main driving force behind the aging process. Thus, in the last decade, there has been a growing interest in the role of free radicals as signalling molecules. Collectively this makes understanding mechanisms controlling free radical production extremely important. There is extensive published literature on mammalian models (essentially rat, mouse and guinea pig) however; this is not the case in Drosophila melanogaster. Drosophila is an excellent model to study different physiological and pathological processes. Additionally a robust method to study mtROS is extremely useful. In the present article, we describe a simple--but extremely sensitive--method to study mtROS production in Drosophila. We have performed various experiments to determine which specific respiratory complexes produce free radicals in the electron transport chain of Drosophila melanogaster. Complex I is the main generator of ROS in Drosophila mitochondria, leaking electrons either in the forward or reverse direction. The production of ROS during reverse electron transport can be prevented either by rotenone or by the oxidation of NADH by complex I. These results clearly show that Drosophila mitochondria function in a very similar way to mammalian mitochondria, and therefore are a very relevant experimental model for biochemical studies related to ageing.
- Published
- 2010
- Full Text
- View/download PDF
44. Leadership 99. Interview by Terese Hudson.
- Author
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Butler P, Dalton J Jr, Hawthorne D, Lintjer G Jr, McCutcheon S, Umbdenstock R, Fernandez R, Kaplan G, Lamon J, Ryan-Mitlyng T, Sacks L, Hawthorne D, Folick J, McIlroy G, Muney A, Peddie E, and Van Pelt G
- Subjects
- Community Health Services, Consumer Behavior, Cooperative Behavior, Cost Control, Group Practice organization & administration, Hospital Administration, Hospital Administrators, Humans, Managed Care Programs organization & administration, Physician Executives, United States, Attitude of Health Personnel, Leadership
- Abstract
Cost control, customer service and collaboration among health care sectors rank as top concerns with panelists in H&HN's annual Leadership Report. Efforts to improve community health are a priority, too, but are often frustrated by financial and other constraints. The 16 panelists represent managed care, physicians, and hospitals and health systems.
- Published
- 1999
45. Should you toss Medicaid when it's losing money?
- Author
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McIlroy G and Laszewski R
- Subjects
- Financial Management, Rate Setting and Review, United States, Health Maintenance Organizations economics, Medicaid economics
- Published
- 1999
46. Mobile trolley for an acrylic dispenser.
- Author
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Richardson A, Mercer H, Douglas G, and McIlroy G
- Subjects
- Laboratories, Dental, Acrylic Resins, Dental Equipment
- Published
- 1986
47. Health care cost containment in the 1980s.
- Author
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McIlroy GT
- Subjects
- Health Expenditures trends, United States, Cost Control trends, Health Benefit Plans, Employee organization & administration, Insurance, Health organization & administration
- Abstract
Benefits administrators--and their employers--can no longer ignore the skyrocketing costs of health care. The wide range of measures explored here for controlling these costs include negotiating with providers, analyzing medical claims, enlisting the aid of employee/patients, structuring benefit programs to eliminate excesses, and setting up wellness programs to alter the lifestyles--smoking, drinking, poor nutrition--that result in crippling, even fatal diseases.
- Published
- 1983
- Full Text
- View/download PDF
48. Evaluation of modified R-B system for identification of members of the family Enterobacteriaceae.
- Author
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McIlroy GT, Yu PK, Martin WJ, and Washington JA 2nd
- Subjects
- Carboxy-Lyases metabolism, Citrates metabolism, Clinical Trials as Topic, Culture Media, Enterobacteriaceae enzymology, Enterobacteriaceae growth & development, Enterobacteriaceae metabolism, Evaluation Studies as Topic, Fermentation, Gases biosynthesis, Glucose metabolism, Hydrogen Sulfide biosynthesis, Indoles biosynthesis, Lactose metabolism, Lysine, Ornithine, Urea metabolism, Bacteriological Techniques, Enterobacteriaceae classification
- Abstract
In a paired, double-blind study, the modified ("Beckford tube") R-B system was compared with conventional bacteriological procedures for the identification of members of the family Enterobacteriaceae from clinical isolates and stock cultures. The tests in the R-B system yielding positive reactions comparable to those predicted by Ewing's taxonomic classification of Enterobacteriaceae were production of hydrogen sulfide and presence of lysine and ornithine decarboxylasè activities. The test reactions in the R-B system found to be comparable to those in the conventional method were fermentation of glucose, hydrogen sulfide production, and lysine and ornithine decarboxylase activities. The production of gas from glucose was positive in the R-B system more often than in the conventional method; however, the motility test and the production of indole were positive less often in the R-B system. Adequate preliminary identification of the Enterobacteriaceae with the R-B system is enhanced if Simmons' citrate and Christensen's urea tests are used concomitantly. These findings emphasize the manufacturer's instructions that, in interpretation of results, colonial morphology and biochemical reactions must be used concurrently to make an accurate identification.
- Published
- 1972
- Full Text
- View/download PDF
49. Acute mediastinal emphysema.
- Author
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SCHWARTZ BM, McILROY GH, and WARREN HA
- Subjects
- Humans, Emphysema, Mediastinal Emphysema
- Published
- 1946
- Full Text
- View/download PDF
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