The current generation of ground-based imaging atmospheric Cherenkov telescopes (IACTs) operate in the very-high-energy (VHE) domain from ~100 GeV to ~100 TeV. They use electronic digital trigger ...systems to discern the Cherenkov light flashes emitted by extensive air showers (EASs), from the overwhelming light of the night sky (LoNS) background. Near the telescope energy threshold, the number of emitted Cherenkov photons by gamma-ray-induced EASs is comparable to the fluctuations of the LoNS and the photon distribution at the Cherenkov-imaging camera plane becomes patchy. This results in a severe loss of effectiveness of the digital triggers based on combinatorial logic of thresholded signals. A stereoscopic analog trigger system has been developed for improving the detection capabilities of the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes at the lowest energies. It is based on the analog sum of the photosensor electrical signals. In this article, the architectural design, technical performances, and configuration of this stereoscopic analog trigger, dubbed " Sum-Trigger-II ," are described.
Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in
bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic ...monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an
lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant
(MRSA) clone, ST5. Consequently, we identified another anti-ClfA MAb (SAR114) from human tonsillar B cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific Abs (BiSAbs) comprised of 11H10 or SAR114 as IgG scaffolds and grafted anti-alpha-toxin (MEDI4893*) single-chain variable fragment to the amino or carboxy terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited
potencies similar to those of the parental MAbs, only 11H10-BiSAb, but not SAR114-BiSAb, showed protective activity in murine infection models comparable to the respective MAb combination.
activity with SAR114-BiSAb was observed in infection models with
lacking ClfA. Our data suggest that high-affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both alpha-toxin neutralization and protection
These results indicate that a MAb combination targeting ClfA and alpha-toxin is more promising for future development than the corresponding BiSAb.
The experimental set-up of the RIB in-flight facility EXOTIC Pierroutsakou, D.; Boiano, A.; Boiano, C. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
10/2016, Letnik:
834
Journal Article
Recenzirano
Odprti dostop
We describe the experimental set-up of the Radioactive Ion Beam (RIB) in-flight facility EXOTIC consisting of: (a) two position-sensitive Parallel Plate Avalanche Counters (PPACs), dedicated to the ...event-by-event tracking of the produced RIBs and to time of flight measurements and (b) the new high-granularity compact telescope array EXPADES (EXotic PArticle DEtection System), designed for nuclear physics and nuclear astrophysics experiments employing low-energy light RIBs. EXPADES consists of eight ΔE–Eres telescopes arranged in a cylindrical configuration around the target. Each telescope is made up of two Double Sided Silicon Strip Detectors (DSSSDs) with a thickness of 40/60μm and 300μm for the ΔE and Eres layer, respectively. Additionally, eight ionization chambers were constructed to be used as an alternative ΔE stage or, in conjunction with the entire DSSSD array, to build up more complex triple telescopes. New low-noise multi-channel charge-sensitive preamplifiers and spectroscopy amplifiers, associated with constant fraction discriminators, peak-and-hold and Time to Amplitude Converter circuits were developed for the electronic readout of the ΔE stage. Application Specific Integrated Circuit-based electronics was employed for the treatment of the Eres signals. An 8-channel, 12-bit multi-sampling 50MHz Analog to Digital Converter, a Trigger Supervisor Board for handling the trigger signals of the whole experimental set-up and an ad hoc data acquisition system were also developed. The performance of the PPACs, EXPADES and of the associated electronics was obtained offline with standard α calibration sources and in-beam by measuring the scattering process for the systems 17O+58Ni and 17O+208Pb at incident energies around their respective Coulomb barriers and, successively, during the first experimental runs with the RIBs of the EXOTIC facility.
Purpose
Tumour budding is defined as the presence of isolated or small clusters of malignant cells at the invasive edge of the tumour. It is considered a negative prognostic factor in colorectal ...cancer (CRC) and is associated with a poor outcome and adverse pathological features. Here, we report a meta-analysis of the association of tumour budding and survival in stage II CRC patients.
Methods
PubMed, EMBASE, Web of Science and SCOPUS were searched for studies that assessed the relationship between tumour budding and 5-year overall survival (OS) in stage II CRC patients. Published data were extracted and used to compute odds ratios (ORs) for death at 5 years and hazard ratios (HRs) for survival amongst patients with respect to the extent of tumour budding, using multivariate analysis. Data were pooled using the Mantel–Haenszel random effect model.
Results
We analysed 12 studies that included a total of 1652 patients. High-grade budding was associated with worse OS at 5 years (OR for death, 6.25; 95 % confidence interval CI, 4.04–9.67;
P
< 0.00001). The absolute difference in 5-year OS was −25 % (95 % CI, −18– − 33 %,
P
< 0.00001). It was particularly noteworthy that the presence of high-grade budding was associated with an increased risk of death (HR for death, 3.68; 95 % CI, 2.16–6.28,
P
< 0.00001).
Conclusions
Tumour budding is associated with worse survival in stage II CRC, in particular in pT3N0M0 patients. It could therefore potentially be used when deciding whether to administer adjuvant chemotherapy in high-risk node negative CRC patients.
A fascinating aspect of viral evolution relates to the ability of viruses to escape the adaptive immune response. The widely held view has been that the great variability of viral glycoproteins would ...be an absolute obstacle to the development of antibody-based therapies or vaccines that could confer broad and long-lasting protection. In the past five years, new approaches have been developed to interrogate human memory B cells and plasma cells with high efficiency and to isolate several broadly neutralizing antiviral antibodies against highly variable pathogens such as HIV-1 and influenza virus. These antibodies not only provide new tools for prophylaxis and therapy for viral diseases but also identify conserved epitopes that may be used to design new vaccines capable of conferring broader protection.
The current competitive context puts manufacturers under increasing pressure to provide products and services that meet the particular requirements of individual customers, calling for high ...flexibility in business processes. The complexity and the uncertainty of demand are particularly high in customized contexts, such as the make-to-order (MTO) and engineer-to-order (ETO) sectors, where the ability to deal with more and more differentiated requirements in terms of product features, delivery lead time and cost is crucial. In order to be competitive in such a context, due date (DD) quotation and capacity evaluation at the customer enquiry stage are of strategic importance, having a large impact on the company performance. Despite the large impact on company performance, the importance of DD setting and order acceptance processes and related decisions is often underestimated in practice and the issue is underexposed in the literature. As the applicability of most of the proposed models is limited and there are too few empirical studies describing the practices adopted for capacity and delivery lead-time management in industrial contexts, this study is aimed at developing an understanding of these practices based on a sample of 15 Italian capital goods manufacturers. An interpretative framework is proposed in order to identify the main contextual factors impacting company choices. A model that formalizes the decision process for setting DDs in the analyzed cases is then proposed, suggesting different procedures depending on the type of enquiry submission (DD set by companies or customers) and customer order (fast or slow).
Recent studies suggest that phthalates may have a role in the development of allergic diseases, probably due to an adjuvant effect. The present study aimed to investigate the possible adjuvant effect ...of dibutyl phthalate (DBP) in two in vitro models of contact-allergen induced cell activation, namely the NCTC 2544 IL-18 assay and the THP-1 activation assay. Results show no adjuvant effect in the human keratinocyte cell line NCTC 2544, indicated by lack of increase in interleukin 18 (IL-18) production after exposure to p-Phenylenediamine (PPD) in association with DBP. On the contrary, increased upregulation of CD86 and interleukin 8 (IL-8) production were observed in THP-1 cells exposed to combinations of citral (Cit) or imidazolidinyl urea (IMZ) with DBP, indicative of an adjuvant effect. Additionally, higher production of reactive oxygen species (ROS) in THP-1 cells treated with DBP associated to Cit supports that oxidative stress could be part of the molecular mechanism of the observed adjuvant effect. In conclusion, we demonstrate that DBP presents in vitro an adjuvant effect for immune stimulation in dendritic cells but not in keratinocytes. Future studies are necessary to elucidate the precise mechanism underlying the adjuvant effect of DBP in vitro and in vivo.
•Adjuvant effect of dibutyl phthalate in allergen induced cell activation is reported.•The adjuvant effect was observed in dendritic cells but not in keratinocytes.•Oxidative stress plays a role in the molecular mechanism of this adjuvant effect.
•We realized a detection array for Exotic Radioactive Ion Beams.•High granularity (32×32 pixels 2×2mm wide for 8 telescopes).•High solid angle (8 telescopes 64×64mm wide in a cylindrical ...configuration covering up to 2.6sr).•We tested each component of the array by both alpha particles and in-beam environment.•We measured the angular distribution for 17O elastic scattering on a 58Ni target.
The EXPADES (EXotic PArticle DEtection System) detector array consists of 16 Double Side Silicon Strip Detectors (DSSSD) with active areas of 64×64mm2, arranged in 8 ΔE (40/50μm)–E (300μm) telescopes. All detector faces are segmented into 32×2-mm wide strips, ensuring a 2×2mm2 pixel configuration. Eight ionization chambers can be alternatively used as ΔE stages or, if needed, as an additional third layer for more complex triple telescopes. The signals from silicon ΔE layers and from ionization chambers are read by standard electronics, while innovative 32-channel ASIC chips are employed for the readout of the E stages. The results of off-line tests with alpha sources and from the first in-beam experiment with a 17O beam are presented.
Despite dysphagia large prevalence and the growing ageing phenomenon occurring in European countries, aspiration events among inpatients are often underestimated, given their frequent spontaneous ...resolution or silent contribution to aspiration syndromes. Our main objective was to evaluate the incidence of aspiration events among medical inpatients and to identify risk factors influencing the outcome of the event.
Prospective observational study.
Data about aspiration events - day, hour, type and outcome of the event occurred - along with underlying patient clinical conditions at the admission were collected. Between May 2015 and September 2016, data about aspiration event occurred among medical inpatients were collected in three large Italian hospitals.
Patients affected by aspiration events were 135 on 102,619 cumulative days of hospitalization; they were mostly females (53%) with an average age of 82. The total incidence of aspiration events was of 1.4 every 1,000 days of hospitalization (C.I. 95%: 1.2-1.7) and the most frequent manifestation was cough (61.6%). The addition of drugs or an infection diagnosis during the 24 hours preceding the event acted as risk factors for those events that needed additional interventions during the hospitalization (OR 3.1 e OR 1.9 respectively), while the elimination of one or more prescribed drugs seemed to lead to aspiration events without impact on the hospitalization.
Results showed a large incidence of aspiration events within medical wards, many of them influencing patient outcomes. Healthcare professionals' attention concerning aspiration events should be fostered during the first hours and days of hospitalization.
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