A paper-fluidic platfrom to detect Neisseria gonorrhoeae infections in patient urethral and vaginal swab samples

Globally, the microbe Neisseria gonorrhoeae (NG) causes 106 million newly documented sexually transmitted infections each year. Once appropriately diagnosed, NG infections can be treated with readily available antibiotics, but patients in low-resource settings often do not return to the clinic for results. As current NG diagnostic gold standards suffer from slow turnaround time to result, a rapid, sensitive molecular diagnostic would help increase appropriate treatment at the point-of-care. Here, we report on the design and development of a minimally-instrumented paper-fluidic POC diagnostic that incorporates patient swab sample lysis, isothermal nucleic acid capture, thermophilic helicase-dependent amplification (tHDA), an internal amplification control (NGIC), and lateral flow visual detection. Limits of NG detection for the NG/NGIC multiplex tHDA assay were determined within the device, and device clinical performance was validated retroactively against qPCR-quantified patient samples in a proof-of-concept sensitivity and specificity study. This proof-of-principle paper-fluidic diagnostic, which can be completed within 80 minutes, selectively amplifies and detects NG in multiplex with NGIC. It has a clinically relevant limit of detection of 1000 NG cells per device. In urethral swab sample trials (N=20), the device approaches current gold standard NG diagnostic capabilities with 90% sensitivity and 100% specificity and vaginal swab sample trials (N=20) surpass the gold standard with 100% sensitivity and 100% specificity

A paperfluidic platform to detect Neisseria gonorrhoeae in clinical samples

Globally, the microbe Neisseria gonorrhoeae (NG) causes 106 million newly documented sexually transmitted infections each year. Once appropriately diagnosed, NG infections can be readily treated with antibiotics, but high-risk patients often do not return to the clinic for treatment if results are not provided at the point of care. A rapid, sensitive molecular diagnostic would help increase NG treatment and reduce the prevalence of this sexually transmitted disease. Here, we report on the design and development of a rapid, highly sensitive, paperfluidic device for point-of-care diagnosis of NG. The device integrates patient swab sample lysis, nucleic acid extraction, thermophilic helicase-dependent amplification (tHDA), an internal amplification control (NGIC), and visual lateral flow detection within an 80 min run time. Limits of NG detection for the NG/NGIC multiplex tHDA assay were determined within the device, and clinical performance was validated retroactively against qPCR-quantified patient samples in a proof-of-concept study. This paperfluidic diagnostic has a clinically relevant limit of detection of 500 NG cells per device with analytical sensitivity down to 10 NG cells per device. In triplicate testing of 40 total urethral and vaginal swab samples, the device had 95% overall sensitivity and 100% specificity, approaching current laboratory-based molecular NG diagnostics. This diagnostic platform could increase access to accurate NG diagnoses to those most in need.This work was funded by the National Institute of Health National Institute of Allergy and Infectious Diseases award number R01 AI113927 to Boston University and the NIH National Institute of Biomedical and Bioengineering award number U54 EB007958 to Johns Hopkins University. (R01 AI113927 - National Institute of Health National Institute of Allergy and Infectious Diseases; U54 EB007958 - NIH National Institute of Biomedical and Bioengineering)Accepted manuscrip

Activin-A and Bmp4 Levels Modulate Cell Type Specification during CHIR-Induced Cardiomyogenesis

The use of human pluripotent cell progeny for cardiac disease modeling, drug testing and therapeutics requires the ability to efficiently induce pluripotent cells into the cardiomyogenic lineage. Although direct activation of the Activin-A and/or Bmp pathways with growth factors yields context-dependent success, recent studies have shown that induction of Wnt signaling using low molecular weight molecules such as CHIR, which in turn induces the Activin-A and Bmp pathways, is widely effective. To further enhance the reproducibility of CHIR-induced cardiomyogenesis, and to ultimately promote myocyte maturation, we are using exogenous growth factors to optimize cardiomyogenic signaling downstream of CHIR induction. As indicated by RNA-seq, induction with CHIR during Day 1 (Days 0–1) was followed by immediate expression of Nodal ligands and receptors, followed later by Bmp ligands and receptors. Co-induction with CHIR and high levels of the Nodal mimetic Activin-A (50–100 ng/ml) during Day 0–1 efficiently induced definitive endoderm, whereas CHIR supplemented with Activin-A at low levels (10 ng/ml) consistently improved cardiomyogenic efficiency, even when CHIR alone was ineffective. Moreover, co-induction using CHIR and low levels of Activin-A apparently increased the rate of cardiomyogenesis, as indicated by the initial appearance of rhythmically beating cells by Day 6 instead of Day 8. By contrast, co-induction with CHIR plus low levels (3–10 ng/ml) of Bmp4 during Day 0–1 consistently and strongly inhibited cardiomyogenesis. These findings, which demonstrate that cardiomyogenic efficacy is improved by optimizing levels of CHIR-induced growth factors when applied in accord with their sequence of endogenous expression, are consistent with the idea that Nodal (Activin-A) levels toggle the entry of cells into the endodermal or mesodermal lineages, while Bmp levels regulate subsequent allocation into mesodermal cell types

Psychological Determinants of Consumer Acceptance of Personalised Nutrition in 9 European Countries

YesObjective: To develop a model of the psychological factors which predict people’s intention to adopt personalised nutrition. Potential determinants of adoption included perceived risk and benefit, perceived self-efficacy, internal locus of control and health commitment. Methods: A questionnaire, developed from exploratory study data and the existing theoretical literature, and including validated psychological scales was administered to N = 9381 participants from 9 European countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway). Results: Structural equation modelling indicated that the greater participants’ perceived benefits to be associated with personalised nutrition, the more positive their attitudes were towards personalised nutrition, and the greater their intention to adopt it. Higher levels of nutrition self-efficacy were related to more positive attitudes towards, and a greater expressed intention to adopt, personalised nutrition. Other constructs positively impacting attitudes towards personalised nutrition included more positive perceptions of the efficacy of regulatory control to protect consumers (e.g. in relation to personal data protection), higher self-reported internal health locus of control, and health commitment. Although higher perceived risk had a negative relationship with attitude and an inverse relationship with perceived benefit, its effects on attitude and intention to adopt personalised nutrition was less influential than perceived benefit. The model was stable across the different European countries, suggesting that psychological factors determining adoption of personalised nutrition have generic applicability across different European countries. Conclusion: The results suggest that transparent provision of information about potential benefits, and protection of consumers’ personal data is important for adoption, delivery of public health benefits, and commercialisation of personalised nutrition.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n u 265494 (http://cordis.europa.eu/fp7/home_en.html). Food4Me is the acronym of the project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges’’ (http://www.food4me.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

IMPACTOS DA TAXA MÉDIA DA SELIC NAS CARTEIRAS DE INVESTIMENTOS DOS RPPS DA REGIÃO METROPOLITANA DE CURITIBA NOS OITO PRIMEIROS MESES DE AGOSTO DE 2022

Dentre as possibilidades de investimentos financeiros dos Regimes Próprios de Previdência Social (RPPS), a aplicação em ativos de renda fixa tem sido a principal modalidade de alocação de recursos disponível para estes fundos de aposentadorias e pensões ao longo dos anos. Em parte, esta concentração de recursos em ativos desta natureza decorrem da regulamentação imposta pelo Conselho Monetário Nacional (CMN). Grande parte dos ativos de renda fixa adquiridos pelas entidades de previdência são originários de títulos do governo registrados no Sistema Especial de liquidação e Custódia (SELIC), ofertados pelo Tesouro Nacional. A precificação e a rentabilidade destes títulos estão sujeitos aos ventos da situação econômica do Brasil o que associado a um campo restrito de oportunidades de investimento, torna o alcance da meta atuarial um objetivo consideravelmente desafiador. Este trabalho tem por objetivo buscar evidências, de como a variação da taxa SELIC afetou a composição dos investimentos em renda fixa dos três maiores RPPS da Região Metropolitana de Curitiba nos oito primeiros meses do ano de 2022. A metodologia empregada, quanto aos fins, foi majoritariamente quantitativa de estudo de caso, quanto aos meios, constituída de pesquisas bibliográficas e documentais. Com os resultados foi possível constatar que, em decorrência da alta da taxa SELIC, os RPPS abrangidos pela pesquisa abandonaram totalmente a política de investimentos originalmente proposta para o ano de 2022, notadamente quanto a aquisição direta de títulos públicos

Cut-off values for normal sperm morphology and toxicology for automated analysis of rat sperm morphology and morphometry

International audienceWe used automated sperm morphology analysis to investigate rat sperm morphometry and morphology in Sprague-Dawley and Wistar rats in three research centers to develop normal baseline values for sperm morphometry and to quantify the percentage of morphologically normal sperm in healthy rats. The participating centers were IRSN in Paris, France (SpragueDawley rats), University of the Western Cape, South Africa (Wistar rats) and Stellenbosch University (Wistar rats), South Africa. All three centers used identical sperm isolation techniques from the cauda epididymis, the same staining protocols, identical computer-aided sperm morphometry analysis (CASMA) software and microscopes with similar optics. With CASMA, fully automated analysis of the different parts of stained sperm, e.g., head, acrosome, mid-piece, can be performed, many sperm morphometric features can be measured accurately and eventually normal sperm morphology can be defined. We found that it is possible to distinguish sperm morphometric characteristics of Sprague-Dawley and Wistar rats. We also developed cut-off values for evaluating the percentage normal sperm in these two rat strains using the automatic analysis mode. Normal sperm morphology varied between 67 and 74% by contrast with previous findings of > 90%