Effects of gestational age at birth on cognitive performance : a function of cognitive workload demands

Objective: Cognitive deficits have been inconsistently described for late or moderately preterm children but are consistently found in very preterm children. This study investigates the association between cognitive workload demands of tasks and cognitive performance in relation to gestational age at birth. Methods: Data were collected as part of a prospective geographically defined whole-population study of neonatal at-risk children in Southern Bavaria. At 8;5 years, n = 1326 children (gestation range: 23–41 weeks) were assessed with the K-ABC and a Mathematics Test. Results: Cognitive scores of preterm children decreased as cognitive workload demands of tasks increased. The relationship between gestation and task workload was curvilinear and more pronounced the higher the cognitive workload: GA2 (quadratic term) on low cognitive workload: R2 = .02, p<0.001; moderate cognitive workload: R2 = .09, p<0.001; and high cognitive workload tasks: R2 = .14, p<0.001. Specifically, disproportionally lower scores were found for very (<32 weeks gestation) and moderately (32–33 weeks gestation) preterm children the higher the cognitive workload of the tasks. Early biological factors such as gestation and neonatal complications explained more of the variance in high (12.5%) compared with moderate (8.1%) and low cognitive workload tasks (1.7%). Conclusions: The cognitive workload model may help to explain variations of findings on the relationship of gestational age with cognitive performance in the literature. The findings have implications for routine cognitive follow-up, educational intervention, and basic research into neuro-plasticity and brain reorganization after preterm birth

A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer

International audienceBACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n=55), 10 mg/kg Q3W (n=238), or 10 mg/kg Q2W (n=156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady-state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and nonlinear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events of interest based on their immune etiology. RESULTS: Overall response rates were 15% (95% confidence interval [CI] 7%-28%) at 2 Q3W, 25% (18%-33%) at 10 Q3W, and 21% (95% CI 14% to 30%) at 10 Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6week indicated a flat relationship (regression slope P\textgreater0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the adverse event incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2 mg/kg to 10 mg/kg. These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.ClinicalTrials.gov registry: NCT0129582

Identification of a Protein in Several Borrelia Species which is Related to OspC of the Lyme Disease Spirochetes.

Using oligonucleotide probes which have previously been shown to be specific for the ospC gene found in the Lyme disease spirochete species Borrelia burgdorferi, B. garinii, and group VS461, we detected an ospC homolog in other Borrelia species including B. coriaceae, B. hermsii, B. anserina, B. turicatae, and B. parkeri. In contrast to the Lyme disease spirochetes, which carry the ospC gene on a 26-kb circular plasmid, we mapped the gene in other Borrelia species to linear plasmids which varied in size among the isolates tested. Some isolates carry multiple copies of the gene residing on linear plasmids of different sizes. The analyses conducted here also demonstrate that these Borrelia species contain a linear chromosome. Northern (RNA) blot analyses demonstrated that the gene is transcriptionally expressed in all species examined. High levels of transcriptional expression were observed in some B. hermsii isolates. Transcriptional start site analyses revealed that the length of the untranslated leader sequence was identical to that observed in the Lyme disease spirochete species. By Western blotting (immunoblotting) with antiserum (polyclonal) raised against the OspC protein of B. burgdorferi, we detected an immunoreactive protein of the same molecular weight as the OspC found in Lyme disease spirochete species. The results presented here demonstrate the presence of a protein that is genetically and antigenically related to OspC which is expressed in all species of the genus Borrelia tested

Analysis of the Distribution and Molecular Heterogeneity of the ospD Gene among the Lyme Disease Spirochetes: Evidence for Lateral Gene Exchange

Analysis of the ospD gene has revealed that this gene is not universal among Lyme disease spirochete isolates. The gene was found to be carried by 90, 50, and 24% of the Borrelia garinii, B. afzelii, and B. burgdorferi isolates tested. Size variability in the ospD-encoding plasmid was also observed. Sequence analysis has demonstrated the presence of various numbers of a 17-bp repeated sequence in the upstream control (promoter) region of the gene. In addition, a region within the coding sequence where various insertions, deletions, and direct repeats occur was identified. ospD gene sequences from 31 different isolates were determined and utilized in pairwise sequence comparisons and construction of a gene tree. These analyses suggest that the ospD gene was the target of several recombinational events and that the gene was recently acquired by Lyme disease spirochetes and laterally transferred between species

Executive functions in preschool children with aggressive behavior: impairments in inhibitory control

The question whether executive function (EF) deficits in children are associated with conduct problems remains controversial. Although the origins of aggressive behavior are to be found in early childhood, findings from EF studies in preschool children with aggressive behavior are inconsistent. The current study aimed to investigate whether preschool children with aggressive behavior show impairments in EF. From a population-based sample, 82 preschool children who were showing aggressive behavior as indicated by scores at or above the 93rd percentile on the Aggressive Behavior Scale of the CBCL 1 1/2-5 were selected. These children with aggressive behavior were matched on IQ to a group of typically developing control children (N=99). Six neuropsychological tasks were administered to assess set shifting, inhibition, working memory and verbal fluency. A factor analysis was conducted which yielded one clear factor: inhibition. Aggressive preschool children showed poorer performance on this inhibition factor than control children and boys performed worse on this factor than girls. This association between aggressive behavior and inhibition deficits was maintained after controlling for attention problems. In addition, gender differences in all EFs measured were found with boys exhibiting more impairment in EF than girls. These findings demonstrate that preschool children with aggressive behavior show impairments in inhibition, irrespective of attention problems

US hegemony and the origins of Japanese nuclear power : the politics of consent

This paper deploys the Gramscian concepts of hegemony and consent in order to explore the process whereby nuclear power was brought to Japan. The core argument is that nuclear power was brought to Japan as a consequence of US hegemony. Rather than a simple manifestation of one state exerting material ‘power over' another, bringing nuclear power to Japan involved a series of compromises worked out within and between state and civil society in both Japan and the USA. Ideologies of nationalism, imperialism and modernity underpinned the process, coalescing in post-war debates about the future trajectory of Japanese society, Japan's Cold War alliance with the USA and the role of nuclear power in both. Consent to nuclear power was secured through the generation of a psychological state in the public mind combining the fear of nuclear attack and the hope of unlimited consumption in a nuclear-fuelled post-modern world

Physiological characteristics of dysphagia following thermal burn injury

The study aim was to document the acute physiological characteristics of swallowing impairment following thermal burn injury. A series of 19 participants admitted to a specialised burn centre with thermal burn injury were identified with suspected aspiration risk by a clinical swallow examination (CSE) conducted by a speech-language pathologist and referred to the study. Once medically stable, each then underwent more detailed assessment using both a CSE and fiberoptic evaluation of swallowing (FEES). FEES confirmed six individuals (32%) had no aspiration risk and were excluded from further analyses. Of the remaining 13, CSE confirmed that two had specific oral-phase deficits due to orofacial scarring and contractures, and all 13 had generalised oromotor weakness. FEES revealed numerous pharyngeal-phase deficits, with the major findings evident in greater than 50% being impaired secretion management, laryngotracheal edema, delayed swallow initiation, impaired sensation, inadequate movement of structures within the hypopharynx and larynx, and diffuse pharyngeal residue. Penetration and/or aspiration occurred in 83% (n = 10/12) of thin fluids trials, with a lack of response to the penetration/aspiration noted in 50% (n = 6/12 penetration aspiration events) of the cases. Most events occurred post swallow. Findings support the fact that individuals with dysphagia post thermal burn present with multiple risk factors for aspiration that appear predominantly related to generalised weakness and inefficiency and further impacted by edema and sensory impairments. Generalised oromotor weakness and orofacial contractures (when present) impact oral-stage swallow function. This study has identified a range of factors that may contribute to both oral- and pharyngeal-stage dysfunction in this clinical population and has highlighted the importance of using a combination of clinical and instrumental assessments to fully understand the influence of burn injury on oral intake and swallowing

Une intervention de groupe brève pour favoriser le bien-être des femmes enceintes pendant la pandémie de COVID-19 et soutenir la résilience des familles

Contexte: La pandémie de COVID-19 a été associée à une augmentation de la détresse psychologique chez les femmes enceintes. Le présent article vise à évaluer l’acceptabilité du programme STEP-COVID (Soutenir la Transition et l’Engagement dans la Parentalité dans le contexte de la pandémie de COVID-19), une intervention prénatale de groupe en ligne, en mode synchrone, visant à soutenir le bien-être, la mentalisation et la résilience. Méthode: Vingt et une femmes enceintes québécoises ont participé au programme et ont complété des mesures des symptômes psychologiques et de la mentalisation avant et après l’intervention ainsi qu’une échelle évaluant leur perception de changements sur des domaines associés à la résilience. Après chaque rencontre, elles ont rempli un questionnaire évaluant leur appréciation du programme. Résultats: Les 18 participantes (86&nbsp;%) ayant complété le programme ont rapporté de hauts taux de satisfaction après chacune des rencontres et au terme de l’intervention. Une diminution des symptômes anxio-dépressifs et des symptômes de stress post-traumatiques et une amélioration des fonctions réflexives sont observées entre le début et la fin du programme. Les participantes ont également rapporté des changements positifs sur des sphères de fonctionnement associées à la résilience. Conclusion: Les résultats soutiennent l’acceptabilité du programme STEP-COVID et suggèrent que l’offre d’une intervention de groupe brève en ligne est appréciée par les participantes, semble favoriser une diminution de la détresse psychologique et une amélioration de la mentalisation et pourrait contribuer à la résilience dans le contexte de la pandémie de COVID-19