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1.
J Am Med Inform Assoc ; 26(4): 276-285, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840079

RESUMO

OBJECTIVE: The study sought to describe patient-entered supplemental information on symptomatic adverse events (AEs) in cancer clinical research reported via a National Cancer Institute software system and examine the feasibility of mapping these entries to established terminologies. MATERIALS AND METHODS: Patients in 3 multicenter trials electronically completed surveys during cancer treatment. Each survey included a prespecified subset of items from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Upon completion of the survey items, patients could add supplemental symptomatic AE information in a free text box. As patients typed into the box, structured dropdown terms could be selected from the PRO-CTCAE item library or Medical Dictionary for Regulatory Activities (MedDRA), or patients could type unstructured free text for submission. RESULTS: Data were pooled from 1760 participants (48% women; 78% White) who completed 8892 surveys, of which 2387 (26.8%) included supplemental symptomatic AE information. Overall, 1024 (58%) patients entered supplemental information at least once, with an average of 2.3 per patient per study. This encompassed 1474 of 8892 (16.6%) dropdowns and 913 of 8892 (10.3%) unstructured free text entries. One-third of the unstructured free text entries (32%) could be mapped post hoc to a PRO-CTCAE term and 68% to a MedDRA term. DISCUSSION: Participants frequently added supplemental information beyond study-specific survey items. Almost half selected a structured dropdown term, although many opted to submit unstructured free text entries. Most free text entries could be mapped post hoc to PRO-CTCAE or MedDRA terms, suggesting opportunities to enhance the system to perform real-time mapping for AE reporting. CONCLUSIONS: Patient reporting of symptomatic AEs using a text box functionality with mapping to existing terminologies is both feasible and informative.


Assuntos
Antineoplásicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Software , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Idoso de 80 Anos ou mais , Avaliação de Medicamentos , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Autorrelato , Estados Unidos , Interface Usuário-Computador
2.
JMIR Hum Factors ; 5(3): e10070, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30012546

RESUMO

BACKGROUND: The US National Cancer Institute (NCI) developed software to gather symptomatic adverse events directly from patients participating in clinical trials. The software administers surveys to patients using items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) through Web-based or automated telephone interfaces and facilitates the management of survey administration and the resultant data by professionals (clinicians and research associates). OBJECTIVE: The purpose of this study was to iteratively evaluate and improve the usability of the PRO-CTCAE software. METHODS: Heuristic evaluation of the software functionality was followed by semiscripted, think-aloud protocols in two consecutive rounds of usability testing among patients with cancer, clinicians, and research associates at 3 cancer centers. We conducted testing with patients both in clinics and at home (remotely) for both Web-based and telephone interfaces. Furthermore, we refined the software between rounds and retested. RESULTS: Heuristic evaluation identified deviations from the best practices across 10 standardized categories, which informed initial software improvement. Subsequently, we conducted user-based testing among 169 patients and 47 professionals. Software modifications between rounds addressed identified issues, including difficulty using radio buttons, absence of survey progress indicators, and login problems (for patients) as well as scheduling of patient surveys (for professionals). The initial System Usability Scale (SUS) score for the patient Web-based interface was 86 and 82 (P=.22) before and after modifications, respectively, whereas the task completion score was 4.47, which improved to 4.58 (P=.39) after modifications. Following modifications for professional users, the SUS scores improved from 71 to 75 (P=.47), and the mean task performance improved significantly (4.40 vs 4.02; P=.001). CONCLUSIONS: Software modifications, informed by rigorous assessment, rendered a usable system, which is currently used in multiple NCI-sponsored multicenter cancer clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01031641; https://clinicaltrials.gov/ct2/show/NCT01031641 (Archived by WebCite at http://www.webcitation.org/708hTjlTl).

3.
Structure ; 26(1): 20-27.e3, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29249605

RESUMO

Eukaryotic cyclic nucleotide-modulated channels perform their diverse physiological roles by opening and closing their pores to ions in response to cyclic nucleotide binding. We here present a structural model for the cyclic nucleotide-modulated potassium channel homolog from Mesorhizobium loti, MloK1, determined from 2D crystals in the presence of lipids. Even though crystals diffract electrons to only ∼10 Å, using cryoelectron microscopy (cryo-EM) and recently developed computational methods, we have determined a 3D map of full-length MloK1 in the presence of cyclic AMP (cAMP) at ∼4.5 Å isotropic 3D resolution. The structure provides a clear picture of the arrangement of the cyclic nucleotide-binding domains with respect to both the pore and the putative voltage sensor domains when cAMP is bound, and reveals a potential gating mechanism in the context of the lipid-embedded channel.


Assuntos
Proteínas de Bactérias/química , AMP Cíclico/química , Bicamadas Lipídicas/química , Mesorhizobium/química , Canais de Potássio de Abertura Dependente da Tensão da Membrana/química , Potássio/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Clonagem Molecular , Microscopia Crioeletrônica/métodos , AMP Cíclico/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Ativação do Canal Iônico , Canais Iônicos/química , Canais Iônicos/genética , Canais Iônicos/metabolismo , Bicamadas Lipídicas/metabolismo , Mesorhizobium/metabolismo , Modelos Moleculares , Potássio/metabolismo , Canais de Potássio/química , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia Estrutural de Proteína , Termodinâmica
4.
Sci Rep ; 7(1): 8667, 2017 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-28819229

RESUMO

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD), and currently one of the most promising therapeutic targets for drug design in Parkinson's disease. In contrast, LRRK1, the closest homologue to LRRK2, does not play any role in PD. Here, we use cryo-electron microscopy (cryo-EM) and single particle analysis to gain structural insight into the full-length dimeric structures of LRRK2 and LRRK1. Differential scanning fluorimetry-based screening of purification buffers showed that elution of the purified LRRK2 protein in a high pH buffer is beneficial in obtaining high quality cryo-EM images. Next, analysis of the 3D maps generated from the cryo-EM data show 16 and 25 Å resolution structures of full length LRRK2 and LRRK1, respectively, revealing the overall shape of the dimers with two-fold symmetric orientations of the protomers that is closely similar between the two proteins. These results suggest that dimerization mechanisms of both LRRKs are closely related and hence that specificities in functions of each LRRK are likely derived from LRRK2 and LRRK1's other biochemical functions. To our knowledge, this study is the first to provide 3D structural insights in LRRK2 and LRRK1 dimers in parallel.


Assuntos
Microscopia Crioeletrônica , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Multimerização Proteica , Proteínas Serina-Treonina Quinases/química , Soluções Tampão , Detergentes/farmacologia , Humanos , Imageamento Tridimensional , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Dobramento de Proteína/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Soluções
5.
J Natl Cancer Inst ; 106(9)2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25265940

RESUMO

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. These items were refined in a cognitive interviewing study among patients on active cancer treatment with diverse educational, racial, and geographic backgrounds. Favorable measurement properties of the items, including construct validity, reliability, responsiveness, and between-mode equivalence, were determined prospectively in a demographically diverse population of patients receiving treatments for many different tumor types. A software platform was built to administer PRO-CTCAE items to clinical trial participants via the internet or telephone interactive voice response and was refined through usability testing. Work is ongoing to translate the PRO-CTCAE into multiple languages and to determine the optimal approach for integrating the PRO-CTCAE into clinical trial workflow and AE analyses. It is envisioned that the PRO-CTCAE will enhance the precision and patient-centeredness of adverse event reporting in cancer clinical research.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Autorrelato , Terminologia como Assunto , Humanos , National Cancer Institute (U.S.) , Avaliação de Resultados da Assistência ao Paciente , Inquéritos e Questionários , Estados Unidos
6.
Nat Commun ; 5: 3106, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24469021

RESUMO

Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1-S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an 'open' conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels.


Assuntos
Proteínas de Bactérias/química , Mesorhizobium/metabolismo , Canais de Potássio/química , Proteínas de Bactérias/metabolismo , Microscopia Crioeletrônica , Cristalografia por Raios X , AMP Cíclico/metabolismo , Ativação do Canal Iônico , Ligantes , Microscopia de Força Atômica , Modelos Moleculares , Canais de Potássio/metabolismo
7.
Cancer J ; 17(4): 231-4, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21799330

RESUMO

Understanding the potential profile of adverse events associated with cancer treatment is essential in balancing safety versus benefits. Multiple stakeholders make use of this information for decision making, including patients, clinicians, researchers, regulators, and payors. Currently, adverse events are reported by clinical research staff, yet evidence suggests that this may contribute to underreporting of symptom events. Direct patient reporting via electronic interfaces offers a promising mechanism to enhance the efficiency and precision of our current approach and may complement clinician reports of adverse events. The National Cancer Institute has contracted to develop and test an item bank and software system for directly eliciting adverse symptom event information from patients in cancer clinical research, called the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. The validity, usability, and scalability of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events prototype are currently being examined in academic and community-based settings.


Assuntos
Antineoplásicos/efeitos adversos , Redes de Comunicação de Computadores , Monitoramento de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Relatório de Pesquisa , Software , Antineoplásicos/uso terapêutico , Humanos , Resultado do Tratamento
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