Randomly controlled drivers using minimally invasive sampling: assessment of drug prevalence in Western Switzerland over two time periods.

According to the World Health Organization, road traffic injuries lead to 1.3 million deaths each year and represent the leading cause of death for young adults under 30 years old. The use of psychoactive substances, including alcohol, drugs and pharmaceuticals, is a well-known risk factor for road traffic injuries. Our study aims to assess the prevalence of substances consumed by drivers in western Switzerland. Such studies are pivotal to improving prevention and developing public awareness campaigns. To assess the prevalence of psychoactive substances among drivers, roadside controls were performed in collaboration with local police, using their classical sampling procedures to detect drivers under the influence of drugs or alcohol over two time periods (P1: 2006-2008, P2: 2017-2020). When impaired driving was not suspected by the police, minimally invasive sampling strategies (i.e., oral fluids during P1 and dried blood spots during P2) were performed on volunteer drivers after a road safety survey. A posteriori analyses and statistical interpretation were then performed. Among the 1605 drivers included in the study, 1048 volunteers provided an oral fluid sample, while 299 provided a dried blood spot sample. The percentage of drivers testing positive for at least one substance that can impact driving abilities was stable over time, with a rate of 10.5% positivity measured over both periods. Considering the different categories of substances, a slight variation was observed between both periods, with 7.6 and 6.3% of pharmaceuticals and 3.6 and 4.9% of illicit drugs for P1 and P2, respectively. Regarding the consumption of illicit drugs, the highest percentage of positivity was measured in biological fluids of drivers under the age of 35, during nights and week-ends, periods which are considered particularly prone to fatal accidents for this age group. Disturbingly, the road safety survey highlighted that drivers' perception of the risk of getting positively controlled while driving after drug consumption is low (3.3 on a 1-to-10 scale, N = 299). The number of positive cases measured in voluntary drivers who passed the preliminary police check demonstrates the importance of systematic biofluid sampling strategies regarding driving under the influence of psychoactive substances. Although the number of fatal road accidents globally has decreased over time, the results of this study reveal the need for both better prevention and deterrent processes that could potentially reduce the risk of fatal road accidents associated with drug consumption

Carcinoma cuniculatum of the larynx

Carcinoma cuniculatum (CC) is a rare clinicopathologic variant of squamous cell carcinoma. Histologically, it is characterized by invasive growth of bland, acanthotic, and keratinizing squamous epithelium that forms multiple rabbit burrow-like, keratin-filled crypts and sinuses. We present a 51-year-old male smoker with CC of the left vocal cord. The tumor was staged T1a and the patient was disease-free 12 months after surgery. To our knowledge, this is the fourth case of CC of the larynx reported in the English literature and the first, due to its early diagnosis, where radical surgery was not performed. We highlight the necessity for awareness of this entity and coordination between otolaryngologists, radiologists, and pathologists for early diagnosis and organ-sparing surgical treatment

Millennials: estudio de la intención de compra de smartphones en plataformas online

El presente trabajo consiste en una investigación cuantitativa que tiene como objetivo analizar el impacto que poseen la calidad de sitio, la reputación de marca, el riesgo percibido y la satisfacción de compra online del cliente en la intención de compra a través de plataformas online de smartphones en la generación millennials, que residen en Córdoba Capital, Argentina. Se arribó a que la satisfacción es un factor clave que influye en la intención de compra de los consumidores millennials en plataformas para la compra de smartphones. A su vez, la reputación de marca influye en la satisfacción por lo cual es indispensable tenerla en cuenta a la hora de desarrollar las estrategias de comercialización online en las organizaciones. Por último, se comprobó que es necesario trabajar en la calidad de sitio web con el fin de incrementar la misma, para disminuir el riesgo percibido.Fil: Gigy Gregoret, Luciana. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Gilardi Blanco, Agostina. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Lozada Chaves, Federica. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Mariel Sonzini, Mariana. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina

Transcriptional regulatory logic of the diurnal cycle in the mouse liver.

Many organisms exhibit temporal rhythms in gene expression that propel diurnal cycles in physiology. In the liver of mammals, these rhythms are controlled by transcription-translation feedback loops of the core circadian clock and by feeding-fasting cycles. To better understand the regulatory interplay between the circadian clock and feeding rhythms, we mapped DNase I hypersensitive sites (DHSs) in the mouse liver during a diurnal cycle. The intensity of DNase I cleavages cycled at a substantial fraction of all DHSs, suggesting that DHSs harbor regulatory elements that control rhythmic transcription. Using chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), we found that hypersensitivity cycled in phase with RNA polymerase II (Pol II) loading and H3K27ac histone marks. We then combined the DHSs with temporal Pol II profiles in wild-type (WT) and Bmal1-/- livers to computationally identify transcription factors through which the core clock and feeding-fasting cycles control diurnal rhythms in transcription. While a similar number of mRNAs accumulated rhythmically in Bmal1-/- compared to WT livers, the amplitudes in Bmal1-/- were generally lower. The residual rhythms in Bmal1-/- reflected transcriptional regulators mediating feeding-fasting responses as well as responses to rhythmic systemic signals. Finally, the analysis of DNase I cuts at nucleotide resolution showed dynamically changing footprints consistent with dynamic binding of CLOCK:BMAL1 complexes. Structural modeling suggested that these footprints are driven by a transient heterotetramer binding configuration at peak activity. Together, our temporal DNase I mappings allowed us to decipher the global regulation of diurnal transcription rhythms in the mouse liver

Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). We show that Pparg <sup>Δ/Δ</sup> lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into Pparg <sup>Δ/Δ</sup> recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIP <sup>tg/+</sup> mice, another lipodystrophic mouse model with normal PPARγ expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis

When Food Meets Man: the Contribution of Epigenetics to Health

Post-translational modifications of chromatin contribute to the epigenetic control of gene transcription. The response to food intake and individual nutrients also includes epigenetic events. Bile acids are necessary for lipid digestion and absorption, and more recently have emerged as signaling molecules. Their synthesis is transcriptionally regulated also in relation to the fasted-to-fed cycle, and interestingly, the underlying mechanisms include chromatin remodeling at promoters of key genes involved in their metabolism. Several compounds present in nutrients affect gene transcription through epigenetic mechanisms and recent studies demonstrate that, beyond the well known anti-cancer properties, they beneficially affect energy metabolism

Quantifying ChIP-seq data:A spiking method providing an internal reference for sample-to-sample normalization

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments are widely used to determine, within entire genomes, the occupancy sites of any protein of interest, including, for example, transcription factors, RNA polymerases, or histones with or without various modifications. In addition to allowing the determination of occupancy sites within one cell type and under one condition, this method allows, in principle, the establishment and comparison of occupancy maps in various cell types, tissues, and conditions. Such comparisons require, however, that samples be normalized. Widely used normalization methods that include a quantile normalization step perform well when factor occupancy varies at a subset of sites, but may miss uniform genome-wide increases or decreases in site occupancy. We describe a spike adjustment procedure (SAP) that, unlike commonly used normalization methods intervening at the analysis stage, entails an experimental step prior to immunoprecipitation. A constant, low amount from a single batch of chromatin of a foreign genome is added to the experimental chromatin. This "spike" chromatin then serves as an internal control to which the experimental signals can be adjusted. We show that the method improves similarity between replicates and reveals biological differences including global and largely uniform changes

IL-23 Blockade for Crohn s disease: next generation of anti-cytokine therapy

Adaptive immunity in intestinal inflammation may play a key role in the pathogenesis of Crohn's disease. In particular, interleukin (IL)-23 may be a key mediator in chronic intestinal inflammation by inducing the differentiation of naïve CD4 + T cells into Th17, with the production of several pro-inflammatory cytokines. Furthermore, IL-23 induces interferon-γ (IFN- γ) production from activated T cells, a critical cytokine in innate and adaptive immunity against infections. Areas covered: We aim to review the available data from literature regarding the role of IL-23, with a more specific focus on the recent progresses in the therapeutic modulation of this cytokine. Expert commentary: Increased knowledge regarding the role of IL-23 has allowed for the development of effective therapeutic progresses by blocking the IL-23 mediated pathways. Primary or secondary loss of response to anti-TNF therapies in Crohn's disease patients during the first year is widely described in literature: the development of new drugs, with alternative mechanisms of action, is thus a key point to consider for the optimal management of these subjects. Drugs blocking the IL-12/23 pathway showed a good efficacy and safety profile in immune-mediated diseases Further studies are necessary regarding the role of the single blockade of IL-23