Cardiorespiratory fitness, fatness and the acute blood pressure response to exercise in adolescence

Objective: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) areindependent contributors to cardiovascular risk, but their interrelated associationswith exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness, and the acute BP response to exercise in a large birth cohort ofadolescents.Methods: 2292 adolescents from the Avon Longitudinal Study of Parents andChildren (aged 17.8 ± 0.4 years, 38.5% male) completed a sub-maximal exercisestep test that allowed fitness (VO2 max) to be determined from workload and heart rateusing a validated equation. Exercise BP was measured immediately on test cessationand fatness calculated as the ratio of total fat mass to total body mass measured byDXA.Results: Post-exercise systolic BP decreased stepwise with tertile of fitness (146(18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142(16); 149 (18) mmHg). In separate models, fitness and fatness were associated withpost-exercise systolic BP adjusted for sex, age, height, smoking, and socioeconomicstatus (standardized β: −1.80, 95%CI: −2.64, −0.95 mmHg/SD and 4.31, 95%CI:3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in thesame model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69,5.61 mmHg/SD).Conclusion: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness mayonly be realized with more favorable body composition

Protocol for the Smoking, Nicotine and Pregnancy (SNAP) trial: double-blind, placebo-randomised, controlled trial of nicotine replacement therapy in pregnancy

Background: Smoking in pregnancy remains a public health challenge. Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant people, but because women metabolise nicotine and cotinine much faster in pregnancy, it is unclear whether this will be effective for smoking cessation in pregnancy. The NHS Health Technology Assessment Programme (HTA)-funded smoking, nicotine and pregnancy ( SNAP) trial will investigate whether or not nicotine replacement therapy ( NRT) is effective, cost-effective and safe when used for smoking cessation by pregnant women. Methods/Design: Over two years, in 5 trial centres, 1050 pregnant women who are between 12 and 24 weeks pregnant will be randomised as they attend hospital for ante-natal ultrasound scans. Women will receive either nicotine or placebo transdermal patches with behavioural support. The primary outcome measure is biochemically-validated, self-reported, prolonged and total abstinence from smoking between a quit date ( defined before randomisation and set within two weeks of this) and delivery. At six months after childbirth self-reported maternal smoking status will be ascertained and two years after childbirth, self-reported maternal smoking status and the behaviour, cognitive development and respiratory symptoms of children born in the trial will be compared in both groups. Discussion: This trial is designed to ascertain whether or not standard doses of NRT ( as transdermal patches) are effective and safe when used for smoking cessation during pregnancy

A Discrete Event Simulation model to evaluate the treatment pathways of patients with Cataract in the United Kingdom

Background The number of people affected by cataract in the United Kingdom (UK) is growing rapidly due to ageing population. As the only way to treat cataract is through surgery, there is a high demand for this type of surgery and figures indicate that it is the most performed type of surgery in the UK. The National Health Service (NHS), which provides free of charge care in the UK, is under huge financial pressure due to budget austerity in the last decade. As the number of people affected by the disease is expected to grow significantly in coming years, the aim of this study is to evaluate whether the introduction of new processes and medical technologies will enable cataract services to cope with the demand within the NHS funding constraints. Methods We developed a Discrete Event Simulation model representing the cataract services pathways at Leicester Royal Infirmary Hospital. The model was inputted with data from national and local sources as well as from a surgery demand forecasting model developed in the study. The model was verified and validated with the participation of the cataract services clinical and management teams. Results Four scenarios involving increased number of surgeries per half-day surgery theatre slot were simulated. Results indicate that the total number of surgeries per year could be increased by 40% at no extra cost. However, the rate of improvement decreases for increased number of surgeries per half-day surgery theatre slot due to a higher number of cancelled surgeries. Productivity is expected to improve as the total number of doctors and nurses hours will increase by 5 and 12% respectively. However, non-human resources such as pre-surgery rooms and post-surgery recovery chairs are under-utilized across all scenarios. Conclusions Using new processes and medical technologies for cataract surgery is a promising way to deal with the expected higher demand especially as this could be achieved with limited impact on costs. Non-human resources capacity need to be evenly levelled across the surgery pathway to improve their utilisation. The performance of cataract services could be improved by better communication with and proactive management of patients.Peer reviewedFinal Published versio

Phenotypic and Functional Changes in Blood Monocytes Following Adherence to Endothelium

Blood monocytes are known to express endothelial-like genes during co-culture with endothelium. In this study, the time-dependent change in the phenotype pattern of primary blood monocytes after adhering to endothelium is reported using a novel HLA-A2 mistyped co-culture model.Freshly isolated human PBMCs were co-cultured with human umbilical vein endothelial cells or human coronary arterial endothelial cells of converse human leukocyte antigen A2 (HLA-A2) status. This allows the tracking of the PBMC-derived cells by HLA-A2 expression and assessment of their phenotype pattern over time. PBMCs that adhered to the endothelium at the start of the co-culture were predominantly CD11b+ blood monocytes. After 24 to 72 hours in co-culture, the endothelium-adherent monocytes acquired endothelial-like properties including the expression of endothelial nitric oxide synthase, CD105, CD144 and vascular endothelial growth factor receptor 2. The expression of monocyte/macrophage lineage antigens CD14, CD11b and CD36 were down regulated concomitantly. The adherent monocytes did not express CD115 after 1 day of co-culture. By day 6, the monocyte-derived cells expressed vascular cell adhesion molecule 1 in response to tumour necrosis factor alpha. Up to 10% of the PBMCs adhered to the endothelium. These monocyte-derived cells contributed up to 30% of the co-cultured cell layer and this was dose-dependent on the PBMC seeding density.Human blood monocytes undergo rapid phenotype change to resemble endothelial cells after adhering to endothelium

Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us

Supernova remnants (SNRs) arise from the interaction between the ejecta of a supernova (SN) explosion and the surrounding circumstellar and interstellar medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However, to understand SNRs as a whole, large samples of SNRs must be assembled and studied. Here, we describe the radio, optical, and X-ray techniques which have been used to identify and characterize almost 300 Galactic SNRs and more than 1200 extragalactic SNRs. We then discuss which types of SNRs are being found and which are not. We examine the degree to which the luminosity functions, surface-brightness distributions and multi-wavelength comparisons of the samples can be interpreted to determine the class properties of SNRs and describe efforts to establish the type of SN explosion associated with a SNR. We conclude that in order to better understand the class properties of SNRs, it is more important to study (and obtain additional data on) the SNRs in galaxies with extant samples at multiple wavelength bands than it is to obtain samples of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by Athem W. Alsabti and Paul Murdin. Final version available at https://doi.org/10.1007/978-3-319-20794-0_90-

Formation of Supermassive Black Holes

Evidence shows that massive black holes reside in most local galaxies. Studies have also established a number of relations between the MBH mass and properties of the host galaxy such as bulge mass and velocity dispersion. These results suggest that central MBHs, while much less massive than the host (~ 0.1%), are linked to the evolution of galactic structure. In hierarchical cosmologies, a single big galaxy today can be traced back to the stage when it was split up in hundreds of smaller components. Did MBH seeds form with the same efficiency in small proto-galaxies, or did their formation had to await the buildup of substantial galaxies with deeper potential wells? I briefly review here some of the physical processes that are conducive to the evolution of the massive black hole population. I will discuss black hole formation processes for `seed' black holes that are likely to place at early cosmic epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final publication is available at http://www.springerlink.co

Investigation into the annotation of protocol sequencing steps in the sequence read archive

BACKGROUND: The workflow for the production of high-throughput sequencing data from nucleic acid samples is complex. There are a series of protocol steps to be followed in the preparation of samples for next-generation sequencing. The quantification of bias in a number of protocol steps, namely DNA fractionation, blunting, phosphorylation, adapter ligation and library enrichment, remains to be determined. RESULTS: We examined the experimental metadata of the public repository Sequence Read Archive (SRA) in order to ascertain the level of annotation of important sequencing steps in submissions to the database. Using SQL relational database queries (using the SRAdb SQLite database generated by the Bioconductor consortium) to search for keywords commonly occurring in key preparatory protocol steps partitioned over studies, we found that 7.10%, 5.84% and 7.57% of all records (fragmentation, ligation and enrichment, respectively), had at least one keyword corresponding to one of the three protocol steps. Only 4.06% of all records, partitioned over studies, had keywords for all three steps in the protocol (5.58% of all SRA records). CONCLUSIONS: The current level of annotation in the SRA inhibits systematic studies of bias due to these protocol steps. Downstream from this, meta-analyses and comparative studies based on these data will have a source of bias that cannot be quantified at present

Use of deep learning to develop continuous-risk models for adverse event prediction from electronic health records

Early prediction of patient outcomes is important for targeting preventive care. This protocol describes a practical workflow for developing deep-learning risk models that can predict various clinical and operational outcomes from structured electronic health record (EHR) data. The protocol comprises five main stages: formal problem definition, data pre-processing, architecture selection, calibration and uncertainty, and generalizability evaluation. We have applied the workflow to four endpoints (acute kidney injury, mortality, length of stay and 30-day hospital readmission). The workflow can enable continuous (e.g., triggered every 6 h) and static (e.g., triggered at 24 h after admission) predictions. We also provide an open-source codebase that illustrates some key principles in EHR modeling. This protocol can be used by interdisciplinary teams with programming and clinical expertise to build deep-learning prediction models with alternate data sources and prediction tasks

Drug-Induced Regulation of Target Expression

Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention