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A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown. To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously. Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors.
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Genes cdc/genética , Origem de Replicação/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Dano ao DNA/genética , DNA Fúngico/química , DNA Fúngico/genética , Regulação Fúngica da Expressão Gênica , Mutação , Fase S , Saccharomyces cerevisiae/crescimento & desenvolvimento , Estresse Fisiológico/genéticaRESUMO
BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).
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Antidepressivos/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Atenção Primária à Saúde , Recidiva , Adulto , Idoso , Antidepressivos/efeitos adversos , Transtornos de Ansiedade/epidemiologia , Citalopram/uso terapêutico , Transtorno Depressivo/epidemiologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Inquéritos e Questionários , Reino Unido , Suspensão de TratamentoRESUMO
BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/diagnóstico , Índice de Gravidade de Doença , Testes de Estado Mental e Demência , Sociedades MédicasRESUMO
BACKGROUND: Mental health rehabilitation services provide specialist treatment to people with particularly severe and complex problems. In 2018, the Care Quality Commission reported that over half the 4,400 mental health inpatient rehabilitation beds in England were provided by the independent sector. They raised concerns that the length of stay and cost of independent sector care was double that of the NHS and that their services tended to be provided much further from people's homes. However, there has been no research comparing the two sectors and we therefore do not know if these concerns are justified. The ACER Study (Assessing the Clinical and cost-Effectiveness of inpatient mental health Rehabilitation services provided by the NHS and independent sector) is a national programme of research in England, funded from 2021 to 2026, that aims to investigate differences in inpatient mental health rehabilitation provided by the NHS and independent sector in terms of: patient characteristics; service quality; patient, carer and staff experiences; clinical and cost effectiveness. METHODS: ACER comprises a:1) detailed survey of NHS and independent sector inpatient mental health rehabilitation services across England; 2) qualitative investigation of patient, family, staff and commissioners' experiences of the two sectors; 3) cohort study comparing clinical outcomes in the two sectors over 18 months; 4) comprehensive national comparison of inpatient service use in the two sectors, using instrumental variable analysis of routinely collected healthcare data over 18 months; 5) health economic evaluation of the relative cost-effectiveness of the two sectors. In Components 3 and 4, our primary outcome is 'successful rehabilitation' defined as a) being discharged from the inpatient rehabilitation unit without readmission and b) inpatient service use over the 18 months. DISCUSSION: The ACER study will deliver the first empirical comparison of the clinical and cost-effectiveness of NHS and independent sector inpatient mental health rehabilitation services. TRIAL REGISTRATION: ISRCTN17381762 retrospectively registered.
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Reabilitação Psiquiátrica , Humanos , Medicina Estatal , Estudos de Coortes , Análise de Custo-Efetividade , Análise Custo-Benefício , Pacientes InternadosRESUMO
Consistently achieving wound closure requires a broad understanding of wound physiology, anatomy and wound healing phases. The multifaceted principles of wound closure are comprised of: perfusion evaluation; diabetes control; nutritional optimisation; infection control; mechanical stress avoidance; oedema management; wound bed preparation; and community care. Optimisation of each element is crucial to timely and durable resolution of acute and hard-to-heal wounds. This objective is realisable only through an interdisciplinary approach to wound healing. The reconstructive ladder represents the graduation of complex wound management as applied by the specialty of plastic surgery. The approach to reconstruction typically begins with the least invasive option, which is considered reliable. However, there are instances when the most reliable option on the reconstructive ladder is not a viable option and creative solutions for wound closure are required. The following case report demonstrates a unique approach to lower extremity salvage in a subacute compound fracture surgical site infection using a limited reconstructive ladder.
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Cateterismo Periférico , Fraturas Cominutivas/cirurgia , Fraturas Expostas/cirurgia , Traumatismos da Perna , Procedimentos de Cirurgia Plástica/métodos , Fraturas da Tíbia/cirurgia , Cicatrização/fisiologia , Idoso , Complicações do Diabetes , Diabetes Mellitus , Humanos , Extremidade Inferior , Masculino , Resultado do TratamentoRESUMO
OBJECTIVES: To determine the importance placed by patients on attributes associated with whole-body MRI (WB-MRI) and standard cancer staging pathways and ascertain drivers of preference. METHODS: Patients recruited to two multi-centre diagnostic accuracy trials comparing WB-MRI with standard staging pathways in lung and colorectal cancer were invited to complete a discrete choice experiment (DCE), choosing between a series of alternate pathways in which 6 attributes (accuracy, time to diagnosis, scan duration, whole-body enclosure, radiation exposure, total scan number) were varied systematically. Data were analysed using a conditional logit regression model and marginal rates of substitution computed. The relative importance of each attribute and probabilities of choosing WB-MRI-based pathways were estimated. RESULTS: A total of 138 patients (mean age 65, 61% male, lung n = 72, colorectal n = 66) participated (May 2015 to September 2016). Lung cancer patients valued time to diagnosis most highly, followed by accuracy, radiation exposure, number of scans, and time in the scanner. Colorectal cancer patients valued accuracy most highly, followed by time to diagnosis, radiation exposure, and number of scans. Patients were willing to wait 0.29 (lung) and 0.45 (colorectal) weeks for a 1% increase in pathway accuracy. Patients preferred WB-MRI-based pathways (probability 0.64 [lung], 0.66 [colorectal]) if they were equivalent in accuracy, total scan number, and time to diagnosis compared with a standard staging pathway. CONCLUSIONS: Staging pathways based on first-line WB-MRI are preferred by the majority of patients if they at least match standard pathways for diagnostic accuracy, time to diagnosis, and total scan number. KEY POINTS: ⢠WB-MRI staging pathways are preferred to standard pathways by the majority of patients provided they at least match standard staging pathways for accuracy, total scan number, and time to diagnosis. ⢠For patients with lung cancer, time to diagnosis was the attribute valued most highly, followed by accuracy, radiation dose, number of additional scans, and time in a scanner. Preference for patients with colorectal cancer was similar. ⢠Most (63%) patients were willing to trade attributes, such as faster diagnosis, for improvements in pathway accuracy and reduced radiation exposure.
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Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Estadiamento de Neoplasias/métodos , Preferência do Paciente/estatística & dados numéricos , Imagem Corporal Total/métodos , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Análise de Regressão , Inquéritos e Questionários , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: The centralisation of specialist cancer surgical services across London Cancer and Greater Manchester Cancer, England, may significantly change how patients experience care. These centres are changing specialist surgical pathways for several cancers including prostate, bladder, kidney, and oesophago-gastric cancers, increasing the specialisation of centres and providing surgery in fewer hospitals. While there are potential benefits related to centralising services, changes of this kind are often controversial. The aim of this study was to identify factors related to the centralisation of specialist surgical services that are important to patients, carers and health care professionals. METHODS: This was a questionnaire-based study involving a convenience sample of patient and public involvement (PPI) and cancer health care professional (HCP) sub-groups in London and Greater Manchester (n = 186). Participants were asked to identify which of a list of factors potentially influenced by the centralisation of specialist cancer surgery were important to them and to rank these in order of importance. We ranked and shortlisted the most important factors. RESULTS: We obtained 52 responses (28% response rate). The factors across both groups rated most important were: highly trained staff; likelihood and severity of complications; waiting time for cancer surgery; and access to staff members from various disciplines with specialised skills in cancer. These factors were also ranked as being important separately by the PPI and HCP sub-groups. There was considerable heterogeneity in the relative ordering of factors within sub-groups and overall. CONCLUSIONS: This study examines and ranks factors important to patients and carers, and health care professionals in order to inform the implementation of centralisation of specialist cancer surgical services. The most important factors were similar in the two stakeholder sub-groups. Planners should consider the impact of reorganising services on these factors, and disseminate this information to patients, the public and health care professionals when deciding whether or not and how to centralise specialist cancer surgical services.
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Cuidadores , Pessoal de Saúde , Pacientes , Oncologia Cirúrgica/normas , Inglaterra , Humanos , Masculino , Preferência do Paciente , Oncologia Cirúrgica/tendências , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Recruiting patients to health promotion programmes who will benefit is crucial to success. A key policy driver for health promotion in older people is to reduce health and social care use. Our aim was to describe service use among older people taking part in the Multi-dimensional Risk Appraisal for Older people primary care health promotion programme. METHODS: A random sample of 1 in 3 older people (≥65 years old) was invited to participate in the Multi-dimensional Risk Appraisal for Older people project across five general practices in London and Hertfordshire. Data collected included socio-demographic characteristics, well-being and functional ability, lifestyle factors and service use. Latent class analysis (LCA) was used to identify groups based on use of the following: secondary health care, primary health care, community health care, paid care, unpaid care, leisure and local authority resources. Differences in group characteristics were assessed using univariate logistic regression, weighted by probability of class assignation and clustered by GP practice. RESULTS: Response rate was 34% (526/1550) with 447 participants presenting sufficient data for analysis. LCA using three groups gave the most meaningful interpretation and best model fit. About a third (active well) were fit and active with low service use. Just under a third (high NHS users) had high impairments with high primary, secondary and community health care contact, but low non-health services use. Just over a third (community service users) with high impairments used community health and other services without much hospital use. CONCLUSION: Older people taking part in the Multi-dimensional Risk Appraisal for Older people primary care health promotion can be described as three groups: active well, high NHS users, and community service users.
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Promoção da Saúde/métodos , Serviços de Saúde para Idosos/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Feminino , Medicina Geral/estatística & dados numéricos , Humanos , Londres , MasculinoRESUMO
BACKGROUND: With population ageing, research is needed into new low-cost, scalable methods of effective promotion of health and wellbeing for older people. We aimed to assess feasibility, reach and costs of implementing a new tailored computer-aided health and social risk appraisal system in primary care. METHODS: Design: Feasibility study. SETTING: Five General Practices in London (Ealing) and Hertfordshire, United Kingdom (UK) Participants: Random sample of patients aged 65 + years. INTERVENTION: The Multi-dimensional Risk Appraisal for Older people (MRA-O) system includes: 1) Postal questionnaire including health, lifestyle, social and environmental domains; 2) Software system generating a personalised feedback report with advice on health and wellbeing; 3) Follow-up of people with new concerning or complex needs by GPs or practice nurses. EVALUATION: Feasibility of implementation; participant wellbeing, functional ability and quality of life; social needs, health risks, potential lifestyle changes; and costs of implementation. RESULTS: Response rates to initial postal invitations were low (526/1550, 34%). Of these, 454/526 (86%) completed MRA-O assessments. Compared to local UK Census data on older people, participants were younger, more were owner-occupiers and fewer were from ethnic minority groups than expected. A range of problems was identified by participants, including pain in last week (269/438, 61.4%), low physical activity (173/453, 38.2%), sedentary lifestyle (174/447, 38.3%), falls (117/439, 26.7%), incontinence (111/441 25.2%), impaired vision 116/451 (25.7%), impaired hearing (145/431, 33.6%), depressed mood (71/451, 15.7%), impaired memory (44/444 9.9%), social isolation (46/449, 10.2%) and loneliness (31/442, 7.0%). Self-rated health was good/excellent in 312/437 (71.4%), and quality of life and well-being were slightly above age-specific population norms. Implementation costs were low. Practices reviewed medical records of 143/454 (31.5%) of participants as a consequence of their responses, and actively followed up 110/454 (24.2%) of their patients. CONCLUSIONS: A computer-aided risk appraisal system was feasible for General Practices to implement, yields useful information about health and social problems, and identifies individual needs. Participation rates were however low, particularly for the oldest old, the poorest, and ethnic minority groups, and this type of intervention may increase inequalities in access. Widespread implementation of this approach would require work to address potential inequalities.
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Envelhecimento/fisiologia , Promoção da Saúde/organização & administração , Vida Independente/estatística & dados numéricos , Atenção Primária à Saúde/organização & administração , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Desenho Assistido por Computador , Avaliação da Deficiência , Exercício Físico/fisiologia , Estudos de Viabilidade , Feminino , Avaliação Geriátrica , Nível de Saúde , Humanos , Vida Independente/psicologia , Estilo de Vida , Masculino , Medição de Risco , População Rural , Reino Unido , População UrbanaRESUMO
A multicentre cohort evaluation was undertaken by 15 clinicans in 11 centres across Staffordshire community care on chitosan gelling fibre dressing (Kytocel(®)). The aim of this evaluation was to examine whether the new fibre dressing improved healing outcomes for patients with chronic non-healing wounds of 6 weeks or more, observations were made regarding tissue type, fluid handling, haemostasis in bleeding friable wounds and increased granulation. Quality of life observations regarding leaking, strikethrough, pain, wear time and malodour were observed over a 4-week period or until healed. A total of 18 patients took part; 13 women and 5 men, with a mean age of 60.7 years. Fifteen (83%) had wounds in excess of 12 weeks and nine (50%) received care within wound clinics compared to home visits. Eleven (61%) patients' wounds healed within 4 weeks. A number of quality-of-life issues were addressed successfully, namely reduction in malodour and fluid handling. Sixteen (89%) rated the dressing's overall performance as very good to good.
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Curativos Hidrocoloides , Materiais Biocompatíveis/uso terapêutico , Quitosana/uso terapêutico , Qualidade de Vida , Cicatrização/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inglaterra , Feminino , Géis , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Several studies have reported associations between low-cost blood-based measurements and lung cancer but their role in risk prediction is unclear. We examined the value of expanding lung cancer risk models for targeting low-dose computed tomography (LDCT), including blood measurements of liver function and urate. METHODS: We analysed a cohort of 388,199 UK Biobank participants with 1873 events and calculated the c-index and fraction of new information (FNI) for models expanded to include combinations of blood measurements, lung function (forced expiratory volume in 1 s - FEV1), alcohol status and waist circumference. We calculated the hypothetical cost per lung cancer case detected by LDCT for different scenarios using a threshold of ≥ 1.51 % risk at 6 years. RESULTS: The c-index was 0.805 (95 %CI:0.794-0.816) for the model containing conventional predictors. Expanding to include blood measurements increased the c-index to 0.815 (95 %CI: 0.804-0.826;p < 0.0001;FNI:0.06). Expanding to include FEV1, alcohol status, and waist circumference increased the c-index to 0.811 (95 %CI: 0.800-0.822;p < 0.0001;FNI: 0.04). The c-index for the fully expanded model containing all variables was 0.819 (95 %CI:0.808-0.830;p < 0.0001;FNI:0.09). Model expansion had a greater impact on the c-index and FNI for people with a history of smoking cigarettes relative to the full cohort. Compared with the conventional risk model, the expanded models reduced the number of participants meeting the criteria for LDCT screening by 15-21 %, and lung cancer cases detected by 7-8 %. The additional cost per lung cancer case detected relative to the conventional model was £ 1018 for adding blood tests and £ 9775 for the fully expanded model. CONCLUSION: Blood measurements of liver function and urate made a modest improvement to lung cancer risk prediction compared with a model containing conventional risk factors. There was no evidence that model expansion would improve the cost per lung cancer case detected in UK healthcare settings.
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Neoplasias Pulmonares , Ácido Úrico , Humanos , Estudos de Coortes , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/diagnóstico , Pulmão , Fatores de Risco , Fígado , Detecção Precoce de Câncer/métodosRESUMO
INTRODUCTION: The prevalence of dementia is almost five times higher in people with intellectual disabilities compared with the general population. However, evidence-based treatments for this population are lacking, as most randomised controlled trials for dementia interventions have not included people with intellectual disabilities. Cognitive stimulation therapy (CST) has a robust evidence base in the general dementia population, consistently showing benefits to cognition, quality of life and being cost-effective. We are conducting a mixed-methods feasibility trial of group CST for people with intellectual disabilities and dementia, to determine if a future definitive randomised controlled trial is feasible. METHODS AND ANALYSIS: Fifty individuals with intellectual disabilities and dementia will be randomised to either the intervention arm (14 sessions of group CST plus treatment as usual) or the control arm (treatment as usual). Randomisation will occur after informed consent has been obtained and baseline assessments completed. Each arm will have 25 participants, with the intervention arm divided into five or more CST groups with three to five participants in each. The outcomes will be feasibility of recruitment, acceptability and adherence of the intervention, suitability of study outcome measures and feasibility of collecting resource use data. Quantitative and qualitative approaches, including semistructured interviews with group participants, carers and group facilitators, will be employed to assess these outcomes. ETHICS AND DISSEMINATION: This study has been approved by Essex REC (Ref: 21/EE/027) and the HRA ethical approval process through the Integrated Research Application System (IRAS ID: 306 756). We plan to publish the results in peer-reviewed journals and conferences as well as provide feedback to funders, sponsors and study participants. TRIAL REGISTRATION NUMBER: ISRCTN88614460.
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Demência , Deficiência Intelectual , Humanos , Demência/terapia , Demência/psicologia , Deficiência Intelectual/terapia , Qualidade de Vida , Estudos de Viabilidade , Cognição , Reino Unido , Análise Custo-Benefício , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Background: Mental health acute crisis episodes are associated with high inpatient costs. Self-management interventions may reduce readmission by enabling individuals to manage their condition. Delivery of such interventions by Peer Support Workers (PSWs) may be cost-effective. CORE, a randomized control trial of a PSW self-management intervention compared to usual care, found a significant reduction in admissions to acute mental healthcare for participants receiving the intervention. This paper aims to evaluate the cost-effectiveness of the intervention over 12 months from a mental health service perspective. Analysis methods of increasing complexity were used to account for data missingness and distribution. Methods: Participants were recruited from six crisis resolution teams in England from 12 March 2014 to 3 July 2015 (trial registration ISRCTN: 01027104). Resource use was collected from patient records at baseline and 12 months. The EQ-5D-3L was collected at baseline and 4 and 18 months, and linear interpolation was used to calculate 12-month values for quality-adjusted life-years (QALYs). The primary analysis of adjusted mean incremental costs and QALYs for complete cases are calculated separately using OLS regression. Secondly, a complete-case non-parametric two-stage bootstrap (TSB) was performed. The impacts of missing data and skewed cost data were explored using multiple imputation using chained equations and general linear models, respectively. Results: Four hundred and forty-one participants were recruited to CORE; 221 randomized to the PSW intervention and 220 to usual care plus workbook. The probability that the PSW intervention was cost-effective compared with the workbook plus usual care control at 12 months varied with the method used, and ranged from 57% to 96% at a cost-effectiveness threshold of £20,000 per QALY gained. Discussion: There was a minimum 57% chance that the intervention was cost-effective compared to the control using 12-month costs and QALYs. The probability varied by 40% when methods were employed to account for the relationship between costs and QALYs, but which restricted the sample to those who provided both complete cost and utility data. Caution should therefore be applied when selecting methods for the evaluation of healthcare interventions that aim to increase precision but may introduce bias if missing data are heavily unbalanced between costs and outcomes.
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INTRODUCTION: Prostate MRI is a well-established tool for the diagnostic work-up for men with suspected prostate cancer (PCa). Current recommendations advocate the use of multiparametric MRI (mpMRI), which is composed of three sequences: T2-weighted sequence (T2W), diffusion-weighted sequence (DWI) and dynamic contrast-enhanced sequence (DCE). Prior studies suggest that a biparametric MRI (bpMRI) approach, omitting the DCE sequences, may not compromise clinically significant cancer detection, though there are limitations to these studies, and it is not known how this may affect treatment eligibility. A bpMRI approach will reduce scanning time, may be more cost-effective and, at a population level, will allow more men to gain access to an MRI than an mpMRI approach. METHODS: Prostate Imaging Using MRI±Contrast Enhancement (PRIME) is a prospective, international, multicentre, within-patient diagnostic yield trial assessing whether bpMRI is non-inferior to mpMRI in the diagnosis of clinically significant PCa. Patients will undergo the full mpMRI scan. Radiologists will be blinded to the DCE and will initially report the MRI using only the bpMRI (T2W and DWI) sequences. They will then be unblinded to the DCE sequence and will then re-report the MRI using the mpMRI sequences (T2W, DWI and DCE). Men with suspicious lesions on either bpMRI or mpMRI will undergo prostate biopsy. The main inclusion criteria are men with suspected PCa, with a serum PSA of ≤20 ng/mL and without prior prostate biopsy. The primary outcome is the proportion of men with clinically significant PCa detected (Gleason score ≥3+4 or Gleason grade group ≥2). A sample size of at least 500 patients is required. Key secondary outcomes include the proportion of clinically insignificant PCa detected and treatment decision. ETHICS AND DISSEMINATION: Ethical approval was obtained from the National Research Ethics Committee West Midlands, Nottingham (21/WM/0091). Results of this trial will be disseminated through peer-reviewed publications. Participants and relevant patient support groups will be informed about the results of the trial. TRIAL REGISTRATION NUMBER: NCT04571840.
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Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Masculino , Humanos , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Imageamento por Ressonância Magnética/métodos , Biópsia , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. METHODS/DESIGN: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Nivolumabe/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Qualidade de Vida , Neoplasias Renais/tratamento farmacológico , ImunoterapiaRESUMO
BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.
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Doença de Parkinson , Humanos , Consenso , Progressão da Doença , Avaliação de Resultados em Cuidados de Saúde , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/psicologia , Qualidade de VidaRESUMO
BACKGROUND: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. OBJECTIVE: To present consensus voting results for select questions from APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. RESULTS AND LIMITATIONS: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. CONCLUSIONS: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/diagnóstico , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. OBJECTIVE: To present the voting results of the APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. RESULTS AND LIMITATIONS: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. CONCLUSIONS: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. TWITTER SUMMARY: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. TAKE-HOME MESSAGE: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.
Assuntos
COVID-19 , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Diagnóstico por Imagem , HormôniosRESUMO
BACKGROUND: The reconfiguration of specialist hospital services, with service provision concentrated in a reduced number of sites, is one example of major system change (MSC) for which there is evidence of improved patient outcomes. This paper explores the reconfiguration of specialist oesophago-gastric (OG) cancer surgery services in a large urban area of England (Greater Manchester, GM), with a focus on the role of history in this change process and how reconfiguration was achieved after previous failed attempts. METHODS: This study draws on qualitative research from a mixed-methods evaluation of the reconfiguration of specialist cancer surgery services in GM. Forty-six interviews with relevant stakeholders were carried out, along with ~160 hours of observations at meetings and the acquisition of ~300 pertinent documents. Thematic analysis using deductive and inductive approaches was undertaken, guided by a framework of 'simple rules' for MSC. RESULTS: Through an awareness of, and attention to, history, leaders developed a change process which took into account previous unsuccessful reconfiguration attempts, enabling them to reduce the impact of potentially challenging issues. Interviewees described attending to issues involving competition between provider sites, change leadership, engagement with stakeholders, and the need for a process of change resilient to challenge. CONCLUSION: Recognition of, and response to, history, using a range of perspectives, enabled this reconfiguration. Particularly important was the way in which history influenced and informed other aspects of the change process and the influence of stakeholder power. This study provides further learning about MSC and the need for a range of perspectives to enable understanding. It shows how learning from history can be used to enable successful change.