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Background: The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis., Methods: We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis., Results: Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac-/- mice to that of antibiotic-treated control mice., Conclusions: MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Despite recent studies linking air pollution to neurodegenerative illness, evidence relating air pollution and Parkinson's disease (PD) remains scarce. We conducted a population-based cohort study in Ontario, Canada, to determine the association between air pollution and incident PD., Methods: Using health administrative databases, we identified all adults aged 55-85 years, free of PD, and who lived in Ontario on 1 April 2001 (∼2.2 million). Individuals were followed up until 31 March 2013. We derived long-term average exposures to fine particulate matter (particles ≤2.5 µm in diameter, or PM2.5), nitrogen dioxide (NO2) and ozone from satellite-based estimates, land-use regression models and optimal interpolation methods, respectively. Using 2-year lags in exposures, we linked these estimates to individuals' annual postal codes from 1994 (7 years before cohort inception). We applied spatial random-effects Cox proportional hazards models, adjusting for individual- and area-level characteristics. We also performed sensitivity analyses, such as considering longer lags in exposures and stratifying by selected characteristics., Results: During the study period, we identified 38 745 newly diagnosed cases of PD. Each interquartile increment (3.8 µg/m3) of PM2.5 was associated with a 4% increase in incident PD (95% confidence interval, 1.01-1.08) after adjusting for various covariates. We also found positive associations for NO2 and ozone [hazard ratios (HRs) ranged from 1.03 to 1.04]. The associations for all exposures were unaltered with various sensitivity analyses except for considering longer lags, which somewhat attenuated the estimates, particularly for NO2 and ozone., Conclusions: Exposure to air pollution, especially PM2.5, was found to be related to incident PD.

Objectives: To estimate the level of agreement and identify notable differences in occupational exposures (agents) between men and women from retrospective assessments by expert coders., Methods: Lifetime occupational histories of 1657 men and 2073 women from two case-control studies, were translated into exposure estimates to 243 agents, from data on 13882 jobs. Exposure estimates were summarized as proportions and frequency-weighted intensity of exposure for 59 occupational codes by sex. Agreement between metrics of exposure in men's and women's jobs was determined with intraclass correlation coefficients (ICC) and weighted Kappa coefficients, using as unit of analysis ('cell') a combination of occupational code and occupational agent. 'Notable' differences between men and women were identified for each cell, according to a Bayesian hierarchical model for both proportion and frequency-weighted intensity of exposure., Results: For cells common to both men and women, the ICC for continuous probability of exposure was 0.84 (95% CI: 0.83-0.84) and 7.4% of cells showed notable differences with jobs held by men being more often exposed. A weighted kappa of 0.67 (95% CI: 0.61-0.73) was calculated for intensity of exposure, and an ICC of 0.67 (95% CI: 0.62-0.71) for frequency-weighted intensity of exposure, with a tendency of higher values of exposure metrics in jobs held by men., Conclusions: Exposures were generally in agreement between men and women. Some notable differences were identified, most of them explained by differential sub-occupations or industries or dissimilar reported tasks within the studied occupations.

Objectives: We developed a job-exposure matrix called CANJEM using data generated in population-based case-control studies of cancer. This article describes some of the decisions in developing CANJEM, and some of its performance characteristics., Methods: CANJEM is built from exposure information from 31673 jobs held by study subjects included in our past case-control studies. For each job, experts had evaluated the intensity, frequency, and likelihood of exposure to a predefined list of agents based on jobs histories and descriptions of tasks and workplaces. The creation of CANJEM involved a host of decisions regarding the structure of CANJEM, and operational decisions regarding which parameters to present. The goal was to produce an instrument that would provide great flexibility to the user. In addition to describing these decisions, we conducted analyses to assess how well CANJEM covered the range of occupations found in Canada., Results: Even at quite a high level of resolution of the occupation classifications and time periods, over 90% of the recent Canadian working population would be covered by CANJEM. Prevalence of exposure of specific agents in specific occupations ranges from 0% to nearly 100%, thereby providing the user with basic information to discriminate exposed from unexposed workers. Furthermore, among exposed workers there is information that can be used to discriminate those with high exposure from those with low exposure., Conclusions: CANJEM provides good coverage of the Canadian working population and possibly that of several other countries. Available in several occupation classification systems and including 258 agents, CANJEM can be used to support exposure assessment efforts in epidemiology and prevention of occupational diseases.

Background: Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and tumor initiating cell maintenance. The rate-limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in glioblastoma (GBM; grade IV astrocytoma) is guanosine triphosphate (GTP) cyclohydrolase 1 (GCH1). We sought to define the role of GCH1 in the regulation of GBM growth and brain tumor initiating cell (BTIC) maintenance., Methods: We examined GCH1 mRNA and protein expression in patient-derived xenografts, clinical samples, and glioma gene expression datasets. GCH1 levels were modulated using lentiviral expression systems, and effects on cell growth, self-renewal, reactive species production, and survival in orthotopic patient-derived xenograft models were determined., Results: GCH1 was expressed in GBMs with elevated but not exclusive RNA and protein levels in BTICs in comparison to non-BTICs. Overexpression of GCH1 in GBM cells increased cell growth in vitro and decreased survival in an intracranial GBM mouse model. In converse experiments, GCH1 knockdown with short hairpin RNA led to GBM cell growth inhibition and reduced self-renewal in association with decreased CD44 expression. GCH1 was critical for controlling reactive species balance, including suppressing reactive oxygen species production, which mediated GCH1 cell growth effects. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence, and worse survival., Conclusions: GCH1 expression in established GBMs is pro-tumorigenic, causing increased growth due, in part, to promotion of BTIC maintenance and suppression of reactive oxygen species.

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers., Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided., Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed., Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking., Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates., Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer., Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report., (© The Author 2015. Published by Oxford University Press.)

In the first 6.5 years of Operation Iraqi Freedom (OIF), U.S. military casualties exceeded 3,400 hostile deaths, 800 nonhostile deaths (due to disease, nonbattle injury, and other causes), and over 31,000 troops wounded in action. Casualty rates in Iraq have been considerably lower that during the Vietnam conflict, and a greater proportion of troops wounded in Iraq survive their wounds. Before the surge in troop levels that began in early 2007, the survival rate was 90.4% in Iraq as compared to 86.5% in Vietnam. Wounded-in-action rates increased during the first few months of the surge, but declined below presurge levels after the number of U.S. brigades in Iraq climbed from 15 to its maximum level of 20. Wounds during the surge were somewhat more lethal than previously, but because there were fewer wounding incidents the net effect was a reduction in the hostile death rate.

The authors investigated the association between daily variations in ozone and cause-specific mortality. Fixed-site air pollution monitors in Montreal, Quebec, provided daily mean levels of ozone, particles, and other gaseous pollutants. Information on the date and underlying cause of death was obtained for residents of Montreal who died in the city between 1984 and 1993. The authors regressed the logarithm of daily counts of cause-specific mortality on mean levels of ozone, after accounting for seasonal and subseasonal fluctuations in the mortality time series, non-Poisson dispersion, and weather variables. The effect of ozone on mortality was generally higher in the warm season and among persons aged 65 years or over. For an increase in the 3-day running mean concentration of ozone of 21.3 microg/m(3), the percentage of increase in daily deaths in the warm season was the following: nonaccidental deaths, 3.3% (95% confidence interval (CI): 1.7, 5.0); cancer, 3.9% (95% CI: 1.0, 6.91); cardiovascular diseases, 2.5% (95% CI: 0.2, 5.0); and respiratory diseases, 6.6% (95% CI: 1.8, 11.8). These results were independent of the effects of other pollutants and were consistent with a log-linear response function.