Cx3cr1-deficient microglia exhibit a premature aging transcriptome.

CX3CR1, one of the highest expressed genes in microglia in mice and humans, is implicated in numerous microglial functions. However, the molecular mechanisms underlying Cx3cr1 signaling are not well understood. Here, we analyzed transcriptomes of Cx3cr1-deficient microglia under varying conditions by RNA-sequencing (RNA-seq). In 2-mo-old mice, Cx3cr1 deletion resulted in the down-regulation of a subset of immune-related genes, without substantial epigenetic changes in markers of active chromatin. Surprisingly, Cx3cr1-deficient microglia from young mice exhibited a transcriptome consistent with that of aged Cx3cr1-sufficient animals, suggesting a premature aging transcriptomic signature. Immunohistochemical analysis of microglia in young and aged mice revealed that loss of Cx3cr1 modulates microglial morphology in a comparable fashion. Our results suggest that CX3CR1 may regulate microglial function in part by modulating the expression levels of a subset of inflammatory genes during chronological aging, making Cx3cr1-deficient mice useful for studying aged microglia

Reducing the risk of criminal exploitation using multi-systemic therapy (the RESET Study) : study protocol for a feasibility study and process evaluation

Background Child criminal exploitation is a form of child abuse that poses a serious risk to the welfare, safety, and wellbeing of young people. Multisystemic therapy (MST) is an intensive family and community-based intervention for young people with anti-social behavioral problems, many of whom will be at risk of criminal exploitation. This protocol describes a pilot feasibility study and process evaluation, designed to examine MST for children at risk of criminal exploitation. Methods This pilot feasibility study and process evaluation involves two phases with associated subphases: phase 1.1 involved the collaborative refinement of the logic model adapting MST for children at risk of criminal exploitation; phase 1.2 involved pre-pilot interviews with MST therapists, families, and young people; phase 2.1 is a pilot modeling study of MST for children at risk of criminal exploitation, and; Phase 2.2 is a process evaluation that will involve interviewing stakeholders, MST therapists and employees, families, and young people. The dataset for the process evaluation will include questionnaires completed by parents and young people at baseline, mid-treatment, end of treatment, and 6 months after treatment. We will supplement these data with participant-level data linkage from MST sites and services. Results Accrual to the pilot stage of this project opened on 6th August 2021 and is due to close on 31st May 2022. We aim to publish the results of this feasibility study and process evaluation in 2023. Conclusions The results of this feasibility study and process evaluation will inform the decision as to whether it is advisable to progress to a pilot clinical trial of MST for children at risk of criminal exploitation

The utility of presentation and 4-hour high sensitivity troponin I to rule-out acute myocardial infarction in the emergency department

Objectives: International guidance recommends that early serial sampling of high sensitivity troponin be used to accurately identify acute myocardial infarction (AMI) in chest pain patients. The background evidence for this approach is limited. We evaluated whether on presentation and 4-hour high-sensitivity troponin I (hs-cTnI) could be used to accurately rule-out AMI. Design and methods: hs-cTnI was measured on presentation and at 4-hours in adult patients attending an emergency department with possible acute coronary syndrome. We determined the sensitivity for AMI for at least one hs-cTnI above the 99th percentile for a healthy population or alone or in combination with new ischemic ECG changes. Both overall and sex-specific 99th percentiles were assessed. Patients with negative tests were designated low-risk. Results: 63 (17.1%) of 368 patients had AMI. The median (interquartile range) time from symptom onset to first blood sampling was 4.8. h (2.8-8.6). The sensitivity of the presentation and 4. h hs-cTnI using the overall 99th percentile was 92.1% (95% CI 82.4% to 97.4%) and negative predictive value 95.4% (92.3% to 97.4%) with 78.3% low-risk. Applying the sex-specific 99th percentile did not change the sensitivity. The addition of ECG did not change the sensitivity. Conclusion: Hs-cTnI >. 99th percentile thresholds measured on presentation and at 4-hours was not a safe strategy to rule-out AMI in this clinical setting irrespective of whether sex-specific 99th percentiles were used, or whether hs-cTnI was combined with ECG results

Interleukin-6 and Associated Cytokine Responses to An Acute Bout of High-intensity Interval Exercise: the Effect of Exercise Intensity and Volume

Acute increases in interleukin (IL)-6 following prolonged exercise are associated with the induction of a transient anti-inflammatory state (e.g., increases in IL-10) that is partly responsible for the health benefits of regular exercise. The purposes of this study were to investigate the IL-6–related inflammatory response to high-intensity interval exercise (HIIE) and to determine the impact of exercise intensity and volume on this response. Ten participants (5 males and 5 females) completed 3 exercise bouts of contrasting intensity and volume (LOW, MOD, and HIGH). The HIGH protocol was based upon standard HIIE protocols, while the MOD and LOW protocols were designed to enable a comparison of exercise intensity and volume with a fixed duration. Inflammatory cytokine concentrations were measured in plasma (IL-6, IL-10) and also determined the level of gene expression (IL-6, IL-10, and IL-4R) in peripheral blood. The plasma IL-6 response to exercise (reported as fold changes) was significantly greater in HIGH (2.70 ± 1.51) than LOW (1.40 ± 0.32) (P = 0.04) and was also positively correlated to the mean exercise oxygen uptake (r = 0.54, P < 0.01). However, there was no change in anti-inflammatory IL-10 or IL-4R responses in plasma or at the level of gene expression. HIIE caused a significant increase in IL-6 and was greater than that seen in low-intensity exercise of the same duration. The increases in IL-6 were relatively small in magnitude, and appear to have been insufficient to induce the acute systemic anti-inflammatory effects, which are evident following longer duration exercise

Miniature exoplanet radial velocity array I: design, commissioning, and early photometric results

The MINiature Exoplanet Radial Velocity Array (MINERVA) is a US-based observational facility dedicated to the discovery and characterization of exoplanets around a nearby sample of bright stars. MINERVA employs a robotic array of four 0.7 m telescopes outfitted for both high-resolution spec- troscopy and photometry, and is designed for completely autonomous operation. The primary science program is a dedicated radial velocity survey and the secondary science objective is to obtain high precision transit light curves. The modular design of the facility and the flexibility of our hardware allows for both science programs to be pursued simultaneously, while the robotic control software provides a robust and efficient means to carry out nightly observations. In this article, we describe the design of MINERVA including major hardware components, software, and science goals. The telescopes and photometry cameras are characterized at our test facility on the Caltech campus in Pasadena, CA, and their on-sky performance is validated. New observations from our test facility demonstrate sub-mmag photometric precision of one of our radial velocity survey targets, and we present new transit observations and fits of WASP-52b—a known hot-Jupiter with an inflated radius and misaligned orbit. The process of relocating the MINERVA hardware to its final destination at the Fred Lawrence Whipple Observatory in southern Arizona has begun, and science operations are expected to commence within 2015

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Metal-enriched halo gas across galaxy overdensities over the last 10 billion years

We present a study of metal-enriched halo gas traced by Mg II and C IV absorption at z 1. It is clear from our results that environmental processes have a significant impact on the distribution of metals around galaxies and need to be fully accounted for when analysing correlations between gaseous haloes and galaxy properties

Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice

Study objective A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. Methods This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. Results Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference −2.1% [−10.3% to 6.0%], P=.65). Conclusion There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates