RESUMEN
The overall intent of clinical testing is to establish, in a series of phased studies, the clinical tolerance and acceptable "safety" of the candidate vaccine, as well as the type, level and persistence of the immune response after its inoculation, to a representative target population, according to a convenient administration schedule. The final stages involve the direct or indirect demonstration of protective efficacy, if possible in the population(s) for which the vaccine is intended. In addition, consistency of production must be demonstrated. At all these stages, the amount of prior information from preclinical and other studies affects and informs the objectives and design of subsequent studies. Progression from one testing phase to the next is dependent upon attaining the pre-set objectives of each series of studies. The precise objectives to be met will be decided on a case-by-case basis. The earliest assessments in humans (Phase I) involve evaluation of short-term clinical tolerance as measured by local and general reactogenicity, and gross assessments of immunogenicity, in a small number of highly selected individuals in an idealised situation. The selection of "optimal" dose and schedule are the result of further dose-ranging investigations (Phase II), involving more volunteers, with longer, more detailed follow-up assessments. It is at this stage that the accumulated evidence on its immunogenicity profile should be sufficient to assess whether or not the vaccine is worthy of further development. The next level of investigation (Phase III) aims to measure with greater precision the vaccine protective efficacy in the intended target population(s) by comparison of infection and/or disease attack rates in vaccine and placebo recipients. In consistency studies different production lots, manufactured at commercial scale, are tested to demonstrate consistency of manufacture. Additional bridging studies to establish similarity of lots at different production scales, or studies of the duration of the immunity conferred, are conducted in parallel with the progression of the studies in the different phases mentioned above. These latter types of studies are usually carried out concurrently with Phase III studies. This progression continues into the post-marketing period (Phase IV) with surveillance of long term efficacy and observational studies of possible rare adverse events to establish "safety" with more confidence. This paper examines, in general, the aims and designs of studies in each phase as an introduction to the more specific publications that follow.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Vacunas/farmacología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Controlados como Asunto , Tolerancia a Medicamentos , Humanos , Seguridad , Vacunas/efectos adversos , Vacunas/inmunologíaRESUMEN
This review provides a synopsis of the developments over the past decade in mathematical and statistical methodology in response to the AIDS epidemic. This review includes highlights of the development of epidemic models, approaches to describing the natural history of HIV infection, and the methods developed for HIV therapeutic or prevention research. A bibliography, which is extensive but purposely not intended to be comprehensive, is included. The intention is to provide a historical perspective on the methodologic developments and a framework for identifying HIV/AIDS-related needs for the future.
Asunto(s)
Métodos Epidemiológicos , Infecciones por VIH/epidemiología , Modelos Biológicos , Fármacos Anti-VIH/uso terapéutico , Brotes de Enfermedades/estadística & datos numéricos , Progresión de la Enfermedad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Proyectos de InvestigaciónAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Antivirales/uso terapéutico , Ensayos Clínicos como Asunto/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/mortalidad , Antivirales/efectos adversos , Sesgo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Estudios de Seguimiento , Infecciones por VIH/inmunología , Infecciones por VIH/mortalidad , Humanos , Recuento de Leucocitos/efectos de los fármacos , Tasa de Supervivencia , Zidovudina/efectos adversos , Zidovudina/uso terapéuticoRESUMEN
Stroke recurrence has been investigated primarily with respect to prognostic factors predictive of recurrence. Several parametric functions are considered in modeling the distribution of ischemic stroke recurrences recorded within the Stroke Data Bank. A linear hazard function is shown to be the best-fitting function among those considered. This method of parametric modeling may lead to a more informed approach to treatment of ischemic stroke and secondary prevention and may enhance future investigations of prognostic factors as well.
Asunto(s)
Trastornos Cerebrovasculares/mortalidad , Bases de Datos Factuales , Modelos Estadísticos , Infarto Cerebral/mortalidad , Estudios de Seguimiento , Humanos , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Recurrencia , Análisis de Regresión , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Analytic issues in stroke data base research are reviewed, drawing upon relevant experiences in the analyses of three observational data bases from a variety of clinical fields. The specifics of the data base construct, statistical issues and variations in possible interpretations of results are discussed. Responsible analyses of and conservative inferences from observational data bases are stressed.
Asunto(s)
Trastornos Cerebrovasculares/epidemiología , Recolección de Datos , Interpretación Estadística de Datos , Bases de Datos Factuales/estadística & datos numéricos , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Sesgo , Lesiones Encefálicas/epidemiología , Estudios de Cohortes , Humanos , InvestigaciónRESUMEN
The present study was conducted to further our understanding of the relationship between performance on neuropsychological tests and functional status after head injury and to provide information on the relative usefulness of neuropsychological tests as outcome measures in clinical trials of brain injury. We sought to select the fewest number of 19 neuropsychological tests administered to 110 patients that, in combination, were most closely related to outcome (as measured by the Glasgow Outcome Scale (GOS) and to the remaining neuropsychological measures. The relationship of memory and intellectual deficits to functional status was also considered. To address these questions, we analyzed 19 neuropsychological measures and GOS scores of 110 severely brain injured patients from the Traumatic Coma Data Bank. Of 19 neuropsychological measures compared with GOS at 3 and 6 months, four tests (Controlled Oral Word Association, Grooved Pegboard, Trailmaking Part B, and Rey-Osterrieth Complex Figure Delayed Recall) provided the closest relationship to GOS and to the remaining 15 tests. Similar analyses were performed on 30 moderately injured patients to test the generality of our findings across different levels of patient severity. The same four tests were found to be highly predictive of GOS. Grooved Pegboard, a test of fine motor coordination, accounted for 80% of the variation in GOS. Fifteen percent of 116 patients with severe brain injury could not complete a neuropsychological battery and 39% were excluded because of previous brain injury or known substance abuse.
Asunto(s)
Lesiones Encefálicas/clasificación , Escala de Coma de Glasgow , Pruebas Neuropsicológicas , Desempeño Psicomotor , Resultado del Tratamiento , Adolescente , Adulto , Anciano , Lesiones Encefálicas/psicología , Lesiones Encefálicas/terapia , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Estudios de Cohortes , Bases de Datos Factuales , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Análisis Multivariante , PronósticoRESUMEN
For the 183 of 1276 patients in the NINDS Stroke Data Bank with convexity infarction in the middle cerebral artery territory, the size of the infarct did not differ between the two sides but the location of the main site of the infarct differed: on the left side, it was centred in the inferior parietal region, and was mid-frontal on the right. There was a good correlation between infarct size and weakness severity whether estimated by overall motor function on one side, arm, or hand alone. There was a poor correlation, however, for lesion location (lower third, middle third or upper third on either side of the Rolandic fissure) and any of the specific syndromes of focal weakness, no two cases sharing the same lesion for the same syndrome and several cases sharing the same lesion with a different syndrome. The findings indicated a difference in weakness syndromes between the two hemispheres and great individual variation of the acute syndrome caused by a given site of focal infarction along the Rolandic convexity. These variations may explain some of the difficulties showing effects of a given therapeutic agent in studies of acute ischaemic stroke. Large sample sizes will be required for the reliable assessment of any treatment using currently popular clinical stroke scales.
Asunto(s)
Corteza Cerebral/fisiopatología , Infarto Cerebral/fisiopatología , Dominancia Cerebral/fisiología , Hemiplejía/fisiopatología , Mapeo Encefálico , Infarto Cerebral/clasificación , Infarto Cerebral/diagnóstico , Estudios de Cohortes , Bases de Datos Factuales , Estudios de Seguimiento , Hemiplejía/clasificación , Hemiplejía/diagnóstico , Humanos , Examen Neurológico , Tomografía Computarizada por Rayos XRESUMEN
We compared clinical and radiologic features between 246 cardiac embolism (EMB) and 66 arterial embolic (tandem arterial pathology [TAP]) patients selected from the 1,273 patients with cerebral infarction in the Stroke Data Bank. Diagnostic definitions accounted for the increased frequency of cardiac disease among patients with EMB compared with TAP (78.4% versus 29.3%), while transient ischemic attacks (32.3% versus 13.1%) and carotid artery bruit (15.1% versus 3.3%) were more prevalent in TAP than in EMB. Multiple logistic regression differentiated TAP and EMB further. The probability of a TAP diagnosis was increased by the CT finding of a superficial infarct alone (odds ratio [OR] = 4.6; 95% CI = 1.5 to 13.7) or by a higher admission hematocrit. The probability of EMB was greater in patients with an initial decreased consciousness (OR = 39.2; 95% CI = 4.0 to 381.3) or with an abnormal first CT (OR = 3.2; 95% CI = 1.2 to 8.6). These findings indicate that the two infarct subtypes differ in the location and extent of the cortical infarction, which argues for a smaller particle size, with smaller and more distal infarction in embolism from an arterial source compared with cardiogenic embolism.
Asunto(s)
Estenosis Carotídea/complicaciones , Enfermedades Arteriales Cerebrales/complicaciones , Infarto Cerebral/etiología , Embolia/complicaciones , Cardiopatías/complicaciones , Anciano , Estenosis Carotídea/diagnóstico , Angiografía Cerebral , Enfermedades Arteriales Cerebrales/diagnóstico , Infarto Cerebral/diagnóstico por imagen , Diagnóstico Diferencial , Ecocardiografía , Electrocardiografía Ambulatoria , Embolia/diagnóstico , Femenino , Cardiopatías/diagnóstico , Humanos , Modelos Logísticos , Masculino , Examen Neurológico , Oportunidad Relativa , Estudios Prospectivos , Análisis de Regresión , Tomografía Computarizada por Rayos XRESUMEN
Outcome as a function of employment status or return to school was evaluated in severely head-injured patients. A priori we selected the most salient demographic, physiological, neuropsychological and psychosocial outcome predictors with the aim of identifying which of there variables captured at baseline or 6 months would best predict employability at 6 or 12 months. Based on the patients evaluated at 6 months, 18% of former workers had returned to gainful employment and 62% of former students had returned to school. For those not back to work or school at 6 months, 31% of the former workers and 66% of the former students had returned by 12 months. Age, length of coma, speed for both attending and motor movements, spatial integration, and intact vocabulary were all significantly related to returning to work or school. The three most potent predictors for returning to work or school were intactness of the patient's verbal intellectual power, speed of information processing and age.
Asunto(s)
Daño Encefálico Crónico/rehabilitación , Lesiones Encefálicas/rehabilitación , Actividades Cotidianas/psicología , Adolescente , Adulto , Anciano , Daño Encefálico Crónico/psicología , Lesiones Encefálicas/psicología , Niño , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Escala de Coma de Glasgow , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Pruebas Neuropsicológicas , Rehabilitación Vocacional/psicología , Resultado del TratamientoRESUMEN
As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.
Asunto(s)
Lesiones Encefálicas/clasificación , Traumatismos Craneocerebrales/clasificación , Hipotensión/diagnóstico , Hipoxia/diagnóstico , Escala Resumida de Traumatismos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Lesiones Encefálicas/etiología , Niño , Preescolar , Traumatismos Craneocerebrales/complicaciones , Bases de Datos Factuales , Femenino , Escala de Coma de Glasgow , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/complicaciones , Evaluación de Resultado en la Atención de Salud , Valor Predictivo de las PruebasRESUMEN
The influence of site of hemorrhage on presentation, clinical profile, hospital course, and outcome was examined in 225 patients with intracerebral hemorrhage in the NINDS Stroke Data Bank. Mode of presentation differed by hemorrhage site (coma at onset was most typical of pontine hemorrhage and headache with vomiting was most typical of cerebellar hemorrhage, whereas onset of focal deficit sometimes with headache was typical of lobar and and basal ganglionic hemorrhages). Distinct clinical profiles were found for cerebellar (ataxia, drowsiness, and horizontal gaze paresis), pontine (quadriparesis, coma, vertical and horizontal gaze paresis), and caudate hemorrhages (drowsiness and hemiparesis). Putaminal, thalamic, and lobar hemorrhages presented similarly with hemiparesis, sensory loss, and higher cortical function deficits. However, thalamic hemorrhages had more sensory loss, putaminal hemorrhages had more weakness, and lobar hemorrhages had more higher cortical function deficits. Hemorrhage volume was greatest for the lobar and putaminal hemorrhages and smallest for the pontine and cerebellar hemorrhages. Clot evacuations were performed for 28.9% of the lobar hemorrhages and 48.2% of the cerebellar hemorrhages. Few basal ganglionic hemorrhages or pontine hemorrhages had clot evacuations. Thirty-day survival was lowest for caudate hemorrhage (46.2%) and highest for cerebellar hemorrhage (81.5%). Hydrocephalus, intraventricular blood, larger size, and mass effect were adverse predictors of survival at most but not all hemorrhage sites. History of hypertension was the most prevalent risk factor for hemorrhage (64.0% of the patients). Other risk factors for hemorrhage included anticoagulants, platelet antiaggregating drugs, aneurysms, arteriovenous malformations, pregnancy, alcohol use, amyloid angiopathy, thrombocytopenia, renal and liver failure, and cocaine use. The most common medical complications were pneumonia (15.5%), urinary tract infection (15.0%), arrhythmias (8.4%), and seizures (8.0%).
RESUMEN
In order to define the role of intracranial and extracranial complications in determining outcome from severe head injury, 734 patients from the Traumatic Coma Data Bank were analyzed. Nine classes of intracranial and 13 classes of extracranial complications occurring within the first 14 days after admission were analyzed, while controlling for age, admission Glasgow Coma Scale motor score, early hypoxia or hypotension, and severe extracranial trauma. Outcome for survivors was based on the last recorded Glasgow Outcome Scale score, obtained a median of 521 days after injury. Intracranial complications did not significantly alter outcome for the study group. Of the extracranial complications, pulmonary, cardiovascular, coagulation, and electrolyte disorders occurred most frequently at 2 to 4 days. Infections developed later, peaking at 5 to 11 days. Gastrointestinal, renal, and hepatic complications followed no specific time course. Electrolyte abnormalities were the most frequent occurrence (59% of patients) but did not alter outcome. Pulmonary infections (41%), shock (29%, systemic blood pressure < or = 90 mm Hg for 30 minutes or more), coagulopathy (19%), and septicemia (10%) were significant independent predictors of an unfavorable outcome. Backward-elimination, stepwise logistic regression modeling indicated that the estimated reduction of unfavorable outcome was 2.9% for the elimination of pneumonia, 3.1% for coagulation disturbances, 1.5% for septicemia, and 9.3% for shock. These data suggest that extracranial complications are highly influential in determining the outcome from severe head injury and that significant improvements in outcome in a sizeable proportion of patients could be accomplished by improving the ability to prevent or reverse pneumonia, hypotension, coagulopathy, and sepsis.
Asunto(s)
Traumatismos Craneocerebrales/complicaciones , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Trastornos de la Coagulación Sanguínea/epidemiología , Trastornos de la Coagulación Sanguínea/etiología , Niño , Preescolar , Traumatismos Craneocerebrales/diagnóstico , Femenino , Escala de Coma de Glasgow , Humanos , Hipotensión/epidemiología , Hipotensión/etiología , Incidencia , Lactante , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Neumonía/epidemiología , Neumonía/etiología , Estudios Prospectivos , Análisis de Regresión , Sensibilidad y Especificidad , Sepsis/epidemiología , Sepsis/etiología , Choque/epidemiología , Choque/etiología , Resultado del TratamientoRESUMEN
Predictors of outcome were examined in this prospective study of 151 patients severely injured by civilian gunshot wounds. Of the 151 patients, 133 (88%) died. Of the 123 patients with an initial Glasgow Coma Scale score of 3-5, 116 (94%) died, whereas of the 20 with an initial Glasgow Coma Scale score of 6-8, 14 (70%) died. There were no good outcomes, and only three moderate recoveries in patients who had initial scores of 8 or less. In those patients who survived long enough for intracranial pressure monitoring, intracranial hypertension predicted a very poor outcome. Computed tomographic scan characteristics such as midline shift, compression or obliteration of the mesencephalic cisterns, the presence of subarachnoid blood, intraventricular hemorrhage, and the presence of hyperdense or mixed-density lesions greater than 15 mL, either bilateral or unilateral, were all associated with a poor outcome. However, neither the caliber of gun nor the distance of the gun from the head significantly affected the risk of dying.
Asunto(s)
Traumatismos Craneocerebrales/mortalidad , Bases de Datos Factuales , Escala de Coma de Glasgow , Heridas por Arma de Fuego/mortalidad , Adolescente , Adulto , Traumatismos Craneocerebrales/fisiopatología , Femenino , Humanos , Presión Intracraneal , Masculino , National Institutes of Health (U.S.) , Valor Predictivo de las Pruebas , Estudios Prospectivos , Análisis de Regresión , Tomografía Computarizada por Rayos X , Estados Unidos/epidemiología , Heridas por Arma de Fuego/fisiopatologíaRESUMEN
BACKGROUND AND PURPOSE: Our purpose was to describe and further understand the determinants of the time of onset of parenchymatous intracerebral hemorrhage and subarachnoid hemorrhage in patients enrolled in the Stroke Data Bank. METHODS: We analyzed the observed times of onset of intracerebral hemorrhage (n = 237 patients) and subarachnoid hemorrhage (n = 243 patients) compared with expected times of onset if the probability of onset was constant across all time intervals. We also analyzed the role of clinical features (if any) in explaining the findings. RESULTS: For intracerebral hemorrhage, 52.5% of patients reported onset times between 0600 hours and 1400 hours, with peak onset between 1000 and 1200 hours (chi 2 = 62.94, df = 11, p less than 0.001). Patients with subarachnoid hemorrhage were more likely to lack a history of hypertension compared with patients who had intracerebral hemorrhage (chi 2 = 23.3, df = 1, p less than 0.001). Patients with subarachnoid hemorrhage were more likely to have more uniform onset time throughout the day (chi 2 = 12.92, df = 7, p = 0.074). However, subarachnoid hemorrhage patients with a history of hypertension were more likely to have peak onset times in mid-to-late morning compared with patients without such a history (chi 2 = 35.25, df = 10, p less than 0.001). The nonuniformity of onset times for intracerebral hemorrhage persisted even if patients with unknown onset times were treated as through their onset times were randomly distributed between 0000 and 0800 hours. Seasonal periodicity and the relation between initial systolic or diastolic blood pressure and time of onset for either type of hemorrhage were not observed. CONCLUSIONS: Our data suggest that the time of onset for both intracerebral hemorrhage and subarachnoid hemorrhage patients with a history of hypertension is similar to the diurnal variation in blood pressure.
Asunto(s)
Presión Sanguínea , Hemorragia Cerebral/etiología , Ritmo Circadiano , Hipertensión/complicaciones , Hemorragia Subaracnoidea/etiología , Adolescente , Adulto , Anciano , Hemorragia Cerebral/epidemiología , Femenino , Humanos , Masculino , Maryland , Persona de Mediana Edad , Sistema de Registros , Hemorragia Subaracnoidea/epidemiologíaRESUMEN
The outcome at discharge, 6 months, and 1 year after they had sustained severe head injuries was investigated in children (0-15 yr old at injury) who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank. Of 103 eligible children, the quality of recovery was assessed by the Glasgow Outcome Scale (GOS) at 6 months after injury in 92 patients (86% of series) and at 1 year in 82 patients (73% of series). The lowest post-resuscitation Glasgow Coma Scale score and pupillary reactivity were predictive of the 6-month GOS as were their interaction. Analysis of the first computed tomographic scan disclosed that bilateral swelling with/without midline shift was related to a poor outcome as was the presence of mass lesions. Comparison of age-defined subgroups of patients revealed that outcome was poorest in the 0- to 4-year-old patients, as reflected by their mortality, which increased to 62% by 1 year. Distinctive features of the injuries in the 0- to 4-year-olds included evacuated subdural hematomas (20% of patients) and hypotension (32% of patients). The most favorable outcome was attained by 5- to 10-year-olds (2/3 had a good recovery by 1 yr), whereas the GOS distribution of adolescents was intermediate between the children and adults. In summary, the GOS data reflect heterogeneity in the quality of outcome after severe head injury depending on age, neurological indices, and computed tomographic scan diagnostic category.
Asunto(s)
Coma/etiología , Traumatismos Craneocerebrales/complicaciones , Bases de Datos Factuales , Adolescente , Factores de Edad , Niño , Preescolar , Traumatismos Craneocerebrales/diagnóstico por imagen , Traumatismos Craneocerebrales/fisiopatología , Escala de Coma de Glasgow , Humanos , Lactante , Recién Nacido , Presión Intracraneal , Sistema Nervioso/fisiopatología , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
Thalamic strokes in 62 patients selected from the Stroke Data Bank were studied to determine differences among 18 infarctions (INF), 23 localized hemorrhages (ICH), and 21 hematomas with ventricular extension (IVH). Stupor or coma at onset occurred more frequently in the IVH (62%) than in the INF (6%) or ICH (13%) groups and was reflected in significantly lower median Glasgow Coma Scores in the IVH group (7) than in the INF (15) and ICH (14) groups. Although ocular movements were more frequently abnormal in the IVH group compared with the ICH and INF groups, no significant differences were found in the frequency of motor or sensory deficits. Among the 62 strokes, 32 had restricted lesions of the posterolateral (n = 9), anterior (n = 3), paramedian (n = 7), and dorsal (n = 13) portions of the thalamus. Differences in consciousness and in motor, sensory, and oculomotor deficits were found among the topographic subgroups. Stroke-related deaths occurred in 52% of IVH cases, 13% of ICH cases, and no cases of INF. Median lesion volume as detected with computed tomography was greater in hemorrhages (INF, 2 cm3; ICH, 10 cm3; IVH, 16 cm3), with mortality related to increasing hematoma size. Coma, Glasgow Coma Score lower than 9, weakness score greater than 15 of a possible 30, abnormal ocular movements, and fixed pupils were also associated with stroke-related mortality. We conclude that the initial neurologic syndrome does not discriminate infarcts from intrathalamic hemorrhages. Ventricular extension, however, causes significantly more severe deficits and higher mortality.