RESUMEN
Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.
Asunto(s)
Biomarcadores de Tumor , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Difusión de la Información/legislación & jurisprudencia , Oncología Médica/legislación & jurisprudencia , Medicina de Precisión/tendencias , United States Department of Veterans Affairs , Ensayos Clínicos como Asunto/estadística & datos numéricos , ADN de Neoplasias/genética , Genómica , Humanos , Oncología Médica/estadística & datos numéricos , Estados UnidosRESUMEN
A tri-federal initiative arising out of the Cancer Moonshot has resulted in the formation of a program to utilize advanced genomic and proteomic expression platforms on high-quality human biospecimens in near-real-time in order to identify potentially actionable therapeutic molecular targets, study the relationship of molecular findings to cancer treatment outcomes, and accelerate novel clinical trials with biomarkers of prognostic and predictive value.
Asunto(s)
Oncología Médica , National Cancer Institute (U.S.) , Proteogenómica , United States Department of Defense , United States Department of Veterans Affairs , Sistemas de Liberación de Medicamentos , Humanos , Estados UnidosRESUMEN
INTRODUCTION: Lack of access to safe drinking water is a major health issue for more than one billion people globally. In areas where community-wide water treatment is not possible, point-of-use (POU) solutions are necessary. The biosand filter (BSF) is one of several such POU technologies available to treat water in the home to reduce the risk of infection. This study was conducted to evaluate the use and performance of BSFs in the rural communities surrounding San Juan del Sur, Nicaragua. Approximately 600 filters had been installed in this area over the preceding 2 years by local workers supported by US and Canadian NGOs. METHODS: This field study was conducted In July and August 2009. Unannounced household visits were carried out by US volunteers supported by a local interpreter and driver. Visits were made to a convenience sample of 199 households where BSFs had been in place for an average of 12 months. Water for analysis was collected from wells, filter spouts and storage buckets and an 11 item questionnaire was administered. Laboratory analyses were performed on water samples using the membrane filtration method to determine Escherichia coli colony forming units (CFUs). RESULTS: Forty-five of 199 households visited had discontinued use of their BSF. In the 154 households tested, median CFU of E. coli per 100 mL of water from the source, filter spout and storage vessel were 313, 72, and 144, respectively. Median bacterial removal efficiency for the filters was 80%. Although biosand filtration reduced CFUs in 74% of households in which it was used, in only 26 cases (17%) did it reduce CFUs to <10 CFUs/100 mL. Recontamination was an important problem and reduced the overall efficacy (from well to storage bucket) to 48%. Participants were generally satisfied with their filter's performance, citing improved health and better tasting water. CONCLUSION: Water quality testing of BSFs deployed in the field showed results somewhat inferior to previous reports. Possible explanations include lack of use of best practices and the inclusion of some filers in the analysis that may not have been in active use. Despite these results and high rates of recontamination in the storage bucket, most households members were pleased with their filters and claimed that their use had enhanced their health. This inconsistency could be due to inaccurate responses to the questionnaire for purposes of secondary gain.
Asunto(s)
Países en Desarrollo , Infecciones por Escherichia coli/prevención & control , Filtración/métodos , Promoción de la Salud/organización & administración , Población Rural/estadística & datos numéricos , Purificación del Agua/métodos , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/microbiología , Femenino , Conductas Relacionadas con la Salud , Vivienda , Humanos , Higiene , Masculino , Nicaragua/epidemiología , Dióxido de Silicio , Encuestas y Cuestionarios , Microbiología del Agua , Abastecimiento de AguaRESUMEN
Anaphylactoid reactions in patients receiving intravenously administered vitamin K have been reported in the literature. To summarize the known data on anaphylactoid reactions from administration of vitamin K, we reviewed all published and unpublished reports of this adverse reaction. Published reports were obtained through medline (1966--1999) and EMBASE (1971--1999) searches of the English language literature and review of references from identified case reports. Unpublished reports were obtained using the Spontaneous Reporting System Adverse Reaction database of the United States Food and Drug Administration (FDA) between August 1968 and September 1997. All adverse drug reactions to vitamin K were categorized by route of drug administration, dose and standard adverse reaction code. In the FDA reports, we defined anaphylactoid reactions as any adverse drug reaction coded as either anaphylaxis, allergic reaction, apnea, dyspnea, death, heart arrest, hypotension, shock or vasodilatation. Additionally, all fatal and life-threatening FDA reported reactions were reviewed to determine if they could represent an anaphylactoid reaction missed by the above definition. The literature review uncovered a total of 23 cases (3 fatal) of anaphylactoid reactions from intravenous vitamin K. The FDA database contained a total of 2236 adverse drug reactions reported in 1019 patients receiving vitamin K by all routes of administration. Of the 192 patients with reactions reported for intravenous vitamin K, 132 patients (69 %) had a reaction defined as anaphylactoid, with 24 fatalities (18 %) attributed to the vitamin K reaction. There were 21 patients with anaphylactoid reactions and 4 fatalities reported with doses of intravenous vitamin K of less than 5 mgs. For the 217 patients with reactions reported due to vitamin K via a non-intravenous route of administration, 38 patients had reactions meeting the definition of anaphylactoid (18 %), with 1 fatality (3 %) attributed to the drug. The absolute risk of an anaphylactoid reaction to intravenous vitamin K cannot be determined by this study, but the relatively small number of documented cases despite widespread use of this drug suggest that the reaction is rare. Anaphylactic reactions and case fatality reports were found even when intravenous vitamin K was given at low doses by slow dilute infusion. The pathogenesis of this reaction is unknown and may be multifactorial with etiologies including vasodilation induced by the solubilizing vehicle or immune-mediated processes. We conclude that use of intravenous vitamin K should be limited to patients with serious hemorrhage due to a coagulopathy that is secondary to a relative or absolute deficiency of vitamin K.
Asunto(s)
Anafilaxia/inducido químicamente , Hipersensibilidad a las Drogas/etiología , Vitamina K/análogos & derivados , Vitamina K/efectos adversos , Sistemas de Registro de Reacción Adversa a Medicamentos , Anafilaxia/mortalidad , Animales , Anticoagulantes/efectos adversos , Anticoagulantes/farmacología , Anticoagulantes/uso terapéutico , Vías de Administración de Medicamentos , Hipersensibilidad a las Drogas/mortalidad , Interacciones Farmacológicas , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Humanos , Estados Unidos , United States Food and Drug Administration , Vasodilatación/efectos de los fármacos , Vitamina K/química , Vitamina K/uso terapéutico , Deficiencia de Vitamina K/tratamiento farmacológicoRESUMEN
The factor V Leiden mutation, a G-->A transition at position 1691 in exon 10 of the gene that codes for factor V, produces an Arg506Gln substitution and is the most common genetic risk factor for venous thrombosis. We have developed a rapid, sensitive, and specific method to detect the factor V Leiden mutation in genomic DNA from whole blood by PCR amplification and microparticle enzyme immunoassay detection using the Abbott LCx instrument. We compared this automated method with the standard procedure using restriction endonuclease digestion of PCR products followed by gel electrophoresis in blinded experiments. In 130 patients (from Veterans Affairs medical centers) with deep venous thromboses, including 24 heterozygotes with the factor V Leiden mutation, there was complete agreement between the two methods. The assay was also able to distinguish heterozygotes from homozygotes. This method, which carries a low potential for cross-contamination of samples, should be a useful routine test for the factor V Leiden mutation in clinical laboratories with sufficient demand for molecular diagnostic assays using the LCx instrument.
Asunto(s)
Factor V/genética , Juego de Reactivos para Diagnóstico , Autoanálisis , Análisis Mutacional de ADN/métodos , Electroforesis en Gel de Poliacrilamida , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Anticoagulation with warfarin has been shown to be effective in preventing ischemic stroke in patients with atrial fibrillation. However, physicians have been reluctant to prescribe this therapy for patients age 60 and older because of the associated risk of bleeding during antithrombotic therapy. Four clinical features independently increase the risk of stroke in individuals with atrial fibrillation: previous stroke or transient ischemic attack, diabetes, history of hypertension, and advancing age. In individual patients, bleeding complications can be reduced by eliminating loading doses, monitoring therapy frequently during the initiation phase, targeting lower INRs, recognizing the potential for drug interactions, and identifying clinical risk factors.
Asunto(s)
Anticoagulantes/uso terapéutico , Aspirina/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Warfarina/uso terapéutico , Factores de Edad , Anciano , Fibrilación Atrial/complicaciones , Embolia/etiología , Embolia/fisiopatología , Corazón/fisiopatología , Humanos , Persona de Mediana Edad , Factores de RiesgoRESUMEN
We performed a metaanalysis of five randomized controlled trials to compare the efficacy and safety of combined oral anticoagulant and antiplatelet therapy versus oral anticoagulants alone after prosthetic heart-valve replacement. The combined regimen reduced embolism and overall mortality by approximately 67% (pooled odds ratio [OR] 0.33; 95% confidence interval [CI] 0.16 to 0.69; p = 0.0032) and 40% (OR 0.60; 95% CI 0.32 to 1.12; p = 0.11), respectively, but increased the risk of hemorrhage by approximately 65% (OR 1.65; 95% CI 1.15 to 2.39; p = 0.0069) and of major gastrointestinal hemorrhage by approximately 250% (OR 3.47; 95% CI 1.43 to 8.40; p = 0.0058). It is estimated that for every 1.6 patients who had their stroke prevented by combination therapy, there was an excess of one major gastrointestinal bleed. This metaanalysis suggests that the benefits derived from the enhanced antithrombotic potential of combined therapy outweigh the toxic effects resulting from the enhanced anticoagulant potential of this regimen.
Asunto(s)
Anticoagulantes/uso terapéutico , Prótesis Valvulares Cardíacas , Inhibidores de Agregación Plaquetaria/uso terapéutico , Cuidados Posoperatorios , Administración Oral , Anticoagulantes/efectos adversos , Intervalos de Confianza , Quimioterapia Combinada , Humanos , Oportunidad Relativa , Inhibidores de Agregación Plaquetaria/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Seguridad , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
The term hemostasis refers to the critical physiologic response to arterial injury that serves to limit hemorrhage. Thrombosis, a pathologic process, results when the coagulation system is excessively activated in the absence of bleeding. The mechanisms that regulate these processes, as well as the mode of action of pharmacologic agents that attenuate thrombosis, are discussed.
Asunto(s)
Hemostasis , Trombosis , Angina Inestable/sangre , Angina Inestable/etiología , Factores de Coagulación Sanguínea , Fibrinólisis , Fibrinolíticos , Humanos , Infarto del Miocardio/sangre , Infarto del Miocardio/etiología , Activación Plaquetaria , Trombosis/sangreRESUMEN
This article addresses the efficacy and safety of antiplatelet and anticoagulant agents following acute myocardial infarction. Major trials are reviewed for both of these treatment modalities in the order in which they were published. Accompanying editorial comments highlight the key findings of the studies and places them in historical context. Current recommendations for treatment are summarized. Antithrombotic therapy used as an adjuvant to thrombolytic therapy is discussed elsewhere.
Asunto(s)
Anticoagulantes/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Anticoagulantes/administración & dosificación , Ensayos Clínicos como Asunto , Humanos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Proyectos de InvestigaciónRESUMEN
The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.
Asunto(s)
Tiempo de Protrombina , Tromboplastina/química , Warfarina/administración & dosificación , Administración Oral , Anciano , Método Doble Ciego , Monitoreo de Drogas/métodos , Femenino , Humanos , Masculino , Estudios Prospectivos , Estándares de Referencia , Warfarina/efectos adversosRESUMEN
We implement a digital fringe-counting technique to measure in real time the relative mirror displacement of a suspended Michelson interferometer with modulated optical path length for oscillations much larger than the laser wavelength (λ). This provides the proper error signal for a servo mechanism that reduces the relative displacement within λ/2. The implemented technique does not require extra optics or polarizers and thus can be used for interferometric gravitational wave detectors as a starting procedure to get the system locked.
RESUMEN
We discuss the application of digital systems to the automatic control of dual-wave optical interferometers. We show that, if the mechanical-modulation technique is used for error-signal extraction, digital techniques can be used both for error-signal extraction and for control-signal generation. Therefore, apart from two front/end amplifiers that are necessary to match the dynamics of the detectors and actuators to the dynamics of the analog-to-digital converters and digital-to-analog converters, no other analog devices are required. In particular, the mechanical-modulation technique requires the synchronous demodulation of the photodiode output signal. Hence we need to implement a digital lock-in amplifier whose algorithm is described here. Finally, we describe one of the possible applications of this digital control procedure, such as the control of a classic Mach-Zehnder interferometer in air.
RESUMEN
The ability of the prothrombin time to measure the anticoagulant effect of warfarin sodium varies depending on the particular tissue thromboplastin used in performing the test. Based on studies using sensitive thromboplastins, lower therapeutic ranges of anticoagulation are recommended. The adequacy of monitoring therapy in this lower range with the relatively insensitive thromboplastins commonly used in North America is unestablished. This 16-month prospective study used a standard North American thromboplastin to monitor 157 anticoagulated patients treated in a low therapeutic range. Of the 1734 prothrombin times generated, 876 (56%) were therapeutic, with 400 (23%) below and 458 (26%) above the therapeutic range. These results are comparable with those published in trials in which more sensitive thromboplastins were used in a similar therapeutic range. We conclude that standard North American thromboplastins are adequately suited to monitor therapy in this lower range.
Asunto(s)
Anticoagulantes/administración & dosificación , Monitoreo Fisiológico , Tromboplastina , Anciano , Anticoagulantes/uso terapéutico , Femenino , Humanos , Cooperación Internacional , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tiempo de Protrombina , Estándares de Referencia , Análisis de Regresión , Sensibilidad y Especificidad , Tromboplastina/químicaRESUMEN
Intracoronary thrombus formation may be involved in the pathogenesis of arterial closure after coronary angioplasty and may contribute to restenosis. It is hypothesized that, unlike markers of platelet activation and fibrin formation, D-dimer, a product of plasmin-mediated proteolysis of cross-linked fibrin, is not subject to significant catheter-induced artifact and could be used to study intracoronary fibrin degradation during angioplasty. No significant difference in D-dimer levels was noted in serial plasma samples obtained from an 8Fr arterial sheath and the wire lumen of an angioplasty balloon catheter, indicating that sampling through the catheter lumen did not induce artifactual D-dimer elevations. Translesion (proximal and distal to the lesion) coronary blood samples were collected in 31 patients undergoing elective coronary angioplasty pretreated with aspirin, dipyridamole and heparin. In 20 of those in whom translesion coronary samples for plasma D-dimer levels (mean +/- standard deviation) were collected before balloon dilation, there was no evidence of ongoing intracoronary fibrinolysis (proximal D-dimer levels, 289 +/- 145 ng/ml; distal, 299 +/- 156 ng/ml; difference not significant). After coronary angioplasty (n = 31), there was a relatively small, but significant (p less than 0.001) increase (45 +/- 71 ng/ml) in translesional D-dimer levels (proximal, 396 +/- 223 ng/ml; distal, 441 +/- 257 ng/ml). The results from this study suggest (1) D-dimer levels are not subject to significant catheter-induced artifact and may be useful for assessment of intracoronary fibrin metabolism, and (2) intracoronary degradation of fibrin can be detected after (but not before) routine coronary angioplasty despite pretreatment with antithrombotic therapy, presumably in response to balloon-induced arterial injury and fibrin formation.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Enfermedad Coronaria/terapia , Trombosis Coronaria/etiología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Anciano , Enfermedad Coronaria/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The authors measured the template bleeding time in 11 normal people before and 2, 4, 12, 24, and 48 hours after the subjects ingested a single dose of 74 mg of aspirin (ASA). The entire experiment was repeated twice at two-week intervals, with the dose of ASA increased to 325 mg and finally 3,900 mg. The mean increase was maximal at 4 and 12 hours, regardless of the dose administered, with a return to baseline by 48 hours. The authors then performed bleeding times in a prospective randomized double-blinded fashion on an additional 39 subjects at baseline and seven hours after they ingested either placebo or ASA 325 mg. The mean baseline bleeding time was 5.2 minutes (SD +/- 1.4), with a mean prolongation after ASA of 2.1 minutes (SD +/- 1.9). The authors identified 5 of 37 (14%) subjects as hyper-responders (HRs) using the criterion of a bleeding time prolongation of greater than 5.9 minutes (greater than 2 SD beyond the mean prolongation). Neither baseline bleeding time, threshold sensitivity of collagen-induced platelet aggregation, nor other tests of hemostatic function discriminated HRs from normals. The authors conclude that in subjects with normal baseline bleeding times, a prolongation of greater than 5.9 minutes when measured seven hours after the administration of a single dose of 325 mg of ASA can discriminate HRs from normals.