The effect of assessing genetic risk of prostate cancer on the use of PSA tests in primary care: a cluster randomized controlled trial

Background Assessing genetic lifetime risk for prostate cancer has been proposed as a means of risk stratification to identify those for whom prostate-specific antigen (PSA) testing is likely to be most valuable. This project aimed to test the effect of introducing a genetic test for lifetime risk of prostate cancer in general practice on future PSA testing. Methods and findings We performed a cluster randomized controlled trial with randomization at the level of general practices (73 in each of two arms) in the Central Region (Region Midtjylland) of Denmark. In intervention practices, men were offered a genetic test (based on genotyping of 33 risk-associated single nucleotide polymorphisms) in addition to the standard PSA test that informed them about lifetime genetic risk of prostate cancer and distinguished between “normal” and “high” risk. The primary outcome was the proportion of men having a repeated PSA test within 2 years. A multilevel logistic regression model was used to test the association. After applying the exclusion criteria, 3,558 men were recruited in intervention practices, with 1,235 (34.7%) receiving the genetic test, and 4,242 men were recruited in control practices. Men with high genetic risk had a higher propensity for repeated PSA testing within 2 years than men with normal genetic risk (odds ratio [OR] = 8.94, p < 0.01). The study was conducted in routine practice and had some selection bias, which is evidenced by the relatively large proportion of younger and higher income participants taking the genetic test. Conclusions Providing general practitioners (GPs) with access to a genetic test to assess lifetime risk of prostate cancer did not reduce the overall number of future PSA tests. However, among men who had a genetic test, knowledge of genetic risk significantly influenced future PSA testing

The contributions to long-term health-relevant particulate matter at the UK EMEP supersites between 2010 and 2013: Quantifying the mitigation challenge

Human health burdens associated with long-term exposure to particulate matter (PM) are substantial. The metrics currently recommended by the World Health Organization for quantification of long-term health-relevant PM are the annual average PM10 and PM2.5 mass concentrations, with no low concentration threshold. However, within an annual average, there is substantial variation in the composition of PM associated with different sources. To inform effective mitigation strategies, therefore, it is necessary to quantify the conditions that contribute to annual average PM10 and PM2.5 (rather than just short-term episodic concentrations). PM10, PM2.5, and speciated water-soluble inorganic, carbonaceous, heavy metal and polycyclic aromatic hydrocarbon components are concurrently measured at the two UK European Monitoring and Evaluation Programme (EMEP) ‘supersites’ at Harwell (SE England) and Auchencorth Moss (SE Scotland). In this work, statistical analyses of these measurements are integrated with air-mass back trajectory data to characterise the ‘chemical climate’ associated with the long-term health-relevant PM metrics at these sites. Specifically, the contributions from different PM concentrations, months, components and geographic regions are detailed. The analyses at these sites provide policy-relevant conclusions on mitigation of (i) long-term health-relevant PM in the spatial domain for which these sites are representative, and (ii) the contribution of regional background PM to long-term health-relevant PM. At Harwell the mean (±1 sd) 2010–2013 annual average concentrations were PM10 = 16.4 ± 1.4 μg m−3 and PM2.5 = 11.9 ± 1.1 μg m−3 and at Auchencorth PM10 = 7.4 ± 0.4 μg m−3 and PM2.5 = 4.1 ± 0.2 μg m−3. The chemical climate state at each site showed that frequent, moderate hourly PM10 and PM2.5 concentrations (defined as approximately 5–15 μg m−3 for PM10 and PM2.5 at Harwell and 5–10 μg m−3 for PM10 at Auchencorth) determined the magnitude of annual average PM10 and PM2.5 to a greater extent than the relatively infrequent high, episodic PM10 and PM2.5 concentrations. These moderate PM10 and PM2.5 concentrations were derived across the range of chemical components, seasons and air-mass pathways, in contrast to the highest PM concentrations which tended to associate with specific conditions. For example, the largest contribution to moderate PM10 and PM2.5 concentrations – the secondary inorganic aerosol components, specifically NO3− – were accumulated during the arrival of trajectories traversing the spectrum of marine, UK, and continental Europe areas. Mitigation of the long-term health-relevant PM impact in the regions characterised by these two sites requires multilateral action, across species (and hence source sectors), both nationally and internationally; there is no dominant determinant of the long-term PM metrics to target

The early monocytic response to cytomegalovirus infection is MyD88 dependent but occurs independently of common inflammatory cytokine signals

Cytomegalovirus latently infects myeloid cells; however, the acute effects of the virus on this cell subset are poorly characterised. We demonstrate that systemic cytomegalovirus infection induced rapid activation of monocytes in the bone marrow, characterised by upregulation of CD69, CD11c, Ly6C and M-CSF receptor. Activated bone marrow monocytes were more sensitive to M-CSF and less sensitive to granulocyte-monocyte colony stimulating factor in vitro, resulting in the generation of more macrophages and fewer dendritic cells, respectively. Monocyte activation was also observed in the periphery and resulted in significant accumulation of monocytes in the spleen. MyD88 expression was required within the haematopoietic compartment to initiate monocyte activation and recruitment. However, monocytes lacking MyD88 were activated and recruited in the presence of MyD88-sufficient cells in mixed bone marrow chimeras, indicating that once initiated, the process was MyD88 independent. Interestingly, we found that monocyte activation occurred in the absence of the common inflammatory cytokines, namely type I interferons (IFNs), IL-6, TNF-α and IL-1 as well as the NLRP3 inflammasome adaptor protein, ASC. We also excluded a role for the chemokine-like protein MCK-2 (m131/129) expressed by murine CMV. Taken together, these results challenge the notion that a single inflammatory cytokine mediates activation and recruitment of monocytes in response to infection