Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage

Item does not contain fulltextThe ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal immunoglobulin G (IgG) to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model, samples were collected from PCV and control-vaccinated adults. In PCV-vaccinated subjects, IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared with pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS-specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity

Does Childhood Executive Function Predict Adolescent Functional Outcomes in Girls with ADHD?

We prospectively followed an ethnically and socioeconomically diverse sample of preadolescent girls with ADHD (n = 140) and matched comparison girls (n = 88) over a period of 5 years, from middle childhood through early/mid-adolescence. Our aim was to examine the ability of measures of childhood executive function (EF) to predict functional outcomes in adolescence. Measures of neuropsychological functioning comprised the childhood predictors, with academic, social, and global functioning serving as adolescent criterion measures. Results indicated that childhood EF predicted (a) academic achievement and social functioning across our entire sample (independent of diagnostic group status) and (b) global functioning only in girls with ADHD (independent of IQ). These results highlight the non-specificity of EF deficits and suggest the importance of assessing and developing interventions that target EF impairments, particularly in those at high-risk for negative outcomes, in order to prevent long-term difficulties across a range of important functional domains

Efficiency of immediate postoperative inpatient physical therapy following total knee arthroplasty: an RCT

BACKGROUND: The main goal of physical therapy treatment (PT) in the clinical stage following total knee arthroplasty (TKA) is to prepare patients for discharge from the hospital as soon as possible after their operation. Although aggressive rehabilitation is believed to be important, evidence of effects of different exercise programmes following TKA is limited. This led to the question whether the intensity of PT (once versus twice daily) following TKA affects short-term recovery, measured as range of motion. METHODS: A randomised controlled trial compared an exercise regimen of two sessions per day with a similar programme administered once daily. Primary outcome measure was ROM. RESULTS: At the time of hospital discharge, there was no difference between the experimental and control groups in range of motion. CONCLUSION: This study shows that in our setting twice daily PT sessions do not produce different results as daily PT sessions. It may be questioned whether multiple daily therapy sessions are needed as an in-hospital PT regimen in OA total knee patients

Specific Cognitive Deficits in ADHD: A Diagnostic Concern in Differential Diagnosis

We present a critical account of existing tools used to diagnose children with Attention Deficit Hyperactivity Disorder and to make a case for the assessment of cognitive impairments as a part of diagnostic system. Surveys have shown that clinicians rely almost entirely upon subjective reports or their own clinical judgment when arriving at diagnostic decisions relating to this prevalent disorder. While information from parents and teachers should always be carefully considered, they are often influenced by a host of emotional and perceptual factors. It increases the possibility for misdiagnosis of a condition like ADHD. Recent experimental literature on ADHD has identified unique underlying cognitive dysfunction, specific to ADHD. Therefore, we propose that there is a need to incorporate information on cognitive mechanisms underlying ADHD and inculcate such information in the diagnostic system, which will provide a more sensitive as well as specific tool in differential diagnosis of ADHD

Highly Active Microbial Phosphoantigen Induces Rapid yet Sustained MEK/Erk- and PI-3K/Akt-Mediated Signal Transduction in Anti-Tumor Human γδ T-Cells

BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR)-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+) T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+) TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vgamma9(+) T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials

Evaluation of Intervention Impact on Health Inequality for Resource Allocation

Introduction. We describe a simplified distributional cost-effectiveness analysis based on aggregate data to estimate the health inequality impact of public health interventions. Methods. We extracted data on costs, health outcomes expressed as quality-adjusted life years (QALYs), and target populations for interventions within National Institute for Health and Care Excellence (NICE) public health guidance published up to October 2016. Evidence on variation by age, gender, and index of multiple deprivation informed socioeconomic distributions of incremental QALYs, health opportunity costs, and the baseline distribution of health. Total population QALYs, summary measures of inequality, and a health equity impact plane show results by intervention and by guideline. A value for inequality aversion from a general population survey in England let us combine impacts on health inequality and total health into a single measure of intervention value. Results. Our estimates suggest that of 134 interventions considered by NICE, 70 (52%) reduce inequality and increase health, 21 (16%) involve a tradeoff between improving health and improving health inequality, and 43 (32%) reduce health and increase health inequality. Fully implemented, the potential impact of all recommendations was 23,336,181 additional QALYs for the population of England and Wales and a reduction of the gap in quality-adjusted life expectancy between the healthiest and least healthy from 13.78 to 13.34 QALYs. The combined value of the additional health and reduction in inequality was 28,723,776 QALYs. Discussion. Our analysis takes account of the fact that existing public health spending likely benefits the most disadvantaged. This simple method applied separately to economic evaluation produces evidence of intervention impacts on the distribution of health that is vital in determining value for money when health inequality reduction is a policy goal

IL1B-CGTC haplotype is associated with colorectal cancer in admixed individuals with increased African ancestry

Single-nucleotide polymorphisms (SNPs) in cytokine genes can affect gene expression and thereby modulate inflammation and carcinogenesis. However, the data on the association between SNPs in the interleukin 1 beta gene (IL1B) and colorectal cancer (CRC) are conflicting. We found an association between a 4-SNP haplotype block of the IL1B (-3737C/-1464G/-511T/-31C) and CRC risk, and this association was exclusively observed in individuals with a higher proportion of African ancestry, such as individuals from the Coastal Colombian region (odds ratio, OR 2.06; 95% CI 1.31–3.25; p < 0.01). Moreover, a significant interaction between this CRC risk haplotype and local African ancestry dosage was identified in locus 2q14 (p = 0.03). We conclude that Colombian individuals with high African ancestry proportions at locus 2q14 harbour more IL1B-CGTC copies and are consequently at an increased risk of CRC. This haplotype has been previously found to increase the IL1B promoter activity and is the most frequent haplotype in African Americans. Despite of limitations in the number of samples and the lack of functional analysis to examine the effect of these haplotypes on CRC cell lines, our results suggest that inflammation and ethnicity play a major role in the modulation of CRC risk

How Distinctive are ADHD and RD? Results of a Double Dissociation Study

The nature of the comorbidity between Attention-Deficit/Hyperactivity Disorder (ADHD) and Reading Disability (RD) was examined using a double dissociation design. Children were between 8 and 12 years of age and entered into four groups: ADHD only (n = 24), ADHD+RD (n = 29), RD only (n = 41) and normal controls (n = 26). In total, 120 children participated in the study; 38 girls and 82 boys. Both ADHD and RD were associated with impairments in inhibition and lexical decision, although inhibition and lexical decision were more severely impaired in RD than in ADHD. Visuospatial working memory deficits were specific to children with only ADHD. It is concluded that there was overlap on lexical decision and to a lesser extent on inhibition between ADHD and RD. In ADHD, impairments were dependent on IQ, which suggest that the overlap in lexical decision and inhibition is different in origin for ADHD and RD. The ADHD only group was specifically characterized by deficits in visuospatial working memory. Hence, no double dissociation between ADHD and RD was found on executive functioning and lexical decision