Experts' consensus on use of electronic cigarettes: a Delphi survey from Switzerland.

OBJECTIVES: In some countries, nicotine-containing electronic cigarettes (e-cigarettes) are considered a consumer product without specific regulations. In others (eg, Switzerland), the sale of e-cigarettes containing nicotine is forbidden, despite the eagerness of many smokers to obtain them. As scientific data about efficacy and long-term safety of these products are scarce, tobacco control experts are divided on how to regulate them. In order to gain consensus among experts to provide recommendations to health authorities, we performed a national consensus study. SETTING: We used a Delphi method with electronic questionnaires to bring together the opinion of Swiss experts on e-cigarettes. PARTICIPANTS: 40 Swiss experts from across the country. OUTCOME MEASURES: We measured the degree of consensus between experts on recommendations regarding regulation, sale, use of and general opinion about e-cigarettes containing nicotine. New recommendations and statements were added following the experts' answers and comments. RESULTS: There was consensus that e-cigarettes containing nicotine should be made available, but only under specific conditions. Sale should be restricted to adults, using quality standards, a maximum level of nicotine and with an accompanying list of authorised ingredients. Advertisement should be restricted and use in public places should be forbidden. CONCLUSIONS: These recommendations encompass three principles: (1) the reality principle, as the product is already on the market; (2) the prevention principle, as e-cigarettes provide an alternative to tobacco for actual smokers, and (3) the precautionary principle, to protect minors and non-smokers, since long-term effects are not yet known. Swiss authorities should design specific regulations to sell nicotine-containing e-cigarettes.

Adolescents et cigarettes électroniques [Adolescents and electronic cigarettes].

L'usage de cigarettes électroniques (vapotage) augmente chez les jeunes et les professionnels de la santé se sentent démunis. Ce court article donne quelques informations pratiques. L'usage (vapotage) de cigarettes électroniques (e-cigarettes) est un phénomène relativement récent qui est en train de prendre une ampleur inattendue, surtout chez les jeunes. Bien que les taux de prévalence soient extrêmement variables d'un pays à l'autre, ils sont en net augmentation: tant parmi ceux qui les ont seulement essayées que chez ceux qui les utilisent habituellement, les taux de prévalence ont doublé ou presque triplé en à peine une année. En outre, une proportion notable d'utilisateurs d'e-cigarettes (de 8 à 33% selon les études)n'avaient jamais fumé de cigarettes conventionnelles. Ce phénomène pourrait faire des e-cigarettes la porte d'entrée au tabagisme parmi les jeunes. Adolescents and electronic cigarettes: The use of electronic cigarettes (vaping) is increasing among young people and health professionals feel ill-prepared. This short article provides some practical information The use of electronic cigarettes (vaping) is increasing among young people and health professionals feel ill-prepared. This short article provides some practical information.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.

Managing the Sick Child in the Era of Declining Malaria Transmission: Development of ALMANACH, an Electronic Algorithm for Appropriate Use of Antimicrobials.

OBJECTIVE: To review the available knowledge on epidemiology and diagnoses of acute infections in children aged 2 to 59 months in primary care setting and develop an electronic algorithm for the Integrated Management of Childhood Illness to reach optimal clinical outcome and rational use of medicines. METHODS: A structured literature review in Medline, Embase and the Cochrane Database of Systematic Review (CDRS) looked for available estimations of diseases prevalence in outpatients aged 2-59 months, and for available evidence on i) accuracy of clinical predictors, and ii) performance of point-of-care tests for targeted diseases. A new algorithm for the management of childhood illness (ALMANACH) was designed based on evidence retrieved and results of a study on etiologies of fever in Tanzanian children outpatients. FINDINGS: The major changes in ALMANACH compared to IMCI (2008 version) are the following: i) assessment of 10 danger signs, ii) classification of non-severe children into febrile and non-febrile illness, the latter receiving no antibiotics, iii) classification of pneumonia based on a respiratory rate threshold of 50 assessed twice for febrile children 12-59 months; iv) malaria rapid diagnostic test performed for all febrile children. In the absence of identified source of fever at the end of the assessment, v) urine dipstick performed for febrile children <2 years to consider urinary tract infection, vi) classification of 'possible typhoid' for febrile children >2 years with abdominal tenderness; and lastly vii) classification of 'likely viral infection' in case of negative results. CONCLUSION: This smartphone-run algorithm based on new evidence and two point-of-care tests should improve the quality of care of <5 year children and lead to more rational use of antimicrobials.

Life-course socioeconomic status and DNA methylation of genes regulating inflammation

BACKGROUND: In humans, low socioeconomic status (SES) across the life course is associated with greater diurnal cortisol production, increased inflammatory activity and higher circulating antibodies for several pathogens, all suggesting a dampened immune response. Recent evidence suggests that DNA methylation of pro-inflammatory genes may be implicated in the biological embedding of the social environment. METHODS: The present study examines the association between life-course SES and DNA methylation of candidate genes, selected on the basis of their involvement in SES-related inflammation, in the context of a genome-wide methylation study. Participants were 857 healthy individuals sampled from the EPIC Italy prospective cohort study. RESULTS: Indicators of SES were associated with DNA methylation of genes involved in inflammation. NFATC1, in particular, was consistently found to be less methylated in individuals with low vs high SES, in a dose-dependent manner. IL1A, GPR132 and genes belonging to the MAPK family were also less methylated among individuals with low SES. In addition, associations were found between SES and CXCL2 and PTGS2, but these genes were consistently more methylated among low SES individuals. CONCLUSIONS: Our findings support the hypothesis that the social environment leaves an epigenetic signature in cells. Although the functional significance of SES-related DNA methylation is still unclear, we hypothesize that it may link SES to chronic disease risk.

Prediction of multiple infections after severe burn trauma: a prospective cohort study.

OBJECTIVE: To develop predictive models for early triage of burn patients based on hypersusceptibility to repeated infections. BACKGROUND: Infection remains a major cause of mortality and morbidity after severe trauma, demanding new strategies to combat infections. Models for infection prediction are lacking. METHODS: Secondary analysis of 459 burn patients (≥16 years old) with 20% or more total body surface area burns recruited from 6 US burn centers. We compared blood transcriptomes with a 180-hour cutoff on the injury-to-transcriptome interval of 47 patients (≤1 infection episode) to those of 66 hypersusceptible patients [multiple (≥2) infection episodes (MIE)]. We used LASSO regression to select biomarkers and multivariate logistic regression to built models, accuracy of which were assessed by area under receiver operating characteristic curve (AUROC) and cross-validation. RESULTS: Three predictive models were developed using covariates of (1) clinical characteristics; (2) expression profiles of 14 genomic probes; (3) combining (1) and (2). The genomic and clinical models were highly predictive of MIE status [AUROCGenomic = 0.946 (95% CI: 0.906-0.986); AUROCClinical = 0.864 (CI: 0.794-0.933); AUROCGenomic/AUROCClinical P = 0.044]. Combined model has an increased AUROCCombined of 0.967 (CI: 0.940-0.993) compared with the individual models (AUROCCombined/AUROCClinical P = 0.0069). Hypersusceptible patients show early alterations in immune-related signaling pathways, epigenetic modulation, and chromatin remodeling. CONCLUSIONS: Early triage of burn patients more susceptible to infections can be made using clinical characteristics and/or genomic signatures. Genomic signature suggests new insights into the pathophysiology of hypersusceptibility to infection may lead to novel potential therapeutic or prophylactic targets.

CNDOL: A fast and reliable method for the calculation of electronic properties of very large systems. Applications to retinal binding pocket in rhodopsin and gas phase porphine.

Very large molecular systems can be calculated with the so called CNDOL approximate Hamiltonians that have been developed by avoiding oversimplifications and only using a priori parameters and formulas from the simpler NDO methods. A new diagonal monoelectronic term named CNDOL/21 shows great consistency and easier SCF convergence when used together with an appropriate function for charge repulsion energies that is derived from traditional formulas. It is possible to obtain a priori molecular orbitals and electron excitation properties after the configuration interaction of single excited determinants with reliability, maintaining interpretative possibilities even being a simplified Hamiltonian. Tests with some unequivocal gas phase maxima of simple molecules (benzene, furfural, acetaldehyde, hexyl alcohol, methyl amine, 2,5 dimethyl 2,4 hexadiene, and ethyl sulfide) ratify the general quality of this approach in comparison with other methods. The calculation of large systems as porphine in gas phase and a model of the complete retinal binding pocket in rhodopsin with 622 basis functions on 280 atoms at the quantum mechanical level show reliability leading to a resulting first allowed transition in 483 nm, very similar to the known experimental value of 500 nm of "dark state." In this very important case, our model gives a central role in this excitation to a charge transfer from the neighboring Glu(-) counterion to the retinaldehyde polyene chain. Tests with gas phase maxima of some important molecules corroborate the reliability of CNDOL/2 Hamiltonians.

Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach.

Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i) there was no support for local adaptation; ii) there was a male-biased infection rate; iii) infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild.

Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.

PURPOSE: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion gene-negative RMS (FN-RMS) patients, but this has not been independently validated. The goal of this study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. EXPERIMENTAL DESIGN: Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS, and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathologic characteristics as well as overall and event-free survival. RESULTS: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N = 57; HR, 7.3; 95% CI, 1.9-27.0; P = 0.003) and failure-free survival (N = 57; HR, 6.1; 95% CI, 1.9-19.7; P = 0.002). CONCLUSIONS: This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk stratification in future prospective clinical trials. Clin Cancer Res; 21(20); 4733-9. ©2015 AACR.

Cigarette électronique : le point en 2015 [Electronic cigarette: what do we know in 2015?].

La cigarette électronique produit de la vapeur à inhaler contenant du propylène-glycol, des arômes et de la nicotine libérée rapidement. 6,7% de la population suisse, surtout des fumeurs, ont essayé la cigarette électronique et 0,1% l'utilise quotidiennement. Malgré l'incertitude due au bas niveau de preuves, la cigarette électronique pourrait être efficace pour cesser ou réduire le tabagisme. La sécurité de la cigarette électronique est démontrée à court terme mais pas à long terme ; sa toxicité semble très inférieure à celle du tabac. Les non-fumeurs et les jeunes utilisent peu la cigarette électronique qui ne semble pas les amener au tabagisme. Les mesures de santé publique recommandées sont la régulation du produit avec contrôle de la qualité ainsi que l'interdiction d'usage dans les lieux publics, de publicité et de vente aux mineurs. Electronic cigarettes are devices producing vapour containing propylene-glycol, flavourings and quickly delivered nicotine. 6.7% of the Swiss population, mainly smokers, experimented the electronic cigarette while 0.1% use it daily. Despite uncertainty due to the low level of evidence, electronic cigarettes might be effective for smoking cessation and reduction. The safety of electronic cigarettes is demonstrated at short-term but not at long-term; however its eventual toxicity is likely to be much lower than tobacco. Use of electronic cigarettes by non-smokers and youth who do not smoke is low and seems unlikely to lead them to tobacco use. Recommended public health measures include product regulation with quality control, ban in public places, prohibition of advertising and sales to minors.

Lésions induites par les pistolets à impulsion électrique de type Taser [Health Risks Concerning Electronic Control Devices]

Les pistolets à impulsion électrique (PIE) sont de plus en plus fréquemment utilisés en Europe ces dernières années, le modèle le plus connu étant le Taser®. Les connaissances scientifiques concernant les PIE et leurs effets potentiels restent toutefois limitées. Nous avons conduit une revue de littérature afin d'évaluer les implications potentielles de leur utilisation en termes de sécurité, de morbidité et de mortalité. Une exposition unique chez un individu sain peut généralement être considérée comme peu dangereuse. Les sujets à risque de complications sont les individus exposés à de multiples décharges, les personnes sous l'influence de substances psychoactives, ceux qui montrent des signes d'agitation extrême, ou encore les individus présentant des comorbidités médicales. L'éventail des complications pouvant survenir lors de leur exposition est large et inclut les lésions provoquées par les impacts des électrodes, les traumatismes liés à la chute induite par la paralysie transitoire ou des complications cardiovasculaires. Dans ce contexte, les personnes exposées doivent être examinées attentivement, et les éventuelles lésions traumatiques doivent être exclues. The use of electronic control devices (ECD), such as the Taser®, has increased in Europe over the past decade. However, scientific data concerning the potential health impact of ECD usage remains limited. We reviewed the scientific literature in order to evaluate the safety, mortality, and morbidity associated with ECD use. Exposure of a healthy individual to a single ECD electroshock can be considered generally safe. Complications can, however, occur if the patient is subject to multiple electroshocks, if the patient has significant medical comorbidities, or when exposure is associated with drug abuse or agitated delirium. The broad spectrum of potential complications associated with ECD exposure includes direct trauma caused by the ECD electrodes, injuries caused by the transient paralysis-induced fall, and cardiovascular events. An ECD-exposed patient requires careful examination during which traumatic injuries are actively sought out.

Déclaration et traitement des événements indésirables en médecine interne [Incident-reporting electronic-based system in internal medicine].

How to recognize, announce and analyze incidents in internal medicine units is a daily challenge that is taught to all hospital staff. It allows suggesting useful improvements for patients, as well as for the medical department and the institution. Here is presented the assessment made in the CHUV internal medicine department one year after the beginning of the institutional procedure which promotes an open process regarding communication and risk management. The department of internal medicine underlines the importance of feedback to the reporters, ensures the staff of regular follow-up concerning the measures being taken and offers to external reporters such as general practioners the possibility of using this reporting system too.