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OBJECTIVES: In France, decisions for pricing and reimbursement for medicinal products are based on appraisals performed by the National authority for health (Haute Autorité de Santé (HAS)). During the appraisal process, additional real-world evidence can be requested as "Post-Registration Studies" (PRS) when there are uncertainties in evidence that could be resolved by additional data collection. To facilitate PRS planning, a retrospective exploratory analysis was conducted to identify the characteristics of medicinal products associated with a PRS request. METHODS: This analysis encompassed all appraisals finalized between January 1, 2016 and December 31, 2021 and compared products for which the appraisal led to a PRS request with those that did not. RESULTS: Six hundred positive opinions for reimbursement were identified, with a PRS request present in 17 percent (n = 103) of cases. The independent characteristics associated with a PRS request were a mild or moderate clinical benefit score, a major to moderate or minor clinical added value score, previous availability under an early access program, and certain therapeutic areas (neurology, pulmonology, and endocrinology). These findings suggest two different profiles of PRS requests: (i) products for which there is uncertainty in the size of the clinical benefit and (ii) innovative products for which a substantial benefit is expected but uncertainties persist. CONCLUSIONS: These results will assist health technology developers to better anticipate data generation to promptly address uncertainties identified by HAS. It may also help HAS and other assessment agencies to work together to improve postlaunch evidence generation according to the characteristics of the medicinal products.
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Avaliação da Tecnologia Biomédica , Avaliação da Tecnologia Biomédica/organização & administração , Estudos Retrospectivos , França , Humanos , Estudos de Casos e ControlesRESUMO
Symptomatic effects of mental disorders in parents could bias their reporting on their child's mental health. This study aimed to investigate the measurement invariance of the French version of the parental Strengths and Difficulties Questionnaire (SDQ) across parental mental health in a sample (N = 20,765) of parents of children aged 3 to 17 years in France. Confirmatory factor analysis (CFA) and Exploratory Structural Equation Modelling (ESEM) were used to evaluate the fit of three known alternative SDQ factor structures (five, three, or second-order factor structures). Invariance was tested across parental mental health (present anxiety and depressive symptoms, psychiatric history) and across socio-demographic characteristics (child's age, child's gender, parent's gender, parent's educational level). CFA models showed a poor fit, while all ESEM models achieved acceptable or good fit, with the five-factor model presenting the best fit. Invariance was observed for all characteristics tested, indicating that the SDQ can be used to study the links between parental mental health and their child's mental health without bias. However, ESEM showed that the hyperactivity/inattention and conduct problems dimensions were not well differentiated in the French version of the SDQ.
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BACKGROUND: In recent years, many studies have explored the associations among impulsivity, history of abuse, the emergence of eating disorders with episodes of binge eating (EDBE) and their severity. Nevertheless, factors associated with successful clinical outcomes of EDBE are still unknown. Our study aimed to test the hypothesis that a history of abuse is associated with unsuccessful clinical outcomes of EDBE through an effect mediated by impulsivity. METHODS: We assessed patients older than 15 years, 3 months with EDBE at inclusion and at 1 year. Recovery was defined as the absence of eating disorders at 1 year. A mediation analysis was performed by means of structural equation modelling. RESULTS: We included 186 patients in our analyses (54% bulimia nervosa, 29% anorexia nervosa binge eating/purging type and 17% binge-eating disorder); 179 (96%) were female. One-third (n = 63) of patients reported a history of abuse, and recovery was observed for 20% of the sample (n = 38). Contrary to our assumption, a history of abuse was not associated with the absence of recovery of EDBE at 1 year. Factors unfavourable for achieving recovery were anxiety disorders (odds ratio [OR] 0.41), vomiting (OR 0.39), physical hyperactivity (OR 0.29), negative urgency and a lack of perseverance (OR 0.85 for both). Only positive urgency was positively associated with recovery (OR 1.25). LIMITATIONS: We excluded 219 patients lost to the 1-year follow-up. CONCLUSION: Our findings may help to deconstruct the empirical belief that traumatic events may interfere with the successful course of treatment for eating disorders. A high level of positive urgency may be associated with more receptivity to care.
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Anorexia Nervosa , Transtorno da Compulsão Alimentar , Bulimia , Transtornos da Alimentação e da Ingestão de Alimentos , Humanos , Feminino , Masculino , Estudos Longitudinais , Comportamento ImpulsivoRESUMO
Interpreting observed changes over time in Patient-Reported Outcomes (PRO) measures is still considered a challenge. Indeed, concluding an observed change at group level is statistically significant does not necessarily equate this change is meaningful from the perspective of the patient. To help interpret within and/or between group changes in the measure over time, the estimation of the Minimal Important Difference (MID) of the instrument - the smallest value that patients consider as a perceived change - is useful. In the last 30 years, a plethora of methods and estimators have been proposed to derive this MID value using clinical data from sample of patients. MIDs for hundreds of PROs have been estimated, with frequently a substantial variability in the results depending on the method used. Nonetheless, a rigorous assessment of the statistical performances of numerous proposed methods for estimating MIDs by experimental design such as Monte-Carlo study has never been performed. The purpose of this paper is to thoroughly depict a protocol for a large-scale simulation study designed to investigate the statistical performances, especially bias against a true populational value, of the common proposed estimators for MID. This paper depicts how investigated methods and estimators were retained after the conduct of a systematic review, the design of a conceptual model that formally defines what is the true populational MID value and the translation of the conceptual model into a model allowing the simulation of responses of items to a hypothetical PRO at two times of measurement along with the response to a Patient Global Rating of Change at the second time under the constraint of a known true MID value. A statistical analysis plan is depicted in order to conclude if working hypotheses on what could be appropriate MID estimators will be verified. Strengths, assumptions, and limits of the simulation model are exposed. Finally, we show how this protocol could be the basis for fostering future methodological research on the issue of interpreting changes in PRO measures.
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Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Projetos de Pesquisa , Revisões Sistemáticas como AssuntoRESUMO
PURPOSE: Our aim is to advance response shift research by explicating the implications of published syntheses by the Response Shift - in Sync Working Group in an integrative way and suggesting ways for improving the quality of future response shift studies. METHODS: Members of the Working Group further discussed the syntheses of the literature on definitions, theoretical underpinnings, operationalizations, and response shift methods. They outlined areas in need of further explication and refinement, and delineated additional implications for future research. RESULTS: First, the proposed response shift definition was further specified and its implications for the interpretation of results explicated in relation to former, published definitions. Second, the proposed theoretical model was further explained in relation to previous theoretical models and its implications for formulating research objectives highlighted. Third, ways to explore alternative explanations per response shift method and their implications for response shift detection and explanation were delineated. The implications of the diversity of the response shift methods for response shift research were presented. Fourth, the implications of the need to enhance the quality and reporting of the response shift studies for future research were sketched. CONCLUSION: With our work, we intend to contribute to a common language regarding response shift definitions, theory, and methods. By elucidating some of the major implications of earlier work, we hope to advance response shift research.
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Modelos Teóricos , Qualidade de Vida , Humanos , Qualidade de Vida/psicologia , Projetos de PesquisaRESUMO
During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.
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Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Avaliação da Tecnologia Biomédica , Antineoplásicos/efeitos adversos , França , Órgãos Governamentais , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Patient-Reported Outcomes (PROs) are standardized questionnaires used to measure subjective outcomes such as quality of life in healthcare. They are considered paramount to assess the results of therapeutic interventions. However, because their calibration is relative to internal standards in people's mind, changes in PRO scores are difficult to interpret. Knowing the smallest value in the score that the patient perceives as change can help. An estimator linking the answers to a Patient Global Rating of Change (PGRC: a question measuring the overall feeling of change) with change in PRO scores is frequently used to obtain this value. In the last 30 years, a plethora of methods have been used to obtain these estimates, but there is no consensus on the appropriate method and no formal definition of this value. METHODS: We propose a model to explain changes in PRO scores and PGRC answers. RESULTS: A PGRC measures a construct called the Perceived Change (PC), whose determinants are elicited. Answering a PGRC requires discretizing a continuous PC into a category using threshold values that are random variables. Therefore, the populational value of the Minimal Perceived Change (MPC) is the location parameter value of the threshold on the PC continuum defining the switch from the absence of change to change. CONCLUSIONS: We show how this model can help to hypothesize what are the appropriate methods to estimate the MPC and its potential to be a rigorous theoretical basis for future work on the interpretation of change in PRO scores.
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Análise de Dados , Qualidade de Vida , Emoções , Humanos , Medidas de Resultados Relatados pelo Paciente , Inquéritos e QuestionáriosRESUMO
PURPOSE: The extant response shift definitions and theoretical response shift models, while helpful, also introduce predicaments and theoretical debates continue. To address these predicaments and stimulate empirical research, we propose a more specific formal definition of response shift and a revised theoretical model. METHODS: This work is an international collaborative effort and involved a critical assessment of the literature. RESULTS: Three main predicaments were identified. First, the formal definitions of response shift need further specification and clarification. Second, previous models were focused on explaining change in the construct intended to be measured rather than explaining the construct at multiple time points and neglected the importance of using at least two time points to investigate response shift. Third, extant models do not explicitly distinguish the measure from the construct. Here we define response shift as an effect occurring whenever observed change (e.g., change in patient-reported outcome measures (PROM) scores) is not fully explained by target change (i.e., change in the construct intended to be measured). The revised model distinguishes the measure (e.g., PROM) from the underlying target construct (e.g., quality of life) at two time points. The major plausible paths are delineated, and the underlying assumptions of this model are explicated. CONCLUSION: It is our hope that this refined definition and model are useful in the further development of response shift theory. The model with its explicit list of assumptions and hypothesized relationships lends itself for critical, empirical examination. Future studies are needed to empirically test the assumptions and hypothesized relationships.
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Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Qualidade de Vida/psicologiaRESUMO
PURPOSE: The Working Group undertook a critical, comprehensive synthesis of the response shift work to date. We aimed to (1) describe the rationale for this initiative; (2) outline how the Working Group operated; (3) summarize the papers that comprise this initiative; and (4) discuss the way forward. METHODS: Four interdisciplinary teams, consisting of response shift experts, external experts, and new investigators, prepared papers on (1) definitions and theoretical underpinnings, (2) operationalizations and response shift methods, (3) implications for healthcare decision-making, and (4) on the published magnitudes of response shift effects. Draft documents were discussed during a two-day meeting. Papers were reviewed by all members. RESULTS: Vanier and colleagues revised the formal definition and theory of response shift, and applied these in an amended, explanatory model of response shift. Sébille and colleagues conducted a critical examination of eleven response shift methods and concluded that for each method extra steps are required to make the response shift interpretation plausible. Sawatzky and colleagues created a framework for considering the impact of response shift on healthcare decision-making at the level of the individual patient (micro), the organization (meso), and policy (macro). Sajobi and colleagues are conducting a meta-analysis of published response shift effects. Preliminary findings indicate that the mean effect sizes are often small and variable across studies that measure different outcomes and use different methods. CONCLUSION: Future response shift research will benefit from collaboration among diverse people, formulating alternative hypotheses of response shift, and conducting the most conclusive studies aimed at testing these (falsification).
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Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Qualidade de Vida/psicologiaRESUMO
OBJECTIVE: In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed, lacking precision or inadequately calibrated. We developed a matrix to predict RRP with high precision and adequate calibration. METHODS: Post-hoc analysis by pooling individual data from cohorts (ESPOIR and Leuven cohorts) and clinical trials (ASPIRE, BeSt and SWEFOT trials). Adult DMARD-naïve patients with active early RA for which the first therapeutic strategy after inclusion was to prescribe methotrexate or leflunomide were included. A logistic regression model to predict RRP was built. The best model was selected by 10-fold stratified cross-validation by maximizing the Area Under the Curve. Calibration and discriminatory power of the model were checked. The probabilities of RRP for each combination of levels of baseline characteristics were estimated. RESULTS: 1306 patients were pooled. 20.6% exhibited RRP. Four predictors were retained: rheumatoid factor positivity, presence of at least one RA erosion on X-rays, CRP > 30mg/l, number of swollen joints. The matrix estimates RRP probability for 36 combinations of level of baseline characteristics with a greatly enhanced precision compared with previously published matrices (95% CI: from ± 0.02 minimum to ± 0.08 maximum) and model calibration is excellent (P = 0.79). CONCLUSION: A matrix proposing RRP probability with high precision and excellent calibration in early RA was built. Although the matrix has moderate sensitivity and specificity, it is easily usable and may help physicians and patients to make treatment decisions in daily clinical practice.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Metotrexato/uso terapêutico , Adulto , Artrite Reumatoide/tratamento farmacológico , Bases de Dados Factuais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiografia , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Using a real dataset, we highlighted several major methodological issues raised by the estimation of the Minimal Clinically Important Difference (MCID) of a Patient-Reported Outcomes instrument. We especially considered the management of missing data and the use of more than two times of measurement. While inappropriate missing data management and inappropriate use of multiple time points can lead to loss of precision and/or bias in MCID estimation, these issues are almost never dealt with and require cautious considerations in the context of MCID estimation. METHODS: We used the LIGALONGO study (French Randomized Controlled Trial). We estimated MCID on the SF-36 General Health score by comparing many methods (distribution or anchor-based). Different techniques for imputation of missing data were performed (simple and multiple imputations). We also consider all measurement occasions by longitudinal modeling, and the dependence of the score difference on baseline. RESULTS: Three hundred ninety-three patients were studied. With distribution-based methods, a great variability in MCID was observed (from 3 to 26 points for improvement). Only 0.2 SD and 1/3 SD distribution methods gave MCID values consistent with anchor-based methods (from 4 to 7 points for improvement). The choice of missing data imputation technique clearly had an impact on MCID estimates. Simple imputation by mean score seemed to lead to out-of-range estimate, but as missing not at random mechanism can be hypothesized, even multiple imputations techniques can have led to an slight underestimation of MCID. Using 3 measurement occasions for improvement led to an increase in precision but lowered estimates. CONCLUSION: This practical example illustrates the substantial impact of some methodological issues that are usually never dealt with for MCID estimation. Simulation studies are needed to investigate those issues. TRIAL REGISTRATION: NCT01240772 (ClinicalTrials.gov) registered on November 15, 2010.
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Gerenciamento de Dados/organização & administração , Diferença Mínima Clinicamente Importante , Medidas de Resultados Relatados pelo Paciente , Conjuntos de Dados como Assunto , Humanos , Qualidade de VidaRESUMO
BACKGROUND: Disease activity may change over time in axial spondyloarthritis (axSpA). The objectives were to identify patterns of disease activity evolution in patients with early axSpA. METHODS: Patients from the prospective early axSpA cohort (DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR)) who fulfilled the Assessment in SpondyloArthritis Society (ASAS) criteria for axSpA at baseline and with at least three Ankylosing Spondylitis Disease Activity Score (ASDAS) values available over the 3â years of follow-up were analysed. Statistical analyses: trajectories were estimated by group-based trajectory modelling; predisposing baseline factors for such trajectories were identified by univariate and multivariable multinomial (logit) regression; work disability over time was compared between the trajectories by Cox hazard model. RESULTS: In all, 370 patients were analysed: mean disease duration was 1.6 (±0.9) years. The five distinct trajectories of disease activity over the 3â years were (t1) 'persistent moderate disease activity' (n=134 (36.2%)); (t2) 'persistent inactive disease' (n=66 (17.8%); (t3) 'changing from very high disease activity to inactive disease' ((n=29 (7.8%)); (t4) 'persistent high disease activity' (n=126 (34.1%)) and (t5) 'persistent very high disease activity' (n=15 (4.1%)). After adjustment for other characteristics, t2 was associated with a white-collar job (OR=2.6 (95% CI 1.0 to 6.7)) and t3 with male gender (OR=7.1 (1.6 to 32.2)), higher education level (OR=9.4 (1.4 to 63.4)) and peripheral joint involvement (OR=6.2 (1.23 to 31.32)). Patients from (t4) and (t5) were more often declared work disabled over follow-up (HR=5.2 (1.5 to 18.0) and HR=8.0 (1.3 to 47.9), respectively). CONCLUSIONS: Trajectory modelling of disease activity was feasible in early axSpA: more than 30% patients (141/370) were in a trajectory with a persistent high disease activity. Persistent high disease activity trajectories were significantly associated with consequences on work. TRIAL REGISTRATION NUMBER: NCT01648907.
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Modelos Estatísticos , Espondiloartropatias/tratamento farmacológico , Adulto , Escolaridade , Humanos , Estudos Longitudinais , Análise Multivariada , Ocupações , Prognóstico , Estudos Prospectivos , Articulação Sacroilíaca , Índice de Gravidade de Doença , Fatores Sexuais , Avaliação de Sintomas , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Avaliação da Capacidade de Trabalho , Adulto JovemRESUMO
BACKGROUND: In patients with rheumatoid arthritis in remission, a disease activity-driven tapering of adalimumab or etanercept relying on progressive injection spacing has not been shown to be equivalent to a maintenance strategy at full dose in terms of disease activity in the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS) trial. OBJECTIVES: To evaluate the cost-effectiveness of such a spacing strategy based on the data of the STRASS trial. METHODS: This is a cost-utility analysis of the STRASS trial, a French multicenter 18-month equivalence randomized open-label controlled trial that included patients at stable dose for at least 1 year, in remission for at least 6 months. Effectiveness was assessed in quality-adjusted life-years (QALYs). Costs involved in the study period were assessed from a payer perspective. The decremental cost-effectiveness ratio (DCER) was calculated in the complete cases sample (n = 98). Several sensitivity analyses were conducted and the impact of missing data on DCER estimate was investigated. An acceptability analysis was performed. RESULTS: In the spacing arm, TNF-blockers were stopped for 34.1% of the patients, tapered for 43.2%, and maintained at full dose for 18.2%. The spacing strategy was associated with less QALYs gain (mean difference of -0.158; 95% confidence interval [CI] -0.085 to -0.232) and reduced costs (mean difference of -8,440; 95% CI -6,507 to -10,212). The estimated DCER of the spacing strategy over the maintenance at full dose was 53,417 saved per QALY lost (95% CI 32,230 to 104,700). CONCLUSIONS: The spacing strategy appears cost-effective, but the acceptability of such a QALY loss reported to the cost avoided remains to be evaluated, because no consensual threshold has been determined for willingness to accept as compared with willingness to pay.
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Antirreumáticos/administração & dosagem , Antirreumáticos/economia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/economia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/economia , Custos de Medicamentos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Esquema de Medicação , Feminino , França , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Postoperative operative pulmonary complications (PPCs) after hepatic surgery are associated with increased length of hospital stays. Intraoperative blood transfusion, extensive resection and different comorbidities have been identified. Other parameters, like time of hepatic ischemia, have neither been clinically studied, though experimental studies show that hepatic ischemia can provide lung injury. The objective of this study was to determinate the risk factors of postoperative pulmonary complications (PPCs) after hepatic resection within 7 postoperative days. METHOD: Ninety-four patients consecutively who underwent elective hepatectomy between January and December 2013. Demographic data, pathological variables, and preoperative, intraoperative, and postoperative variables had been prospectively collected in a data base. The dependant variables studied were the occurrence of PPCs, defined before analysis of the data. RESULTS: PPCs occurred in 32 (34%) patients. A multivariate analysis allowed identifying the risk factors for PPCs. On multivariate analysis, preoperative gamma-glutamyltransferase (GGT) elevation OR =5,12 [1,85-15,69] p = 0,002, liver ischemia duration OR = 1,03 [1,01-1,06] p = 0,01 and the intraoperative use of vasopressor OR = 4,40 [1,58-13,36] p = 0,006 were independently associated with PPCs. For every 10 min added in ischemia duration, the OR of the risk of PPCs was estimated to be 1.37 (CI95% = [1.08-1.81], p = 0.01). CONCLUSION: Three risk factors for PPCs have been identified in a population undergoing liver resection: preoperative GGT elevation, ischemia duration and the intraoperative use of vasopressor. PPCs after liver surgery could be related to lung injury induced by liver ischemia reperfusion and not solely by direct infectious process. That could explain why factors influencing directly or indirectly liver ischemia were independently associated with PPCs.
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Hepatectomia/efeitos adversos , Pneumopatias/etiologia , Estudos de Coortes , Feminino , Humanos , Isquemia/complicações , Fígado/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Fatores de Risco , Fatores de Tempo , Vasoconstritores/efeitos adversos , gama-Glutamiltransferase/sangueRESUMO
OBJECTIVE: To report the speech performance and sound localization in adult patients 5 years after bilateral simultaneous cochlear implantation and to evaluate the change in speech scores between 1 and 5 years. DESIGN: In this prospective multicenter study, 26 patients were evaluated 5 years after implantation using long straight electrode arrays (MED-EL Combi 40+, standard electrode array, 31 mm). Speech perception was measured using disyllabic words in quiet and noise, with the speech coming from the front and a cocktail party background noise coming from 5 loudspeakers. Speech localization measurements were performed in noise under the same test conditions. These results were compared to those obtained at 1 year reported in a previous study. RESULTS: Five years after implantation, an improvement in speech performance scores compared to 1 year after implantation was found for the poorer ear both in quiet and in noise (+12.1 ± 2.6%, p < 0.001). The lower the speech score of the poorer ear at 1 year, the greater the improvement at 5 years, both in quiet (r = -0.62) and at a signal-to-noise ratio of +15 dB (r = -0.58). The sound localization on the horizontal plane in noise provided by bilateral implantation was better than the unilateral one and remained stable after the results observed at 1 year. CONCLUSION: In adult patients simultaneously and bilaterally implanted, the poorest speech scores improved between 1 and 5 years after implantation. These findings are an additional element to recommend bilateral implantation in adult patients. The use of both cochlear implants and speech training sessions for patients with poor performance should continue in the period after 1 year following implantation, since the speech scores will improve over time.
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Implante Coclear/métodos , Implantes Cocleares , Surdez/reabilitação , Perda Auditiva Bilateral/reabilitação , Localização de Som , Percepção da Fala , Adulto , Idoso , Feminino , Audição , Testes Auditivos , Humanos , Masculino , Pessoa de Meia-Idade , Ruído , Estudos Prospectivos , Razão Sinal-Ruído , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Triple-negative breast cancers need to be refined in order to identify therapeutic subgroups of patients. METHODS: We conducted an unsupervised analysis of microarray gene-expression profiles of 107 triple-negative breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. A triple-negative external cohort (n=87) was used for validation. RESULTS: Fuzzy clustering separated triple-negative tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean=64.6 years) than C2 (mean=56.8 years; P=0.03) and C3 patients (mean=51.9 years; P=0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P<0.0001 for both comparisons). Significant event-free survival (P=0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P=0.01) and C2 (P=0.02). Event-free survival analysis results were confirmed when our cohort was pooled with the external cohort (n=194; P=0.01). Functional annotation showed that 22% of triple-negative patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response and low M2-like macrophages were a hallmark of C3, and that these patients had a better event-free survival than C2 patients, characterized by low immune response and high M2-like macrophages: P=0.02 for our cohort, and P=0.03 for pooled cohorts. CONCLUSIONS: We identified three subtypes of triple-negative patients: luminal androgen receptor (22%), basal-like with low immune response and high M2-like macrophages (45%), and basal-enriched with high immune response and low M2-like macrophages (33%). We noted out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in triple-negative basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype triple-negative patients.
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Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais , Análise por Conglomerados , Biologia Computacional , Feminino , Humanos , Imunidade Inata , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Transcriptoma , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Carga TumoralRESUMO
OBJECTIVE: This simulation study was designed to provide data on the performance of Oort's procedure (OP) for response shift (RS) detection (regarding type I error, power, and overall performance), according to sample characteristics, at item level. A specific objective was to assess the impact of using different information criteria (IC), as alternatives to the LRT (likelihood-ratio test), for global assessment of RS occurrence. METHODS: Responses to five binary items at two times of measurement were simulated. Thirty-six combinations of sample characteristics [sample size (n), "true change," correlations between the two latent variables and presence/absence of uniform recalibration RS (ur)] were considered. A thousand datasets were generated for each combination. RS detection was performed on each dataset following OP. Type I error and power of the global assessment of RS occurrence, as well as overall performance of the OP, were assessed. RESULTS: The estimated type I error was close to 5 % for the LRT and lower than 5 % for the IC. The estimated power was higher for the LRT as compared to the AIC, which was the highest among the other IC. For the LRT, the estimated power for n = 100 and for the combination of n = 200 and ur = 1 item was below 80 %. Otherwise, for other combinations of sample characteristics, the estimated power was above 90 %. CONCLUSION: For the LRT, higher values of power were estimated compared to IC with appropriate values of type I error. These results were consistent with Oort's proposal to use the LRT as the criterion to assess global RS occurrence.
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Doença Crônica/psicologia , Modelos Estatísticos , Avaliação de Resultados em Cuidados de Saúde/métodos , Qualidade de Vida/psicologia , Algoritmos , Humanos , Neoplasias/psicologia , Projetos Piloto , Projetos de Pesquisa , Tamanho da AmostraRESUMO
PURPOSE: Some IRT models have the advantage of being robust to missing data and thus can be used with complete data as well as different patterns of missing data (informative or not). The purpose of this paper was to develop an algorithm for response shift (RS) detection using IRT models allowing for non-uniform and uniform recalibration, reprioritization RS recognition and true change estimation with these forms of RS taken into consideration if appropriate. METHODS: The algorithm is described, and its implementation is shown and compared to Oort's structural equation modeling (SEM) procedure using data from a clinical study assessing health-related quality of life in 669 hospitalized patients with chronic conditions. RESULTS: The results were quite different for the two methods. Both showed that some items of the SF-36 General Health subscale were affected by response shift, but those items usually differed between IRT and SEM. The IRT algorithm found evidence of small recalibration and reprioritization effects, whereas SEM mostly found evidence of small recalibration effects. CONCLUSION: An algorithm has been developed for response shift analyses using IRT models and allows the investigation of non-uniform and uniform recalibration as well as reprioritization. Differences in RS detection between IRT and SEM may be due to differences between the two methods in handling missing data. However, one cannot conclude on the differences between IRT and SEM based on a single application on a dataset since the underlying truth is unknown. A next step would be to implement a simulation study to investigate those differences.
Assuntos
Algoritmos , Modelos Estatísticos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Avaliação de Resultados da Assistência ao Paciente , Projetos de Pesquisa/estatística & dados numéricos , Doença Crônica , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Qualidade de Vida , Autorrelato , Inquéritos e QuestionáriosRESUMO
Purpose: To investigate the clinical and virologic-associated and predictive factors of intraocular pressure (IOP) evolution over time and its severity in Fuchs' heterochromic iridocyclitis (FHC). Methods: Consecutive patients with both clinical FHC and intraocular synthesis of rubella virus (RV)-specific antibodies were included in this study. Specific ocular production of RV antibodies was confirmed using the quotient of serum/aqueous humor ratio of RV IgGs (Crv) and control antiviral IgGs (Cctl), using quantitative serology methods. Epidemiologic, clinical, biological, and virologic data at referral were collected and correlated with IOP values over time, occurrence, and severity of glaucoma. Results: Sixty-eight eyes of 68 patients were included. Mean age at diagnosis was 40.7 ± 11.1 years. Mean follow-up was 4.3 ± 4.3 years. Mean baseline Crv and Cctl values were 12.34 ± 14.67 and 216.70 ± 98.4, respectively. Mean baseline IOP was 17.2 ± 7.2 mm Hg (range, 9-40) and 15.6 ± 5.6 (range, 3-30) 5 years after referral. The predictive factors for pejorative IOP evolution over time and glaucoma severity were male sex (P = 0.03) and decreased Crv (P = 0.04) and presence of iris nodules (P < 0.001) and decreased Cctl (P = 0.02), respectively. Diagnostic delay was associated with increased likelihood of undergoing glaucoma surgery (P = 0.02). Conclusions: Time to diagnosis, male sex, presence of iris nodules at baseline, and decreased Crv and Cctl ratios were associated with increased likelihood of pejorative IOP evolution over time. Given the aggressiveness of glaucoma in FHC, these results provide interesting insight into what category of patients should need the closest screening.