The Quantity and Quality of African Children's IgG Responses to Merozoite Surface Antigens Reflect Protection against Plasmodium falciparum Malaria

Contains fulltext : 81196.pdf (publisher's version ) (Open Access)BACKGROUND: Antibodies, particularly cytophilic IgG subclasses, with specificity for asexual blood stage antigens of Plasmodium falciparum, are thought to play an important role in acquired immunity to malaria. Evaluating such responses in longitudinal sero-epidemiological field studies, allied to increasing knowledge of the immunological mechanisms associated with anti-malarial protection, will help in the development of malaria vaccines. METHODS AND FINDINGS: We conducted a 1-year follow-up study of 305 Senegalese children and identified those resistant or susceptible to malaria. In retrospective analyses we then compared post-follow-up IgG responses to six asexual-stage candidate malaria vaccine antigens in groups of individuals with clearly defined clinical and parasitological histories of infection with P. falciparum. In age-adjusted analyses, children resistant to malaria as well as to high-density parasitemia, had significantly higher IgG1 responses to GLURP and IgG3 responses to MSP2 than their susceptible counterparts. Among those resistant to malaria, high anti-MSP1 IgG1 levels were associated with protection against high-density parasitemia. To assess functional attributes, we used an in vitro parasite growth inhibition assay with purified IgG. Samples from individuals with high levels of IgG directed to MSP1, MSP2 and AMA1 gave the strongest parasite growth inhibition, but a marked age-related decline was observed in these effects. CONCLUSION: Our data are consistent with the idea that protection against P. falciparum malaria in children depends on acquisition of a constellation of appropriate, functionally active IgG subclass responses directed to multiple asexual stage antigens. Our results suggest at least two distinct mechanisms via which antibodies may exert protective effects. Although declining with age, the growth inhibitory effects of purified IgG measurable in vitro reflected levels of anti-AMA1, -MSP1 and -MSP2, but not of anti-GLURP IgG. The latter could act on parasite growth via indirect parasiticidal pathways

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome

Background: Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods: This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results: We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions: This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Pour une relecture critique des travaux de Pierre Oléron sur les enfants sourds

Courtin Cyril. Pour une relecture critique des travaux de Pierre Oléron sur les enfants sourds. In: Bulletin de psychologie, tome 50 n°427, 1996. 50 ans de psychologie de l'enfant – Hommage au Professeur Pierre Oléron. pp. 57-62

Le cas des théories de l'esprit chez les enfants sourds : impact de la langue des signes

Theory of mind in deaf children : Consequences of sign language communication We assumed that the ability to understand visual perspective diversity could result in the ability to understand conceptual perspectives, such as those estimated by false belief attribution tasks. This hypothesis is here tested by comparing the performances of hearing children and deaf children of signing Deaf parents, aged 5 and 6 years. Sign language, necessiting the use of multiple visual perspectives could promote the acquisition of theories of mind. Data support the hypothesis, as deaf children outperform hearing children. This leads to stress the importance of environmental background (linguistic one in this paper) on cognitive development.On fait l'hypothèse que la capacité de compréhension des perspectives visuelles mènerait à la compréhension des perspectives conceptuelles, telles qu'évaluées notamment par les épreuves d'attribution de fausses croyances. Cette hypothèse est mise à l'épreuve en comparant des enfants entendants et des enfants sourds de parents Sourds signeurs, âgés de 5 et de 6 ans. La langue des signes pourrait en effet favoriser l'acquisition de théories de l'esprit en augmentant la fréquence des confrontations à des perspectives visuelles multiples. Les meilleures performances des enfants sourds aux épreuves d'attribution de fausses croyances montrent qu'une telle hypothèse peut être retenue. Ceci amène alors à souligner l'importance de la variable environnementale (ici linguistique) pour le développement cognitifCourtin Cyril. Le cas des théories de l'esprit chez les enfants sourds : impact de la langue des signes. In: Enfance, n°3, 1999. Comment l'esprit vient aux enfants, sous la direction de Anne-Marie Melot et Jacqueline Nadel. pp. 248-257

Conséquences cognitives des transferts en langue des signes

National audienceThe aim of this study is to bring new elements to the debate on the relationship between language and thought through the study of a sign language. This paper combines in a pioneering way some key concepts of cognitive psychology and linguistics of French Sign Language. We tried to determine how personal transfers (also called role taking) influence cognitive development in two specific areas: theories of mind and cognitive flexibility. In order to do this, an experimental study (Trail Making Test, TMT) was performed with 28 native deaf signing children and 36 non signing hearing children, aged 5 to 7 years. The results confirm the hypothesis that the personal transfers help to make perspective-taking and moving of visual attention from one point to another in space. The signing deaf children perform better than hearing children on the TMT. However, this is not only transfers that lead to perspective-taking, there are also other syntactic processes such as spatialization of signs. In addition, further study is necessary to determine what specific types of personal transfers (double, semi-transfer, stereotype, etc.) carry which types of perspective-taking.L’objectif de cette étude est d’apporter des éléments nouveaux au débat sur les relations entre langage et pensée grâce à l’étude d’une langue des signes. Cet article associe de manière originale des concepts clés de la psychologie cognitive et de la linguistique de la langue des signes française. Nous avons tenté de déterminer en quoi les transferts de personne (appelés aussi prises de rôle) influencent le développement cognitif dans deux domaines précis : les théories de l’esprit et la flexibilité cognitive. Pour ce faire, une étude expérimentale (Trail Making Test, TMT) a été réalisée avec 28 enfants sourds signeurs natifs et 36 enfants entendants non signeurs, âgés de 5 à 7 ans. Les résultats confirment l’hypothèse que les transferts de personne aident aux levées de perspectives et au déplacement de l’attention visuelle d’un point à un autre de l’espace. Les enfants sourds signeurs ont de meilleures performances que les enfants entendants sur l’épreuve du TMT. Cependant, il n’y a pas que les transferts qui amènent aux levées de perspectives, il y a aussi d’autres procédés syntaxiques tels que la spatialisation des signes. Par ailleurs, une étude ultérieure est nécessaire pour déterminer quels types précis de transferts de personne (double, semi-transfert personnel, stéréotype, etc.) entrainent quels types de levées de perspectives

Évaluer les compétences linguistiques des enfants en langue des signes française : une expérience pionnière

Reproduit avec la permission de la revue LIA "Langage, Interaction et Acquisition" Reproduced with permission from the journal LIA "Language, Interaction and Acquisition"International audienceDespite the urgent need for assessment of signers' levels of linguistic skills for many different purposes, there still exists no test to address children's proficiency in French sign language (LSF). We have tried to adapt this sign language a test already valid for another sign language. We chose the BSL test designed by Herman et al. (1999), because its usage is rather simple and can specially be useful both for researchers and for teacher of/in LSF. We have adapted the BSL to LSF and tested 129 deaf children of Deaf or hearing parents with different levels of efficiency in LSF, aged 3 to 14, in order to control for the validity of our adaptation. Although the results show that our LSF version is not valid, this study nonetheless provides us with useful information that can teach us how to solve methodological problems in order to construct a valid and reliable test in the future that will serve as a tool to address theoretical questions in sign language research, such as the concept of critical age for linguistic and cognitive development.Devant l'absence de test d'évaluation des aptitudes linguistiques en langue des signes française (LSF) des enfants signeurs et les besoins exprimés par les nombreux professionnels et chercheurs concernés, nous avons tenté d'adapter à la LSF un test déjà validé pour une autre langue des signes. Notre choix s'est porté sur le test de BSL de Herman et al. (1999), car son usage est relativement simple et peut être utilisé tant pour les besoins de la recherche que par les professeurs de/en LSF. Les résultats obtenus auprès de 129 enfants sourds de parents Sourds ou entendants, de différents niveaux de LSF, âgés de 3 à 14 ans, montrent cependant que notre adaptation du test anglais n'est pas valide : le test n'évalue pas ce qu'il était censé évaluer. Ce qui, à première vue, semble un échec offre cependant plusieurs enseignements sur une méthodologie et des pistes à explorer pour construire un test cette fois fiable et valide qui permettrait de revenir sur des questions essentielles telles que l'idée d'âge critique pour le développement linguistique ou cognitif