RESUMEN
Many substances used in daily life, such as coffee, alcohol, and pharmaceutical treatment for hypertension, have been accused of "menace" in causing cancer or other major diseases. Although some of the accusations have subsequently been refuted or withdrawn, they have usually been based on statistical associations in epidemiologic studies that could not be done with the customary experimental methods of science. With these epidemiologic methods, however, the fundamental scientific standards used to specify hypotheses and groups, get high-quality data, analyze attributable actions, and avoid detection bias may also be omitted. Despite peer-review approval, the current methods need substantial improvement to produce trustworthy scientific evidence.
Asunto(s)
Epidemiología/normas , Humanos , Proyectos de Investigación , Factores de RiesgoRESUMEN
From data obtained in the patient's history, the clinical rate of progression of disease in breast cancer patients can be estimated as slow, intermediate, or rapid. The strata defined by these rates had previously been shown to create prognostic gradients within groups of patients similar in anatomic stage or nodal status. In a second, validating cohort of 465 women with primary breast cancer, the strata delineating rate of disease progression were shown to have a cogent prognostic impact when the proportional hazards model was used to control simultaneously for nodal and anatomic status. In addition, the distinctions persisted when different types of treatment were taken into account. These findings from a multivariate analysis employing the Cox method confirmed the importance of clinical rate of disease progression in estimating prognosis of breast cancer.
Asunto(s)
Neoplasias de la Mama/patología , Adenocarcinoma/patología , Adulto , Anciano , Neoplasias de la Mama/radioterapia , Femenino , Humanos , Mastectomía , Menopausia , Persona de Mediana Edad , Metástasis de la Neoplasia , PronósticoRESUMEN
To compare the effects of stage migration in the "traditional" 3-stage TNM (tumor, node, metastasis) system with those in a new "expanded" 5-stage system, which has two additional stages for the poor prognostic groups, we used both systems to classify a cohort of 178 patients with primary lung cancer. To check for migrations, the stages in both systems were first assigned using only "old" technological information and were then reassigned using all the available "new" as well as old technological data. Although the 5-stage system had more migrations than the 3-stage system, survival rates were relatively unaffected for patients in the two new stages with poor prognosis. In both TNM staging patterns, the effects of stage migration on survival statistics were most impressive in the prognostically better (TNM I and II) stages. A solution to the migration problem is offered by the "clinical severity" (CS) staging system. Like the expanded TNM system, the CS system has 5 stages and a sharp prognostic gradient among stages. The CS system, however, had fewer technology-induced stage migrations than either TNM system, and the migrations had no substantial impact on stage-specific survival results. The excellent prognostic discrimination and secular stability of the CS system make it superior to the TNM system for comparing treatment results from different eras, especially for patients with stage I and II disease.
Asunto(s)
Neoplasias Pulmonares/patología , Estadificación de Neoplasias , Humanos , Neoplasias Pulmonares/terapia , Metástasis de la Neoplasia , Estadificación de Neoplasias/métodos , PronósticoRESUMEN
A system of scientific classification should have a suitable basic axis of organization, standardized names, clearly specified operational criteria, and multiaxial arrangements for citing important attributes beyond those included in the basic axis. During the past century, the main nosologic system for identifying human ailments has been the International Classification of Diseases (ICD), which has a well-organized and well-accepted nomenclature, but which lacks operational criteria and an appropriate multiaxial pattern. Two new systems of classification during the past two decades are intended for other purposes and would not be satisfactory as nosologic substitutes. The Problem-Oriented Record (POR) does not have a standardized nomenclature or criteria; and the Diagnosis-Related Group (DRG) approach was organized mainly for fiscal goals. As the basic taxonomy used for classifying human ailments, the ICD needs substantial improvement to fulfill its scientific role in statistics for the occurrence and treatment of disease.
Asunto(s)
Grupos Diagnósticos Relacionados , Enfermedad/clasificación , Registros Médicos Orientados a Problemas , Registros Médicos , Grupos Diagnósticos Relacionados/historia , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia Antigua , Humanos , Registros Médicos/normas , Registros Médicos Orientados a Problemas/normas , Terminología como AsuntoRESUMEN
Although reserpine has an important role in treating patients with hypertension, its appeal was sharply reduced a decade ago when an alleged relationship to breast cancer was reported in case-control studies. Since the relationship was not confirmed in subsequent research and analyses, the original association is now regarded as erroneous. Since patients with cardiovascular disease were rejected as possible controls in the original reserpine-breast cancer case-control study, we suspected that the false association may have been produced by a phenomenon called exclusion bias. This bias can arise in case-control studies if patients with a particularly high (or low) rate of prior exposure to the alleged etiologic agent are excluded from the selection of either cases or controls, but not from both. To test that suspicion, we recapitulated the original study, in another medical setting. The cases were 257 women with breast cancer; and the controls were 257 hospitalized women matched according to date of admission, age, and race. The overall data showed no association between reserpine and breast cancer (odds ratio [OR] = 1.1), but when we excluded 101 women with cardiovascular disease from the control group, the OR rose to 2.5. The results suggest that exclusion bias played an important role in creating the false association between reserpine and breast cancer.
Asunto(s)
Neoplasias de la Mama/inducido químicamente , Reserpina/efectos adversos , Anciano , Enfermedades Cardiovasculares/tratamiento farmacológico , Métodos Epidemiológicos , Femenino , Humanos , Menopausia , Persona de Mediana Edad , Reserpina/uso terapéutico , Estadística como AsuntoRESUMEN
Epidemiologic studies of causes of disease rarely contain adjustments for inequalities in diseases susceptibility caused by baseline differences in clinical phenomena. In the controversial association between estrogens and endometrial cancer, the menopausal syndrome was suspected as an independent risk factor for the development of endometrial cancer, irrespective of estrogen use. To investigate this suspicion, personal interview data from a case-control investigation were collected and analyzed. The odds ratio for the association between menopausal symptoms and endometrial cancer was 1.12 and 0.85 for two different sets of cases and controls assembled at the same institution. When the data were partitioned according to estrogen usage, the odds ratios became consistently less than one. The results suggest that the menopausal syndrome is not a risk factor for endometrial cancer.
Asunto(s)
Métodos Epidemiológicos , Menopausia , Neoplasias Uterinas/etiología , Anciano , Connecticut , Congéneres del Estradiol/farmacología , Femenino , Humanos , Entrevistas como Asunto , Persona de Mediana Edad , Pronóstico , Proyectos de Investigación , Estudios Retrospectivos , Riesgo , Estadística como Asunto , SíndromeRESUMEN
We assessed the principle of temporal precedence in recent case-control studies demonstrating the alleged associations between tampon use and toxic shock syndrome and between aspirin use and Reye's syndrome. For both relationships, we considered four components of the exposure-disease association, including: (1) establishing that the agent preceded the disease, (2) selecting an index time, (3) defining criteria for classifying a patient as "exposed," and (4) avoiding the bias that occurs when use of the etiologic agent was influenced by an early manifestation of the disease. The problems can be minimized by interviewing patients early during the course of their illness and by improving strategies for data analysis.
Asunto(s)
Métodos Epidemiológicos , Adulto , Aspirina/efectos adversos , Niño , Femenino , Humanos , Proyectos de Investigación , Síndrome de Reye/etiología , Riesgo , Choque Séptico/etiología , Tampones Quirúrgicos/efectos adversos , Factores de TiempoRESUMEN
The 1960s epidemic of asthma deaths that affected young persons in England and Wales, as well as in other countries, was attributed to the effect of newly available pressurized aerosols containing sympathomimetic bronchodilators. The subsequent decision to ban the nonprescription sale of these agents in the United Kingdom represented a unique use of national and international mortality data. The application of such data for decisions about therapeutic agents has implications for the current rise of asthma deaths in New Zealand, for the recent United States regulatory action regarding the nonprescription sale of aerosolized bronchodilators, and for the appraisal of adverse reactions to other pharmaceutical substances. This article is concerned with the quality of the scientific evidence used to implicate bronchodilators in the 1960s epidemic, and also with the strengths and weaknesses of the ecologic studies on which the implication depended. After concluding that the causal link between asthma deaths and bronchodilators was not supported by satisfactory scientific evidence, we present new data and an alternative diagnostic-exchange hypothesis that may, in part, help explain the original association.
Asunto(s)
Asma/mortalidad , Broncodilatadores/efectos adversos , Métodos Epidemiológicos/normas , Adolescente , Adulto , Aerosoles/efectos adversos , Niño , Preescolar , Ecología , Humanos , Estadística como Asunto , Reino UnidoRESUMEN
The correct diagnosis had not been made during life in 26% of 153 patients with lung cancer found in necropsies performed between 1971 and 1982. The likelihood of a correct antemortem diagnosis showed distinctive gradients in relation to the patients' history and amount of cigarette smoking, symptomatic manifestations, and anatomic extensiveness of the cancers. However, cigarette smoking still exerted a diagnostic effect in patients with similar symptoms and similar degrees of anatomic spread. Furthermore, if a lesion was present, chest films were more likely to be radiologically interpreted as a cancer in smokers. The results suggest that smokers receive preferential consideration regarding the diagnosis of lung cancer. This detection bias can have adverse scientific consequences in depriving nonsmokers of suitable therapy, in leading to falsely high estimates of the true magnitude of the smoking/lung cancer association, and in distracting etiologic attention from other agents that may cause lung cancer.
Asunto(s)
Neoplasias Pulmonares/diagnóstico , Fumar , Adulto , Autopsia , Errores Diagnósticos , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Registros Médicos , Probabilidad , RadiografíaRESUMEN
To classify the clinical severity of acute leukemia, we have used the degrees of pretherapeutic infection and hemorrhage to construct a taxonomy containing three "stages". The stages are associated with survival gradients that are clinically and statistically distinctive in both acute lymphoblastic leukemia and acute nonlymphoblastic leukemia. Median survival ranged from 64.0 months for stage 1 to 10.5 months for stage 3 in acute lymphoblastic leukemia, and from 7.1 months for stage 1 to 1.2 months for stage 3 in acute nonlymphoblastic leukemia. The gradients, which persist when other prognostic factors and secular therapeutic changes are taken into account, are more distinctive than those found with other forms of stratification.
Asunto(s)
Leucemia Linfoide/patología , Leucemia/patología , Enfermedad Aguda , Adolescente , Anciano , Niño , Preescolar , Hemorragia/etiología , Humanos , Infecciones/etiología , Leucemia/complicaciones , Leucemia/terapia , Leucemia Linfoide/complicaciones , Leucemia Linfoide/terapia , Pronóstico , Factores de TiempoRESUMEN
Existing systems of staging for patients with rectal cancer depend almost exclusively on anatomic evidence. Consequently, the stages cannot be determined in advance of therapeutic decisions and cannot be used for patients treated without surgery. Furthermore, the stages contain no provision for important prognostic distinctions, that cannot be discerned from anatomic data. After preparing a taxonomy for hiterto unclassified medical data, we developed and tested two new systems of staging in a cohort if 318 patients. The first system which can be applied before treatment, is divided into four composite stages that contain elements of symptomatic, chronometric, co-morbid, and para-morbid data, as well as information obtained from physical examination, sigmoidoscopy, and roentgenography. The second system, applicable to patients with resected tumors, is based on a combination of pre-therapeutic clinical information and post-surgical anatomic evidence. The two systems produce prognostic gradients that are clinically distinctive and statistically efficacious.
Asunto(s)
Neoplasias del Recto/patología , Humanos , Pronóstico , Neoplasias del Recto/diagnósticoRESUMEN
Two new biologically composite systems of staging were used to analyze the patterns of presentation, therapy, and outcome for 318 patients with rectal cancer. Selectional bias was evident in therapeutic decisions. The patients chosen for surgical exploration and possible resection came mainly from prognostically favorable stages and had higher survival rates than the "inoperable" patients wven when the tumor was not resected. In patients with tumors located 8 cm or higher above the anus, survival rates in each composite symptom-anatomic (S-A) stage were essentially similar with radical and simple resections. Radical surgery gave better survival rates than simple surgery for tumors at 5 to 7 cm and was an anatomic necessity to remove tumors at 0 to 4 cm. Regardless of the extensiveness of surgery, the S-A stages were directly related to rates of postoperative infection, postoperative death, subsequent quality of life, and deaths due either to cancer or to noncancer causes.
Asunto(s)
Neoplasias del Recto/cirugía , Humanos , Complicaciones Posoperatorias , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patologíaRESUMEN
BACKGROUND: Although the cure of breast cancer by "early detection" and prompt treatment rests on the belief that all breast cancers grow at the same rate, many cancers have been shown to grow rapidly and others slowly. In particular, mammography screening may often detect the slow-growing, nonaggressive tumors that might not be found until much later, if at all. METHODS: We reviewed the medical records of a natural cohort of 233 patients. The cohort comprised all women who received their first antineoplastic treatment for breast cancer at Yale-New Haven Hospital during the period from January 1 through December 31, 1988, and had a median follow-up thereafter of 82.4 months. RESULTS: The mammography screen-detected group (MSDG) contained 97 (42%) of the 233 breast cancers. The rates of subsequent freedom from cancer deaths or recurrences were 95% (92 patients) in the MSDG and 79% (107 patients) in all other patients (log-rank 2P<.001). This superiority occurred partly because 90 (93%) of the MSDG were in the good prognosis TNM stages 0, I, and IIA, compared with 92 (68%) of the non-MSDG (chi2 2P = .001). Of the 31 patients with stage 0 (carcinoma in situ), all of whom had disease-free survival, 24 (77%) were found by mammography screening. Even within similar TNM stages, however, the MSDG had distinctly better disease-free survival results than the non-MSDG. For patients in TNM stages I and IIA, the "failure events" had respective rates of 2% and 13% (log-rank 2P = .02). CONCLUSIONS: The results suggest that many of the breast cancers found by mammography screening have excellent prognosis not just because of early detection, but also because many of the cancers are relatively benign, requiring minimal therapy.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Mamografía , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Factores de TiempoRESUMEN
Because prognostic adjustment in epidemiologic studies of disease etiology has usually been limited to matchings or stratifications based on demographic characteristics, clinical sources of susceptibility bias have received little attention. This may have led to an incorrect association in two prominent epidemiologic relationships: that between clear-cell vaginal carcinoma and the use of diethylstilbestrol to treat women with bleeding or previous pregnancy loss; and that in the conflicting results of the studies linking sex steroids to the risk of birth defects. The recognition and management of susceptibility bias requires attention to the patients' clinical status at the time of exposure to the alleged causative agent, and also requires collecting and analyzing clinical data excluded or ignored in most epidemiologic studies. To avoid susceptibility bias, data about bleeding, threatened abortion, and other clinical reasons for prescribing therapy are needed for the appropriate matchings or stratifications.
Asunto(s)
Susceptibilidad a Enfermedades/etiología , Métodos Epidemiológicos , Anomalías Inducidas por Medicamentos/etiología , Adenocarcinoma/inducido químicamente , Adulto , Dietilestilbestrol/efectos adversos , Susceptibilidad a Enfermedades/diagnóstico , Estrógenos/efectos adversos , Femenino , Humanos , Recién Nacido , Estudios Longitudinales , Embarazo , Progestinas/efectos adversos , Pronóstico , Distribución Aleatoria , Estudios Retrospectivos , Riesgo , Neoplasias Vaginales/inducido químicamenteRESUMEN
In cancers of the lung, larynx, rectum, and breast, the patients' initial clinical manifestations and comorbid diseases have shown important prognostic distinctions that are not evident in the customary systems of anatomic staging. This study was done to see whether the same phenomena occurred for cancer of the endometrium. In 142 consecutive cases of endometrial carcinoma, strikingly high five-year survival rates were found in women who had no symptoms attributable to the cancer or whose only symptoms might have been caused either by concomitant uterine or cervical disease or by replacement estrogen therapy. A distinct decline in survival was associated with systemic symptoms and with major comorbid ailments. Estimation of prognosis and evaluation of therapy can be improved with a new composite staging system, formed by combining the new clinical categories and the standard morphologic stages of the International Federation of Gynecology and Obstetrics (FIGO) system.
Asunto(s)
Neoplasias Uterinas/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Antineoplásicos/uso terapéutico , Connecticut , Femenino , Humanos , Persona de Mediana Edad , Mortalidad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Ultrasonografía , Neoplasias Uterinas/clasificación , Neoplasias Uterinas/patologíaRESUMEN
BACKGROUND: Constructing diagnostic criteria, a common problem in clinical medicine, is particularly difficult for diseases that lack a pathognomonic "gold standard." To develop an improved strategy for constructing such criteria, we used the eosinophilia-myalgia syndrome as an example. The goal, for research classifications, was to construct validated clinically sensible criteria and to develop improved methods that can be used for other disorders. METHODS: Using a "pattern-based" approach with data from several separate sources, a committee of investigators first prepared and informally tested criteria for the diagnosis of eosinophilia-myalgia syndrome. A gold standard challenge set of reports of cases and noncases was independently generated and separately validated by an external panel of clinical experts. The criteria were then tested using the gold standard set, and interobserver variability and diagnostic accuracy were determined. RESULTS: Interobserver variability showed the following mean proportionate agreements: 98.7% for the presence of specific criteria elements, 99% to 100% for diagnosis, and 97% to 98% for diagnostic pattern. kappa Values were correspondingly high. Diagnostic accuracy showed sensitivity at 88%, specificity at 97%, and overall accuracy at 92%. CONCLUSIONS: The proposed criteria are accurate and reproducible, and can be used in future clinical investigations of the eosinophilia-myalgia syndrome. The new strategy and methods developed for this challenge can be valuable for solving analogous problems in constructing criteria for other clinical disorders.
Asunto(s)
Técnicas y Procedimientos Diagnósticos/normas , Síndrome de Eosinofilia-Mialgia/diagnóstico , Humanos , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
This work was done to determine the reasons for variation in the reported rates--ranging from less than 1% to greater than 50%--of sensitivity to aspirin and cross-reactivity to acetaminophen and ibuprofen. In 47 studies that reported rates of sensitivity and in 23 reports that contained series of sensitive patients, we examined the research setting, source of patients, clinical attributes of the study group, admission process, and selection, operational definition, and method of determining sensitivity reactions. In five studies with reasonably well-specified methods, the reported sensitivity rates to aspirin were lowest (0.3% to 0.9%) for patients without allergic tendencies, higher in asthmatics, and highest if patients had nasal polyps or severe atopy. Although not determined in any of these studies, the rate of sensitivity in a general (nonclinical) population would doubtlessly be substantially lower than the rate of three per 1000 reported for nonallergic patients. The admixture of different clinical groups, varying definitions, and ascertainment of a sensitivity reaction seem to be responsible for the variations in the reported rates of sensitivity and cross-reactivity.
Asunto(s)
Aspirina/efectos adversos , Hipersensibilidad a las Drogas/etiología , Proyectos de Investigación , Acetaminofén/efectos adversos , Humanos , Ibuprofeno/efectos adversosRESUMEN
A recently developed algorithm for the diagnosis of adverse drug reaction (ADR) was used to investigate the quality of evidence in reported cases of ADRs to 1% gamma benzene hexachloride (GBH), a popular scabicide and pediculicide currently under suspicion as a cause of central nervous system (CNS) toxicity, especially in children. Of the 53 reported cases of alleged toxicity, 37 were associated with lindane insecticide (greater than 1% GBH), which is not a pharmaceutical preparation. Of these 37 cases, 34 scored as definite or probable reactions on the algorithm. Of the 26 reports associated with the drug, 1% GBH, none scored as definite and only 6 as probable ADRs. Of these 6 probable cases, 5 represented inappropriate application or unintended ingestion. The use of rigorous operational criteria, such as those developed in this algorithm, permits a scientifically disciplined assessment of whether or not a drug has been fairly indicted, and also provides valuable clinical information about other aspects of suspected drug toxicity.
Asunto(s)
Hexaclorociclohexano/toxicidad , Escabiosis/tratamiento farmacológico , Médula Ósea/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Niño , Hexaclorociclohexano/administración & dosificación , Humanos , Lactante , Matemática , Convulsiones/inducido químicamente , Factores de Tiempo , Estados Unidos , United States Food and Drug AdministrationRESUMEN
OBJECTIVE: Debates about the suspected association between kidney disease and use of analgesics have led to concern about whether caffeine could stimulate an undesirable overuse of phenacetin-free combined analgesics. A committee was asked to critically review the pertinent literature and to suggest guides for clinical practice and for consideration of international regulatory authorities. PARTICIPANTS: A group of international scientists, jointly selected by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry. EVIDENCE: All invited experts evaluated relevant literature and reports and added further information and comments. CONCLUSIONS: Caffeine has a synergistic effectiveness with analgesics. Although caffeine has a dependence potential, the potential is low. Experimental data regarding dependence potential for caffeine alone may not correspond to the conditions in patients with pain. Withdrawal is not likely to cause stimulation or sustainment of analgesic intake. For drug-induced headache, no single or combined analgesic was consistently identified as causative, and no evidence exists for a special role of caffeine. Strong dependence behavior was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics/analgesics and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics. SUMMARY: Although more experimental and long-term data would be desirable to show possible mechanisms of dependence and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.
Asunto(s)
Analgésicos/efectos adversos , Cafeína/efectos adversos , Medicina Basada en la Evidencia , Cefalea/inducido químicamente , Fenacetina/efectos adversos , Síndrome de Abstinencia a Sustancias , Sinergismo Farmacológico , Humanos , Trastornos Relacionados con Sustancias/fisiopatologíaRESUMEN
The prognostic staging of cancer in general, and lung cancer in particular, has customarily depended mainly on morphologic distinctions. The gross anatomic extensiveness of cancers is cited with TNM stages that describe the primary tumor (T), spread to regional lymph nodes (N), and metastatic dissemination (M) to distant sites. Microscopic characteristics are cited according to the cancer's cell type (e.g., adenocarcinoma, epidermoid carcinoma) and/or grade of differentiation (e.g., well differentiated, poorly differentiated, anaplastic). Although the clinical manifestations, functional effects, and associated co-morbidity of a cancer are universally recognized as having major prognostic importance, they have not been classified with a standard system of taxonomy. When considered at all, clinical phenomena have been cited with a surrogate index of "performance status" that ignores the underlying clinical dysfunctions while being greatly affected by non-clinical phenomena, such as the patient's psychic status, economic motivations, and system of social support. The current research was done to develop a standard system of taxonomy (or "staging") for the prognostic impact of clinical distinctions in patients with primary lung cancer. Appropriate data were obtained, computer-coded, and analyzed from medical records for the complete clinical course of an inception cohort of 1266 patients who were first treated at either the Yale-New Haven Hospital or the West Haven Veterans Administration Hospital during the interval January 1, 1953-December 31, 1964. The information under analysis included clinical phenomena as well as anatomic extensiveness (TNM stage), microscopic histology, the chronometric duration of the interval from the first symptom of lung cancer to zero time, the iatrotropic reason why the patient sought medical attention, the presence of anemia, the amount of customary cigarette use, and the conventional demographic data for age and gender. The main clinical phenomena were expressed in variables for symptom pattern severity, and co-morbidity. Symptom pattern referred to the existence of specific pulmonic symptoms (e.g., hemoptysis), systemic symptoms (e.g., complaint of weight loss), and metastatic symptoms that might be mediastinal (e.g., superior vena cava syndrome), regional (e.g., the Horner syndrome), or distantly metastatic (e.g., central nervous system). The symptom severity variable included the amount of weight loss, and the existence of severe dyspnea or particularly severe tumor effects (such as mental obtundation, rather than hemiparesis in patients with CNS metastasis). Prognostic co-morbidity was cited for coexisting diseases, such as recurrent myocardial infarctions, that might be more lethal than the lung cancer itself.(ABSTRACT TRUNCATED AT 400 WORDS)