RESUMO
BACKGROUND: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs. OBJECTIVE: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD). DESIGN: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members. SETTING: The in-person meeting was held in Baltimore, MD. PARTICIPANTS: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers. INTERVENTION: N/A. MEASUREMENTS: N/A. RESULTS: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence." CONCLUSIONS: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.
Assuntos
Doença de Alzheimer/prevenção & controle , Ensaios Clínicos como Assunto/normas , Desenvolvimento de Medicamentos/normas , Intervenção Médica Precoce/normas , Projetos de Pesquisa/normas , Humanos , Participação do Paciente , Participação dos InteressadosRESUMO
The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.
Assuntos
Aminoácidos/uso terapêutico , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Polimorfismo de Nucleotídeo Único , Receptores de Glutamato Metabotrópico/agonistas , Esquizofrenia/tratamento farmacológico , Adulto , Feminino , Haplótipos , Humanos , Íntrons , Masculino , Neuregulina-1/genética , Olanzapina , Farmacogenética , Fenótipo , Receptor 5-HT2A de Serotonina/genética , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Federação Russa , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Resultado do Tratamento , Estados UnidosRESUMO
A F2 population derived from a cross between European Large White and Chinese Meishan pigs was established in order to study the genetic basis of breed differences for growth and fat traits. Chromosome 4 was chosen for initial study as previous work had revealed quantitative trait loci (QTLs) on this chromosome affected growth and fat traits in a Wild Boar x Large White cross. Individuals in the F2 population were typed for nine markers spanning a region of approximately 124 CM. We found evidence for QTLs affecting growth between weaning and the end of test (additive effect: 43.4 g/day) and fat depth measured in the mid-back position (additive effect: 1.82 mm). There was no evidence of interactions between the QTLs and sex, grandparents or F1 sires, suggesting that the detected QTLs were fixed for alternative alleles in the Meishan and Large White breeds. Comparison of locations suggests that these QTLs could be the same as those found in the Wild Boar x Large White cross.
Assuntos
Cromossomos , Característica Quantitativa Herdável , Suínos/genética , Animais , Mapeamento Cromossômico/veterinária , Feminino , Genótipo , Masculino , FenótipoRESUMO
Four parkinsonian patients who had shown evidence of an impairment of predictive manual control and 4 age-matched normal subjects were tested for the predictive control of eye movements. Subjects tracked a target with their eyes as it moved in either irregular "noise" or regular (predictable) linear ramp or sine waveforms. Eye movements were monitored by electrooculography, and the overall tracking time lag for each condition was determined by cross-correlation. Both normal and parkinsonian subjects showed prediction in eye tracking on the regular waveforms (zero time lag or anticipation of the target track), indicating that (1) the parkinsonian loss of predictive control in manual tasks is not due to defective control of eye movements, and (2) there may be separate predictor mechanisms in the brain for eyes and hands.
Assuntos
Movimentos Oculares , Doença de Parkinson/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
1. The focal length and positions of the principal planes of an isolated Daphnia lens were determined, and the refractive index of the rhabdom was measured. 2. The lens can form an image, but this always lies well behind the rhabdom. This was confirmed by direct observation of images inside a clear-eye mutant Daphnia eye. 3. The rhabdom was shown to be unlikely to function as a waveguide, and a ray optics model is proposed to enable the prediction of ommatidial receptive fields from the lens data. 4. The predicted receptive fields have wide plateaus and steep sides, and there are virtually no totally blind gaps between neighbouring ommatidia.