Hill's Criteria For Causality Research Articles

Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer's Disease.

Oxidative stress, inflammation, and amyloid-β are Alzheimer's disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch's postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients' brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently in preclinical AD and AD patients' hippocampal neurons, and in AD patients' neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents' brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1β, and interferon-β. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons and/or inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients' blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mice's hippocampi triggered antiviral interferon-β secretion; interferon-β injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patient's Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized.

Rosacea, an infectious disease: why rosacea with papulopustules should be considered a demodicosis. A narrative review.

Rosacea and demodicosis are common facial conditions in dermatology practice. While demodicosis is clearly the result of Demodex mite infestation, the pathogenicity of rosacea is still not sufficiently explained, so that it is defined by its symptoms, and not by its cause. It is usually considered as a disease of the immune system associated with neurogenic inflammation triggered by various factors (ultraviolet light, heat, spicy food, alcohol, stress and microorganisms). Its links with demodicosis remain controversial, although there is increasing evidence that Demodex mites may play a key role in the inflammatory process. Indeed, high Demodex densities are observed in nearly all cases of rosacea with papulopustules (PPR) and the papulopustules of rosacea can be effectively treated with topical acaricidal agents. Recent studies suggest that Demodex induces two opposite actions on host immunity: a defensive immune response aimed at eliminating the mite and an immunosuppressive action aimed at favouring its own proliferation. Moreover, the initial defensive immune response is likely diverted towards benefit for the mite, via T-cell exhaustion induced by the immunosuppressive properties of vascular endothelial growth factor, which may also explain the favourable influence that the altered vascular background of rosacea seems to exert on Demodex proliferation. In this review, the evidence for and against a causal role of Demodex in rosacea is discussed, applying three systems traditionally used to attribute causality to a disease (modified Koch criteria, Hill criteria for causality and Rothman model). The findings suggest that PPR can reasonably be attributed to Demodex proliferation, which appears to be a necessary factor in the centre of a causal network in which multiple co-factors interact and influence the occurrence and severity of inflammatory symptoms, from limited (pityriasis folliculorum) to more marked (PPR). PPR could, therefore, be considered as a chronic infection by Demodex mites with associated T-cell exhaustion.

The prevalence of familial form of atrioventricular nodal reentry tachycardia in south-eastern regions of Poland

Abstract Introduction Atrioventricular nodal reentry tachycardia (AVNRT) is one of the most common regular supraventricular arrhythmia referred for catheter ablation (CA). Although, several families with familial form of AVNRT (FAVNRT) in Subcarpathia province (SP, Poland), the comparison or prevalence of FAVNRT and comparison of their incidence in other provinces in Poland were not prospectively validated. Methods Data was derived from prospective multicenter registry of CA (ELEKTRO- ELMedica Network). Between year 2010 to 2018, the clinical data of 1544 patients with invasively documented AVNRT were verify for family history of FAVNRT. From December 2016 to March 2019 each patient with AVNRT were consulted with detailed family history and family residence origin with up to three-generation pedigree. Families with substantiate form of FAVNRT (at least two persons from the family after invasive validation of AVNRT and CA) divided into three groups according to their origin. Results From 1544 recruited patients 932 had origin in south-eastern provinces (SEP) of Poland [n=379, from SP; n=34, from Lubelskie; n=214, from Lesser Poland; and n=305 from Holy Cross]. The rest of the group (n=612) consisted of patients from other, not SEP parts of the country – other part of Poland (RPP). Finally, 45 (2,91%) patients from 24 families had diagnosed FAVNRT. The incidence of FAVNRT was significantly higher in SEP than RPP (4.02% vs 1.17%). Moreover, patients from SP has the highest prevalence of FAVNRT (6.33%) as compared to other provinces of SEP (2.47%). In SP and in bordering SEP provinces as well as the RPP appropriate risk (according to previous region) of FAVNRT was respectively 2.67 (95% CI: 1.36–5.23; P<0.004), 2.14 (95% CI: 0.86–5.34; P<0.10) according to reference RPP were observed. Conclusion Based on Hill's Criteria for Causality observed biological monotonic risk gradient of FAVNRT is proving geographical cause of increased prevalence of FAVNT. The closer they are the higher they is to the most endangered provinces in Poland- SP that also adjoined to Ucraine and Slovakia. Further, international, trans-border cooperation and genetic testing are required to validate genetic impact of FAVNRT in past Galicia region of Central Europe. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Study is funding by the research grant DI2015 021945 from budget resources in 2015 to 2017, as a research project in “Diamentowy Grant” program from “Narodowe Centrum Badan i Rozwoju (PL)”.

Asbestos in Talc and Mesothelioma: Review of the Causality Using Epidemiology

Talcum powder has long been contaminated with asbestos fibers depending on the source of the talc.  Pleural and peritoneal mesothelioma are scientifically established as caused by asbestos exposures.  However, when investigating causality of mesothelioma from asbestos fibers in talcum powder, epidemiology is complicated by various methodological issues and inadequacies in existing studies.  The occupational and case studies are explored in an effort to bring clarity to the issue of talcum powder usage and mesothelioma.   Talc is randomly and sporadically contaminated with asbestos fibers including chrysotile, tremolite and anthophyllite.  Case studies of mesothelioma victims whose only asbestos exposure was to talc, found anthophyllite, tremolite and chrysotile asbestos fibers in their tissues.  Exposure to all three types of asbestos fibers increases the risk of mesothelioma.   The Hill criteria of causality, which considers all aspects of toxicology, biology and epidemiology, are applied to the issue.  This analysis results in compelling evidence that asbestos in talcum powder is causative for mesothelioma.  Thus, precaution would dictate the avoidance of the use of talcum powders. 

The Precautionary Principle Meets the Hill Criteria of Causation

ABSTRACTThis article examines the relationship between the precautionary principle and the well-known Hill criteria of causation. Some have charged that the Hill criteria are anti-precautionary because they are strongly inclined towards false negatives in multi-causal contexts typical of environmental and public health issues. However, we argue that without guidance on how to interpret and weight the criteria, no such claims can be supported. Using a case study of tuberculosis among South African goldmine workers, we consider the implications of different weightings of the Hill criteria and how they might be appropriate depending on the stakes of error.

Is exposure to aluminium adjuvants associated with social impairments in mice? A pilot study

BackgroundOur group has shown that significant correlations exist between rates of Autism Spectrum Disorder (ASD) and total aluminum adjuvants given to children through vaccines in several Western countries. These correlations satisfied eight out of nine Hill criteria for causality. Experimental studies have demonstrated a range of behavioural abnormalities in young mice after postnatal exposure to aluminium. To build on our previous work, the current study will investigate the effect of aluminium adjuvants on social behaviour in mice. Anomalies in social interaction are a key characteristic of those with ASD. MethodsNeonatal CD-1 mice pups were injected with either a total of 550μg of aluminum hydroxide gel (experimental group) or saline (control) spread out during the first two weeks of postnatal life. The mice were then subjected to behavioural tests for social interest and social novelty at postnatal week 8, 17 and 29. p-Values were calculated using the Mann-Whitney and Kruskal Wallis tests. ResultsAluminum injected mice showed diminished social interest compared to controls at week 8 (p=0.016) and 17 (p=0.012). They also demonstrated abnormal social novelty from controls at week 8 (p=0.002) and week 29 (p=0.042). ConclusionThis is the first experimental study, to our knowledge, to demonstrate that aluminum adjuvants can impair social behaviour if applied in the early period of postnatal development. The study, however, is insufficient to make any assertive claims about the link between aluminium adjuvants and ASD in humans.

Environmental Moisture, Molds, and Asthma—Emerging Fungal Risks in the Context of Climate Change

ABSTRACTThe trend toward increasing frequency and intensity of storms has exacerbated mold and other moisture-related health problems, and can be extrapolated to the future. Mold growth therefore exhibits increasing significance in the context of changing climate. The decades-old hypothesis of mold causation and/or exacerbation of asthma previously has been deemed unproven, though not rejected. The present investigation assesses the status of this hypothesis within the industrial, regulatory, scientific, medical, and legal communities. To assure accuracy, statements from these communities are quoted. Recent high-level reviews, such as by the National Academy of Sciences Institute of Medicine and the United Nations World Health Organization, have failed to consider literature that was available, and studies postdating NAS IOM and UN WHO reviews have confirmed and augmented available literature. As a result, all nine of the Hill criteria of causation in epidemiology now are satisfied. I conclude that, with exposure of sufficient intensity and duration, some molds can cause asthma and/or exacerbate preexisting asthma, and that the hypothesis indeed has been accorded broad acceptance in the communities considered.

A critical assessment of the association between postnatal toxoplasmosis and epilepsy in immune-competent patients

While postnatal toxoplasmosis in immune-competent patients is generally considered a self-limiting and mild illness, it has been associated with a variety of more severe clinical manifestations. The causal relation with some manifestations, e.g. myocarditis, has been microbiologically proven, but this is not unequivocally so for other reported associations, such as with epilepsy. We aimed to systematically assess causality between postnatal toxoplasmosis and epilepsy in immune-competent patients. A literature search was performed. The Bradford Hill criteria for causality were used to score selected articles for each component of causality. Using an arbitrary but defined scoring system, the maximal score was 15 points (13 for case reports). Of 704 articles, five case reports or series and five case–control studies were selected. The strongest evidence for a causal relation was provided by two case reports and one case–control study, with a maximal causality score of, respectively, 9/13, 10/13 and 10/15. The remaining studies had a median causality score of 7 (range 5–9). No selection bias was identified, but 6/10 studies contained potential confounders (it was unsure whether the infection was pre- or postnatal acquired, or immunodeficiency was not specifically excluded). Based on the evaluation of the available literature, although scanty and of limited quality, a causal relationship between postnatal toxoplasmosis and epilepsy seems possible. More definite proof requires further research, e.g. by performing Toxoplasma serology in all de novo epilepsy cases.

Chronic Aluminum Intake Causes Alzheimer's Disease: Applying Sir Austin Bradford Hill's Causality Criteria

Industrialized societies produce many convenience foods with aluminum additives that enhance various food properties and use alum (aluminum sulfate or aluminum potassium sulfate) in water treatment to enable delivery of large volumes of drinking water to millions of urban consumers. The present causality analysis evaluates the extent to which the routine, life-long intake, and metabolism of aluminum compounds can account for Alzheimer's disease (AD), using Austin Bradford Hill's nine epidemiological and experimental causality criteria, including strength of the relationship, consistency, specificity, temporality, dose-dependent response, biological rationale, coherence with existing knowledge, experimental evidence, and analogy. Mechanisms that underlie the risk of low concentrations of aluminum relate to (1) aluminum's absorption rates, allowing the impression that aluminum is safe to ingest and as an additive in food and drinking water treatment, (2) aluminum's slow progressive uptake into the brain over a long prodromal phase, and (3) aluminum's similarity to iron, in terms of ionic size, allows aluminum to use iron-evolved mechanisms to enter the highly-active, iron-dependent cells responsible for memory processing. Aluminum particularly accumulates in these iron-dependent cells to toxic levels, dysregulating iron homeostasis and causing microtubule depletion, eventually producing changes that result in disconnection of neuronal afferents and efferents, loss of function and regional atrophy consistent with MRI findings in AD brains. AD is a human form of chronic aluminum neurotoxicity. The causality analysis demonstrates that chronic aluminum intake causes AD.

Breastfeeding and Health: A Review of the Evidence

Some commentators have claimed that breastfeeding benefits are overstated or that breastfeeding is not the cause of the improved health outcomes. In 2007, the Agency for Healthcare Research and Quality (AHRQ) issued a definitive report summarizing the body of evidence on various maternal and infant health outcomes in developed countries. The weight of this and subsequent evidence supports an association between breastfeeding and health outcomes in mothers and infants. While confounding factors exist, this association is likely to be causal for many or most of these conditions based on the Bradford Hill criteria for causation. Policy discussions need to consider the substantial maternal health effects of breastfeeding.

Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes

Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in paediatric vaccines in several Western countries. The correlation between ASD rate and Al adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality. We have now sought to provide an animal model to explore potential behavioural phenotypes and central nervous system (CNS) alterations using s.c. injections of Al hydroxide in early postnatal CD-1 mice of both sexes. Injections of a “high” and “low” Al adjuvant levels were designed to correlate to either the U.S. or Scandinavian paediatric vaccine schedules vs. control saline-injected mice. Both male and female mice in the “high Al” group showed significant weight gains following treatment up to sacrifice at 6months of age. Male mice in the “high Al” group showed significant changes in light–dark box tests and in various measures of behaviour in an open field. Female mice showed significant changes in the light–dark box at both doses, but no significant changes in open field behaviours. These current data implicate Al injected in early postnatal life in some CNS alterations that may be relevant for a better understanding of the aetiology of ASD.

Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria?

A wide range of epidemiologic and laboratory studies combined provide compelling evidence of a protective role of vitamin D on risk of breast cancer. This review evaluates the scientific evidence for such a role in the context of the A.B. Hill criteria for causality, in order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk. After evaluation of this evidence in the context of Hill’s criteria, it was found that the criteria for a causal relationship were largely satisfied. Studies in human populations and the laboratory have consistently demonstrated that vitamin D plays an important role in the prevention of breast cancer. Vitamin D supplementation is an urgently needed, low cost, effective, and safe intervention strategy for breast cancer prevention that should be implemented without delay. In the meantime, randomized controlled trials of high doses of vitamin D3 for prevention of breast cancer should be undertaken to provide the necessary evidence to guide national health policy.

Epidemiologists and causation in an intricate world

Epidemiologists and causation in an intricate world

``Controversies in epidemiology'', teaching causality in context at the University at Albany, School of Public Health

Social inequalities relate not only to disparities in health but also are the social context for theories of disease causality being legitimized or denied. In the discipline of epidemiology, conventional discussions on whether or not a given exposure "causes" a specific disease are framed almost exclusively as debates of validity and whether there is sufficient accumulation of evidence to satisfy "Hill's Causal Criteria". However, the way in which the conceptualization of disease processes is restricted to conform to the current causal paradigm, which is based on socially determined ideas of individualism, reductionism, monocausality and the legitimacy of social inequalities, can be identified as a fundamental assumption underlying conventional epidemiological debates of causality. Any argument that social inequalities are an important determinant of poor public health must also explicitly critique the current causal paradigm, which disallows epidemiologists from conceptualizing social relationships as causal of poor health in populations.

Butadiene epidemiology: a summary of results and outstanding issues

Published epidemiologic studies of butadiene workers, individually and in aggregate, find rates similar to expected for essentially all forms of cancer, with the possible exception of lymphohematopoietic cancers. Reviewers of the literature have disagreed about whether butadiene is a cause of human lymphohematopoietic cancers. This article reviews the available butadiene epidemiologic studies and focuses on the bases for disagreement among reviewers. The disagreement seems to be due to different conventions in applying, explicitly or implicitly, Hill's causal criteria, fostered, in part, by deficiencies in the available epidemiologic studies. Many of these deficiencies will be remedied by updated studies presented at this Symposium or are remediable by other analyses of the existing data.

On the Origin of Hillʼs Causal Criteria

The rules to assess causation formulated by the eighteenth century Scottish philosopher David Hume are compared to Sir Austin Bradford Hill's causal criteria. The strength of the analogy between Hume's rules and Hill's causal criteria suggests that, irrespective of whether Hume's work was known to Hill or Hill's predecessors, Hume's thinking expresses a point of view still widely shared by contemporary epidemiologists. The lack of systematic experimental proof to causal inferences in epidemiology may explain the analogy of Hume's and Hill's, as opposed to Popper's, logic.