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Nat Commun ; 12(1): 1107, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597541


One of the primary tools that researchers use to predict risk is the case-control study. We identify a flaw, temporal bias, that is specific to and uniquely associated with these studies that occurs when the study period is not representative of the data that clinicians have during the diagnostic process. Temporal bias acts to undermine the validity of predictions by over-emphasizing features close to the outcome of interest. We examine the impact of temporal bias across the medical literature, and highlight examples of exaggerated effect sizes, false-negative predictions, and replication failure. Given the ubiquity and practical advantages of case-control studies, we discuss strategies for estimating the influence of and preventing temporal bias where it exists.

Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto/normas , Seleção de Pacientes , Projetos de Pesquisa/normas , Viés , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Estudos de Casos e Controles , Ensaios Clínicos como Assunto/métodos , Previsões , Humanos , Reprodutibilidade dos Testes
JAMA Netw Open ; 4(2): e2037640, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606033


Importance: Medical research has not equitably included members of racial/ethnic minority groups or female and older individuals. There are limited data on participant demographic characteristics in vaccine trials despite the importance of these data to current trials aimed at preventing coronavirus disease 2019. Objective: To investigate whether racial/ethnic minority groups and female and older adults are underrepresented among participants in vaccine clinical trials. Design, Setting, and Participants: This cross-sectional study examined data from completed US-based vaccine trials registered on from July 1, 2011, through June 30, 2020. The terms vaccine, vaccination, immunization, and inoculation were used to identify trials. Only those addressing vaccine immunogenicity or efficacy of preventative vaccines were included. Main Outcomes and Measures: The numbers and percentages of racial/ethnic minority, female, and older individuals compared with US census data from 2011 and 2018. Secondary outcome measures were inclusion by trial phase and year of completion. Results: A total of 230 US-based trials with 219 555 participants were included in the study. Most trials were randomized (180 [78.3%]), included viral vaccinations (159 [69.1%]), and represented all trial phases. Every trial reported age and sex; 134 (58.3%) reported race and 79 (34.3%) reported ethnicity. Overall, among adult study participants, White individuals were overrepresented (77.9%; 95% CI, 77.4%-78.4%), and Black or African American individuals (10.6%; 95% CI, 10.2%-11.0%) and American Indian or Alaska Native individuals (0.4%; 95% CI, 0.3%-0.5%) were underrepresented compared with US census data; enrollment of Asian individuals was similar (5.7%; 95% CI, 5.5%-6.0%). Enrollment of Hispanic or Latino individuals (11.6%; 95% CI, 11.1%-12.0%) was also low even among the limited number of adult trials reporting ethnicity. Adult trials were composed of more female participants (75 325 [56.0%]), but among those reporting age as a percentage, enrollment of participants who were aged 65 years or older was low (12.1%; 95% CI, 12.0%-12.3%). Black or African American participants (10.1%; 95% CI, 9.7%-10.6%) and Hispanic or Latino participants (22.5%; 95% CI, 21.6%-23.4%) were also underrepresented in pediatric trials. Among trials reporting race/ethnicity, 65 (48.5%) did not include American Indian or Alaska Native participants and 81 (60.4%) did not include Hawaiian or Pacific Islander participants. Conclusions and Relevance: This cross-sectional study found that among US-based vaccine clinical trials, members of racial/ethnic minority groups and older adults were underrepresented, whereas female adults were overrepresented. These findings suggest that diversity enrollment targets should be included for all vaccine trials targeting epidemiologically important infections.

Ensaios Clínicos como Assunto/normas , Grupos Étnicos/estatística & dados numéricos , Seleção de Pacientes , Sexismo/estatística & dados numéricos , Vacinas , Adulto , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Grupos de Populações Continentais/etnologia , Grupos de Populações Continentais/estatística & dados numéricos , Estudos Transversais , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Grupo com Ancestrais Oceânicos/etnologia , Grupo com Ancestrais Oceânicos/estatística & dados numéricos , Sexismo/etnologia
Lancet Glob Health ; 9(3): e366-e371, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33340453


Inclusion of pregnant women in COVID-19 clinical trials would allow evaluation of effective therapies that might improve maternal health, pregnancy, and birth outcomes, and avoid the delay of developing treatment recommendations for pregnant women. We explored the inclusion of pregnant women in treatment trials of COVID-19 by reviewing ten international clinical trial registries at two timepoints in 2020. We identified 155 COVID-19 treatment studies of non-biological drugs for the April 7-10, 2020 timepoint, of which 124 (80%) specifically excluded pregnant women. The same registry search for the July 10-15, 2020 timepoint, yielded 722 treatment studies, of which 538 (75%) specifically excluded pregnant women. We then focused on studies that included at least one of six drugs (remdesivir, lopinavir-ritonavir, interferon beta, corticosteroids, chloroquine and hydroxychloroquine, and ivermectin) under evaluation for COVID-19. Of 176 such studies, 130 (74%) listed pregnancy as an exclusion criterion. Of 35 studies that evaluated high-dose vitamin treatment for COVID-19, 27 (77%) excluded pregnant women. Despite the surge in treatment studies for COVID-19, the proportion excluding pregnant women remains consistent. Exclusion was not well justified as many of the treatments being evaluated have no or low safety concerns during pregnancy. Inclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.

/tratamento farmacológico , Ensaios Clínicos como Assunto/normas , Seleção de Pacientes/ética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Ensaios Clínicos como Assunto/ética , Definição da Elegibilidade , Feminino , Humanos , Gravidez
Pediatrics ; 147(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33334920


It is widely agreed that an effective response to the coronavirus disease 2019 pandemic needs to include a vaccine that is safe and effective for minors. However, many current vaccine trials have no plans for when to enroll minors. Others have recently proposed enrolling minors as young as 12 years old. This lack of a systematic approach raises 2 concerns. Waiting too long to enroll minors could unjustly deny minors and their families the benefits of a vaccine and has the potential to delay an effective response to the pandemic by a year or longer. At the same time, enrolling minors too soon runs the risk of exposing them to excessive risks. With these concerns in mind, in the present article, we propose recommendations for when and how to enroll minors in vaccine trials for the coronavirus disease 2019.

Ensaios Clínicos como Assunto/normas , Voluntários Saudáveis , Menores de Idade , Adolescente , /efeitos adversos , Criança , Ensaios Clínicos como Assunto/ética , Participação da Comunidade , Comitês de Ética em Pesquisa , Humanos , Consentimento Informado por Menores , Pandemias/prevenção & controle
Cancer Treat Rev ; 92: 102137, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33340965


The mitogen-activated protein kinase (MAPK) pathway plays a vital role in cellular processes such as gene expression, cell proliferation, cell survival, and apoptosis. Also known as the RAS-RAF-MEK-ERK pathway, the MAPK pathway has been implicated in approximately one-third of all cancers. Mutations in RAS or RAF genes such as KRAS and BRAF are common, and these mutations typically promote malignancies by over-activating MEK and ERK downstream, which drives sustained cell proliferation and uninhibited cell growth. Development of drugs targeting this pathway has been a research area of great interest, especially drugs targeting the inhibition of MEK. In vitro and clinical studies have shown promise for certain MEK inhibitors (MEKi) , and MEKi have become the first treatment option for certain cancers. Despite promising results, not all patients have a response to MEKi, and mechanisms of resistance typically arise in patients who do have a positive initial response. This paper summarizes recent developments regarding MEKi, the mechanisms of adaptive resistance to MEKi, and the potential solutions to the issue of adaptive MEKi resistance.

Ensaios Clínicos como Assunto/normas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Humanos
Farm. hosp ; 44(6): 254-271, nov.-dic. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-197694


OBJETIVO: Desarrollar un cuestionario en español dirigido a evaluar el proceso de información y obtención del consentimiento informado en investigación clínica desde la perspectiva del paciente. Con esta herramienta se pretende analizar en los pacientes que participan en un ensayo clínico los siguientes aspectos: la experiencia y desarrollo práctico del proceso de consentimiento informado, su nivel de satisfacción con dicho proceso y su nivel de comprensión del estudio. MÉTODO: Estudio de desarrollo, adaptación y validación de un cuestionario autocumplimentable para evaluar el proceso de consentimiento informado a través de la información obtenida de los pacientes. Los pasos seguidos fueron: revisión bibliográfica, generación de un pool de ítems, redacción del cuestionario, revisión por expertos, pilotaje, optimización y análisis de legibilidad. También se realizó una evaluación, selección, traducción y adaptación al español de una herramienta disponible en lengua inglesa que permitiese valorar la comprensión del paciente de la información. RESULTADOS: El cuestionario quedó conformado por cuatro apartados que permiten evaluar: 1) datos sociodemográficos, 2) aspectos prácticos relacionados con el desarrollo del proceso de consentimiento informado, 3) valoración del paciente del proceso (satisfacción, expectativas y motivaciones), 4) grado de comprensión. Para valorar la comprensión se seleccionó el cuestionario Quality of Informed Consent questionnaire, que fue traducido por tres traductores bilingües. Se incluyeron tres preguntas adicionales para evaluar la comprensión de conceptos relacionados con el equívoco terapéutico y el enmascaramiento de los tratamientos. La validez de contenido fue evaluada mediante consulta con un panel de expertos. En el análisis de legibilidad se obtuvo un valor de Índice de Flesch-Szigriszt de 64,34 equivalente a un grado de dificultad "normal" en la escala Inflesz. En el estudio piloto se entrevistó a 32 pacientes que mostraron no tener dificultades para comprender las preguntas ni problemas a la hora de utilizar las escalas de respuesta. El tiempo medio de cumplimentación del cuestionario fue de 16,6 minutos. CONCLUSIONES: La herramienta desarrollada es útil a la hora de conocer y valorar el proceso de consentimiento informado desde la perspectiva del paciente al que se le invita a participar en un estudio. Su aplicación podría resultar de ayuda a los investigadores para verificar que se ha seguido un adecuado proceso y para identificar aspectos concretos que son susceptibles de ser modificados y optimizados

OBJECTIVE: To develop a Spanish-language questionnaire aimed at evaluating patients' perception of the way they are briefed and their consent is obtained prior to participating in clinical trials. The tool was conceived to evaluate the following aspects: patients' personal experience, the way the informed consent process was implemented in practice, patients' level of satisfaction with the process, and their level of understanding of the study itself. METHOD: This study looked into the development, adaptation and validation of a self-administered questionnaire intended to evaluate the informed consent process on the basis of information provided by respondents. The steps followed included: literature review, generation of an items pool, drawing up of the questionnaire, expert review, piloting, and reading ease optimization and analysis. A commonly-used English-language questionnaire was evaluated, translated into Spanish and adapted so as to determine the extent to which subjects understood the information conveyed to them. RESULTS: In its final version, the questionnaire came to comprise four sections intended to evaluate: 1) socio-demographic data; 2) practical aspects related with the development of the informed consent process; 3) patients' perception of the process (satisfaction, expectations and motivations); and 4) their level of understanding. Understanding was gaged using the QuIC questionnaire, translated by three bilingual translators. Additional questions were included to evaluate the understanding of concepts related with blinding and therapeutic misconception. The validity of the contents was evaluated by consulting with an expert panel. The reading ease analysis yielded an IFSZ score of 64.34, equivalent to an "average difficulty" grade on the Inflesz scale. In the pilot study, interviews were held with 32 patients, who did not appear to have any difficulties in understanding the questions asked of them or in using Likert-type scales to respond. Mean completion time was 16.6 minutes. CONCLUSIONS: The tool developed as part of this study has shown itself capable of providing an understanding and an assessment of the informed consent process from the perspective of a patient who is invited to participate in a clinical trial. Implementation of the questionnaire could help investigators ascertain that the process has been correctly executed and identify specific aspects that may require to be changed or optimized

Humanos , Ensaios Clínicos como Assunto/normas , Consentimento Livre e Esclarecido , Sujeitos da Pesquisa/educação , Educação de Pacientes como Assunto/métodos , Seleção de Pacientes , Satisfação do Paciente , Tomada de Decisões , Projetos Piloto