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The predominant geometry for a neutron imaging experiment is that of a pinhole camera. This is primarily due to the difficulty in focusing neutrons due to the weak refractive index, which is also strongly chromatic. Proof of concept experiments demonstrated that neutron image forming lenses based on reflective Wolter mirrors can produce quantitative, high spatial resolution neutron images while also increasing the time resolution compared to the conventional pinhole camera geometry. Motivated by these results, we report the design of a neutron microscope where two Wolter mirrors replace condensing and objective lenses, in direct analogy with typical visible light microscopes. Ray tracing results indicate that this system will yield 3 µm spatial resolution images with an acquisition time of order <1 s (104 faster than currently possible at this spatial resolution) with a field of view of about 5 mm in diameter.
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BACKGROUND: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF. METHODS: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (nâ¯=â¯22); CF (nâ¯=â¯63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, nâ¯=â¯22), low length (CF LL, nâ¯=â¯23), and low weight (CF LW, nâ¯=â¯15). RESULTS: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins. CONCLUSIONS: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).
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Fibrose Cística/urina , Metabolômica , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Feminino , Humanos , Lactente , Masculino , Redes e Vias Metabólicas , Estado Nutricional , Estudos ProspectivosRESUMO
The need for a time-resolved monochromatic x-ray imaging diagnostic at photon energies >15 keV has motivated the development of a Wolter optic to study x-ray sources on the Z-machine at Sandia National Laboratories. The work is performed in both the LLNL's x-ray calibration facility and SNL's micro-focus x-ray lab. Characterizations and calibrations include alignment, measurement of throughput within the field of view (FOV), the point-spread function within the FOV both in and out of focus, and bandpass in the FOV. These results are compared with ray tracing models, showing reasonable agreement.
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Recent breakthroughs in the fabrication of small-radii Wolter optics for astrophysics allow high energy density facilities to consider such optics as novel x-ray diagnostics at photon energies of 15-50 keV. Recently, the Lawrence Livermore National Laboratory, Sandia National Laboratories (SNL), the Smithsonian Astrophysical Observatory, and the NASA Marshall Space Flight Center jointly developed and fabricated the first custom Wolter microscope for implementation in SNL's Z machine with optimized sensitivity at 17.5 keV. To achieve spatial resolution of order 100-200 microns over a field of view of 5 × 5 × 5 mm3 with high throughput and narrow energy bandpass, the geometry of the optic and its multilayer required careful design and optimization. While the geometry mainly influences resolution and the field of view of the diagnostic, the mirror coating determines the spectral response and throughput. Here we outline the details of the design and fabrication process for the first multilayer-coated Wolter I optic for SNL's Z machine (Z Wolter), including its W/Si multilayer, and present results of raytrace simulations completed to predict and verify the performance of the optic.
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A new Wolter x-ray imager has been developed for the Z machine to study the emission of warm (>15 keV) x-ray sources. A Wolter optic has been adapted from observational astronomy and medical imaging, which uses curved x-ray mirrors to form a 2D image of a source with 5 × 5 × 5 mm3 field-of-view and measured 60-300-µm resolution on-axis. The mirrors consist of a multilayer that create a narrow bandpass around the Mo Kα lines at 17.5 keV. We provide an overview of the instrument design and measured imaging performance. In addition, we present the first data from the instrument of a Mo wire array z-pinch on the Z machine, demonstrating improvements in spatial resolution and a 350-4100× increase in the signal over previous pinhole imaging techniques.
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A literature review was conducted to determine the best way to provide chemotherapy education to patients. Sixteen articles that employed various teaching methods (e.g., video recordings, in-person class) were identified. Some educational methods have been proven to decrease anxiety, which allows patients to retain more information. Many ways can be used to provide chemotherapy education, and no method has been proven to be significantly more effective than another. Maximum retention is largely based on patient preference.
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Neoplasias/tratamento farmacológico , Educação de Pacientes como Assunto/métodos , Ansiedade , Humanos , Neoplasias/psicologiaRESUMO
BACKGROUND: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. PURPOSE: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. STUDY DESIGN: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L) from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. CONCLUSIONS: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF.
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Fibrose Cística/complicações , Volume Expiratório Forçado/fisiologia , Pneumopatias/etiologia , Testes de Função Respiratória/métodos , Protocolos Clínicos , Fibrose Cística/fisiopatologia , Serviços de Assistência Domiciliar , Humanos , Pulmão/fisiopatologia , Pneumopatias/fisiopatologia , Monitorização Fisiológica/métodos , EspirometriaRESUMO
RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.
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Amicacina/administração & dosagem , Amicacina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Fibrose Cística/fisiopatologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Adolescente , Adulto , Análise de Variância , Criança , Fibrose Cística/complicações , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Nebulizadores e Vaporizadores , Qualidade de Vida , Escarro/microbiologia , Adulto JovemRESUMO
We have developed a pixellated high energy X-ray detector instrument to be used in a variety of imaging applications. The instrument consists of either a Cadmium Zinc Telluride or Cadmium Telluride (Cd(Zn)Te) detector bump-bonded to a large area ASIC and packaged with a high performance data acquisition system. The 80 by 80 pixels each of 250 µm by 250 µm give better than 1 keV FWHM energy resolution at 59.5 keV and 1.5 keV FWHM at 141 keV, at the same time providing a high speed imaging performance. This system uses a relatively simple wire-bonded interconnection scheme but this is being upgraded to allow multiple modules to be used with very small dead space. The readout system and the novel interconnect technology is described and how the system is performing in several target applications.
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BACKGROUND: Cystic fibrosis (CF) specific patient-derived and reported symptom tools are critical steps toward evaluating the outcomes of new therapies for CF. METHODS: We conducted 25 in-depth qualitative interviews using the Day Reconstruction Method and 9 cognitive interviews at two CF programs, the University of Washington and Seattle Children's Hospital and Regional Medical Center. The interviews were audio-recorded and transcribed, and then coded and analyzed for themes relating to pulmonary symptoms and related psychosocial impacts. RESULTS: Six pulmonary symptoms were identified as central to CF: cough, sputum production, wheeze, chest tightness, difficulty breathing/shortness of breath, and fever. Emotional impacts included frustration, sadness/depression, irritability, worry, difficulty sleeping; while activity impacts included time spent sitting or lying down, reduction of usual activities, and missing school or work. In all, 8 symptom items, 4 emotional impacts items, and 4 activity impacts were selected for inclusion on a new daily diary. We also assessed triggers for seeking care. CONCLUSIONS: Using a qualitative inductive methodology, we have obtained patient centered data regarding pulmonary symptoms and burdens and have created a novel patient reported outcome measure for CF. Future studies will assess the validity of the instruments.
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Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Criança , Pré-Escolar , Tosse/etiologia , Tosse/fisiopatologia , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Prontuários Médicos , Pesquisa Qualitativa , Sons Respiratórios/etiologia , Sons Respiratórios/fisiopatologiaRESUMO
BACKGROUND: Stenotrophomonas maltophilia (SM) is a Gram-negative non-fermenting bacteria cultured from the sputum of patients with cystic fibrosis (CF). To date, no information is available regarding the effect of this organism on lung function in CF. METHODS: A cohort study was conducted to assess the effect of SM on lung function among CF patients aged > or =6 years in the CF Foundation National Patient Registry from 1994 to 1999. Repeated measures regression was used to assess the association between SM and lung function. RESULTS: The cohort consisted of 20 755 patients with median age at entry of 13.8 years and median follow up time of 3.8 years; 2739 patients (13%) were positive at least once for SM and 18 016 (87%) were never positive. After adjusting for sex, height and age, patients with SM had a mean forced expiratory volume in 1 second which was 0.09 l less (95% CI 0.05 to 0.14) than those without SM. The mean rate of decline associated with SM positivity was 0.025 l/year (95% CI 0.012 to 0.037) but, after adjusting for confounders (sex, height, weight, intravenous antibiotic courses, hospital admissions, pancreatic insufficiency, and Pseudomonas aeruginosa and Burkholderia cepacia status), the mean rate of decline decreased to 0.008 l/year (-0.008, 95% CI -0.019 to 0.003). CONCLUSIONS: Although CF patients with SM have worse lung function at the time of positivity, no association was found between SM and increased rate of decline after controlling for confounders.
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Fibrose Cística/microbiologia , Infecções por Bactérias Gram-Negativas/complicações , Stenotrophomonas maltophilia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/fisiopatologia , Feminino , Volume Expiratório Forçado/fisiologia , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/fisiopatologia , Humanos , Lactente , MasculinoRESUMO
Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.
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Ensaios Clínicos como Assunto/tendências , Redes de Comunicação de Computadores/organização & administração , Fibrose Cística/terapia , Informática em Saúde Pública/organização & administração , Doenças Raras/terapia , Ensaios Clínicos como Assunto/história , Fibrose Cística/história , História do Século XX , História do Século XXI , Humanos , Internet , Estudos Multicêntricos como Assunto/história , Estudos Multicêntricos como Assunto/métodos , Doenças Raras/história , Projetos de Pesquisa , Estados UnidosRESUMO
OBJECTIVES: To assess the serum and lower respiratory tract tobramycin concentrations (C(T)) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients with cystic fibrosis (CF) 6 months to 6 years of age. STUDY DESIGN: We performed a dose escalation study of serum C(T) measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) C(T) was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. RESULTS: A 180-mg dose of inhaled tobramycin produced a mean peak serum C(T) of 0.5 microg/mL (SD 0.4; range, <0.2 to 1.4 microg/mL). A 300-mg dose produced a mean peak serum C(T) of 0.6 microg/mL (SD 0.5; range, <0.2 to 1.2 microg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 microg/mL). The target ELF C(T) was 20 microg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 microg/mL). Mean ELF C(T) was 90 microg/mL (SD 54; range, 16 to 204 microg/mL) and exceeded the target concentration in 11 patients. CONCLUSION: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract.
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Antibacterianos/administração & dosagem , Antibacterianos/metabolismo , Fibrose Cística/metabolismo , Mucosa Respiratória/metabolismo , Tobramicina/administração & dosagem , Tobramicina/metabolismo , Administração por Inalação , Lavagem Broncoalveolar , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Nebulizadores e VaporizadoresRESUMO
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.
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Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/terapia , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Pneumopatias/terapia , Adulto , Alelos , Células Cultivadas , Fibrose Cística/genética , Citocinas/metabolismo , DNA Complementar/metabolismo , Dependovirus/genética , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Vetores Genéticos , Células HeLa , Humanos , Imuno-Histoquímica , Pulmão/fisiologia , Masculino , Mutação , Nebulizadores e Vaporizadores , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
A thorough understanding of the early natural history of cystic fibrosis (CF) lung disease is critical for the development of effective interventions in the youngest patients. We assessed the evolution of pulmonary infection, inflammation, and clinical course among 40 infants over a 2-year period through annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semiannual infant pulmonary function testing, and quarterly clinical evaluations. Both the prevalence of CF pathogens and their density in BAL fluid increased with age. Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered. Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P. aeruginosa or another pathogen. IL-10 concentrations were similar in CF subjects and non-CF historical controls. Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping). Subjects from whom CF pathogens were isolated at > 10(5) cfu/mL had the worst air trapping and lowest Brasfield chest X-ray scores. Our findings provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy.
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Fibrose Cística/fisiopatologia , Líquido da Lavagem Broncoalveolar , Broncoscopia , Pré-Escolar , Citocinas/análise , Feminino , Humanos , Lactente , Mediadores da Inflamação/análise , Masculino , Estudos Prospectivos , Fator de Necrose Tumoral alfa/análiseRESUMO
OBJECTIVES: Despite the central importance of pulmonary exacerbations (PExs) as an outcome measure in cystic fibrosis clinical trials, no standardized definition of PEx exists. We conducted a prospective, multicenter study to establish a standardized PEx definition and score for use in clinical trials, based on clinical status rather than on treatment decisions. STUDY DESIGN: Subjects were 246 patients enrolled in the placebo arm of a randomized, controlled trial of tobramycin for inhalation. Physician-investigators completed PEx questionnaires on all subjects at scheduled intervals during the 6-month study, indicating new or worsening symptoms, physical examination findings, and impression of PEx status (presence or absence and severity). Logistic regression was used to assess the relative importance of each of the characteristics in predicting a PEx. RESULTS: We developed 2 PEx scores that use easily ascertained symptoms and chest examination findings; one also includes change in forced expiratory volume in 1 second over the preceding month. Both scores were sensitive and specific for predicting the presence of a PEx (sensitivity, 86%; specificity, 86%). The scores were validated in subjects in the intervention arm of the trial. CONCLUSION: We hope that the proposed PEx score might serve as a standardized outcome measure for future clinical trials in cystic fibrosis, allowing meaningful comparisons of study results.
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Antibacterianos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Pneumopatias/fisiopatologia , Tobramicina/uso terapêutico , Administração por Inalação , Adulto , Feminino , Humanos , Masculino , Fluxo Expiratório Máximo , Estudos Multicêntricos como Assunto , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Inquéritos e QuestionáriosRESUMO
Manufacturers of aerosolized medications, approved by the Food and Drug Administration, specify the nebulizer(s) and compressor to be used with their product, in an attempt to achieve efficacy comparable to that obtained in the clinical trials. The need to limit the compressor to that used in the trials has not been investigated in detail. We suggest a technique to determine the equivalency of different compressors such that a chosen nebulizer's performance is not significantly altered. Aerosol particle size (MMD) was measured with a laser; compressor flow and pressure were measured with a mass flow meter and pressure gauge, respectively. For all models of nebulizer, increased flow or driving pressure caused a decrease in aerosol MMD. The flow resistance of nebulizer models varied, and the flow output of compressors decreased as imposed nebulizer resistance increased. However, for any specific compressor-nebulizer combination there is a unique flow and pressure, and the nebulizer generates a given MMD. We demonstrate methods to choose alternate compressors that may be used to drive a nebulizer and yet keep the nebulizer's MMD and performance within predetermined limits. Once an acceptable range of variance in a nebulizer's MMD is defined, alternate compressors may be safely chosen. We recommend that these techniques be used by manufacturers of medications and of compressors to safely determine the acceptability of several rather than a single model compressor to drive a chosen nebulizer. The techniques assure consistency of the nebulizer's clinically demonstrated performance characteristics.
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Aerossóis/administração & dosagem , Força Compressiva , Nebulizadores e Vaporizadores/normas , Resistência das Vias Respiratórias/efeitos dos fármacos , Fenômenos Biomecânicos , Desenho de Equipamento , Segurança de Equipamentos , Humanos , Pulmão/efeitos dos fármacos , Tamanho da Partícula , Sensibilidade e EspecificidadeRESUMO
Cystic fibrosis (CF) is characterized by defective cystic fibrosis transmembrane regulator (CFTR) expression and function, associated with abnormal ion transport and mucociliary clearance, and clinical lung disease. Triphosphate nucleotides such as uridine-5'-triphosphate (UTP) and INS 365, may be useful for CF through actions, mediated via P2Y(2) extracellular receptors, on chloride and liquid secretion, and ciliary beat frequency. INS 365 may offer chemical stability advantages over UTP. In a randomized, double-blind, multicenter phase I study, we studied the safety and maximally tolerated dose of escalating, single doses of aerosolized INS 365, in adult and pediatric patients with mild to moderate CF lung disease (FEV(1) > or = 45% predicted). In four successive dose cohorts of adult patients (n = 12 per cohort, age > or = 18 years) and four successive pediatric dose cohorts (n = 12 per cohort, age 5-12 years), patients were randomized 3:1 active/placebo (0.9% saline) to evaluate doses of 20, 40, 80, and 100 mg INS 365 delivered by nebulizer (Pari Star ). Sputum was collected pre- and post-dosing to obtain preliminary results on clinical efficacy. After each dose cohort, a Data Safety Monitoring Committee (DSMC) reviewed the data. Forty-eight adult and 36 pediatric patients completed the protocol (up to 100 mg for adults, 80 mg for pediatric patients). The predominant adverse events were cough, wheezing, chest tightness, and a decrease in FEV(1) (occurring in 8/48 adults, and 5/36 pediatric patients), which occurred predominantly in the 80-mg and 100-mg dose cohorts. Though a few adult patients had a tendency to increase sputum production, there was little consistent effect noted on sputum production in this acute, single-dose study. The data suggest that aerosolized INS 365 is safe when delivered at single doses of up to 40 mg in adults and children with CF, but that higher doses are unlikely to be tolerated.
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Fibrose Cística/tratamento farmacológico , Soluções Oftálmicas/farmacologia , Polifosfatos , Nucleotídeos de Uracila , Adolescente , Aerossóis , Criança , Tosse/induzido quimicamente , Fibrose Cística/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/efeitos adversos , Sons Respiratórios , EscarroRESUMO
Rachman (Rachman, S. (1993). Obsessions, responsibility, and guilt. Behaviour Research and Therapy, 31, 149-154) suggested that patients with OCD may interpret thoughts as having special importance, thus experiencing thought-action fusion (TAF). Shafran, Thordarson and Rachman (Shafran, R., Thordarson, D. S. & Rachman, S. (1996). Thought-action fusion in obsessive compulsive disorder. Journal of Anxiety Disorders, 710, 379-391) developed a questionnaire (TAF) and found that obsessives scored higher than non-obsessives on the measure. In the current study, we modified the TAF to include a scale that assessed the "likelihood of events happening to others" as well as ratings of the responsibility and cost for having these thoughts. Replicating previous findings, we found that individuals with OC symptoms gave higher ratings to the likelihood of negative events happening as a result of their negative thoughts. Individuals with OC symptoms also rated the likelihood that they would prevent harm by their positive thoughts higher than did individuals without OC symptoms. These results suggest that the role of thought-action fusion in OCs may extend to exaggerated beliefs about thoughts regarding the reduction of harm.