The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

Age disparities in stage‐specific colon cancer survival across seven countries: an International Cancer Benchmarking Partnership SURVMARK‐2 population‐based study

We sought to understand the role of stage at diagnosis in observed age disparities in colon cancer survival among people aged 50 to 99 years using population‐based cancer registry data from seven high‐income countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom. We used colon cancer incidence data for the period 2010 to 2014. We estimated the 3‐year net survival, as well as the 3‐year net survival conditional on surviving at least 6 months and 1 year after diagnosis, by country and stage at diagnosis (categorised as localised, regional or distant) using flexible parametric excess hazard regression models. In all countries, increasing age was associated with lower net survival. For example, 3‐year net survival (95% confidence interval) was 81% (80‐82) for 50 to 64 year olds and 58% (56‐60) for 85 to 99 year olds in Australia, and 74% (73‐74) and 39% (39‐40) in the United Kingdom, respectively. Those with distant stage colon cancer had the largest difference in colon cancer survival between the youngest and the oldest patients. Excess mortality for the oldest patients with localised or regional cancers was observed during the first 6 months after diagnosis. Older patients diagnosed with localised (and in some countries regional) stage colon cancer who survived 6 months after diagnosis experienced the same survival as their younger counterparts. Further studies examining other prognostic clinical factors such as comorbidities and treatment, and socioeconomic factors are warranted to gain further understanding of the age disparities in colon cancer survival

Faulting Processes Unveiled by Magnetic Properties of Fault Rocks

As iron-bearing minerals—ferrimagnetic minerals in particular—are sensitive to stress, temperature, and presence of fluids in fault zones, their magnetic properties provide valuable insights into physical and chemical processes affecting fault rocks. Here, we review the advances made in magnetic studies of fault rocks in the past three decades. We provide a synthesis of the mechanisms that account for the magnetic changes in fault rocks and insights gained from magnetic research. We also integrate nonmagnetic approaches in the evaluation of the magnetic properties of fault rocks. Magnetic analysis unveils microscopic processes operating in the fault zones such as frictional heating, energy dissipation, and fluid percolation that are otherwise difficult to constrain. This makes magnetic properties suited as a “strain indicator,” a “geothermometer,” and a “fluid tracer” in fault zones. However, a full understanding of faulting-induced magnetic changes has not been accomplished yet. Future research should focus on detailed magnetic property analysis of fault zones including magnetic microscanning and magnetic fabric analysis. To calibrate the observations on natural fault zones, laboratory experiments should be carried out that enable to extract the exact physicochemical conditions that led to a certain magnetic signature. Potential avenues could include (1) magnetic investigations on natural and synthetic fault rocks after friction experiments, (2) laboratory simulation of fault fluid percolation, (3) paleomagnetic analysis of postkinematic remanence components associated with faulting processes, and (4) synergy of interdisciplinary approaches in mineral-magnetic studies. This would help to place our understanding of the microphysics of faulting on a much stronger footing