Inherent thermometry in a hybrid superconducting tunnel junction

We discuss inherent thermometry in a Superconductor - Normal metal - Superconductor tunnel junction. In this configuration, the energy selectivity of single-particle tunneling can provide a significant electron cooling, depending on the bias voltage. The usual approach for measuring the electron temperature consists in using an additional pair of superconducting tunnel junctions as probes. In this paper, we discuss our experiment performed on a different design with no such thermometer. The quasi-equilibrium in the central metallic island is discussed in terms of a kinetic equation including injection and relaxation terms. We determine the electron temperature by comparing the micro-cooler experimental current-voltage characteristic with isothermal theoretical predictions. The limits of validity of this approach, due to the junctions asymmetry, the Andreev reflection or the presence of sub-gap states are discussed

Rapid cognitive decline, one-year institutional admission and one-year mortality: Analysis of the ability to predict and inter-tool agreement of four validated clinical frailty indexes in the safes cohort

Objectives: To evaluate the predictive ability of four clinical frailty indexes as regards one-year rapid cognitive decline (RCD — defined as the loss of at least 3 points on the MMSE score), and one-year institutional admission (IA) and mortality respectively; and to measure their agreement for identifying groups at risk of these severe outcomes. Design: One-year follow-up and multicentre study of old patients participating in the SAFEs cohort study. Setting: Nine university hospitals in France. Participants: 1,306 patients aged 75 or older (mean age 85±6 years; 65% female) hospitalized in medical divisions through an Emergency department. Measurements: Four frailty indexes (Winograd; Rockwood; Donini; and Schoevaerdts) reflecting the multidimensionality of the frailty concept, using an ordinal scoring system able to discriminate different grades of frailty, and constructed based on the accumulation of identified deficits after comprehensive geriatric assessment conducted during the first week of hospital stay, were used to categorize participants into three different grades of frailty: Gl — not frail; G2 — moderately frail; and G3 — severely frail. Comparisons between groups were performed using Fisher's exact test. Agreement between indexes was evaluated using Cohen's Kappa coefficient. Results: All patients were classified as frail by at least one of the four indexes. The Winograd and Rockwood indexes mainly classified subjects as G2 (85% and 96%), and the Donini and Schoevaerdts indexes mainly as G3 (71% and 67%). Among the SAFEs cohort population, 250, 1047 and 1,306 subjects were eligible for analyses of predictability for RCD, 1-year IA and 1-year mortality respectively. At 1 year, 84 subjects (34%) experienced RCD, 377 (36%) were admitted into an institutional setting, and 445 (34%) had died With the Rockwood index, all subjects who expenenced RCD were classified in G2; and in G2 and G3 when the Donini and Schoevaerdts indexes were used No significant difference was found between frailty grade and RCD, whereas frailty grade was significantly associated with an increased risk of IA and death, whatever the frailty index considered. Agreement between the different indexes of frailty was poor with Kappa coefficients ranging from −0.02 to 0.15. Conclusion: These findings confirm the poor clinimetric properties of these current indexes to measure frailty, underlining the fact that further work is needed to develop a better and more widely-accepted definition of frailty and therefore a better understanding of its pathophysiolog

Comparative study of statistical methods for detecting association with rare variants in exome-resequencing data

Genome-wide association studies for complex traits are based on the common disease/common variant (CDCV) and common disease/rare variant (CDRV) assumptions. Under the CDCV hypothesis, classical genome-wide association studies using single-marker tests are powerful in detecting common susceptibility variants, but under the CDRV hypothesis they are not as powerful. Several methods have been recently proposed to detect association with multiple rare variants collectively in a functional unit such as a gene. In this paper, we compare the relative performance of several of these methods on the Genetic Analysis Workshop 17 data. We evaluate these methods using the unrelated individual and family data sets. Association was tested using 200 replicates for the quantitative trait Q1. Although in these data the power to detect association is often low, our results show that collapsing methods are promising tools. However, we faced the challenge of assessing the proper type I error to validate our power comparisons. We observed that the type I error rate was not well controlled; however, we did not find a general trend specific to each method. Each method can be conservative or nonconservative depending on the studied gene. Our results also suggest that collapsing and the single-locus association approaches may not be affected to the same extent by population stratification. This deserves further investigation

Functional evaluation of mandibular reconstruction with bone free flap. A GETTEC study

peer reviewedObjectives: To assess the functional results of oromandibular reconstruction by free bone flap, in terms of swallowing, speech and esthetics. Materials and methods: A transverse multicenter study included 134 patients reconstructed by free bone flap between 1998 and 2016, with more than 6 months’ follow-up, in 9 centers. A standardized questionnaire collected data on patients and treatment. Study endpoints comprised: weight loss, mouth opening, gastrostomy dependence, type of feeding, and DHI score. The impact of patient baseline characteristics on these functional criteria was explored by uni/multivariate analysis. Results: Ninety of the 134 patients had cancer. Fibula flap was mainly used (80%). 94% of reconstructions were primary successes. 71% of patients had pre- or post-operative radiation therapy. 88% had less than 50% lingual resection. 97% recovered oral feeding. 89% had intelligible speech. 86% judged their esthetic appearance as good/average. 9% had dental prosthetic rehabilitation. Radiation therapy and extensive lingual resection significantly impacted swallowing function (P = 0.04 and P = 0.03, respectively). Radiation therapy and oropharyngeal extension significantly increased gastrostomy dependence (P = 0.04 and P = 0.02, respectively). Conclusion: Oromandibular reconstruction by free bone flap enabled return to oral feeding in most cases. More than 80% of patients were satisfied with their result in terms of speech and esthetics. However, the rate of dental rehabilitation was low and the rate of complications was high. © 202

A multilingual preregistered replication of the semantic mismatch effect on serial recall

Visual-verbal serial recall is disrupted when task-irrelevant background speech has to be ignored. Contrary to previous suggestion, it has recently been shown that the magnitude of disruption may be accentuated by the semantic properties of the irrelevant speech. Sentences ending with unexpected words that did not match the preceding semantic context were more disruptive than sentences ending with expected words. This particular instantiation of a deviation effect has been termed the semantic mismatch effect. To establish a new phenomenon, it is necessary to show that the effect can be independently replicated and does not depend on specific boundary conditions such as the language of the stimulus material. Here we report a preregistered replication of the semantic mismatch effect in which we examined the effect of unexpected words in 4 different languages (English, French, German, and Swedish) across 4 different laboratories. Participants performed a serial recall task while ignoring sentences with expected or unexpected words that were recorded using text-to-speech software. Independent of language, sentences ending with unexpected words were more disruptive than sentences ending with expected words. In line with previous results, there was no evidence of habituation of the semantic mismatch effect in the form of a decrease in disruption with repeated exposure to the occurrence of unexpected words. The successful replication and extension of the effect to different languages indicates the expression of a general and robust mechanism that reacts to violations of expectancies based on the semantic content of the irrelevant speech. (PsycInfo Database Record (c) 2021 APA, all rights reserved

Quantum Dots for Tracking Dendritic Cells and Priming an Immune Response In Vitro and In Vivo

Dendritic cells (DCs) play a key role in initiating adaptive immune response by presenting antigen to T cells in lymphoid organs. Here, we investigate the potential of quantum dots (QDs) as fluorescent nanoparticles for in vitro and in vivo imaging of DCs, and as a particle-based antigen-delivery system to enhance DC-mediated immune responses. We used confocal, two-photon, and electron microscopies to visualize QD uptake into DCs and compared CD69 expression, T cell proliferation, and IFN-γ production by DO11.10 and OT-II T cells in vivo in response to free antigen or antigen-conjugated to QDs. CD11c+ DCs avidly and preferentially endocytosed QDs, initially into small vesicles near the plasma membrane by an actin-dependent mechanism. Within 10 min DCs contained vesicles of varying size, motion, and brightness distributed throughout the cytoplasm. At later times, endocytosed QDs were compartmentalized inside lysosomes. LPS-induced maturation of DCs reduced the rate of endocytosis and the proportion of cells taking up QDs. Following subcutaneous injection of QDs in an adjuvant depot, DCs that had endocytosed QDs were visualized up to 400 µm deep within draining lymph nodes. When antigen-conjugated QDs were used, T cells formed stable clusters in contact with DCs. Antigen-conjugated QDs induced CD69 expression, T cell proliferation, and IFN-γ production in vivo with greater efficiency than equivalent amounts of free antigen. These results establish QDs as a versatile platform for immunoimaging of dendritic cells and as an efficient nanoparticle-based antigen delivery system for priming an immune response

Safety Assessment of Graphene-Based Materials: Focus on Human Health and the Environment

Graphene and its derivatives are heralded as 'miracle' materials with manifold applications in different sectors of society from electronics to energy storage to medicine. The increasing exploitation of graphene-based materials (GBMs) necessitates a comprehensive evaluation of the potential impact of these materials on human health and the environment. Here we discuss synthesis and characterization of GBMs as well as human and environmental hazard assessment of GBMs using in vitro and in vivo model systems with the aim to understand the properties that underlie the biological effects of these materials; not all GBMs are alike, and it is essential that we disentangle the structure-activity relationships for this class of materials

Combination Therapies Targeting Alk-Aberrant Neuroblastoma in Preclinical Models.

BACKGROUND: ALK activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1-2% of cases. Lorlatinib, a third generation ALK inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data has suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. AIMS: To study the preclinical activity of ALK inhibitors alone and combined with chemotherapy or idasanutlin. METHODS: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSION: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma