Significance: The emergence of human infection with a novel H7N9 avian influenza reassortant in China raises a pandemic concern. However, it is not fully understood how these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that a “fittest” genotype (G57) emerged with changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens and caused widespread outbreaks before the H7N9 virus emergence, increasing reassortment between H9N2 and other subtype viruses and finally providing all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.

The physiological basis and mechanistic requirements for a large number of functional immunoreceptor tyrosine-based activation motifs (ITAMs; high ITAM multiplicity) in the complex of the T cell antigen receptor (TCR) and the invariant signaling protein CD3 remain obscure. Here we found that whereas a low multiplicity of TCR-CD3 ITAMs was sufficient to engage canonical TCR-induced signaling events that led to cytokine secretion, a high multiplicity of TCR-CD3 ITAMs was required for TCR-driven proliferation. This was dependent on the formation of compact immunological synapses, interaction of the adaptor Vav1 with phosphorylated CD3 ITAMs to mediate the recruitment and activation of the oncogenic transcription factor Notch1 and, ultimately, proliferation induced by the cell-cycle regulator c-Myc. Analogous mechanistic events were also needed to drive proliferation in response to weak peptide agonists. Thus, the TCR-driven pathways that initiate cytokine secretion and proliferation are separable and are coordinated by the multiplicity of phosphorylated ITAMs in TCR-CD3.

In mental health and psychosocial studies it is often necessary to report on the between-rater agreement of measures used in the study. This paper discusses the concept of agreement, highlighting its fundamental difference from correlation. Several examples demonstrate how to compute the kappa coefficient – a popular statistic for measuring agreement – both by hand and by using statistical software packages such as SAS and SPSS. Real study data are used to illustrate how to use and interpret this coefficient in clinical research and practice. The article concludes with a discussion of the limitations of the coefficient.

Purpose: Children receiving CNS-directed therapy for cancer are at risk for cognitive problems, with few available empirically supported interventions. Cognitive problems indicate neurodevelopmental disruption that may be modifiable with intervention. This study evaluated short-term efficacy of a computerized cognitive training program and neural correlates of cognitive change.Patient and Methods: A total of 68 survivors of childhood acute lymphoblastic leukemia (ALL) or brain tumor (BT) with identified cognitive deficits were randomly assigned to computerized cognitive intervention (male, n = 18; female, n = 16; ALL, n = 23; BT, n = 11; mean age ± standard deviation, 12.21 ± 2.47 years) or waitlist (male, n = 18; female, n = 16; ALL, n = 24; BT, n = 10; median age ± standard deviation, 11.82 ± 2.42 years). Intervention participants were asked to complete 25 training sessions at home with weekly, telephone-based coaching. Cognitive assessments and functional magnetic resonance imaging scans (intervention group) were completed pre- and postintervention, with immediate change in spatial span backward as the primary outcome.Results: Survivors completing the intervention (n = 30; 88%) demonstrated greater improvement than controls on measures of working memory (mean ± SEM; eg, Wechsler Intelligence Scale for Children [fourth edition; WISC-IV] spatial span backward, 3.13 ± 0.58 v 0.75 ± 0.43; P = .002; effect size [ES], 0.84), attention (eg, WISC-IV spatial span forward, 3.30 ± 0.71 v 1.25 ± 0.39; P = .01; ES, 0.65), and processing speed (eg, Conners' Continuous Performance Test hit reaction time, −2.10 ± 1.47 v 2.54 ± 1.25; P = .02; ES, .61) and showed greater reductions in reported executive dysfunction (eg, Conners' Parent Rating Scale III, −6.73 ± 1.51 v 0.41 ± 1.53; P = .002; ES, 0.84). Functional magnetic resonance imaging revealed significant pre- to post-training reduction in activation of left lateral prefrontal and bilateral medial frontal areas.Conclusion: Study findings show computerized cognitive training is feasible and efficacious for childhood cancer survivors, with evidence for training-related neuroplasticity.

The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. Data from at least 2 cognitive and academic assessments were available from 165 patients (ages 3-21 years) treated with surgery, risk-adapted craniospinal irradiation, and 4 courses of chemotherapy with stem cell support. Patients underwent serial evaluation of cognitive and academic functioning from baseline up to 5 years post diagnosis. Serious hearing loss, PFS, younger age at diagnosis, and high-risk status were all significant risk factors for decline in intellectual and academic skills. Serious hearing loss and PFS independently predicted below-average estimated mean intellectual ability at 5 years post diagnosis. Patients with high-risk medulloblastoma and young age at diagnosis (<7 years) exhibited the largest drop in mean scores for intellectual and academic outcomes. Despite a significant decline over time, intellectual and academic outcomes remained within the average range at 5 years post diagnosis for the majority of patients. Future studies should determine if scores remain within the average range at time points further out from treatment. Patients at heightened risk should be closely monitored and provided with recommendations for appropriate interventions.