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Rituximab (RTX), an anti CD20 monoclonal antibody, is now a gold standard treatment for several auto-immune and chronic inflammatory diseases. Receiving RTX exposes patients to more severe infections as vaccinations become virtually inefficient in terms of B cell responses. During the COVID-19 crisis, RTX–exposed patients exhibited more severe forms of the disease, and in some cases, the introduction of RTX was delayed or avoided to protect patients as much as possible against SARS-CoV-2 infections. We retrospectively collected cellular and humoral responses from thirteen patients with dermatological and rheumatological autoimmune diseases who had been vaccinated after receiving RTX. Memory T cells subsets from patients that exposed to RTX showed few differences when compared to a cohort of healthy donors. The IFNᵧ ELISpot assay using SARS-CoV-Prot_S1 showed that eight patients exhibited a positive response that was neither correlated to the time between RTX infusion and the sampling nor to the time between RTX and the vaccination. Conversely, analysis of the SARS-CoV-2 serology showed a clearly lower binding antibody units per mL in case of recent RTX infusion. The safe threshold forconsistently positive serology was to vaccinate at least 300 days after RTX infusion (p = 0.02). Our data illustrate the difficulty in obtaining a satisfactory response to vaccination after RTX treatment within almost a year after the latest infusion, and emphasize the need to better evaluate the risk of relapses in auto-immune diseases before administering RTX in order to maintain RTX only in patients whose medical situation requires it.

IntroductionWhen Coronavirus Disease-19 (COVID-19) struck the world in December 2019, initiatives started to investigate the efficacy of convalescent plasma, a readily available source of passive antibodies, collected from recovered patients as a therapeutic option. This was based on historical observational data from previous virus outbreaks.MethodsA scoping review was conducted on the efficacy and safety of convalescent plasma and hyperimmune immunoglobulins for COVID-19 treatment. This review included the latest Cochrane systematic review update on 30-day mortality and safety. We also covered use in pediatric and immunocompromised patients, as well as the logistic challenges faced in donor recruitment and plasma collection in general. Challenges for low resource countries were specifically highlighted.ResultsA major challenge is the high donation frequency required from first-time donors to ensure a safe product, which minimizes the risk of transfusion-transmitted infectious. This is particularly difficult in low- and middle- income countries due to inadequate infrastructure and insufficient blood product supplies. High-certainty evidence indicates that convalescent plasma does not reduce mortality or significantly improve clinical outcomes in patients with moderate to severe COVID-19 infection. However, CCP may provide a viable treatment for patients unable to mount an endogenous immune response to SARS-CoV-2, based on mostly observational studies and subgroup data of published and ongoing randomized trials. Convalescent plasma has been shown to be safe in adults and children with COVID-19 infection. However, the efficacy in pediatric patients remains unclear.DiscussionData on efficacy and safety of CCP are still underway in ongoing (randomized) studies and by reporting the challenges, limitations and successes encountered to-date, research gaps were identified to be addressed for the future.ConclusionThis experience serves as a valuable example for future pandemic preparedness, particularly when therapeutic options are limited, and vaccines are either being developed or ineffective due to underlying immunosuppression.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Objective To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial).Design Open label, randomised clinical trial.Setting CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021.Participants 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms 40.Main outcome measures Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids.Results 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10).Conclusions In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further.Trial registration ClinicalTrials.gov NCT04345991.

Introduction COVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients.Methods and analysis COVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle.Ethics and dissemination Ethical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings.Trial registration Clinical Trials.gov (NCT05271929), EudraCT (2021-006621-22)

Background and Objectives: In 2016, France allowed men who have sex with men (MSM) to donate blood if they had not had sex with men in the previous 12 months. In April 2020, this restriction was relaxed to 4 months due to the lack of negative impact observed on blood safety. This study assesses the impact of reducing this deferral period on epidemiological surveillance indicators. Materials and Methods: This study compares infection surveillance indicators between two 30‐month periods before (P1) and after (P2) this second deferral change. Results: Overall, 79 donations tested positive for human immunodeficiency virus (HIV) (49 in P1 and 30 in P2), 322 for hepatitis C virus (HCV) (185 and 137), 622 for hepatitis B virus (HBV) (355 and 267) and 1684 for syphilis (799 and 885). Positive donation rates decreased between P1 and P2, except for syphilis: HIV (0.07/10,000 donations vs. 0.04; p > 0.5), HCV (0.25 vs. 0.20; p < 0.05), HBV (0.49 vs. 0.39; p < 0.01) and syphilis (1.10 vs. 1.29; p < 0.001). For all three viruses, residual risks of transmission by transfusion did not increase: HIV (1/7,800,000 donations vs. 1/10,500,000), HCV (1/25,200,000 vs. 1/47,300,000) and HBV (1/6,400,000 vs. 1/6,000,000). Conclusion: Reducing the deferral period for MSM in April 2020 did not negatively impact residual risks, which remained very low, or the rate of positive donations, except for syphilis, which requires careful monitoring. To ensure equal access to blood donation, MSM have been allowed to donate blood under the same conditions as other donors since March 2022 (i.e., no more than one sexual partner in the last 4 months). [ABSTRACT FROM AUTHOR]

The aim of this study is to better understand how teachers use various embodied semiotic modes -- speech, gestures, gaze, and proxemics -- when they present scientific content to the entire class. To analyse the multimodal practices of these teachers, we integrated the social semiotic theory of multimodality and the joint action theory in didactics. We use a case study methodology to analyse the video data and to describe the productions of two teachers from selected short episodes. The results show several similar elements of these teachers' practices. In particular, their use of several coordinated modes to make a coherent meaning to complex aspects of scientific knowledge such as three- dimensional representations of chemical structures or the relation between an experiment and its model of light diffraction. Both teachers create signs by taking everyday things from their environment to re-signify them in a scientific way. Simultaneously they maintain contact with their students through their gaze and their position. In this way, they create or strengthen the classroom habits related to the explanation of knowledge.

Summary: Background: COVID-19 convalescent plasma (CCP) contains neutralising anti-SARS-CoV-2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. Methods: CCP (n = 766) was compared to non-convalescent control plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralising auto-Abs to type I IFNs and reported adverse events in the recipients. Findings: CCP exhibited a statistically significant increase in IL-6 and TNF-alpha levels (0.531 ± 0.04 vs 0.271 ± 0.04; (95% confidence interval [CI], 0.07371–0.4446; p = 0.0061) and 0.900 ± 0.07 vs 0.283 ± 0.07 pg/mL; (95% [CI], 0.3097–0.9202; p = 0.0000829) and lower IL-10 (0.731 ± 0.07 vs 1.22 ± 0.19 pg/mL; (95% [CI], −0.8180 to −0.1633; p = 0.0034) levels than control plasma. Neutralising auto-Abs against type I IFNs were detected in 14/766 (1.8%) CCPs and were not associated with reported adverse events when transfused. Inflammatory markers and bioactivity in CCP with or without auto-Abs, or in CCP whether or not linked to adverse events in transfused patients, did not differ to a statistically significant extent. Interpretation: Overall, CCP exhibited moderately increased inflammatory markers compared to the control plasma with no discernible differences in ex-vivo bioactivity. Auto-Abs to type I IFNs detected in a small fraction of CCP were not associated with reported adverse events or differences in inflammatory markers. Additional studies, including careful clinical evaluation of patients treated with CCP, are required in order to further define the clinical relevance of these findings. Funding: French National Blood Service—EFS, the Association “Les Amis de Rémi” Savigneux, France, the “Fondation pour la Recherche Médicale (Medical Research Foundation)–REACTing 2020”.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be associated with myocardial injury. Identification of at-risk patients and mechanisms underlying cardiac involvement in COVID-19 remains unclear. During hospitalization for COVID-19, high troponin level has been found to be an independent variable associated with in-hospital mortality and a greater risk of complications. Electrocardiographic (ECG) abnormalities could be a useful tool to identify patients at risk of poor prognostic. The aim of our study was to assess if specific ECGs patterns could be related with in-hospital mortality in COVID-19 patients presenting to the ED in a European country. Methods From February 1st to May 31st, 2020, we conducted a multicenter study in three hospitals in France. We included adult patients (≥ 18 years old) who visited the ED during the study period, with ECG performed at ED admission and diagnosed with COVID-19. Demographic, comorbidities, drug exposures, signs and symptoms presented, and outcome data were extracted from electronic medical records using a standardized data collection form. The relationship between ECG abnormalities and in-hospital mortality was assessed using univariate and multivariable logistic regression analyses. Results An ECG was performed on 275 patients who presented to the ED. Most of the ECGs were in normal sinus rhythm (87%), and 26 (10%) patients had atrial fibrillation/flutter on ECG at ED admission. Repolarization abnormalities represented the most common findings reported in the population (40%), with negative T waves representing 21% of all abnormalities. We found that abnormal axis (adjusted odds ratio: 3.9 [95% CI, 1.1–11.5], p = 0.02), and left bundle branch block (adjusted odds ratio: 7.1 [95% CI, 1.9–25.1], p = 0.002) were significantly associated with in-hospital mortality. Conclusions ECG performed at ED admission may be useful to predict death in COVID-19 patients. Our data suggest that the presence of abnormal axis and left bundle branch block on ECG indicated a higher risk of in-hospital mortality in COVID-19 patients who presented to the ED. We also confirmed that ST segment elevation was rare in COVID-19 patients.

Blood products in therapeutic transfusion are now commonly acknowledged to contain biologically active constituents during the processes of preparation. In the midst of a worldwide COVID-19 pandemic, preliminary evidence suggests that convalescent plasma may lessen the severity of COVID-19 if administered early in the disease, particularly in patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms. This study examined the influence of photochemical Pathogen Reduction Treatment (PRT) using amotosalen‐HCl and UVA light in comparison with untreated control convalescent plasma (n= 72 – paired samples) - cFFP, regarding soluble inflammatory factors: sCD40L, IFN-alpha, IFN-beta, IFN-gamma, IL-1 beta, IL-6, IL-8, IL-10, IL-18, TNF-alpha and ex-vivo inflammatory bioactivity on endothelial cells. We didn’t observe significant modulation of the majority of inflammatory soluble factors (8 of 10 molecules tested) pre- or post-PRT. We noted that IL-8 concentrations were significantly decreased in cFFP with PRT, whereas the IL-18 concentration was increased by PRT. In contrast, endothelial cell release of IL-6 was similar whether cFFP was pre-treated with or without PRT. Expression of CD54 and CD31 in the presence of cFFP were similar to control levels, and both were significant decreased in when cFFP had been pre-treated by PRT. It will be interesting to continue investigations of IL-18 and IL-8, and the physiopathological effect of PRT- treated convalescent plasma and in clinical trials. But overall, it appears that cFFP post-PRT were not excessively pro-inflammatory. Further research, including a careful clinical evaluation of CCP-treated patients, will be required to thoroughly define the clinical relevance of these findings.

This study focuses on the teachers' predictions of the students' performances -- in particular the middle-low achievers -- while solving tasks testing inquiry competencies. The tasks come from PISA science. More specifically we study science teachers' predictions for several aspects: levels of difficulty of the tasks, the potential sources of difficulty and the potential difficulty in solving it for medium-low achievers. We also study what assessed competencies are identified by science teachers in the tasks. Our approach is a questionnaire-based study. A sample of French teachers in science and technology (125) responded to the questionnaire. The teachers show a rather good ability to predict inquiry task levels of difficulty for medium-low achievers and are able to identify relevant potential sources of difficulty or easiness in the items. However, they are not aware of some essential difficulties that medium-low students encounter while solving science inquiry tasks. Moreover, the teachers have difficulty identifying the competencies that are tested by an item.

Democracies in the Indo-Pacific are facing an increasingly competitive and securitized environment, as China turns more assertive and the US-China rivalry escalates. Disruptions include uncertainty about the global economic order, technological decoupling, an arms race amidst intense hot spots, an economic security spiral, and larger systemic risks around climate change, AI governance, etc. Countries such as Japan and Korea are actively responding to these risks through a strategic approach to economic security and increased defense spending, active alliance development, and parallel continued investment in global institutions and dialogue. Canada must be jolted out of its-business-as-usual approach and take a cue from its closest partners in Asia. This includes investing rapidly in its security (2% of defense over GDP) and the creation of an economic security council under the Prime Minister. Canada should also join its key partners in effectively investing in key global institutions in times of crisis. [ABSTRACT FROM AUTHOR]

BackgroundRed blood cell (RBC) transfusions are frequently required in the early period after kidney transplantation. However, the consequences of RBC transfusions on long-term outcomes are largely unrecognized.MethodsWe conducted a nationwide French cohort study involving all 31 French kidney transplant centers. Patients having received a first kidney transplant between January 1, 2002 and December 31, 2008 were identified through the national registry of the French BioMedecine Agency (Agence de BioMédecine). Number and date of RBC transfusions were collected from the national database of the French transfusion public service. The primary endpoint was transplant failure defined as graft loss or death with a functional graft.ResultsAmong 12,559 patients included during the study period, 3,483 (28%) were transfused during the first 14 days post-transplant. Median follow-up was 7.6 (7.5-7.8) years. Multivariable analysis determined that post-transplant RBC transfusion was associated with an increased risk in transplant failure (HR 1.650, 95%CI [1.538;1.771] p

Hepatitis E has emerged as a major transfusion-transmitted infectious risk. Two recipients of plasma from 2 lots (A and B) of pooled solvent/detergent–treated plasma were found to be infected by hepatitis E virus (HEV) that was determined to have been transmitted by the solvent/detergent–treated plasma. HEV RNA viral loads were 433 IU in lot A and 55 IU in lot B. Retrospective studies found that 100% (13/13) of evaluable lot A recipients versus 18% (3/17) of evaluable lot B recipients had been infected by HEV (p50,000 IU were infected, most likely by the HEV-containing solvent/detergent–treated plasma, versus only 7% with a transfused HEV RNA load

Convalescent plasma therapy has been described as an attractive approach to treat critically ill patients with COVID-19 (Coronavirus disease 2019). The selection of convalescent plasma donors (CPD) is commonly based on neutralizing antibody titer. A better understanding of the quality of immune responses following COVID-19 will enable the optimization of convalescent donors' selection in convalescent plasma programs. The involvement of SARS-CoV-2 specific T cells in the induction and persistence of high affinity anti-SARS-CoV-2 neutralizing antibody is still poorly investigated. In this study, 115 CPD who presented SARS-CoV-2 and who were eligible for plasma donation were included. Comprehensive analysis of T cells together with humoral responses were performed in regards of sex, age and blood group type. High frequency of T cell responses against SARS-CoV-2 related protein such as spike glycoprotein (80.0%), nucleocapsid (NCAP) (70.4%) and membrane protein (VME1) (74.8%) were detected in CPD by ex vivo IFN-γ and TNF-α ELISpot assays. Among CPD responders, most exhibited poly-specific T cell responses (75%) defined by the ability to mount responses against at least two SARS-CoV-2 antigens. We found a positive correlation between the magnitude and the poly-specificity of anti-SARS-CoV-2 T cell responses in CPD. Notably, both the magnitude and poly-specificity of SARS-CoV-2 T cell responses were highly correlated with neutralizing antibody titer in CPD. The present study highlights that the poly-specificity and strength of SARS-CoV-2 specific T cell responses predicts neutralizing antibody titer following COVID-19. These observations show the interest to combine T cell assays and antibody titer for the selection of CPD and to a latter extend to assess COVID-19 vaccine efficacy in at-risk patients.

Elodie Martin,1 Marc Sorel,2 Véronique Morel,3 Fabienne Marcaillou,4 Pascale Picard,4 Noémie Delage,4 Florence Tiberghien,5 Marie-Christine Crosmary,6 Mitra Najjar,6 Renato Colamarino,6 Christelle Créach,7,8 Béatrice Lietar,7 Géraldine Brumauld de Montgazon,9 Anne Margot-Duclot,10 Marie-Anne Loriot,11,12 Céline Narjoz,11,12 Céline Lambert,13 Bruno Pereira,13 Gisèle Pickering1,31Université Clermont Auvergne, Pharmacologie Fondamentale Et Clinique de la Douleur, Neuro-Dol, Inserm 1107, F-63000 Clermont-Ferrand, France; 2Centre D’evaluation et de Traitement de la Douleur/soins Palliatifs, Nemours, France; 3CHU Clermont-Ferrand, Centre de Pharmacologie Clinique/Centre d’investigation Clinique Inserm 1405, F-63003 Clermont-Ferrand cedex, France; 4Centre d’Evaluation et de Traitement de la Douleur, CHU de Clermont-Ferrand, France; 5Centre d’evaluation et de Traitement de la Douleur/soins Palliatifs, CHU Jean Minjoz, Besançon, France; 6Centre d’evaluation et de Traitement de la Douleur, CH Jacques Lacarin Vichy, France; 7Centre d’evaluation et de Traitement de la Douleur, CHU de Saint-etienne, France; 8Inserm U1028 & Umr 5292, Centre de Neurosciences de Lyon, Université Lyon & Jean-monnet De Saint-etienne, France; 9Centre d’evaluation et de Traitement de la Douleur/soins Palliatifs, CH La Rochelle, France; 10Centre d’evaluation et de Traitement de la Douleur, Fondation A de Rothschild, Paris, France; 11Service de biochimie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France; 12Inserm UMR-S 1147, Université Paris Descartes, Paris, France; 13CHU Clermont-Ferrand, Délégation Recherche Clinique & Innovation - Villa annexe IFSI, 58 Rue Montalembert, F-63003 Clermont-Ferrand cedex, FrancePurpose: Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N-methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine.Patients and methods: A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks.Results: At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p=0.53) and diminished pain paroxysms (p=0.03) while pain intensity increased significantly with memantine and placebo (p=0.04). At 3 months, pain remained lower than at inclusion (p=0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine (p

The understanding of measurement is related to the understanding of the nature of science--one of the main goals of current international science teaching at all levels of education. This case study explores how a first-year university physics course deals with measurement uncertainties in the light of an epistemological analysis of measurement. The data consist of the course documents, interviews with senior instructors, and laboratory instructors' responses to an online questionnaire. During laboratory work, uncertainties are expressed in the large majority of the measurements made by the students but only in less than half of their calculation results. The instructors' expectations are that students systematically estimate uncertainties so that they become aware that measurements and calculations are never exact. However, since uncertainties are not specified for the values given in the laboratory guides, uncertainties are often missing from the results of students' calculations. The potential side effects of students' measurement understanding are discussed and suggestions for improvements are proposed.

The understanding of what makes a question difficult is a crucial concern in assessment. To study the difficulty of test questions, we focus on the case of PISA, which assesses to what degree 15-year-old students have acquired knowledge and skills essential for full participation in society. Our research question is to identify PISA science item characteristics that could influence the item's proficiency level. It is based on an a-priori item analysis and a statistical analysis. Results show that only the cognitive complexity and the format out of the different characteristics of PISA science items determined in our a-priori analysis have an explanatory power on an item's proficiency levels. The proficiency level cannot be explained by the dependence/independence of the information provided in the unit and/or item introduction and the competence. We conclude that in PISA, it appears possible to anticipate a high proficiency level, that is, students' low scores for items displaying a high cognitive complexity. In the case of a middle or low cognitive complexity level item, the cognitive complexity level is not sufficient to predict item difficulty. Other characteristics play a crucial role in item difficulty. We discuss anticipating the difficulties in assessment in a broader perspective.

Trial design Two randomised controlled vaccination trials with artificial challenges were carried out in addition to a serological survey of levels of maternally derived antibodies (MDA) to parainfluenza type 3 virus (PI3V) and bovine respiratory syncytial virus (BRSV) in European calves.Participants Ten-day-old calves with and without MDA were included in the two vaccine trials.Interventions Intranasal administration of a bivalent modified live (PI3V/BRSV) vaccine followed by artificial challenge approximately three months post vaccination.Objective The study aimed to assess the efficacy of a modified live respiratory vaccine, Bovalto Respi Intranasal (Boehringer Ingelheim). In order to assess the interference of MDA, both seropositive and seronegative calves were used.Randomisation PI3V and BRSV serological status was determined seven days before vaccination; calves without maternal antibodies became the MDA− vaccinates. Calves with MDA were ranked according to individual titres and allocated alternately to MDA+ vaccinate and MDA+ control groups.Blinding Treatment was carried out by the unblinded study director. Animal care and veterinary examinations were conducted by personnel unaware of the treatments received. The serological survey used blood samples obtained from calves on commercial farms in five European countries, Germany, Spain, Italy, Ireland and the UK, to determine the levels of MDA to PI3V and BRSV in calves approximately two weeks of age.Results A total of 36 calves were included in the two challenge studies and 32 of these completed the challenge studies. Twenty-one calves were included in the PI3V challenge study, with six of six MDA− and six of seven MDA+ vaccinated calves and five of five MDA+ unvaccinated control calves being challenged with PI3V. Fifteen calves were included in the BRSV challenge study, with five of five MDA− and five of five MDA+ vaccinated calves and five of five MDA+ unvaccinated control calves being challenged with BRSV.Outcome For both challenges, clinical scores and nasal shedding were significantly higher in control animals compared with vaccinates (PI3V challenge: clinical scores P=0.001, nasal shedding P=0.001; BRSV challenge: clinical scores P=0.016, nasal shedding P=0.002) and not significantly different between MDA+ and MDA− vaccinated animals for both challenges (P>0.05). A total of 254 samples from six countries were tested in the serological survey of MDA.Conclusion The results of the challenge studies demonstrated the efficacy of the vaccine in the presence of BRSV and PI3V MDA under laboratory conditions. The field assessment confirmed that the MDA titres in the MDA+ calves corresponded to those typically found on farms.

Individual differences in arithmetic have been explained by differences in cognitive processes and by arithmetic strategy use and selection. In the present study, we investigated the involvement of reactive and proactive control processes. We explored how variation in proactive and reactive control was related to individual differences in strategy selection. We correlated proactive and reactive measures obtained from the AX-CPT and an adjusted N-back task with a measure of strategy adaptiveness during a numerosity judgment task. The results showed that both measures of reactive control (of the AX-CPT and N-back task) correlated positively with strategy adaptiveness, while proactive control was not. This suggests that both cognitive control modes might have a different effect on adaptive strategy selection, where adaptive strategy selection seems to benefit from a transient (late) control mode, reactive control. We discuss these results in the light of the Dual Mechanisms Framework.

Gisèle Pickering,1–3 Elodie Martin,1,3 Florence Tiberghien,4 Claire Delorme,5 Gérard Mick6,7 1Centre de Pharmacologie Clinique, CHU Clermont-Ferrand, 2Inserm, CIC 1405, Neurodol 1107, 3Laboratoire de Pharmacologie, Faculté de Médecine, Clermont Université, Clermont-Ferrand, 4Centre d’Evaluation et de Traitement de la Douleur, CHU Jean Minjoz, Besançon, 5Centre d’Evaluation et Traitement de la Douleur, Bayeux, 6Unité d’Evaluation et Traitement de la Douleur, Voiron, 7Laboratoire AGEIS, Université Grenoble Alpes, Grenoble, France Background: Pain localization is one of the hallmarks for the choice of first-line treatment in neuropathic pain. This literature review has been conducted to provide an overview of the current knowledge regarding the etiology and pathophysiology of localized neuropathic pain (LNP), its assessment and the existing topical pharmacological treatments. Materials and methods: Literature review was performed using Medline from 2010 to December 2016, and all studies involving LNP and treatments were examined. A multidisciplinary expert panel of five pain specialists in this article reports a consensus on topical approaches that may be recommended to alleviate LNP and on their advantages in clinical practice. Results: Successive international recommendations have included topical 5% lidocaine and 8% capsaicin for LNP treatment. The expert panel considers that these compounds can be a first-line treatment for LNP, especially in elderly patients and patients with comorbidities and polypharmacy. Regulatory LNP indications should cover the whole range of LNP and not be restricted to specific etiologies or sites. Precautions for the use of plasters must be followed cautiously. Conclusion: Although there is a real need for more randomized controlled trials for both drugs, publications clearly demonstrate excellent risk/benefit ratios, safety, tolerance and continued efficacy throughout long-term treatment. A major advantage of both plasters is that they have proven efficacy and may reduce the risk of adverse events such as cognitive impairment, confusion, somnolence, dizziness and constipation that are often associated with systemic neuropathic pain treatment and reduce the quality of life. Topical modalities also may be used in combination with other drugs and analgesics with limited drug–drug interactions. Keywords: neuropathic pain, topical, localized, medicated plaster, patch, review

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.

This paper deals with the joint construction of knowledge by the teacher and the students in a physics classroom. It is focused on the status of epistemic certainty/uncertainty of knowledge. The same element of knowledge can be introduced as possible and thus uncertain and then evolve towards a status of epistemic certainty; the status of other elements can do the reverse. The evolution of a certainty/uncertainty status reflects the evolution of the shared knowledge in the classroom. The study of this evolution is based on a previous analysis of the evolution of knowledge in a classroom during a teaching sequence of mechanics at grade 10. From this analysis two notions were selected and the evolution of the elements of knowledge associated was analyzed in terms of epistemic certainty/uncertainty. The results show how the emergence of new epistemic questions depends on the nature and status of student's prior knowledge; in other terms, new epistemic uncertainty emerges from epistemic certainty.

Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.106, 8.106 and 12.106 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3+regulatory T cells and PD-1+ T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

The present study investigated the impact of study-test similarity on face recognition by manipulating, in the same experiment, the expression change (same vs. different) and the task-processing context (inclusion vs. exclusion instructions) as within-subject variables. Consistent with the dual-process framework, the present results showed that participants performed better on the inclusion task than on the exclusion task, with no response bias. A mid-frontal FN400 old/new effect and a parietal old/new effect were found in both tasks. However, modulations of the ERP old/new effects generated by the expression change on recognized faces differed across tasks. The modulations of the ERP old/new effects were proportional to the degree of matching between the study face and the recognition face in the inclusion task, but not in the exclusion task. The observed modulation of the FN400 old/new effect by the task instructions when familiarity and conceptual priming were kept constant indicates that these early ERP correlates of recognition depend on voluntary task-related control. The present results question the idea that FN400 reflects implicit memory processes such as conceptual priming and show that the extent to which the FN400 discriminates between conditions depends on the retrieval orientation at test. They are discussed in relation to recent controversies about the ERP correlates of familiarity in face recognition. This study suggests that while both conceptual and perceptual information can contribute to the familiarity signal reflected by the FN400 effect, their relative contributions vary with the task demands. (Contains 3 tables and 3 figures.)

During Dec-2013, a chikungunya virus (CHIKV) outbreak was first detected in the French-West Indies. Subsequently, the virus dispersed to other Caribbean islands, continental America and many islands in the Pacific Ocean. Previous estimates of the attack rate were based on declaration of clinically suspected cases.Individual testing for CHIKV RNA of all (n = 16,386) blood donations between Feb-24th 2014 and Jan-31st 2015 identified 0·36% and 0·42% of positives in Guadeloupe and Martinique, respectively. The incidence curves faithfully correlated with those of suspected clinical cases in the general population of Guadeloupe (abrupt epidemic peak), but not in Martinique (flatter epidemic growth). No significant relationship was identified between CHIKV RNA detection and age-classes or blood groups. Prospective (Feb-2014 to Jan-2015; n = 9,506) and retrospective (Aug-2013 to Feb-2014; n = 6,559) seroepidemiological surveys in blood donors identified a final seroprevalence of 48·1% in Guadeloupe and 41·9% in Martinique. Retrospective survey also suggested the absence or limited "silent" CHIKV circulation before the outbreak. Parameters associated with increased seroprevalence were: Gender (M>F), KEL-1, [RH+1/KEL-1], [A/RH+1] and [A/RH+1/KEL-1] blood groups in Martiniquan donors. A simulation model based on observed incidence and actual seroprevalence values predicted 2·5 and 2·3 days of asymptomatic viraemia in Martiniquan and Guadeloupian blood donors respectively.This study, implemented promptly with relatively limited logistical requirements during CHIKV emergence in the Caribbean, provided unique information regarding retrospective and prospective epidemiology, infection risk factors and natural history of the disease. In the stressful context of emerging infectious disease outbreaks, blood donor-based studies can serve as robust and cost-effective first-line tools for public health surveys.

In literature, several processes have been suggested to describe conceptual changes being undertaken. However, a few parts of studies analyse in great detail which students' learning processes are involved in physics classes during teaching, and how they are used. Following a socio-constructivist approach using tools coming from discourse analysis, we suggest studying three processes of students' learning: (1) establishing links between ideas, (2) increasing the domain of applicability of ideas, or (3) decreasing the domain of applicability of ideas. Our database consists of video data and written worksheets of two students at the upper-secondary school level (Grade 10 [15-year-old students]) during a one-month teaching sequence about gas. Based on semiotic resources contained in oral and written language, we reconstruct in great detail all the ideas about gas expressed by both students during the entire teaching sequence. Our analysis deals with (1) how learning processes are identified based on the ideas expressed by students, and (2) how the three learning processes are used by the two students during teaching. Our results show that during the teaching sequence: (1) the emergence of the networks of three ideas is supported by networks of two ideas expressed previously by students; (2) both students express more networks of two ideas than networks of three ideas; (3) the process "increasing the domain of applicability" of an idea or a network of ideas is very often involved; and (4) the process "decreasing the domain of applicability" of an idea or network of ideas is rarely used by them. (Contains 10 figures, 3 tables, and 3 notes.)

We screened plasma samples (minipools of 96 samples, corresponding to 53,234 blood donations) from France that had been processed with solvent–detergent for hepatitis E virus RNA. The detection rate was 1 HEV-positive sample/2,218 blood donations. Most samples (22/24) from viremic donors were negative for IgG and IgM against HEV.

Introduction: Adopting a conceptual change perspective yields information not only about the organization of students' conceptions and the mechanisms behind their changes, but also about the most effective teaching interventions for promoting conceptual change. In experimental science, modelling constitutes a basic activity for acquiring and using scientific concepts, and a key method for eliciting conceptual change. The aim of this study was to investigate how modelling activities can elicit conceptual changes concerning the notion of energy. Method: 40 students aged 16-17 years, working in pairs had to construct symbolic representations of three materially present experiments ("Battery-bulb", "Falling object" and "Rising object") drawing on a simple model that introduced them to the properties of energy. In order to track changes in their cognitive processes, we defined a number of specific modelling categories. Results: Results showed that students implemented increasingly complex cognitive processes to solve the three problems. Modelling activities enhance the ability to process the material world and the world of theories and models simultaneously, even when there is no isomorphism between the two. Discussion: The modelling activities we administered to students promoted efficient learning, insofar as the conceptual change mechanism was put in place. Solving the three problems allowed students to draw on their prior knowledge but also to develop new knowledge about the material and theoretical worlds. They acquired the ability to process representations simultaneously from concrete and conceptual worlds and to move freely between them, despite their lack of isomorphism. (Contains 1 figure and 4 tables.)

Design-based research, and particularly its theoretical status, is a subject of debate in the science education community. In the first part of this paper, a theoretical framework drawn up to develop design-based research will be presented. This framework is mainly based on epistemological analysis of physics modelling, learning and teaching hypotheses. It includes grand theories, a specific theory that following Cobb, Confrey, diSessa, Lehrer, and Schauble is a "humble theory" in the sense that it does "real work", and tools for design. In the second part, we will show how this specific theory and its tools led designers to develop teaching resources in the case of a teaching sequence on mechanics (Grade 10). We will explain how the components of the specific theory and tools guide the design at different levels; the conceptual structure of the teaching sequence, the chronology of the activities, the various choices of the type of activity and their wording. This presentation makes the bases of designing teaching resources explicit and therefore allows for scientific debate. (Contains 15 figures, 2 tables, and 3 notes.)

This commentary on Roth, Lee, and Hwang's paper aims at analysing their theoretical approach in terms of its object of study, and the aspects that are brought to the fore, like the cultural activity of conversation, and those that are overshadowed, like the role of the material world and its perception on learning. This analysis, developed on the basis of a pragmatic approach that combines theoretical frameworks, leads to a debate about the relevant components of teaching-learning situations according to the theoretical approaches, and the extent to which, due to the complexity of the studied phenomena, some theoretical frameworks are complementary or concurrent.