Coynevest9033

An athlete challenged the result from an in-competition doping test which returned with an adverse analytical finding for stanozolol, claiming it was due to supplement contamination. Her lawyer asked the laboratory to analyze several hair specimens simultaneously collected from 5 different anatomical regions, head, arm, leg, pubic and armpit, to document the pattern of drug exposure. A specific UPLC-MS/MS method was developed. selleck kinase inhibitor After decontamination with dichloromethane, stanozolol was extracted from hair in presence of stanozolol-D3 used as internal standard, under alkaline conditions, with diethyl ether. Linearity was observed for concentrations ranging from 5 pg/mg to 10 ng/mg. The method has been validated according linearity, precision and matrix effect. Concentrations of stanozolol in head hair, pubic hair, arm hair, leg hair and axillary hair were 73, 454, 238, 244 and 7100 pg/mg, respectively. The concentration of stanozolol in head hair is in accordance with data published in the literature. When comparing the concentrations, body hair concentrations were higher than the concentration found in head hair. These results are consistent with a better incorporation rate of stanozolol in body hair when compared to head hair. The simultaneous positive concentrations in different hair types confirm the adverse analytical finding in urine of the top athlete, as the measured concentrations do not support the theory of contamination. For the first time, an anabolic agent was simultaneously tested in hair collected from 5 different anatomical regions from the same subject, with a large distribution of concentrations, due to anatomical variations and these findings will help interpretation in further doping cases when documented with hair. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email journals.permissions@oup.com.Estrogen is a key hormone involved in the development and homeostasis of several tissue types in both males and females. By binding Estrogen Receptors (ER), estrogen regulates essential functions of gene expression, metabolism, cell growth and proliferation by acting through cytoplasmic signaling pathways or activating transcription in the nucleus. However, disruption or dysregulation of estrogen activity has been shown to play a key role in the pathogenesis and progression of many diseases. This review will expatiate on some of the unconventional roles of estrogen in homeostasis and disease. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.STUDY OBJECTIVES We sought to examine the impact of digital cognitive behavioural therapy (dCBT) for insomnia on both self-reported cognitive impairment and objective cognitive performance. METHODS The DISCO trial was an online, two-arm, single-blind, randomised clinical trial of dCBT versus wait-list control. Participants were aged 25 years and older, met DSM-5 diagnostic criteria for insomnia disorder and reported difficulties with concentration or memory. Assessments were carried out online at baseline, and 10 and 24 weeks post-randomisation. The primary outcome measure was self-reported cognitive impairment, assessed with the British Columbia Cognitive Complaints Inventory (BC-CCI). Secondary outcomes included tests of cognitive performance, insomnia symptoms, cognitive failures, fatigue, sleepiness, depression and anxiety. RESULTS 410 participants with insomnia were recruited and assigned to dCBT (N = 205) or wait-list control (N = 205). At 10 weeks post-randomisation the estimated adjusted mean difference for the BC-CCI was -3.03 [95% CI -3.60,-2.47; p less then .0001, d = -0.86], indicating that participants in the dCBT group reported less cognitive impairment than the control group. These effects were maintained at 24 weeks (d = -0.96) and were mediated, in part, via reductions in insomnia severity and increased sleep efficiency. Treatment effects in favour of dCBT, at both 10 and 24 weeks, were found for insomnia severity, sleep efficiency, cognitive failures, fatigue, sleepiness, depression, and anxiety. We found no between-group differences on objective tests of cognitive performance. link2 CONCLUSIONS Our study shows that dCBT robustly decreases self-reported cognitive impairment at post-treatment and these effects are maintained at 6 months. © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.BACKGROUND Mental health trusts in England were expected to become completely smoke-free and embed smoking cessation practices by 2018. Such policies are fraught with concerns and have received mixed support from mental health staff. Understanding staff attitudes to these practices prior to enforcement of the policy could help design an effective implementation strategy. METHODS A cross-sectional survey was conducted with clinical and non-clinical staff in a Mental Health Trust to understand smoking cessation practices and attitudes to the implementation of a completely smoke-free policy. RESULTS There were 631 responses. Most participants disagreed with the policy on wards (59.6%) and throughout all mental health settings (57.4%). Clinicians expressed significantly lower organizational policy support (P = 0.001) than non-clinicians (P = 0.001). Psychiatrists were more supportive of the organizational items than nurses and allied health professionals. Clinicians' attitudes towards smoking cessation practices were less positive for those who were current smokers (P  less then  0.001), but more positive for clinicians who had received or were interested in attending smoking cessation training (P  less then  0.001). CONCLUSIONS Partial and completely smoke-free policies remain unsupported by staff in mental health settings. Smoking cessation training appears to reinforce rather than alter attitudes towards smoking cessation. © The Author(s) 2020. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, while the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. link3 This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared to the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1,750 and 1,850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural and political debate regarding ancestry, admixture and the mestizaje process in the Americas. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Chromosome conformation-capture technologies are widely used in 3D genomics; however, experimentally, such methods have high-noise limitations and, therefore, require significant bioinformatics efforts to extract reliable distal interactions. Miscellaneous undesired linear DNAs, present during proximity-ligation, represent a main noise source, which needs to be minimized or eliminated. In this study, different exonuclease combinations were tested to remove linear DNA fragments from a circularized DNA preparation. This method efficiently removed linear DNAs, raised the proportion of annulation and increased the valid-pairs ratio from ∼40% to ∼80% for enhanced interaction detection in standard Hi-C. This strategy is applicable for development of various 3D genomics technologies, or optimization of Hi-C sequencing efficiency. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.Megakaryoblastic leukemia 1 (MKL1) promotes the regulation of essential cell processes, including actin cytoskeletal dynamics by co-activating serum response factor. Recently, the first human case with MKL1 deficiency, leading to a novel primary immunodeficiency, was identified. We report a second family with two siblings with a homozygous frameshift mutation in MKL1. The index case deceased as an infant from progressive and severe pneumonia by Pseudomonas aeruginosa and poor wound healing. The younger sib was preemptively transplanted shortly after birth. The immunodeficiency was marked by a pronounced actin polymerization defect and a strongly reduced motility and chemotactic response by MKL1-deficient neutrophils. Apart from the lack of MKL1, subsequent proteomic and transcriptomic analyses of patient neutrophils revealed actin and several actin-related proteins to be downregulated, confirming a role for MKL1 as transcriptional co-regulator. Degranulation was enhanced upon suboptimal neutrophil activation, while production of reactive oxygen species was normal. Neutrophil adhesion was intact but without proper spreading. The latter could explain the observed failure in firm adherence and transendothelial migration under flow conditions. No apparent defect in phagocytosis and bacterial killing was found. Also monocyte-derived macrophages showed intact phagocytosis; lymphocyte counts and proliferative capacity were normal. Non-hematopoietic primary patient fibroblasts demonstrated defective differentiation into myofibroblasts but normal migration and filamentous actin (F-actin) content, most probably due to compensatory mechanisms of MKL2, which is not expressed in neutrophils. Our findings extend current insight into the severe immune dysfunction in MKL1 deficiency, with cytoskeletal dysfunction and defective extravasation of neutrophils as most prominent features. Copyright © 2020 American Society of Hematology.Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.