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  • 1
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 127, No. 6 ( 2022-10-05), p. 1051-1060
    Abstract: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. Methods NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. Results In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. Conclusions NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. Clinical trial registration NCT03494816.
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
    In: eClinicalMedicine, Elsevier BV, Vol. 61 ( 2023-07), p. 102077-
    Type of Medium: Online Resource
    ISSN: 2589-5370
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2946413-4
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  • 3
    In: Neuro-Oncology Practice, Oxford University Press (OUP), Vol. 10, No. 3 ( 2023-05-12), p. 249-260
    Abstract: There are no effective treatments for brain tumor-related fatigue. We studied the feasibility of two novel lifestyle coaching interventions in fatigued brain tumor patients. Methods This phase I/feasibility multi-center RCT recruited patients with a clinically stable primary brain tumor and significant fatigue (mean Brief Fatigue Inventory [BFI] score ≥ 4/10). Participants were randomized in a 1–1–1 allocation ratio to: Control (usual care); Health Coaching (“HC”, an eight-week program targeting lifestyle behaviors); or HC plus Activation Coaching (“HC + AC”, further targeting self-efficacy). The primary outcome was feasibility of recruitment and retention. Secondary outcomes were intervention acceptability, which was evaluated via qualitative interview, and safety. Exploratory quantitative outcomes were measured at baseline (T0), post-interventions (T1, 10 weeks), and endpoint (T2, 16 weeks). Results n = 46 fatigued brain tumor patients (T0 BFI mean = 6.8/10) were recruited and 34 were retained to endpoint, establishing feasibility. Engagement with interventions was sustained over time. Qualitative interviews (n = 21) suggested that coaching interventions were broadly acceptable, although mediated by participant outlook and prior lifestyle. Coaching led to significant improvements in fatigue (improvement in BFI versus control at T1: HC=2.2 points [95% CI 0.6, 3.8], HC + AC = 1.8 [0.1, 3.4] , Cohen’s d [HC] = 1.9; improvement in FACIT-Fatigue: HC = 4.8 points [−3.7, 13.3] ; HC + AC = 12 [3.5, 20.5], d [HC and AC] = 0.9). Coaching also improved depressive and mental health outcomes. Modeling suggested a potential limiting effect of higher baseline depressive symptoms. Conclusions Lifestyle coaching interventions are feasible to deliver to fatigued brain tumor patients. They were manageable, acceptable, and safe, with preliminary evidence of benefit on fatigue and mental health outcomes. Larger trials of efficacy are justified.
    Type of Medium: Online Resource
    ISSN: 2054-2577 , 2054-2585
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2768945-1
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  • 4
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii122-ii122
    Abstract: BT-LIFE is a multi-centre RCT of novel lifestyle coaching treatments for fatigued brain tumour patients. To our knowledge it is also the first example of ‘multi-sectoral research’ to combine healthcare, private, and charity sectors in this population. To maximise learning, the trial team devised a structured reflection opportunity to ask, “What went well and what would we do differently next time?” METHOD After trial closedown we convened a six-hour ‘focus group’ for management, principle investigators, research assistants, interventionists, qualitative researchers, trial statisticians, and the funder. Discussion was structured using a ‘timeline’ wall-chart which attendees freely populated with post-it notes summarising learning points from the trial. Minutes were taken in duplicate. RESULTS In total n=19 team members contributed. Many points were study-specific and will be used internally to plan a larger trial. Among points of wider interest, examples of success included: using regular teleconferences to co-ordinate a cohesive and highly collaborative team; obtaining secure nhs.net email addresses to facilitate multi-sectoral communication; and the clear value of employing one part-time research assistant per centre instead of relying on busy clinical staff to recruit. General future learning points included: speak to the prospective sponsor and ethical committees when writing the grant application to avoid pitfalls and facilitate faster opening if funding is secured; consider preceding emails with a phone call to ‘lay the ground’ in time-sensitive situations; identify staff training requirements as early as possible and cascade aggressively; and be sensitive to the fact that inter-sectoral attitudes and practices may vary widely and need actively monitored and managed. Therefore frequent and secure communication, pro-active problem-spotting, and inter-sectoral value alignment appear critical for success. CONCLUSION BT-LIFE provides many useful lessons for anyone interested in running multi-sectoral research.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 5
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii121-ii121
    Abstract: Fatigue is common and disabling for brain tumour patients. We studied the feasibility of two innovative lifestyle coaching interventions for high fatigue. METHODS Multi-centre phase II feasibility RCT (ISRCTN17883425). Adult primary brain tumour outpatients reporting significant fatigue (Brief Fatigue Inventory [BFI] score 4+), were randomised to one of three arms: Control; Health Coaching (“HC”, comprising eight structured coaching sessions on lifestyle behaviours); or HC plus Activation Coaching (“HC+AC”, adding two structured interviews targeting motivation to change). Outcomes were measured at baseline (T0), after interventions (T1), and at 16 weeks (T2). The primary outcome of feasibility was required for both recruitment (aim: average n= 5 fatigued patients recruited/month) and retention (aim: minimum 60% retention at T2). Secondary pilot outcomes included change in fatigue, depressive symptom, and QOL measures. RESULTS Over a nine-month recruitment period, n= 46 fatigued brain tumour patients were recruited (average n=5.1/month) and n= 34 were retained to endpoint (retention at T2= 73%), meeting the primary outcome of feasibility. Surprisingly, fatigue reduced significantly after HC (T1 mean change in BFI score from T0 baseline, relative to the equivalent change in control group: HC= -2.3 points [95%CI -3.4/-0.3]; HC+AC= -2.0 [-2.9/+0.1] ; ANOVA p= 0.02) and was reduced in magnitude in both intervention groups at T2 (p= N.S). Both interventions also improved depressive symptoms (T1 mean change in HADS-Depression: HC= -2.0 points [-5.6/-0.1]; HC+AC= -2.9 [-6.5/-1.0] ; Kruskal-Wallis p= 0.02). Patient-nominated QOL outcomes improved persistently after HC+AC (T2 mean change in PSYCHLOPS score: HC= -2.4 points [-5.4/+2.8]; HC+AC= -6.1 [-9.2/-0.8] ; ANOVA p= 0.01). CONCLUSION Innovative coaching interventions, focused on lifestyle factors, are feasible to deliver to fatigued brain tumour patients. Preliminary signals suggest that these non-drug approaches may benefit several mediators of quality of life and warrant further study.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 6
    In: BMJ Medicine, BMJ, Vol. 2, No. 1 ( 2023-05), p. e000392-
    Abstract: To implement complex, PINCER (pharmacist led information technology intervention) prescribing indicators, on a national scale with general practice data to describe the impact of the covid-19 pandemic on safe prescribing. Design Population based, retrospective cohort study using federated analytics. Setting Electronic general practice health record data from 56.8 million NHS patients by use of the OpenSAFELY platform, with the approval of the National Health Service (NHS) England. Participants NHS patients (aged 18-120 years) who were alive and registered at a general practice that used TPP or EMIS computer systems and were recorded as at risk of at least one potentially hazardous PINCER indicator. Main outcome measure Between 1 September 2019 and 1 September 2021, monthly trends and between practice variation for compliance with 13 PINCER indicators, as calculated on the first of every month, were reported. Prescriptions that do not adhere to these indicators are potentially hazardous and can cause gastrointestinal bleeds; are cautioned against in specific conditions (specifically heart failure, asthma, and chronic renal failure); or require blood test monitoring. The percentage for each indicator is formed of a numerator of patients deemed to be at risk of a potentially hazardous prescribing event and the denominator is of patients for which assessment of the indicator is clinically meaningful. Higher indicator percentages represent potentially poorer performance on medication safety. Results The PINCER indicators were successfully implemented across general practice data for 56.8 million patient records from 6367 practices in OpenSAFELY. Hazardous prescribing remained largely unchanged during the covid-19 pandemic, with no evidence of increases in indicators of harm as captured by the PINCER indicators. The percentage of patients at risk of potentially hazardous prescribing, as defined by each PINCER indicator, at mean quarter 1 (Q1) 2020 (representing before the pandemic) ranged from 1.11% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 36.20% (amiodarone and no thyroid function test), while Q1 2021 (representing after the pandemic) percentages ranged from 0.75% (age ≥65 years and non-steroidal anti-inflammatory drugs) to 39.23% (amiodarone and no thyroid function test). Transient delays occurred in blood test monitoring for some medications, particularly angiotensin-converting enzyme inhibitors (where blood monitoring worsened from a mean of 5.16% in Q1 2020 to 12.14% in Q1 2021, and began to recover in June 2021). All indicators substantially recovered by September 2021. We identified 1 813 058 patients (3.1%) at risk of at least one potentially hazardous prescribing event. Conclusion NHS data from general practices can be analysed at national scale to generate insights into service delivery. Potentially hazardous prescribing was largely unaffected by the covid-19 pandemic in primary care health records in England.
    Type of Medium: Online Resource
    ISSN: 2754-0413
    Language: English
    Publisher: BMJ
    Publication Date: 2023
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  • 7
    In: BMJ Medicine, BMJ, Vol. 2, No. 1 ( 2023-01), p. e000276-
    Abstract: To ascertain patient eligibility status and describe coverage of antiviral drugs and neutralising monoclonal antibodies (nMAB) as treatment for covid-19 in community settings in England. Design Retrospective, descriptive cohort study, approved by NHS England. Setting Routine clinical data from 23.4 million people linked to data on covid-19 infection and treatment, within the OpenSAFELY-TPP database. Participants Outpatients with covid-19 at high risk of severe outcomes. Interventions Nirmatrelvir/ritonavir (paxlovid), sotrovimab, molnupiravir, casirivimab/imdevimab, or remdesivir, used in the community by covid-19 medicine delivery units. Results 93 870 outpatients with covid-19 were identified between 11 December 2021 and 28 April 2022 to be at high risk of severe outcomes and therefore potentially eligible for antiviral or nMAB treatment (or both). Of these patients, 19 040 (20%) received treatment (sotrovimab, 9660 (51%); molnupiravir, 4620 (24%); paxlovid, 4680 (25%); casirivimab/imdevimab, 50 ( 〈 1%); and remdesivir, 30 ( 〈 1%)). The proportion of patients treated increased from 9% (190/2220) in the first week of treatment availability to 29% (460/1600) in the latest week. The proportion treated varied by high risk group, being lowest in those with liver disease (16%; 95% confidence interval 15% to 17%); by treatment type, with sotrovimab favoured over molnupiravir and paxlovid in all but three high risk groups (Down's syndrome (35%; 30% to 39%), rare neurological conditions (45%; 43% to 47%), and immune deficiencies (48%; 47% to 50%)); by age, ranging from ≥80 years (13%; 12% to 14%) to 50-59 years (23%; 22% to 23%); by ethnic group, ranging from black (11%; 10% to 12%) to white (21%; 21% to 21%); by NHS region, ranging from 13% (12% to 14%) in Yorkshire and the Humber to 25% (24% to 25%) in the East of England); and by deprivation level, ranging from 15% (14% to 15%) in the most deprived areas to 23% (23% to 24%) in the least deprived areas. Groups that also had lower coverage included unvaccinated patients (7%; 6% to 9%), those with dementia (6%; 5% to 7%), and care home residents (6%; 6% to 7%). Conclusions Using the OpenSAFELY platform, we were able to identify patients with covid-19 at high risk of severe outcomes who were potentially eligible to receive treatment and assess the coverage of these new treatments among these patients. In the context of a rapid deployment of a new service, the NHS analytical code used to determine eligibility could have been over-inclusive and some of the eligibility criteria not fully captured in healthcare data. However targeted activity might be needed to resolve apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, ethnic groups, people aged ≥80 years, those living in socioeconomically deprived areas, and care home residents.
    Type of Medium: Online Resource
    ISSN: 2754-0413
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 3128592-2
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  • 8
    In: Blood, American Society of Hematology, Vol. 129, No. 2 ( 2017-01-12), p. 199-208
    Abstract: MHC-II and its master regulator CIITA are downregulated in CML stem/progenitor cells in a BCR-ABL kinase–independent manner. JAK1/2 inhibition increased MHC-II expression, suggesting elevation of CML immunogenicity may provide a way to reduce CML persistence.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: BMC Medicine, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2022-12)
    Abstract: While the vaccines against COVID-19 are highly effective, COVID-19 vaccine breakthrough is possible despite being fully vaccinated. With SARS-CoV-2 variants still circulating, describing the characteristics of individuals who have experienced COVID-19 vaccine breakthroughs could be hugely important in helping to determine who may be at greatest risk. Methods With the approval of NHS England, we conducted a retrospective cohort study using routine clinical data from the OpenSAFELY-TPP database of fully vaccinated individuals, linked to secondary care and death registry data and described the characteristics of those experiencing COVID-19 vaccine breakthroughs. Results As of 1st November 2021, a total of 15,501,550 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: ​107–179). From within this population, a total of 579,780 ( 〈 4%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate (IR) was 98.06 (95% CI 97.93–98.19). There were 28,580 COVID-19-related hospital admissions, 1980 COVID-19-related critical care admissions and 6435 COVID-19-related deaths; corresponding IRs 4.77 (95% CI 4.74–4.80), 0.33 (95% CI 0.32–0.34) and 1.07 (95% CI 1.06–1.09), respectively. The highest rates of breakthrough COVID-19 were seen in those in care homes and in patients with chronic kidney disease, dialysis, transplant, haematological malignancy or who were immunocompromised. Conclusions While the majority of COVID-19 vaccine breakthrough cases in England were mild, some differences in rates of breakthrough cases have been identified in several clinical groups. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the number of positive SARS-CoV-2 tests still occurring is concerning and as numbers of fully vaccinated (and boosted) individuals increases and as follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, to assess vaccine waning and rates of breakthrough COVID-19 between different variants, aimed at identifying individuals at higher risk, are needed.
    Type of Medium: Online Resource
    ISSN: 1741-7015
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2131669-7
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  • 10
    In: BMJ, BMJ
    Abstract: To estimate waning of covid-19 vaccine effectiveness over six months after second dose. Design Cohort study, approved by NHS England. Setting Linked primary care, hospital, and covid-19 records within the OpenSAFELY-TPP database. Participants Adults without previous SARS-CoV-2 infection were eligible, excluding care home residents and healthcare professionals. Exposures People who had received two doses of BNT162b2 or ChAdOx1 (administered during the national vaccine rollout) were compared with unvaccinated people during six consecutive comparison periods, each of four weeks. Main outcome measures Adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, positive SARS-CoV-2 test, and non-covid-19 related death comparing vaccinated with unvaccinated people. Waning vaccine effectiveness was quantified as ratios of adjusted hazard ratios per four week period, separately for subgroups aged ≥65 years, 18-64 years and clinically vulnerable, 40-64 years, and 18-39 years. Results 1 951 866 and 3 219 349 eligible adults received two doses of BNT162b2 and ChAdOx1, respectively, and 2 422 980 remained unvaccinated. Waning of vaccine effectiveness was estimated to be similar across outcomes and vaccine brands. In the ≥65 years subgroup, ratios of adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test ranged from 1.19 (95% confidence interval 1.14 to 1.24) to 1.34 (1.09 to 1.64) per four weeks. Despite waning vaccine effectiveness, rates of covid-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2, and ≥75% for ChAdOx1. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than in unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2 and 1.86 (1.79 to 1.93) for ChAdOx1). Conclusions The rate at which estimated vaccine effectiveness waned was consistent for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test and was similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination.
    Type of Medium: Online Resource
    ISSN: 1756-1833
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1479799-9
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