Growth and Neurodevelopment of HIV-Exposed Uninfected Children: a Conceptual Framework

PURPOSE OF THE REVIEW: The population of HIV-exposed uninfected (HEU) children is expanding rapidly, and over one million HEU infants are born each year globally. Several recent studies have reported that HEU children, particularly in low- and middle-income countries, are at risk of poor outcomes, including impaired growth and neurodevelopment. However, the reasons for poor clinical outcomes amongst HEU children remain unclear. RECENT FINDINGS: We summarise the findings from recent large studies that have characterised growth and neurodevelopment in HEU children, identified risk factors and explored underlying mechanistic pathways. We propose a conceptual framework to explain how exposure to HIV and antiretroviral therapy (ART) may lead to adverse growth and neurodevelopment in uninfected children, and review the available evidence and research gaps. SUMMARY: We propose that HEU children are affected both indirectly, through the augmentation of universal risk factors underlying poor growth and neurodevelopment, and directly through HIV/ART-specific pathways, which ultimately may converge through a series of common pathogenic mechanisms. In the era of universal ART, a better understanding of these pathways is crucial to inform future prevention and intervention strategies

Determining Principal Component Cardinality through the Principle of Minimum Description Length

PCA (Principal Component Analysis) and its variants areubiquitous techniques for matrix dimension reduction and reduced-dimensionlatent-factor extraction. One significant challenge in using PCA, is thechoice of the number of principal components. The information-theoreticMDL (Minimum Description Length) principle gives objective compression-based criteria for model selection, but it is difficult to analytically applyits modern definition - NML (Normalized Maximum Likelihood) - to theproblem of PCA. This work shows a general reduction of NML prob-lems to lower-dimension problems. Applying this reduction, it boundsthe NML of PCA, by terms of the NML of linear regression, which areknown.Comment: LOD 201

Atom probe tomography of a Cu-doped TiNiSn thermoelectric material : nanoscale structure and optimization of analysis conditions

Funding: The Oxford Atom Probe facility is funded by EPSRC (EP/M022803/1) and the Glasgow plasma focused ion beam system was funded by EPSRC grant EP/P001483/1. Thermoelectric materials were developed under joint EPSRC grants EP/N017218/1 and EP/N01717X/1.Cu-doping and crystallographic site occupations within the half-Heusler (HH) TiNiSn, a promising thermoelectric material, have been examined by atom probe tomography. In particular, this investigation aims to better understand the influence of atom probe analysis conditions on the measured chemical composition. Under a voltage-pulsing mode, atomic planes are clearly resolved and suggest an arrangement of elements in-line with the expected HH (F-43m space group) crystal structure. The Cu dopant is also distributed uniformly throughout the bulk material. For operation under laser-pulsed modes, the returned composition is highly dependent on the selected laser energy, with high energies resulting in the measurement of excessively high absolute Ti counts at the expense of Sn and in particular Ni. High laser energies also appear to be correlated with the detection of a high fraction of partial hits, indicating nonideal evaporation behavior. The possible mechanisms for these trends are discussed, along with suggestions for optimal analysis conditions for these and similar thermoelectric materials.PostprintPeer reviewe

Conformal field theories in anti-de Sitter space

In this paper we discuss the dynamics of conformal field theories on anti-de Sitter space, focussing on the special case of the N=4 supersymmetric Yang-Mills theory on AdS_4. We argue that the choice of boundary conditions, in particular for the gauge field, has a large effect on the dynamics. For example, for weak coupling, one of two natural choices of boundary conditions for the gauge field leads to a large N deconfinement phase transition as a function of the temperature, while the other does not. For boundary conditions that preserve supersymmetry, the strong coupling dynamics can be analyzed using S-duality (relevant for g_{YM} >> 1), utilizing results of Gaiotto and Witten, as well as by using the AdS/CFT correspondence (relevant for large N and large 't Hooft coupling). We argue that some very specific choices of boundary conditions lead to a simple dual gravitational description for this theory, while for most choices the gravitational dual is not known. In the cases where the gravitational dual is known, we discuss the phase structure at large 't Hooft coupling.Comment: 57 pages, 1 figure. v2: fixed typo

Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study.

INTRODUCTION: About two-thirds of the excess familial risk associated with breast cancer is still unaccounted for and may be explained by multiple weakly predisposing alleles. A gene thought to be involved in low-level predisposition to the disease is ERBB2 (HER2). This gene is involved in cell division, differentiation, and apoptosis and is frequently amplified in breast tumours. Its amplification correlates with poor prognosis. Moreover, the coding polymorphism I655V has previously been associated with an increased risk of breast cancer. METHODS: We aimed to determine if common polymorphisms (frequency >or= 5%) in ERBB2 were associated with breast cancer risk in a white British population. Five single-nucleotide polymorphisms (SNPs) were selected for study: SNP 1 near the promoter, SNP 2 in intron 1, SNP 3 in intron 4, SNP 4 in exon 17 (I655V), and SNP 5 in exon 27 (A1170P). We tested their association with breast cancer in a large case-control study (n = 2192 cases and 2257 controls). RESULTS: There were no differences in genotype frequencies between cases and controls for any of the SNPs examined. To investigate the possibility that a common polymorphism not included in our study might be involved in breast cancer predisposition, we also constructed multilocus haplotypes. Our set of SNPs generated all existing (n = 6) common haplotypes and no differences were seen in haplotype frequencies between cases and controls (P = 0.44). CONCLUSIONS: In our population, common ERBB2 polymorphisms are not involved in predisposition to breast cancer

Association of asthma symptoms with peak particulate air pollution and effect modification by anti-inflammatory medication use.

Maxima of hourly data from outdoor monitors may capture adverse effects of outdoor particulate matter (PM) exposures in asthmatic children better than do 24-hr PM averages, which form the basis of current regulations in the United States. Also, asthmatic children on anti-inflammatory medications may be protected against the proinflammatory effects of air pollutants and aeroallergens. We examined strengths of pollutant associations with asthma symptoms between subgroups of asthmatic children who were on versus not on regularly scheduled anti-inflammatory medications, and tested associations for different particle averaging times. This is a daily panel study of 22 asthmatic children (9-19 years of age) followed March through April 1996 (1,248 person-days). They lived in nonsmoking households in a semirural area of Southern California within the air inversion mixing zone (range, 1,200-2,100 feet) with transported air pollution from urban areas of Southern California. The dependent variable derived from diary ordinal scores is episodes of asthma symptoms that interfered with daily activities. Minimum to 90th-percentile levels of exposures at the outdoor monitoring site were 12-63 microg/m(3) for 1-hr PM < 10 microm in aerodynamic diameter (PM(10)); 8-46 microg/m(3) for 8-hr PM(10); 7-32 microg/m(3) for 24-hr PM(10); 45-88 ppb for 1-hr O(3); 6-26 ppb for 8-hr NO(2); 70-4,714 particles/m(3) for 12-hr daytime fungi; and 12-744 particles/m(3) for 24-hr pollen. Data were analyzed with generalized estimating equations controlling for autocorrelation. There was no confounding by weather, day of week, or linear time trend. Associations were notably stronger in 12 asthmatic children who were not taking anti-inflammatory medications versus 10 subjects who were. Odds ratios (95% confidence intervals) for asthma episodes in relation to lag 0 minimum to 90th-percentile pollutant changes were, respectively, 1-hr maximum PM(10), 1.92 (1.22-3.02) versus 0.96 (0.25-3.69); 8-hr maximum PM(10), 1.68 (0.91-3.09) versus 0.75 (0.18-3.04); 24-hr average PM(10), 1.35 (0.82-2.22) versus 0.80 (0.24-2.69); 1-hr maximum O(3), 1.28 (0.75-2.17) versus 0.76 (0.24-2.44); 8-hr maximum NO(2), 1.91 (1.07-3.39) versus 1.08 (0.30-3.93); 12-hr fungi, 1.89 (1.24-2.89) versus 0.90 (0.35-2.30); 24-hr pollen, 1.90 (0.99-3.67) versus 0.85 (0.18-3.91). Pollutant associations were stronger during respiratory infections in subjects not on anti-inflammatory medications. Although lag 0 1-hr maximum PM(10) showed the strongest association, the most robust associations were for lag 0 and 3-day moving averages (lags 0-2) of 8-hr maximum and 24-hr mean PM(10) in sensitivity analyses testing for thresholds. Most pollutant effects were largely driven by concentrations in the upper quintile. The divergence of exposure-response relationships by anti-inflammatory medication use is consistent with experimental data on inflammatory mechanisms of airborne pollutants and allergens

Genomic-Bioinformatic Analysis of Transcripts Enriched in the Third-Stage Larva of the Parasitic Nematode Ascaris suum

Differential transcription in Ascaris suum was investigated using a genomic-bioinformatic approach. A cDNA archive enriched for molecules in the infective third-stage larva (L3) of A. suum was constructed by suppressive-subtractive hybridization (SSH), and a subset of cDNAs from 3075 clones subjected to microarray analysis using cDNA probes derived from RNA from different developmental stages of A. suum. The cDNAs (n = 498) shown by microarray analysis to be enriched in the L3 were sequenced and subjected to bioinformatic analyses using a semi-automated pipeline (ESTExplorer). Using gene ontology (GO), 235 of these molecules were assigned to ‘biological process’ (n = 68), ‘cellular component’ (n = 50), or ‘molecular function’ (n = 117). Of the 91 clusters assembled, 56 molecules (61.5%) had homologues/orthologues in the free-living nematodes Caenorhabditis elegans and C. briggsae and/or other organisms, whereas 35 (38.5%) had no significant similarity to any sequences available in current gene databases. Transcripts encoding protein kinases, protein phosphatases (and their precursors), and enolases were abundantly represented in the L3 of A. suum, as were molecules involved in cellular processes, such as ubiquitination and proteasome function, gene transcription, protein–protein interactions, and function. In silico analyses inferred the C. elegans orthologues/homologues (n = 50) to be involved in apoptosis and insulin signaling (2%), ATP synthesis (2%), carbon metabolism (6%), fatty acid biosynthesis (2%), gap junction (2%), glucose metabolism (6%), or porphyrin metabolism (2%), although 34 (68%) of them could not be mapped to a specific metabolic pathway. Small numbers of these 50 molecules were predicted to be secreted (10%), anchored (2%), and/or transmembrane (12%) proteins. Functionally, 17 (34%) of them were predicted to be associated with (non-wild-type) RNAi phenotypes in C. elegans, the majority being embryonic lethality (Emb) (13 types; 58.8%), larval arrest (Lva) (23.5%) and larval lethality (Lvl) (47%). A genetic interaction network was predicted for these 17 C. elegans orthologues, revealing highly significant interactions for nine molecules associated with embryonic and larval development (66.9%), information storage and processing (5.1%), cellular processing and signaling (15.2%), metabolism (6.1%), and unknown function (6.7%). The potential roles of these molecules in development are discussed in relation to the known roles of their homologues/orthologues in C. elegans and some other nematodes. The results of the present study provide a basis for future functional genomic studies to elucidate molecular aspects governing larval developmental processes in A. suum and/or the transition to parasitism

Differential trajectories of hypometabolism across cognitively-defined Alzheimer’s disease subgroups

Disentangling biologically distinct subgroups of Alzheimer’s disease (AD) may facilitate a deeper understanding of the neurobiology underlying clinical heterogeneity. We employed longitudinal [18F]FDG-PET standardized uptake value ratios (SUVRs) to map hypometabolism across cognitively-defined AD subgroups. Participants were 384 amyloid-positive individuals with an AD dementia diagnosis from ADNI who had a total of 1028 FDG-scans (mean time between first and last scan: 1.6 ± 1.8 years). These participants were categorized into subgroups on the basis of substantial impairment at time of dementia diagnosis in a specific cognitive domain relative to the average across domains. This approach resulted in groups of AD-Memory (n = 135), AD-Executive (n = 8), AD-Language (n = 22), AD-Visuospatial (n = 44), AD-Multiple Domains (n = 15) and AD-No Domains (for whom no domain showed substantial relative impairment; n = 160). Voxelwise contrasts against controls revealed that all AD-subgroups showed progressive hypometabolism compared to controls across temporoparietal regions at time of AD diagnosis. Voxelwise and regions-of-interest (ROI)-based linear mixed model analyses revealed there were also subgroup-specific hypometabolism patterns and trajectories. The AD-Memory group had more pronounced hypometabolism compared to all other groups in the medial temporal lobe and posterior cingulate, and faster decline in metabolism in the medial temporal lobe compared to AD-Visuospatial. The AD-Language group had pronounced lateral temporal hypometabolism compared to all other groups, and the pattern of metabolism was also more asymmetrical (left < right) than all other groups. The AD-Visuospatial group had faster decline in metabolism in parietal regions compared to all other groups, as well as faster decline in the precuneus compared to AD-Memory and AD-No Domains. Taken together, in addition to a common pattern, cognitively-defined subgroups of people with AD dementia show subgroup-specific hypometabolism patterns, as well as differences in trajectories of metabolism over time. These findings provide support to the notion that cognitively-defined subgroups are biologically distinct

The influence of the atmospheric boundary layer on nocturnal layers of noctuids and other moths migrating over southern Britain

Insects migrating at high altitude over southern Britain have been continuously monitored by automatically-operating, vertical-looking radars over a period of several years. During some occasions in the summer months, the migrants were observed to form well-defined layer concentrations, typically at heights of 200-400 m, in the stable night-time atmosphere. Under these conditions, insects are likely to have control over their vertical movements and are selecting flight heights which are favourable for long-range migration. We therefore investigated the factors influencing the formation of these insect layers by comparing radar measurements of the vertical distribution of insect density with meteorological profiles generated by the UK Met. Office’s Unified Model (UM). Radar-derived measurements of mass and displacement speed, along with data from Rothamsted Insect Survey light traps provided information on the identity of the migrants. We present here three case studies where noctuid and pyralid moths contributed substantially to the observed layers. The major meteorological factors influencing the layer concentrations appeared to be: (a) the altitude of the warmest air, (b) heights corresponding to temperature preferences or thresholds for sustained migration and (c), on nights when air temperatures are relatively high, wind-speed maxima associated with the nocturnal jet. Back-trajectories indicated that layer duration may have been determined by the distance to the coast. Overall, the unique combination of meteorological data from the UM and insect data from entomological radar described here show considerable promise for systematic studies of high-altitude insect layering

Characteristics of optimum falls prevention exercise programmes for community-dwelling older adults using the FITT principle

peer-reviewedThis review aims to identify the optimal exercise intervention characteristics for falls prevention among community-dwelling adults aged 60 years and over. Articles for inclusion were sourced by searching the Academic Search Premier, AMED, Biomedical Reference Collection: Expanded, CINAHL Plus, MEDLINE and SPORTDiscus databases with the key words ‘falls’, ‘prevention’, ‘exercise’ and ‘community’ and via reference lists of relevant articles. Only articles of level 1 or level 2 evidence (Howick et al. 2011) were included. Other inclusion criteria included recording falls incidence as an outcome measure, examining a community-dwelling population aged 60 years or over and implementing exercise as a single intervention in at least one group. Exercise programme characteristics from 31 articles were examined according to their frequency, intensity, time and type and their effects on falls incidence were reviewed. Exercising for a minimum of 1 h/week for at least 40 h over the course of an intervention is required to successfully reduce falls incidence. The optimal exercise frequency is three times per week, but the optimal duration per bout remains unclear. Specific balance training of sufficiently challenging intensity is a vital programme component, and strength training is most effective when combined with balance training. Flexibility and endurance training may also be included as part of a comprehensive programme. A combination of group and individual home exercise may be most effective for preventing falls and promoting exercise adherence