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The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.
Miners disabled from black lung disease (coal workers' pneumoconiosis, CWP) are entitled to disability benefits under United States federal and state laws. The determination of disability currently involves several scientific controversies. The Federal Department of Labor states that one second forced vital capacity (FEV1) is an important marker of disability from CWP. The Department of Labor also states that disability may occur in simple CWP, in the absence of progressive massive fibrosis (PMF). Both these contentions may reasonably be challenged. To investigate these issues, and to investigate the relation between exercise tolerance and several other variables, including age, weight, radiographic findings, and exposure to mining and smoking, we studied 690 miners. Simple correlation analysis was not helpful because many variables were correlated with each other. Linear regression analysis led to conclusions that were thought to be misleading. Causal modelling provided an analysis that appeared to be most explanatory. In the model tested years of coal mining did not affect FEV1; if this conclusion is substantiated by others FEV1 should be eliminated as an indicator of disability from CWP as it is not related to mining experience. On the other hand, the Department of Labor's position that disability may occur in simple CWP seems reasonable, as years of underground coal mining does affect forced vital capacity (FVC), which in turn impairs exercise capacity, even in the absence of PMF. FVC should be the major spirometric value used in determining disability from CWP because it alone is seen to decrease in relation to mining, and a decrease in FVC does affect exercise capacity. Thus this analysis addresses issues in determining black lung disability and shows the value of casual modelling.
In a worldwide population of 6 billion, in the year 2000, approximately 10 million cancers were diagnosed, and there were an estimated 6.2 million cancer deaths. Whereas the universality of cancer incidence and mortality is established, the burden of cancer by type or organ site is distributed unequally between developing and industrialized nations. Populations in developing countries are disproportionately affected by cancers in which infectious agents are causal. Our review of advances in cancer epidemiology underscores the complexity of pathogenic mechanisms mediated by chronic inflammation, obesity, and gene-environment interactions as in tobacco and alcohol carcinogenesis. Ultimately, the implementation of effective cancer control interventions that will serve to alleviate the cancer burden must integrate basic and applied research in the behavioral, social, biomedical, and population sciences.
In the present investigation we aimed to analyse causally the pattern of determinants leading to the maintenance of functional teeth in adults. Clinical and self-reported information was used. The hypothesis was that socio-economic conditions operate through psychosocial circumstances that influence lifestyle, and are thus related to oral hygiene and levels of remaining teeth. Testing of the patterns for adults residing in high- and low-fluoride areas did not reveal any principal differences in dental health, therefore further testing was combined for both fluoride areas. Further analysis also indicated that testing should be performed separately for each gender. Social structure and dental health-related lifestyle were important in an overall pattern of maintaining functional teeth, but general lifestyle and psychosocial conditions were not found to be part of the pattern influencing dental health. Gender-specific patterns were revealed. New hypotheses may be suggested for further research with regard to studying patterns of dental health in Lithuanian adults.
Two studies investigated the impact of culturally instilled folk theories on the perception of physical events. In Study 1, Americans and Chinese with no formal physics education were found to emphasize different causes in their explanations for eight physical events, with Americans attributing them more to dispositional factors (e.g., weight) and less to contextual factors (e.g., a medium) than did Chinese. In Study 2, Chinese Americans' identity as Asians or as Americans was primed before having them explain the events used in Study 1. Asian-primed participants endorsed dispositional explanations to a lesser degree and contextual explanations to a greater degree than did American-primed participants, although priming effects were observed only for students with little physics education. Together, these studies suggest that culturally instilled folk theories of physics produce cultural differences in the perception of physical causality.
BACKGROUND: Although genome-wide association studies (GWAS) have identified multiple regions conferring genetic risk for juvenile idiopathic arthritis (JIA), we are still faced with the task of identifying the single nucleotide polymorphisms (SNPs) on the disease haplotypes that exert the biological effects that confer risk. Until we identify the risk-driving variants, identifying the genes influenced by these variants, and therefore translating genetic information to improved clinical care, will remain an insurmountable task. We used a function-based approach for identifying causal variant candidates and the target genes on JIA risk haplotypes. METHODS: We used a massively parallel reporter assay (MPRA) in myeloid K562 cells to query the effects of 5,226 SNPs in non-coding regions on JIA risk haplotypes for their ability to alter gene expression when compared to the common allele. The assay relies on 180 bp oligonucleotide reporters ("oligos") in which the allele of interest is flanked by its cognate genomic sequence. Barcodes were added randomly by PCR to each oligo to achieve > 20 barcodes per oligo to provide a quantitative read-out of gene expression for each allele. Assays were performed in both unstimulated K562 cells and cells stimulated overnight with interferon gamma (IFNg). As proof of concept, we then used CRISPRi to demonstrate the feasibility of identifying the genes regulated by enhancers harboring expression-altering SNPs. RESULTS: We identified 553 expression-altering SNPs in unstimulated K562 cells and an additional 490 in cells stimulated with IFNg. We further filtered the SNPs to identify those plausibly situated within functional chromatin, using open chromatin and H3K27ac ChIPseq peaks in unstimulated cells and open chromatin plus H3K4me1 in stimulated cells. These procedures yielded 42 unique SNPs (total = 84) for each set. Using CRISPRi, we demonstrated that enhancers harboring MPRA-screened variants in the TRAF1 and LNPEP/ERAP2 loci regulated multiple genes, suggesting complex influences of disease-driving variants. CONCLUSION: Using MPRA and CRISPRi, JIA risk haplotypes can be queried to identify plausible candidates for disease-driving variants. Once these candidate variants are identified, target genes can be identified using CRISPRi informed by the 3D chromatin structures that encompass the risk haplotypes.
Prospective studies of reproductive outcomes frequently record data at multiple cycles. For example, studies of in vitro fertilization and embryo transfer (IVF-ET) follow women or couples for possibly several IVF cycles and record outcomes such as pregnancy status and embryo implantation. Several time-varying covariates, such as age and diagnostic markers, typically are available as well. When attention is focused on measurement of exposure effects, the use of multiple cycle data poses several complications. If the study is observational, the exposure probability may depend on subject characteristics. Moreover, attrition rates in IVF-ET can be substantial, and the attrition process can be expected to depend heavily on prior outcome. In fact, both success (pregnancy) and failure (lack of embryo implantations) can be prognostic of dropout. In this paper, we illustrate the use of causal modeling for multiple cycle data. Key assumptions are reviewed, and inference based on weighted estimating equations is described in detail. The methods are applied to a study of the effects of hydrosalpinx among women with tubal disease undergoing IVF-ET.
BACKGROUND: It is a widely shared belief that an increase in mental health literacy will result in an improvement of attitudes towards people with mental illness. AIMS: To examine how the German public's causal attributions of schizophrenia and their desire for social distance from people with schizophrenia developed over the 1990s. METHOD: A trend analysis was carried out using data from two representative population surveys conducted in the Lander constituting the former Federal Republic of Germany in 1990 and 2001. RESULTS: Parallel to an increase in the public's tendency to endorse biological causes, an increase in the desire for social distance from people with schizophrenia was found. CONCLUSIONS: The assumption underlying current anti-stigma programmes that there is a positive relationship between endorsing biological causes and the acceptance of people with mental illness appears to be problematic.
Non-Hodgkin's lymphoma (NHL) is a malignant neoplasm of the lymphatic system made up of mainly B cell lymphocytes. A large number of studies have shown significant associations between NHL and benzene or benzene-containing solvents and products. This article summarizes studies detailing these associations and indicates those that are significant. Based on an analysis of the literature and the weight of evidence from numerous studies, it is reasonable to conclude that exposure to benzene or to solvents or products containing benzene is causally related to NHL.
This study addresses lay illness understanding and attributions, including attribution of blame, in wives of myocardial infarction (MI) patients concerning the causes of MI. The present study also investigates the association between illness attributions and emotional adjustment, and the associations of relevant third variables with illness attributions. A sample of 37 wives were interviewed during the acute phase of the illness, three months and 10 years post-index MI. Attributions of the MI to multiple causes were common with an strong emphasis on psychosocial risk factors, but attributional content showed a low consistency over time. In retrospect, the wives believed they could have done more to prevent the MI, but self-blame was not a significant issue. However, they blamed the patient for not taking preventive actions. Attributions were not related to background and illness characteristics or denial in any strong and consistent manner. In a short-term perspective, attributing the MI to stress causes and husbands' personality was associated with worse emotional adjustment. Also, the use of magical explanations and blame of the patient were related to a poorer emotional outcome for the wife. The causal attributions made by the wives during the acute phase did not influence the emotional adjustment after 10 years.
Conte (1983) suggested that existing theories of career development are inadequate for disabled populations because they fail to take into consideration the special life events and characteristics of people with a disability. The purpose of this study was to determine if Conte's reservations about contemporary theories could be supported by data. To this end, two causal models of career development were developed: one with five variables unique to the experience of the hearing impaired and the other without. Using data collected from 71 hearing-impaired adolescents, path analyses were conducted and the two models were compared for their ability to explain variance in career maturity. The results suggest that, although the second model may be more descriptive of the career development process for the deaf, it is no more powerful than the first in explaining variance in career maturity.
The objective of this article is to systematize the principal recent research results pertaining to the so-called hygienic hypothesis, which establishes an etiological link between the increasing incidence of allergic diseases and the decreasing incidence of infectious diseases in the industrialized countries of the Western world. The author contends that the current debate on the hygienic hypothesis indicates significant transformations in the understanding of disease etiology, perhaps even as important as the transformations in the 19th century during the process leading to the constitution of modern medicine and the identification of infectious disease causal agents.
One of the most difficult tasks in the evaluation of a medicine is whether it causes a particular rare and unusual (idiosyncratic) adverse effect. Such causality assessments are sometimes done by drug de-challenge and re-challenge. When the adverse effect is potentially serious, there is clearly an important decision to be made as to whether the re-challenge is justifiable and hence ethical. The recent controversy about the potential cardiotoxicity of fexofenadine, the fatalities associated with penicillin re-challenge and the fatalities associated with abacavir re-challenge highlight some of the potential serious risks of drug re-challenge. The associated important ethical issues are discussed. In particular, there is the need to ensure respect for the patient and to consider the scientific and social value of the re-challenge. A framework for evaluating and assessing the appropriateness of a particular drug re-challenge is proposed in the light of recent as well as long-standing discussions of drug re-challenge, patient informed consent and the ethics of human experimentation, in general. It is suggested that a drug re-challenge should be approached with the same rigour and standards of documentation as are currently required of clinical trials. Given the potential conflicts of interest inherent with any drug study, it is argued that the safeguards, as may be provided by scrutiny by an ethics committee, are necessary for a drug re-challenge. For the investigator contemplating the conduct of a drug re-challenge we would recommend the following: (i) a careful risk-benefit assessment as part of the decision-making process; (ii) careful scientific preparation, including appropriate expert support and emergency back-up facilities, if re-challenge is deemed necessary; (iii) the writing of a detailed protocol for independent approval and for safeguarding all concerned; and (iv) meticulous record keeping.
The methods used for the evaluation of drug safety signals (including major signals leading to withdrawal of products from the market) are inconsistent and sometimes of poor quality. While the assessment of the safety of medicines needs to consider specific issues such as drug interactions and variation in compliance, the general principles, which are used to study environmental hazards, can be applied for this purpose. The criteria proposed by Sir Austin Bradford-Hill more than 35 years ago for attributing disease causation to environmental factors have been used widely in epidemiology, are applicable to pharmacovigilance and pharmacoepidemiology. The Austin Bradford-Hill criteria include strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence and analogy. The paper reviews each of these criteria with emphasis on pharmacovigilance and pharmacoepidemiology and with some examples. The application of the Austin Bradford-Hill criteria to the evaluation of causal association in pharmacovigilance and pharmacoepidemiology is very useful. However, it requires understanding of the limitations of the data, such as, under-reporting, poor quality of information from third parties and misclassification. Further work is required to develop strategies to handle these limitations.
Substance abuse continues to be a major health problem compounded by caregivers' negative attitudes toward these patients. We investigated attributions 55 primary care physicians and 315 senior medical students make toward substance abusers. Half of both groups expressed negative causal attributions, with women slightly less negative than men. Mental models based on LISREL regression coefficients showed that higher negative attributions by both physicians and students were related to their increased authoritarianism and depressed mood. Medical students choosing careers in primary care specialties, including psychiatry, expressed a less negative attributional style toward substance abusers than those students entering nonprimary careers. Health professional educators may find that using attribution theory to redefine successful outcomes in management of substance abuse can result in better attitudes for caregivers.
This study explored dimensions of locus of causality, stability, and controllability, of several sources for success and failure, classified by subjects as a function of their socioeconomic status. The sample included 1,320 Portuguese high school students, from high, middle, and low socioeconomic status who classified 17 causes for success and failure according to their meaning on the three dimensions. Analysis showed students from families of low socioeconomic status perceived causes related to ability, effort, and motivation as more unstable than subjects from families of middle and high socioeconomic status, and students from families of high socioeconomic status perceived causes related to ability as more internal than the other two groups.
This article tested relationships among variables depicted in a causal learning model of academic achievement developed by the authors. The Learning and Study Skills (LASSI), Life Experience Survey (LES), and ASSET test were administered to 134 first-semester nursing students at a 2-year community college. The path analysis supported 11 of the 14 pathways tested. Language ability, reading ability, and self-efficacy were found to be direct effects on academic achievement. When self-efficacy was the criterion, students' language ability, math ability, motivation, and concentration and preparation for class were direct effects. Life stress, motivation, and self-monitoring/use of study strategies were found to be direct effects on students' concentration and preparation for class. In turn, when the ability to self-monitor and use study strategies was the criterion, motivation was the only direct effect. Overall, the model explained 46% of the variance in academic achievement.
Although the antiplatelet agent clopidogrel is associated with an increased incidence of thrombotic thrombocytopenic purpura (TTP), available evidence is not sufficient to establish or disprove a causal relationship. We review and assess the evidence and case reports linking clopidogrel use with TTP and discuss how to approach the risk of TTP in patients taking clopidogrel.