Longitudinal Associations Between Physical Health Conditions in Childhood and Attention-Deficit/Hyperactivity Disorder Symptoms at Age 17 Years.

OBJECTIVE: Although evidence suggests significant cross-sectional relationships between attention-deficit/hyperactivity disorder (ADHD) and several physical health conditions, less is known about their longitudinal associations. We investigated the cumulative effect of childhood physical health conditions on ADHD symptoms at age 17 years, controlling for environmental factors, ADHD medication status, and ADHD symptoms at age 3 years. METHOD: Using Millennium Cohort Study data (weighted n = 8,059), we assessed whether 4 physical health clusters (sensory, neurological, atopic, and cardio-metabolic) were associated with scores on the ADHD subscale from the Strengths and Difficulties Questionnaire at age 17 years. Environmental factors were grouped into 5 cumulative risk indices: prenatal, perinatal, postnatal environment, postnatal maternal well-being, and sociodemographic factors. Regression analyses determined whether each physical health cluster was associated with ADHD score while controlling for environmental factors, ADHD medication, and earlier symptoms. RESULTS: Sensory, neurological, and cardio-metabolic clusters were all significantly associated with ADHD symptoms (ß range = 0.04-0.09, p < .001). The overall model explained 2% of the variance. This rose to 21% (ΔR2 = 0.06) after adjusting for confounders. The sensory (ß = 0.06) and neurological (ß = 0.06) clusters remained significant (R2 = 0.21, ΔR2 = 0.06), but the cardio-metabolic cluster was no longer a significant predictor. CONCLUSION: Sensory or neurological conditions in childhood were associated with higher ADHD symptoms aged 17 after adjustment of confounders. This was not the case for atopic or cardio-metabolic conditions. These findings have implications for the care of children with sensory/neurological conditions and future research examining ADHD etiopathophysiology.

Engineered Fc-glycosylation switch to eliminate antibody effector function.

Antibodies mediate effector functions through Fcγ receptor (FcγR) interactions and complement activation, causing cytokine release, degranulation, phagocytosis, and cell death. They are often undesired for development of therapeutic antibodies where only antigen binding or neutralization would be ideal. Effector elimination has been successful with extensive mutagenesis, but these approaches can potentially lead to manufacturability and immunogenicity issues. By switching the native glycosylation site from position 297 to 298, we created alternative antibody glycosylation variants in the receptor interaction interface as a novel strategy to eliminate the effector functions. The engineered glycosylation site at Asn298 was confirmed by SDS-PAGE, mass spectrometry, and X-ray crystallography (PDB code 6X3I). The lead NNAS mutant (S298N/T299A/Y300S) shows no detectable binding to mouse or human FcγRs by surface plasmon resonance analyses. The effector functions of the mutant are completely eliminated when measured in antibody-dependent cell-meditated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. In vivo, the NNAS mutant made on an antibody against a human lymphocyte antigen does not deplete T cells or B cells in transgenic mice, in contrast to wild-type antibody. Structural study confirms the successful glycosylation switch to the engineered Asn298 site. The engineered glycosylation would clash with approaching FcγRs based on reported Fc-FcγR co-crystal structures. In addition, the NNAS mutants of multiple antibodies retain binding to antigens and neonatal Fc receptor, exhibit comparable purification yields and thermal stability, and display normal circulation half-life in mice and non-human primate. Our work provides a novel approach for generating therapeutic antibodies devoid of any ADCC and CDC activities with potentially lower immunogenicity.

A data mining and item response mixture modeling method to retrospectively measure Diagnostic and Statistical Manual of Mental Disorders-5 attention deficit hyperactivity disorder in the 1970 British Cohort Study.

OBJECTIVE: To facilitate future outcome studies, we aimed to develop a robust and replicable method for estimating a categorical and dimensional measure of Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) attention deficit hyperactivity disorder (ADHD) in the 1970 British Cohort Study (BCS70). METHOD: Following a data mining framework, we mapped DSM-5 ADHD symptoms to age 10 BCS70 data (N = 11,426) and derived a 16-item scale (α = 0.85). Mapping was validated by an expert panel. A categorical subgroup was derived (n = 594, 5.2%), and a zero-inflated item response theory (IRT) mixture model fitted to estimate a dimensional measure. RESULTS: Subgroup composition was comparable with other ADHD samples. Relative risk ratios (ADHD/not ADHD) included boys = 1.38, unemployed fathers = 2.07, below average reading = 2.58, and depressed parent = 3.73. Our estimated measures correlated with two derived reference scales: Strengths and Difficulties Questionnaire hyperactivity (r = 0.74) and a Rutter/Conners-based scale (r = 0.81), supporting construct validity. IRT model items (symptoms) had moderate to high discrimination (0.90-2.81) and provided maximum information at average to moderate theta levels of ADHD (0.5-1.75). CONCLUSION: We extended previous work to identify ADHD in BCS70, derived scales from existing data, modeled ADHD items with IRT, and adjusted for a zero-inflated distribution. Psychometric properties were promising, and this work will enable future studies of causal mechanisms in ADHD.

Quantitative Proteomic Profiling Reveals Novel Plasmodium falciparum Surface Antigens and Possible Vaccine Candidates.

Despite recent efforts toward control and elimination, malaria remains a major public health problem worldwide. Plasmodium falciparum resistance against artemisinin, used in front line combination drugs, is on the rise, and the only approved vaccine shows limited efficacy. Combinations of novel and tailored drug and vaccine interventions are required to maintain the momentum of the current malaria elimination program. Current evidence suggests that strain-transcendent protection against malaria infection can be achieved using whole organism vaccination or with a polyvalent vaccine covering multiple antigens or epitopes. These approaches have been successfully applied to the human-infective sporozoite stage. Both systemic and tissue-specific pathology during infection with the human malaria parasite P. falciparum is caused by asexual blood stages. Tissue tropism and vascular sequestration are the result of specific binding interactions between antigens on the parasite-infected red blood cell (pRBC) surface and endothelial receptors. The major surface antigen and parasite ligand binding to endothelial receptors, PfEMP1 is encoded by about 60 variants per genome and shows high sequence diversity across strains. Apart from PfEMP1 and three additional variant surface antigen families RIFIN, STEVOR, and SURFIN, systematic analysis of the infected red blood cell surface is lacking. Here we present the most comprehensive proteomic investigation of the parasitized red blood cell surface so far. Apart from the known variant surface antigens, we identified a set of putative single copy surface antigens with low sequence diversity, several of which are validated in a series of complementary experiments. Further functional and immunological investigation is underway to test these novel P. falciparum blood stage proteins as possible vaccine candidates.