Polypharmacy among anabolic-androgenic steroid users: A descriptive metasynthesis

Background: As far as we are aware, no previous systematic review and synthesis of the qualitative/descriptive literature on polypharmacy in anabolic-androgenic steroid(s) (AAS) users has been published. Method: We systematically reviewed and synthesized qualitative/descriptive literature gathered from searches in electronic databases and by inspecting reference lists of relevant literature to investigate AAS users' polypharmacy. We adhered to the recommendations of the UK Economic and Social Research Council's qualitative research synthesis manual and the PRISMA guidelines. Results: A total of 50 studies published between 1985 and 2014 were included in the analysis. Studies originated from 10 countries although most originated from United States (n = 22), followed by Sweden (n = 7), England only (n = 5), and the United Kingdom (n = 4). It was evident that prior to their debut, AAS users often used other licit and illicit substances. The main ancillary/supplementary substances used were alcohol, and cannabis/cannabinoids followed by cocaine, growth hormone, and human chorionic gonadotropin (hCG), amphetamine/meth, clenbuterol, ephedra/ephedrine, insulin, and thyroxine. Other popular substance classes were analgesics/opioids, dietary/nutritional supplements, and diuretics. Our classification of the various substances used by AAS users resulted in 13 main groups. These non-AAS substances were used mainly to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. Conclusions: Our findings corroborate previous suggestions of associations between AAS use and the use of other licit and illicit substances. Efforts must be intensified to combat the debilitating effects of AAS-associated polypharmacy

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Role of the histone demethylase PHF2 during early neurogenesis

[eng] During neural development, signaling molecules and networks of expressed transcription factors cooperate to control cellular fate. Chromatin acting factors are essential players in cell proliferation and differentiation events. PHF2 is a histone demethylase, previously associated with cancer and autism spectrum disorder (ASD) but despite its clinical relevance its function during neural development remains unclear. PHF2 belongs to the KDM7 family of demethylases. It harbors an N-terminal plant homeodomain, (PHD) a domain that was shown to be associated with methylated lysine residues and an enzymatically active Jumonji-C (JmjC) domain responsible for their demethylase activity towards H3K9me and H3K9me2. PHF2 has been proposed to be a transcriptional coactivator, although, its genomic localization still remains unclear. To address the function of this protein during early neurogenesis constitutes the major goal of this Ph.D. thesis. To do so, we are using in vitro (cortical neural stem cells, NSC) and in vivo (the chick embryo neural tube) models. We demonstrated that this histone demethylase binds mainly promoter regions along the genome and more specifically cell cycle gene promoters facilitating their transcription in NSCs. PHF2 was shown to regulate genes involved in G1-S transition (E2f2/3/7/8, Cdc7, Cdc25a, Cdk4, Mcm3/4/8), DNA replication (Orc1/2/6, Pcna), mitosis (Cdk1, Smc2/3/4, Aurkb, Topo2a), as well as chromatin activity (Cenpa, Kdm1b, Hat1, Parp1, Prmt5). In addition, we demontrated that this demethylase colocalizes with H3K4me2/3 marks, partially colocalizes with E2F1 and E2F4 transcription factors and mediates H3K9 demethylation at global and promoter levels. Moreover, PHF2 binds to the centromeric and pericentromeric regions and requiring its catalytic activity suppresses unprogrammed transcription from satellite repeats. In that way, PHF2 allows neural stem cells proliferation and preserves heterochromatin integrity during progenitor expansion. We also showed that PHF2 interacts with heterochromatic components such as the histone methyltransferase SUV39H1 and the HP1-binding protein 3. Furthermore, PHF2 fine-tunes H3K9 methylation levels, ensuring genome stability and chromatin homeostasis, as we observed that its lack of function leads to γH2Ax and R-loops accumulation in NSCs. Interestingly, we demonstrated that PHF2 is essential for neural progenitor self- renewal in the chick embryo neural tube and for neural subpopulation specification. To conclude, this work helps to move forward our understanding of the multiple crosstalks between epigenetics and developmental programs.[spa] Durante el desarrollo neural, los factores reguladores de la actividad de la cromatina son esenciales en el control de la proliferación y diferenciación de las células. PHF2 es una desmetilasa de histonas, asociada a cáncer y a trastornos del espectro autista (ASD) cuya función en el desarrollo neural no ha sido estudiada. PHF2 pertenece a la familia de desmetilasas KDM7. Contiene un dominio PHD, capaz de unirse a residuos de lysinas metiladas y un dominio Jumonji-C (JmjC) enzimáticamente activo, responsable de la actividad desmetilasa hacía las marcas H3K9me y H3K9me2. PHF2 ha sido propuesta como un activador transcripcional pero su localización genómica no ha sido descrita. El objetivo principal de esta tesis doctoral es abordar la función de esta desmetilasa de histonas durante la neurogénesis temprana. Para ello, hemos usado modelos in vitro (progenitores neurales de córtex, NSCs) e in vivo (el tubo neural del embrión de pollo). Nuestros resultados han permitido identificar los lugares de unión de PHF2 en el genoma, esencialmente promotores y más específicamente promotores de genes de ciclo celular facilitando su transcripción. Además, esta desmetilasa colocaliza con las marcas H3K4me2/3, media desmetilación de las marcas H3K9 a nivel global y en promotores. Los experimentos realizados han demostrado que PHF2 se une a las regiones centromérica y pericentromérica y así mantiene niveles bajos de la transcripción de las secuencias repetidas. De esta forma preserva la integridad de la heterocromatina, asegurando la estabilidad genómica y la homeostasis de la cromatina. Estos resultados han sido validados en nuestro modelo in vivo; en el tubo neural, hemos demostrado que PHF2 es esencial para la proliferación y el mantenimiento de la pluripotencia de los progenitores, así como para la especificación de los diferentes tipos de las poblaciones neurales. En resumen, el trabajo presentado ayuda a avanzar en el conocimiento de las múltiples interacciones moleculares entre los programas de desarrollo y la epigenética

Original paper<br>Neopterin and circulating adhesion molecules as prognostic markers in childhood asthma

Introduction: The purpose of this study was to determine the serum levels of neopterin and circulating adhesion molecules sICAM-1, sE-selectin and sL-selectin in children with stable asthma in order to investigate their possible role in the pathogenesis of chronic inflammation in asthma. We also compared atopic and non-atopic asthmatic children in order to detect differences between groups, possibly reflecting different mechanisms involved in chronic inflammation of the airways. Material and methods: The study included three groups of children: A, B and C. Group A consisted of 30 children with atopic asthma, group B of 30 children with non-atopic asthma and group C (control group) of 20 healthy children. All asthmatic children had been diagnosed with mild to moderate persistent asthma according to the International Paediatric Asthma Consensus Group Reports and were studied during a stable phase of their disease. The asthmatic children were divided into atopic and non-atopic, as judged by the presence of a positive or negative skin prick test or a positive specific IgE test. Results: There were no differences in serum sICAM-1, sE-selectin or sL-selectin levels between groups A, B and C. Atopic asthmatic children had significantly higher levels of neopterin compared to the non-atopic asthmatics or healthy children (p<0.001). Conclusions: Our data support the hypothesis that neopterin is produced and secreted by activated macrophages, the latter playing a role in chronic asthmatic inflammation. This may allow a better understanding of the clinical implications and more insight into the inflammatory processes of bronchial asthma

SociaBowl: A dynamic table centerpiece to mediate group conversations

© 2019 Copyright held by the owner/author(s). In this paper, we introduce SociaBowl, a dynamic table centerpiece to promote positive social dynamics in 2-way cooperative conversations. A centerpiece such as a bowl of food, a decorative flower arrangement, or a container of writing tools, is commonly placed on a table around which people have conversations. We explore the design space for an augmented table and centerpiece to influence how people may interact with one another. We present an initial functional prototype to explore different choices in materiality of feedback, interaction styles, and animation and motion patterns. These aspects are discussed with respect to how it may impact people's awareness of their turn taking dynamics as well as provide an additional channel for expression. Potential enhancements for future iterations in its design are then outlined based on these findings

West Nile Virus in <i>Culex</i> Mosquitoes in Central Macedonia, Greece, 2022

In 2022, Greece was the second most seriously affected European country in terms of the West Nile virus (WNV), after Italy. Specifically, Central Macedonia was the region with the most reported human cases (81.5%). In the present study, 30,816 female Culex pipiens sensu lato mosquitoes were collected from May to September 2022 in the seven regional units of Central Macedonia; they were then grouped into 690 pools and tested for WNV, while next-generation sequencing was applied to the samples, which showed a cycle threshold of Ct < 30 in a real-time RT-PCR test. WNV was detected in 5.9% of pools, with significant differences in the detection rate among regional units and months. It is of interest that in the Thessaloniki regional unit, where most of the human cases were observed, the virus circulation started earlier, peaked earlier, and lasted longer than in the other regional units. All sequences clustered into the Central European subclade of WNV lineage 2, and the virus strain differed from the initial Greek strain of 2010 by 0.52% and 0.27% at the nucleotide and amino acid levels, respectively. Signature substitutions were present, such as S73P and T157A in the prM and E structural proteins, respectively. The screening of mosquitoes provides useful information for virus circulation in a region with a potential for early warning, while the availability of whole-genome sequences is essential for further studies, including virus evolution