Night shift work is associated with increased breast cancer risk, but the molecular mechanisms are not well-understood. The objective of this study was to explore the relationship between night shift ...work parameters (current status, duration/years, and intensity) and methylation in circadian genes as a potential mechanism underlying the carcinogenic effects of night shift work. A cross-sectional study was conducted among 74 female healthcare employees (n = 38 day workers, n = 36 night shift workers). The Illumina Infinium MethylationEPIC beadchip was applied to DNA extracted from blood samples to measure methylation using a candidate gene approach at 1150 CpG loci across 22 circadian genes. Linear regression models were used to examine the association between night shift work parameters and continuous methylation measurements (β-values) for each CpG site. The false-discovery rate (q = 0.2) was used to account for multiple comparisons. Compared to day workers, current night shift workers demonstrated hypermethylation in the 5ʹUTR region of CSNK1E (q = 0.15). Individuals that worked night shifts for ≥10 years exhibited hypomethylation in the gene body of NR1D1 (q = 0.08) compared to those that worked <10 years. Hypermethylation in the gene body of ARNTL was also apparent in those who worked ≥3 consecutive night shifts a week (q = 0.18). These findings suggest that night shift work is associated with differential methylation in core circadian genes, including CSNK1E, NR1D1 and ARNTL. Future, larger-scale studies with long-term follow-up and detailed night shift work assessment are needed to confirm and expand on these findings.
ObjectivesSPECTRUM is a unique multi-disciplinary, cross-sector collaborative research partnership between academics, government, and community organizations in Manitoba working together to address ...complex social problems. In our first research project, partners identified the need for quantitative evidence around outcomes of children involved with Child Protection Services (CPS), using linked administrative data.
ApproachFrom the SPECTRUM partnership, a research team with CPS expertise was established, including government policy-makers, community organizations representing First Nations families, and academics from multiple disciplines. The research is guided by an Advisory Circle of First Nations Knowledge Keepers. Linking health, education, CPS, and justice data we developed a matched cohort identifying children involved with CPS (2007-2018) for whom there was discretion in the decision to 1) place them in out-of-home care (n=19,718), or 2) keep them in their family home while providing services (n=28,154). Instrumental Variable analysis, with CPS agency as the instrument, will be used to compare outcomes.
ResultsFollowing the trajectories of these two groups of CPS-involved children over time, we will compare their mental and physical health, educational achievement, and justice system involvement while accounting for individual-level (e.g., age, sex, chronic health conditions) and family-level (e.g., family income, maternal mental health, number of siblings) factors that may contribute to these outcomes. Preliminary findings will be workshopped with the SPECTRUM partnership to facilitate discussions on framing the evidence for policy makers. The SPECTRUM policy team will then prepare policy recommendations for government to consider. The Advisory Circle and a youth advisory squad will facilitate contextualizing and mobilizing findings. Actions taken by government in response to material provided will be monitored and will inform the development of subsequent research projects conducted by SPECTRUM.
ConclusionGovernment and community stakeholder involvement throughout bolsters the likelihood of evidence translating into program and policy changes. This is not a situation where academics are telling government how to do their jobs – this is government, community organizations, and academics working together with the shared goal of better outcomes for children.
ObjectivesMechanisms underlying the carcinogenicity of night shift work remain uncertain. One compelling yet understudied cancer mechanism may involve altered DNA methylation in circadian genes due ...to melatonin secretion patterns. The objective of this study was to explore the relationship between melatonin secretion patterns and circadian gene methylation among day and night shift workers.MethodsFemale healthcare employees (n=38 day workers, n=36 night shift workers) for whom we had urinary 6-sulfatoxymelatonin secretion data from a previous study were recontacted. New blood samples were collected and used to measure methylation levels at 1150 CpG loci across 22 circadian genes using the Illumina Infinium MethylationEPIC beadchip. Linear regression was used to examine the association between melatonin (acrophase and mesor) and M values for each CpG site (false discovery rate, q=0.2), while testing for effect modification by shift work status.ResultsAmong night shift workers, a higher mesor (24 hours of mean production of melatonin) was associated with increased methylation in the body of RORA (q=0.02) and decreased methylation in the putative promoter region of MTNR1A (q=0.03). Later acrophase (ie, time of peak concentration) was associated with increased methylation in the putative promoter region of MTNR1A (q=0.20) and decreased methylation in the body of PER3 (q=0.20). No associations were identified among day workers.ConclusionsIn conclusion, patterns in melatonin secretion were associated with differential circadian gene methylation among night shift workers. Melatonin and alteration of DNA methylation in circadian genes may be one pathway towards increased cancer risk, although larger-scale studies examining multiple time points are needed.
Background
Our aim was to examine the association between preterm delivery and incident maternal mental disorders using a population-based cohort of mothers in Canada.
Methods
Retrospective matched ...cohort study using Manitoba Centre for Health Policy (MCHP) administrative data in Manitoba. Mothers who delivered preterm babies (<37 weeks gestational age) between 1998 and 2013 were matched 1:5 to mothers of term babies using socio-demographic variables. Primary outcome was any incident mental disorder within 5 years of delivery defined as any of (a) mood and anxiety disorders, (b) psychotic disorders, (c) substance use disorders, and (d) suicide or suicide attempts. Multivariable Poisson regression model was used to estimate the 5-year adjusted incidence rate ratios (IRRs).
Results
Mothers of preterm children (N = 5,361) had similar incidence rates of any mental disorder (17.4% vs. 16.6%, IRR = 0.99, 95% CI, 0.91 to 1.07) compared to mothers of term children (N = 24,932). Mothers of term children had a higher rate of any mental disorder in the first year while mothers of preterm children had higher rates from 2 to 5 years. Being the mother of a child born <28 week (IRR = 1.5, 95% CI, 1.14 to 2.04), but not 28–33 weeks (IRR = 1.03, 95% CI, 0.86 to 1.19) or 34–36 weeks (IRR = 0.96, 95% CI, 0.88 to 1.05), was associated with any mental disorder.
Interpretation
Mothers of preterm and term children had similar rates of incident mental disorders within 5-years post-delivery. Extreme prematurity was a risk factor for any mental disorder. Targeted screening and support of this latter group may be beneficial.
Night shift work has been linked to increased risk of cardiovascular disease (CVD); however, the underlying mechanisms remain unclear. A compelling yet understudied mechanism involves differential ...DNA methylation of circadian genes. To investigate the relevance of this mechanism, we conducted an exploratory cross-sectional study of 74 female hospital personnel (38 day workers, 36 night shift workers). Sociodemographic, lifestyle, and health characteristics as well as shift work status and history were determined through self-report. Fasting blood samples were collected to measure markers of cardiometabolic risk and DNA was extracted to measure DNA methylation of 1150 cytosine-guanine (CpG) sites across 22 circadian genes. Associations between methylation levels at individual CpG sites (β-values) and markers of cardiometabolic risk were analyzed while considering effect modification by shift work status. The false discovery rate was applied to account for multiple comparisons (q ≤ 0.20). Two CpG sites cg06758649 (CRY1) and cg06899802 (CSNK1A1) were differentially associated with waist circumference and body mass index by shift work status, and eight CpG sites cg26103512 (CSNK1D), cg03941313 (CSNK1E), cg18217763 (CSNK1E), cg16682686 (DEC1), cg12061096 (RORA), cg10133825 (RORA), cg19652148 (RORA), and cg22904654 (RORA) were differentially associated with LDL cholesterol concentration by shift work status (all q ≤ 0.20). Our findings suggest that the relationship between DNA methylation of circadian genes and cardiometabolic risk differs by day and night shift worker status, which may contribute to mechanisms of increased risk of CVD observed among night shift workers.
The eradication of bacteria embedded in biofilms is among the most challenging obstacles in the management of chronic wounds. These biofilms are found in most chronic wounds; moreover, the ...biofilm-embedded bacteria are considerably less susceptible to conventional antimicrobial treatment than the planktonic bacteria. Antimicrobial peptides and their mimics are considered attractive candidates in the pursuit of novel therapeutic options for the treatment of chronic wounds and general bacterial eradication. However, some limitations linked to these membrane-active antimicrobials are making their clinical use challenging. Novel innovative delivery systems addressing these limitations represent a smart solution. We hypothesized that incorporation of a novel synthetic mimic of an antimicrobial peptide in liposomes could improve its anti-biofilm effect as well as the anti-inflammatory activity. The small synthetic mimic of an antimicrobial peptide, 7e-SMAMP, was incorporated into liposomes (~280 nm) tailored for skin wounds and evaluated for its potential activity against both biofilm formation and eradication of pre-formed biofilms. The 7e-SMAMP-liposomes significantly lowered inflammatory response in murine macrophages (~30 % reduction) without affecting the viability of macrophages or keratinocytes. Importantly, the 7e-SMAMP-liposomes completely eradicated biofilms produced by Staphylococcus aureus and Escherichia coli above concentrations of 6.25 μg/mL, whereas in Pseudomonas aeruginosa the eradication reached 75 % at the same concentration. Incorporation of 7e-SMAMP in liposomes improved both the inhibition of biofilm formation as well as biofilm eradication in vitro, as compared to non-formulated antimicrobial, therefore confirming its potential as a novel therapeutic option for bacteria-infected chronic wounds.
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•A novel mimic of an antimicrobial peptide was incorporated into liposomes.•The novel system significantly reduced inflammatory response in macrophages.•The novel system inhibited S. aureus, E. coli and P. aeruginosa biofilm formation.•The system improved eradication of S. aureus, E. coli, and P. aeruginosa biofilms relative to the mimic alone.
Abstract Background The Norwegian population has among the highest hip fracture rates in the world. The incidence varies geographically, also within Norway. Calcium in drinking water has been found ...to be beneficially associated with bone health in some studies, but not in all. In most previous studies, other minerals in water have not been taken into account. Trace minerals, for which drinking water can be an important source and even fulfill the daily nutritional requirement, could act as effect-modifiers in the association between calcium and hip fracture risk. The aim of the present study was to investigate the association between calcium in drinking water and hip fracture, and whether other water minerals modified this association. Materials and methods A survey of trace metals in 429 waterworks, supplying 64% of the population in Norway, was linked geographically to the home addresses of patients with incident hip fractures (1994–2000). Drinking water mineral concentrations were divided into “low” (below and equal waterworks average) and “high” (above waterworks average). Poisson regression models were fitted, and all incidence rate ratios (IRRs) were adjusted for age, geographic region, urbanization degree, type of water source, and pH of the water. Effect modifications were examined by stratification, and interactions between calcium and magnesium, copper, zinc, iron and manganese were tested both on the multiplicative and the additive scale. Analyses were stratified on gender. Results Among those supplied from the 429 waterworks (2,110,916 person-years in men and 2,397,217 person-years in women), 5433 men and 13,493 women aged 50–85 years suffered a hip fracture during 1994–2000. Compared to low calcium in drinking water, a high level was associated with a 15% lower hip fracture risk in men (IRR = 0.85, 95% CI: 0.78, 0.91) but no significant difference was found in women (IRR = 0.98, 95%CI: 0.93–1.02). There was interaction between calcium and copper on hip fracture risk in men (p = 0.051); the association between calcium and hip fracture risk was stronger when the copper concentration in water was high (IRR = 0.52, 95% CI: 0.35, 0.78) as opposed to when it was low (IRR = 0.88, 95% CI: 0.81, 0.94). This pattern persisted also after including potential confounding factors and other minerals in the model. No similar variation in risk was found in women. Conclusion In this large, prospective population study covering two thirds of the Norwegian population and comprising 19,000 hip fractures, we found an inverse association between calcium in drinking water and hip fracture risk in men. The association was stronger when the copper concentration in the water was high.
Abstract Background CYP450 polymorphisms result in variable rates of drug metabolism. CYP drug-drug interactions can contribute to altered drug effectiveness and safety. Study objectives The primary ...objective was to determine the percentage of emergency department (ED) patients with cytochrome 2C19 (CYP2C19) drug-drug interactions. The secondary objective was to determine the prevalence of CYP2C19 polymorphisms in a US ED population. Methods We conducted a prospective observational study in an urban academic ED with 72,000 annual visits. Drug ingestion histories for the 48 hours preceding ED visit were obtained; each drug was coded as CYP2C19 substrate, inhibitor, inducer, or not CYP2C19 dependent. Ten percent of patients were randomized to undergo CYP2C19 genotyping using the Roche Amplichip. Results A total of 502 patients were included; 61% were female, 65% were white, and median age was 39 years (interquartile range, 22-53). One hundred thirty-one (26.1%) patients had taken at least 1 CYP2C19-dependent home drug. Eighteen (13.7%) patients who were already taking a CYP2C19-dependent drug were given or prescribed a CYP2C19-dependent drug while in the ED. Among the 53 patients genotyped, 52 (98%) were extensive metabolizers and 1 was a poor metabolizer. Conclusions In a population of ED patients, more than a quarter had taken a CYP2C19-dependent drug in the preceding 48 hours, but few were given or prescribed another CYP2C19-dependent drug in the ED. On genotyping analysis, CYP2C19 polymorphisms were uncommon in our cohort. We conclude that changing prescribing practice due to CYP2C19 drug-drug interaction or genotype is unlikely to be useful in most US ED populations.
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