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1.
Nat Mater ; 23(5): 688-694, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38413812

RESUMO

Enabled by surface-mediated equilibration, physical vapour deposition can create high-density stable glasses comparable with liquid-quenched glasses aged for millions of years. Deposition is often performed at various rates and temperatures on rigid substrates to control the glass properties. Here we demonstrate that on soft, rubbery substrates, surface-mediated equilibration is enhanced up to 170 nm away from the interface, forming stable glasses with densities up to 2.5% higher than liquid-quenched glasses within 2.5 h of deposition. Gaining similar properties on rigid substrates would require 10 million times slower deposition, taking ~3,000 years. Controlling the modulus of the rubbery substrate provides control over the glass structure and density at constant deposition conditions. These results underscore the significance of substrate elasticity in manipulating the properties of the mobile surface layer and thus the glass structure and properties, allowing access to deeper states of the energy landscape without prohibitively slow deposition rates.

2.
BMC Med ; 21(1): 246, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37408015

RESUMO

BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).


Assuntos
Lista de Checagem , Projetos de Pesquisa , Humanos , Consenso , Reprodutibilidade dos Testes , Relatório de Pesquisa
3.
Proc Natl Acad Sci U S A ; 117(39): 24076-24081, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32934146

RESUMO

Enhanced surface mobility is critical in producing stable glasses during physical vapor deposition. In amorphous selenium (a-Se) both the structure and dynamics of the surface can be altered when exposed to above-bandgap light. Here we investigate the effect of light on the properties of vapor-deposited a-Se glasses at a range of substrate temperatures and deposition rates. We demonstrate that deposition both under white light illumination and in the dark results in thermally and kinetically stable glasses. Compared to glasses deposited in the dark, stable a-Se glasses formed under white light have reduced thermal stability, as measured by lower density change, but show significantly improved kinetic stability, measured as higher onset temperature for transformation. While light induces enhanced mobility that penetrates deep into the surface, resulting in lower density during vapor deposition, it also acts to form more networked structures at the surface, which results in a state that is kinetically more stable with larger optical birefringence. We demonstrate that the structure formed during deposition with light is a state that is not accessible through liquid quenching, aging, or vapor deposition in the dark, indicating the formation of a unique amorphous solid state.

4.
Oncologist ; 27(9): 768-777, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35762393

RESUMO

BACKGROUND: Patient-reported adverse events may be a useful adjunct for assessing a drug's tolerability in dose-finding oncology trials (DFOT). We conducted surveys of international stakeholders and the National Cancer Research Institute (NCRI) Consumer Forum to understand attitudes about patient-reported outcome (PRO) use in DFOT. METHODS: A 35-question survey of clinicians, trial managers, statisticians, funders, and regulators of DFOT was distributed via professional bodies examining experience using PROs, benefits/barriers, and their potential role in defining tolerable doses. An 8-question survey of the NCRI Consumer Forum explored similar themes. RESULTS: International survey: 112 responses from 15 September-30 November 2020; 103 trialists [48 clinicians (42.9%), 38 statisticians (34.0%), 17 trial managers (15.2%)], 7 regulators (6.3%), 2 funders (1.8%)]. Most trialists had no experience designing (73, 70.9%), conducting (52, 50.5%), or reporting (88, 85.4%) PROs in DFOT. Most agreed that PROs could identify new toxicities (75, 67.0%) and provide data on the frequency (86, 76.8%) and duration (81, 72.3%) of toxicities. The top 3 barriers were lack of guidance regarding PRO selection (73/103, 70.9%), missing PRO data (71/103, 68.9%), and overburdening staff (68/103, 66.0%). NCRI survey: 57 responses on 21 March 2021. A total of 28 (49.1%) were willing to spend <15 min/day completing PROs. Most (55, 96.5%) preferred to complete PROs online. 61 (54.5%) trialists and 57 (100%) consumers agreed that patient-reported adverse events should be used to inform dose-escalation decisions. CONCLUSION: Stakeholders reported minimal experience using PROs in DFOT but broadly supported their use. Guidelines are needed to standardize PRO selection, analysis, and reporting in DFOT.


Assuntos
Oncologia , Neoplasias , Humanos , National Cancer Institute (U.S.) , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Estados Unidos
5.
Lancet Oncol ; 20(5): 649-662, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948276

RESUMO

BACKGROUND: Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes. METHODS: In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II-IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [to a maximum of 2 mg total dose] intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1-5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m2 intravenously or 1·6 mg/m2 subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing. FINDINGS: Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0-32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0-74·7 vs 74·3%, 69·3-78·7; hazard ratio 0·86, 95% CI 0·65-1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 [87·1%] of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths. INTERPRETATION: This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival. FUNDING: Janssen-Cilag, Bloodwise, and Cancer Research UK.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Bortezomib/administração & dosagem , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Inibidores de Proteassoma/administração & dosagem , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Progressão da Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteassoma/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Suíça , Fatores de Tempo , Reino Unido , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
7.
Eur Heart J ; 38(21): 1632-1637, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28329235

RESUMO

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.


Assuntos
Cardiologia/normas , Guias de Prática Clínica como Assunto , Saúde Pública/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Cardiologia/educação , Cardiologia/ética , Difusão de Inovações , Revelação , Humanos , Consentimento Livre e Esclarecido , Segurança do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Medição de Risco
9.
JAMA ; 319(5): 483-494, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29411037

RESUMO

Importance: Patient-reported outcome (PRO) data from clinical trials can provide valuable evidence to inform shared decision making, labeling claims, clinical guidelines, and health policy; however, the PRO content of clinical trial protocols is often suboptimal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was published in 2013 and aims to improve the completeness of trial protocols by providing evidence-based recommendations for the minimum set of items to be addressed, but it does not provide PRO-specific guidance. Objective: To develop international, consensus-based, PRO-specific protocol guidance (the SPIRIT-PRO Extension). Design, Setting, and Participants: The SPIRIT-PRO Extension was developed following the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework for guideline development. This included (1) a systematic review of existing PRO-specific protocol guidance to generate a list of potential PRO-specific protocol items (published in 2014); (2) refinements to the list and removal of duplicate items by the International Society for Quality of Life Research (ISOQOL) Protocol Checklist Taskforce; (3) an international stakeholder survey of clinical trial research personnel, PRO methodologists, health economists, psychometricians, patient advocates, funders, industry representatives, journal editors, policy makers, ethicists, and researchers responsible for evidence synthesis (distributed by 38 international partner organizations in October 2016); (4) an international Delphi exercise (n = 137 invited; October 2016 to February 2017); and (5) consensus meeting (n = 30 invited; May 2017). Prior to voting, consensus meeting participants were informed of the results of the Delphi exercise and given data from structured reviews evaluating the PRO protocol content of 3 defined samples of trial protocols. Results: The systematic review identified 162 PRO-specific protocol recommendations from 54 sources. The ISOQOL Taskforce (n = 21) reduced this to 56 items, which were considered by 138 international stakeholder survey participants and 99 Delphi panelists. The final wording of the SPIRIT-PRO Extension was agreed on at a consensus meeting (n = 29 participants) and reviewed by external group of experts during a consultation period. Eleven extensions and 5 elaborations to the SPIRIT 2013 checklist were recommended for inclusion in clinical trial protocols in which PROs are a primary or key secondary outcome. Extension items focused on PRO-specific issues relating to the trial rationale, objectives, eligibility criteria, concepts used to evaluate the intervention, time points for assessment, PRO instrument selection and measurement properties, data collection plan, translation to other languages, proxy completion, strategies to minimize missing data, and whether PRO data will be monitored during the study to inform clinical care. Conclusions and Relevance: The SPIRIT-PRO guidelines provide recommendations for items that should be addressed and included in clinical trial protocols in which PROs are a primary or key secondary outcome. Improved design of clinical trials including PROs could help ensure high-quality data that may inform patient-centered care.


Assuntos
Protocolos Clínicos/normas , Ensaios Clínicos como Assunto/normas , Guias como Assunto , Medidas de Resultados Relatados pelo Paciente , Tomada de Decisões , Humanos
10.
Gut ; 66(1): 89-96, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27797935

RESUMO

OBJECTIVE: In 2001, the National Institute for Health Research Cancer Research Network (NCRN) was established, leading to a rapid increase in clinical research activity across the English NHS. Using colorectal cancer (CRC) as an example, we test the hypothesis that high, sustained hospital-level participation in interventional clinical trials improves outcomes for all patients with CRC managed in those research-intensive hospitals. DESIGN: Data for patients diagnosed with CRC in England in 2001-2008 (n=209 968) were linked with data on accrual to NCRN CRC studies (n=30 998). Hospital Trusts were categorised by the proportion of patients accrued to interventional studies annually. Multivariable models investigated the relationship between 30-day postoperative mortality and 5-year survival and the level and duration of study participation. RESULTS: Most of the Trusts achieving high participation were district general hospitals and the effects were not limited to cancer 'centres of excellence', although such centres do make substantial contributions. Patients treated in Trusts with high research participation (≥16%) in their year of diagnosis had lower postoperative mortality (p<0.001) and improved survival (p<0.001) after adjustment for casemix and hospital-level variables. The effects increased with sustained research participation, with a reduction in postoperative mortality of 1.5% (6.5%-5%, p<2.2×10-6) and an improvement in survival (p<10-19; 5-year difference: 3.8% (41.0%-44.8%)) comparing high participation for ≥4 years with 0 years. CONCLUSIONS: There is a strong independent association between survival and participation in interventional clinical studies for all patients with CRC treated in the hospital study participants. Improvement precedes and increases with the level and years of sustained participation.


Assuntos
Pesquisa Biomédica/estatística & dados numéricos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Neoplasias Colorretais/mortalidade , Hospitais/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/cirurgia , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Risco Ajustado , Medicina Estatal , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
11.
Lancet ; 388(10055): 2004-2014, 2016 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-27604504

RESUMO

BACKGROUND: Whole brain radiotherapy (WBRT) and dexamethasone are widely used to treat brain metastases from non-small cell lung cancer (NSCLC), although there have been no randomised clinical trials showing that WBRT improves either quality of life or overall survival. Even after treatment with WBRT, the prognosis of this patient group is poor. We aimed to establish whether WBRT could be omitted without a significant effect on survival or quality of life. METHODS: The Quality of Life after Treatment for Brain Metastases (QUARTZ) study is a non-inferiority, phase 3 randomised trial done at 69 UK and three Australian centres. NSCLC patients with brain metastases unsuitable for surgical resection or stereotactic radiotherapy were randomly assigned (1:1) to optimal supportive care (OSC) including dexamethasone plus WBRT (20 Gy in five daily fractions) or OSC alone (including dexamethasone). The dose of dexamethasone was determined by the patients' symptoms and titrated downwards if symptoms improved. Allocation to treatment group was done by a phone call from the hospital to the Medical Research Council Clinical Trials Unit at University College London using a minimisation programme with a random element and stratification by centre, Karnofsky Performance Status (KPS), gender, status of brain metastases, and the status of primary lung cancer. The primary outcome measure was quality-adjusted life-years (QALYs). QALYs were generated from overall survival and patients' weekly completion of the EQ-5D questionnaire. Treatment with OSC alone was considered non-inferior if it was no more than 7 QALY days worse than treatment with WBRT plus OSC, which required 534 patients (80% power, 5% [one-sided] significance level). Analysis was done by intention to treat for all randomly assigned patients. The trial is registered with ISRCTN, number ISRCTN3826061. FINDINGS: Between March 2, 2007, and Aug 29, 2014, 538 patients were recruited from 69 UK and three Australian centres, and were randomly assigned to receive either OSC plus WBRT (269) or OSC alone (269). Baseline characteristics were balanced between groups, and the median age of participants was 66 years (range 38-85). Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1·06, 95% CI 0·90-1·26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean QALYs was 4·7 days (46·4 QALY days for the OSC plus WBRT group vs 41·7 QALY days for the OSC group), with two-sided 90% CI of -12·7 to 3·3. INTERPRETATION: Although the primary outcome measure result includes the prespecified non-inferiority margin, the combination of the small difference in QALYs and the absence of a difference in survival and quality of life between the two groups suggests that WBRT provides little additional clinically significant benefit for this patient group. FUNDING: Cancer Research UK, Medical Research Council Clinical Trials Unit at University College London, and the National Health and Medical Research Council in Australia.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Dexametasona/uso terapêutico , Cuidados Paliativos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Terapia Combinada , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento
12.
J Psycholinguist Res ; 46(4): 983-995, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28091853

RESUMO

This study assessed the effect of experimentally manipulated emotional arousal on swearing fluency. We hypothesised that swear word generation would be increased with raised emotional arousal. The emotional arousal of 60 participants was manipulated by having them play a first-person shooter video game or, as a control, a golf video game, in a randomised order. A behavioural measure of swearing fluency based on the Controlled Oral Word Association Test was employed. Successful experimental manipulation was indicated by raised State Hostility Questionnaire scores after playing the shooter game. Swearing fluency was significantly greater after playing the shooter game compared with the golf game. Validity of the swearing fluency task was demonstrated via positive correlations with self-reported swearing fluency and daily swearing frequency. In certain instances swearing may represent a form of emotional expression. This finding will inform debates around the acceptability of using taboo language.


Assuntos
Nível de Alerta/fisiologia , Emoções , Idioma , Feminino , Humanos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Inquéritos e Questionários , Comportamento Verbal/fisiologia , Jogos de Vídeo/psicologia , Vocabulário , Adulto Jovem
13.
Cochrane Database Syst Rev ; (3): CD011430, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25730344

RESUMO

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimioterapia Adjuvante , Terapia Combinada/métodos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Carga Tumoral
14.
Proc Natl Acad Sci U S A ; 109(45): 18511-6, 2012 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-23091009

RESUMO

The use of ancient DNA in paleopathological studies of tuberculosis has largely been restricted to confirmation of disease identifications made by skeletal analysis; few attempts at obtaining genotype data from archaeological samples have been made because of the need to perform different PCRs for each genetic locus being studied in an ancient DNA extract. We used a next generation sequencing approach involving hybridization capture directed at specific polymorphic regions of the Mycobacterium tuberculosis genome to identify a detailed genotype for a historic strain of M. tuberculosis from an individual buried in the 19th century St. George's Crypt, Leeds, West Yorkshire, England. We obtained 664,500 sequencing by oligonucleotide ligation and detection (SOLiD) reads that mapped to the targeted regions of the M. tuberculosis genome; the coverage included 218 of 247 SNPs, 10 of 11 insertion/deletion regions, and the repeat elements IS1081 and IS6110. The accuracy of the SOLiD data was checked by conventional PCRs directed at 11 SNPs and two insertion/deletions. The data placed the historic strain of M. tuberculosis in a group that is uncommon today, but it is known to have been present in North America in the early 20th century. Our results show the use of hybridization capture followed by next generation sequencing as a means of obtaining detailed genotypes of ancient varieties of M. tuberculosis, potentially enabling meaningful comparisons between strains from different geographic locations and different periods in the past.


Assuntos
Mycobacterium tuberculosis/genética , Paleontologia , Técnicas de Tipagem Bacteriana , Sequência de Bases , Inglaterra , Feminino , Genoma Bacteriano/genética , Genótipo , Humanos , Dados de Sequência Molecular , Oligonucleotídeos/genética , Filogenia , Reação em Cadeia da Polimerase , Alinhamento de Sequência , Análise de Sequência de DNA
15.
Health Info Libr J ; 32(2): 81-3, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25943969

RESUMO

As a regular referee for the Health Information and Libraries Journal, Richard Stephens--Winner of the 2014 Wellcome Trust Science Writing Prize--has been impressed by the science on offer in the Health Information and Libraries Journal. But he has also been struck by how often similar problems with statistical analysis reporting come up during the review process. Acknowledging that statistics can be scary, he advocates that they should be simply viewed as a means of communicating ideas. In this editorial, he provides some straightforward guidelines on reporting statistical analyses in peer review journal articles, highlights pitfalls to avoid and illustrates best practice to aim for.


Assuntos
Revisão da Pesquisa por Pares/normas , Projetos de Pesquisa , Estatística como Assunto/normas , Humanos , Revisão da Pesquisa por Pares/métodos , Estatística como Assunto/educação
16.
Lancet Oncol ; 15(4): 424-35, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24602760

RESUMO

BACKGROUND: Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL). METHODS: Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931. FINDINGS: Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved. INTERPRETATION: Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. FUNDING: Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Conduta Expectante , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Doenças Assintomáticas , Austrália , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Europa (Continente) , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Nova Zelândia , Seleção de Pacientes , Modelos de Riscos Proporcionais , Qualidade de Vida , Fatores de Risco , Rituximab , Fatores de Tempo , Resultado do Tratamento
17.
BMC Cancer ; 14: 260, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24731512

RESUMO

As the enthusiasm for individualized treatment and targeted therapies continues to gain momentum, it seems timely to re-assess whether our current research tools are fit for purpose. Randomized Clinical Trials compare groups of patients, the Hazard Ratio is a 'group summary statistic', and modeling shows that the same Hazard Ratio score could result from a number of scenarios. Thus the current tools do not provide definitive information as to how to treat an individual patient. We therefore need to concentrate on the use of predictive factor analyses to identify the characteristics of subgroups of patients who respond to specific treatments.


Assuntos
Pesquisa Biomédica , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Terapia de Alvo Molecular
18.
Alcohol Clin Exp Res ; 38(2): 466-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24033827

RESUMO

BACKGROUND: Alcohol hangover is a growing research area, but differences across the life span have not been assessed. Here, we test the hypothesis that the severity of hangovers depends on age. METHODS: A cross-sectional study of 51,645 men and women aged 18 to 94 years old, who participated in the population-based Danish Health Examination Study (DANHES) in Denmark between 2007 and 2008, formed the database for our study. RESULTS: The incidence of severe hangover was lower among older than younger participants. Odds ratios for experiencing severe hangover following an episode of binge drinking were 6.8, 4.8, 3.0, and 2.0 among the 18 to 29, 30 to 39, 40 to 49, and 50 to 59-year-old men, compared with those aged 60+ years. For women, similar results were obtained. This finding could not be explained by the usual amount of alcohol consumption, frequency of binge drinking, or the proportion of alcohol consumed with meals. CONCLUSIONS: We found that hangover following engagement in binge drinking is much more common in the young than in the older age groups.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Intoxicação Alcoólica/epidemiologia , Intoxicação Alcoólica/fisiopatologia , Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Adolescente , Adulto , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/psicologia , Intoxicação Alcoólica/psicologia , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Dinamarca/epidemiologia , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Fatores Socioeconômicos , Adulto Jovem
19.
Front Psychol ; 15: 1416041, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947907

RESUMO

Swearing, or the use of taboo language, has been repeatedly shown to induce hypoalgesia. While reliable hypoalgesic effects have been observed across studies, the mechanisms by which swearing influences pain and the optimal dosage of swearing remain poorly understood. Plausible mechanistic rationale for swearing's impact on pain include sympathetic response, emotion, humor, distraction, aggression, state disinhibition, psychological flow, risky behavior, and self-confidence. It remains unknown how the intensity of the swear word, speech volume, frequency, or timing influences pain modulation. While the majority of evidence demonstrates the efficacy of swearing at attenuating acute pain responses, these studies have utilized healthy populations with controlled experiments in laboratory settings. Comparatively, less is known about how laboratory findings translate practically/clinically to diverse populations, various dosages, and different pain chronicities. A greater understanding of mechanistic underpinnings and practical implications are necessary to feasibly implement swearing as a therapeutic modality to combat pain. The purpose of the following mini-review is to provide an overview of the current evidence on swearing for the reduction of pain, speculate on plausible underlying mechanisms, and discuss the potential for optimization of swearing for real-world translation. Lastly, identifying knowledge gaps to aid in directing future research will be discussed.

20.
BMC Cancer ; 13: 31, 2013 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-23347597

RESUMO

BACKGROUND: Exercise programmes are beneficial for cancer patients however evidence is limited in patients with multiple myeloma (MM), a cancer that is characterised by osteolytic bone disease, giving rise to high levels of bone morbidity including fractures and bone pain. METHODS: We conducted a single arm phase 2 study of an exercise programme (EP) as rehabilitation for treated MM patients, to evaluate feasibility, effects on QOL and physiological parameters. Patients were given individualised programmes, comprising stretching, aerobic and resistance exercises, carried out under supervision for 3 months then at home for a further 3 months. RESULTS: Study uptake was high, 60 of 75 (80%) patients approached consented to the study. Screen failures (11, due to fracture risk and disease relapse) and patient withdrawals (12) resulted in a final 37 patients enrolling on the programme. These 37 patients demonstrated high attendance rates in the supervised classes (87%), and high levels of adherence in home exercising (73%). Patients reported better QOL following the EP, with improvement in FACT-G and Fatigue scores over time from baseline (p<0.01 for both, one-way repeated measures ANOVA) to 6 months. Upper and lower limb strength also improved on the EP, from baseline to 6 months (p<0.01 for both). There were no adverse reactions. CONCLUSIONS: An EP in MM patients is feasible and safe, with high attendance and adherence. Benefits in QOL, fatigue and muscle strength await confirmation in randomized studies, prompting urgent evaluation of the benefits of EP in the rehabilitation of MM patients.


Assuntos
Terapia por Exercício/métodos , Mieloma Múltiplo/reabilitação , Força Muscular/fisiologia , Qualidade de Vida , Idoso , Terapia por Exercício/efeitos adversos , Estudos de Viabilidade , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/psicologia , Exercícios de Alongamento Muscular , Projetos Piloto , Avaliação de Programas e Projetos de Saúde , Sobreviventes/psicologia
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