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1.  Evolution of and Evolutionary Relationships between Extant Vaccinia Virus Strains 
Journal of Virology  2014;89(3):1809-1824.
Although vaccinia virus (VACV) was once used as a vaccine to eradicate smallpox on a worldwide scale, the biological origins of VACV are uncertain, as are the historical relationships between the different strains once used as smallpox vaccines. Here, we sequenced additional VACV strains that either represent relatively pristine examples of old vaccines (e.g., Dryvax, Lister, and Tashkent) or have been subjected to additional laboratory passage (e.g., IHD-W and WR). These genome sequences were compared with those previously reported for other VACVs as well as other orthopoxviruses. These extant VACVs do not always cluster in simple phylogenetic trees that are aligned with the known historical relationships between these strains. Rather, the pattern of deletions suggests that all existing strains likely come from a complex stock of viruses that has been passaged, distributed, and randomly sampled over time, thus obscuring simple historical or geographic links. We examined surviving nonclonal vaccine stocks, like Dryvax, which continue to harbor larger and now rare variants, including one that we have designated “clone DPP25.” DPP25 encodes genes not found in most VACV strains, including an ankyrin-F-box protein, a homolog of the variola virus (Bangladesh) B18R gene which we show can be deleted without affecting virulence in mice. We propose a simple common mechanism by which recombination of a larger and hypothetical DPP25-like ancestral strain, combined with selection for retention of critically important genes near the terminal inverted repeat boundaries (vaccinia virus growth factor gene and an interferon alpha/beta receptor homolog), could produce all known VACV variants.
IMPORTANCE Smallpox was eradicated by using a combination of intensive disease surveillance and vaccination using vaccinia virus (VACV). Interestingly, little is known about the historical relationships between different strains of VACV and how these viruses may have evolved from a common ancestral strain. To understand these relationships, additional strains were sequenced and compared to existing strains of VACV as well as other orthopoxviruses by using whole-genome sequence alignments. Extant strains of VACV did not always cluster in simple phylogenetic trees based on known historical relationships between these strains. Based on these findings, it is possible that all existing strains of VACV are derived from a single complex stock of viruses that has been passaged, distributed, and sampled over time.
PMCID: PMC4300770  PMID: 25410873
3.  Asthma Self-Management is Sub-optimal in Urban Hispanic and African American/Black Early Adolescents with Uncontrolled Persistent Asthma 
Youth as young as 11 are given responsibility to manage their asthma. Yet, little is known regarding early adolescents’ asthma self-management behaviors. This study characterizes urban early adolescents’ asthma self-management behaviors and perceived responsibility to manage asthma, exploring demographic differences and examining the relationship between asthma responsibility and disease management.
317 Hispanic and Black early adolescents (mean age=12.7) with persistent, uncontrolled asthma reported prevention and symptom management steps, and responsibility for asthma care. We used Poisson, cumulative logistic, logistic, and linear mixed-effects regression models to assess relationships between demographic predictors, prevention and management behaviors, and responsibility for asthma care.
50% took 7–9 prevention steps; few saw physicians when asymptomatic or took daily medication. When symptomatic, 92% used medication to treat symptoms, 56% sought medical attention. Controlling for asthma responsibility, fewer older youth reported observing how they feel when asthma is likely to start, observing symptom changes, or asking for help. More boys reported taking medication daily or upon trigger exposure. Controlling for age, gender, and race/ethnicity, those reporting more asthma responsibility were less likely to report taking management steps, seeking preventive care, asking for help, or going to a doctor/hospital for their asthma.
Early adolescents’ asthma self-management is suboptimal. With increasing age, they are less observant regarding their asthma and less likely to seek help. Although they perceive themselves to have greater responsibility for managing their asthma, early adolescents do less to care for their asthma, suggesting they are being given responsibility for asthma care prematurely.
PMCID: PMC4515962  PMID: 22149141
responsibility; inner-city; ethnic minority; chronic illness management
4.  An Inexpensive Co-Intercalated Layered Double Hydroxide Composite with Electron Donor-Acceptor Character for Photoelectrochemical Water Splitting 
Scientific Reports  2015;5:12170.
In this paper, the inexpensive 4,4-diaminostilbene-2,2-disulfonate (DAS) and 4,4-dinitro-stilbene-2,2- disulfonate (DNS) anions with arbitrary molar ratios were successfully co-intercalated into Zn2Al-layered double hydroxides (LDHs). The DAS(50%)-DNS/LDHs composite exhibited the broad UV-visible light absorption and fluorescence quenching, which was a direct indication of photo-induced electron transfer (PET) process between the intercalated DAS (donor) and DNS (acceptor) anions. This was confirmed by the matched HOMO/LUMO energy levels alignment of the intercalated DAS and DNS anions, which was also compatible for water splitting. The DAS(50%)-DNS/LDHs composite was fabricated as the photoanode and Pt as the cathode. Under the UV-visible light illumination, the enhanced photo-generated current (4.67 mA/cm2 at 0.8 V vs. SCE) was generated in the external circuit, and the photoelectrochemical water split was realized. Furthermore, this photoelectrochemical water splitting performance had excellent crystalline, electrochemical and optical stability. Therefore, this novel inorganic/organic hybrid photoanode exhibited potential application prospect in photoelectrochemical water splitting.
PMCID: PMC4502407  PMID: 26174201
5.  Spontaneous Deletion of an “ORFanage” Region Facilitates Host Adaptation in a “Photosynthetic” Cyanophage 
PLoS ONE  2015;10(7):e0132642.
Viruses have been suggested to be the largest source of genetic diversity on Earth. Genome sequencing and metagenomic surveys reveal that novel genes with unknown functions are abundant in viral genomes. Yet few observations exist for the processes and frequency by which these genes are gained and lost. The surface waters of marine environments are dominated by marine picocyanobacteria and their co-existing viruses (cyanophages). Recent genome sequencing of cyanophages has revealed a vast array of genes that have been acquired from their cyanobacterial hosts. Here, we re-sequenced the cyanophage S-PM2 genome after 10 years of near continuous passage through its marine Synechococcus host. During this time a spontaneous mutant (S-PM2d) lacking 13% of the S-PM2 ORFs became dominant in the cyanophage population. These ORFs are found at one loci and are not homologous to any proteins in any other sequenced organism (ORFans). We demonstrate a fitness cost to S-PM2WT associated with possession of these ORFs under standard laboratory growth. Metagenomic surveys reveal these ORFs are present in various aquatic environments, are likely of cyanophage origin and appear to be enriched in environments from the extremes of salinity (freshwater and hypersaline). We posit that these ORFs contribute to the flexible gene content of cyanophages and offer a distinct fitness advantage in freshwater and hypersaline environments.
PMCID: PMC4503421  PMID: 26177354
6.  Cranial Anatomy of Wendiceratops pinhornensis gen. et sp. nov., a Centrosaurine Ceratopsid (Dinosauria: Ornithischia) from the Oldman Formation (Campanian), Alberta, Canada, and the Evolution of Ceratopsid Nasal Ornamentation 
PLoS ONE  2015;10(7):e0130007.
The fossil record of ceratopsid dinosaurs between the occurrence of their proximate sister taxa in the Turonian and the beginning of their well-documented radiation from the late Campanian of North America onwards (approximately 90 and 77 Ma) is poor, with only seven taxa described from this early period in their evolution. We describe a new taxon of a highly adorned basal centrosaurine, Wendiceratops pinhornensis gen. et sp. nov., from the lower part of the Oldman Formation (middle Campanian, approximately 78-79 Ma), Alberta, Canada. Over 200 bones derived from virtually all parts of the skeleton, including multiple well-preserved specimens of the diagnostic parietosquamosal frill, were collected from a medium-density monodominant bonebed, making the new taxon one of the best-represented early ceratopsids. The new taxon is apomorphic in having epiparietals at loci 2 and 3 developed as broad-based, pachyostotic processes that are strongly procurved anterodorsally to overhang the posterior and lateral parietal rami, and an ischium with a broad, rectangular distal terminus. Although the morphology of the nasal is incompletely known, Wendiceratops is inferred to have a large, upright nasal horn located close to the orbits, which represents the oldest occurrence of this feature in Ceratopsia. Given the phylogenetic position of the new taxon within Centrosaurinae, a enlarged nasal horn is hypothesized to have arisen independently at least twice in ceratopsid evolution.
PMCID: PMC4496092  PMID: 26154293
8.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
9.  Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA- C*03:04 and modulate primary NK cell function 
AIDS (London, England)  2014;28(10):1399-1408.
The aim of this study was to assess the consequence of sequence variations in HLA-C*03:04-presented HIV-1 p24 Gag epitopes on binding of the inhibitory NK cell receptor KIR2DL2 to HLA-C*03:04.
HIV-1 may possibly evade recognition by KIR+ NK cells through selection of sequence variants that interfere with the interactions of inhibitory KIRs and their target ligands on HIV-1-infected cells. KIR2DL2 is an inhibitory NK cell receptor that binds to a family of HLA-C ligands. Here, we investigated whether HIV-1 encodes for HLA-C*03:04-restricted epitopes that alter KIR2DL2 binding.
Tapasin-deficient 721.220 cells expressing HLA-C*03:04 were pulsed with overlapping peptides (10mers overlapping by 9 amino acids, spanning the entire HIV-1 p24 Gag sequence) to identify peptides that stabilized HLA-C expression. Then, the impact that sequence variation in HLA-C*03:04-binding HIV-1 epitopes has on KIR2DL2 binding and KIR2DL2+ NK cell function was determined using KIR2DL2-Fc constructs and NK cell degranulation assays.
Several novel HLA-C*03:04 binding epitopes were identified within the HIV-1 p24 Gag consensus sequence. Three of these consensus sequence peptides (Gag144-152, Gag163-171, and Gag295-304) enabled binding of KIR2DL2 to HLA-C*03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Furthermore, naturally occurring minor variants of epitope Gag295-304 enhanced KIR2DL2 binding to HLA-C*03:04.
Our data show that naturally occurring sequence variations within HLA-C*03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR receptors and primary NK cell function.
PMCID: PMC4453925  PMID: 24785948
Innate Immunity; HIV-1 epitopes; Natural Killer cell; Killer cell immunoglobulin-like receptor
10.  Can Economic Analysis Contribute to Disease Elimination and Eradication? A Systematic Review 
PLoS ONE  2015;10(6):e0130603.
Infectious diseases elimination and eradication have become important areas of focus for global health and countries. Due to the substantial up-front investments required to eliminate and eradicate, and the overall shortage of resources for health, economic analysis can inform decision making on whether elimination/eradication makes economic sense and on the costs and benefits of alternative strategies. In order to draw lessons for current and future initiatives, we review the economic literature that has addressed questions related to the elimination and eradication of infectious diseases focusing on: why, how and for whom?
A systematic review was performed by searching economic literature (cost-benefit, cost-effectiveness and economic impact analyses) on elimination/eradication of infectious diseases published from 1980 to 2013 from three large bibliographic databases: one general (SCOPUS), one bio-medical (MEDLINE/PUBMED) and one economic (IDEAS/REPEC).
A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the “for whom?” question, was found. The literature relating to “why?” is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication.
The largest part of the literature has focused on costs and economic benefits of elimination/eradication. To a lesser extent, challenges associated with achieving elimination/eradication and ensuring equity have also been explored. Although elimination and eradication are, for some diseases, good investments compared with control, countries’ incentives to eliminate do not always align with the global good and the most efficient elimination strategies may not prioritize the poorest populations. For any infectious disease, policy-makers will need to consider realigning contrasting incentives between the individual countries and the global community and to assure that the process towards elimination/eradication considers equity.
PMCID: PMC4466479  PMID: 26070135
11.  Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1 
Nature Communications  2015;6:7146.
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.
PMCID: PMC4443427  PMID: 25994336
12.  Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype 
To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.
We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.
We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).
At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6).
By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.
PMCID: PMC4280183  PMID: 24388013
Rhinitis; atopy; selection; genetic correlation; bivariate; single nucleotide polymorphism
13.  Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the pre-fusion conformation of the gp41 protein on cleaved Envelope trimers 
Immunity  2014;40(5):657-668.
Broadly neutralizing antibodies to HIV are much sought-after (a) to guide vaccine design, both as templates and to inform on the authenticity of vaccine candidates, (b) to assist in structural studies and (c) as potential therapeutics. However, the number of targets on the viral envelope spike for such antibodies is limited. Here, we describe a set of human monoclonal antibodies that define a previously undefined target on HIV Env. The antibodies recognize a glycan-dependent epitope on the prefusion conformation of gp41 and unambiguously distinguish cleaved from uncleaved Env trimers, an important property given increasing evidence that cleavage is required for vaccine candidates that seek to mimic the functional HIV envelope spike. The availability of this set of antibodies expands the number of vaccine targets on HIV and provides reagents to characterize the native envelope spike.
PMCID: PMC4070425  PMID: 24768347
14.  Examination of the relationship between variation at 17q21 and childhood wheeze phenotypes 
Genome-wide association studies have identified associations of genetic variants at 17q21 near ORMDL3 with childhood asthma.
To find out whether associations in this region are specific to particular asthma phenotypes and specific to ORMDL3.
We examined associations between 244 independent single nucleotide polymorphisms (SNPs) plus 13 previously identified asthma-related SNPs in the region between 34 and 36 Mb on chromosome 17 and early wheezing phenotypes, doctor-diagnosed asthma and atopy at 7½ years, bronchial hyper-responsiveness and lung function at 8½ years in 7,045 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort study. With this, cis expression quantitative trait loci (eQTL) signals for the same SNPs were assessed in 875 samples across genes in the same region.
The strongest evidence for phenotypic association was seen for persistent wheezing (rs8076131 near ORMDL3, relative risk ratio (RRR) 1.60 (95% CI 1.40, 1.84), p=1.4×10−11, rs2305480 near GSDML 1.60; 1.39-1.83, p=1.5×10−11 and rs9303277 near IKZF3 1.57; 1.37-1.79, p=4.4×10−11). Similar, but less precisely estimated effects were seen for intermediate-onset wheeze, but there was little evidence of associations with other wheezing phenotypes. There was some evidence of associations with bronchial hyper responsiveness. SNPs across the whole region show strong evidence of association with differential levels of expression at GSDML, IKZF3 and MED24, as well as ORMDL3.
Associations of SNPs in the 17q21 locus are specific to asthma and to specific wheezing phenotypes, and are not explained by associations with intermediate phenotypes, such as atopy or lung function.
PMCID: PMC4427593  PMID: 23154084
ALSPAC; wheezing phenotypes; chromosome 17; ORMDL3; gene expression
15.  A genome-wide association study of body mass index across early life and childhood 
Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood.
Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study. Genome-wide significant loci were examined in a further 3918 individuals (48 530 measurements) from Northern Finland. Linear mixed effects models with smoothing splines were used in each cohort for longitudinal modelling of BMI.
Results: A novel SNP, downstream from the FAM120AOS gene on chromosome 9, was detected in the meta-analysis of ALSPAC and Raine. This association was driven by a difference in BMI at 8 years (T allele of rs944990 increased BMI; PSNP = 1.52 × 10−8), with a modest association with change in BMI over time (PWald(Change) = 0.006). Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10−8) with BMI at 8 years and/or change over time.
Conclusions: This GWAS of BMI trajectories over childhood identified a novel locus that warrants further investigation. We also observed genome-wide significance with previously established obesity loci, making the novel observation that these loci affected both the level and the rate of change in BMI. We have demonstrated that the use of repeated measures data can increase power to allow detection of genetic loci with smaller sample sizes.
PMCID: PMC4469798  PMID: 25953783
Body mass index; genome-wide association study; trajectory; childhood; ALSPAC; Raine
16.  Genetic variants in adult bone mineral density and fracture risk genes are associated with the rate of bone mineral density acquisition in adolescence 
Human Molecular Genetics  2015;24(14):4158-4166.
Previous studies have identified 63 single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD) in adults. These SNPs are thought to reflect variants that influence bone maintenance and/or loss in adults. It is unclear whether they affect the rate of bone acquisition during adolescence. Bone measurements and genetic data were available on 6397 individuals from the Avon Longitudinal Study of Parents and Children at up to five follow-up clinics. Linear mixed effects models with smoothing splines were used for longitudinal modelling of BMD and its components bone mineral content (BMC) and bone area (BA), from 9 to 17 years. Genotype data from the 63 adult BMD associated SNPs were investigated individually and as a genetic risk score in the longitudinal model. Each additional BMD lowering allele of the genetic risk score was associated with lower BMD at age 13 [per allele effect size, 0.002 g/cm2 (SE = 0.0001, P = 1.24 × 10−38)] and decreased BMD acquisition from 9 to 17 years (P = 9.17 × 10−7). This association was driven by changes in BMC rather than BA. The genetic risk score explained ∼2% of the variation in BMD at 9 and 17 years, a third of that explained in adults (6%). Genetic variants that putatively affect bone maintenance and/or loss in adults appear to have a small influence on the rate of bone acquisition through adolescence.
PMCID: PMC4476449  PMID: 25941325
17.  Size Distribution of Air Bubbles Entering the Brain during Cardiac Surgery 
PLoS ONE  2015;10(4):e0122166.
Thousands of air bubbles enter the cerebral circulation during cardiac surgery, but whether high numbers of bubbles explain post-operative cognitive decline is currently controversial. This study estimates the size distribution of air bubbles and volume of air entering the cerebral arteries intra-operatively based on analysis of transcranial Doppler ultrasound data.
Transcranial Doppler ultrasound recordings from ten patients undergoing heart surgery were analysed for the presence of embolic signals. The backscattered intensity of each embolic signal was modelled based on ultrasound scattering theory to provide an estimate of bubble diameter. The impact of showers of bubbles on cerebral blood-flow was then investigated using patient-specific Monte-Carlo simulations to model the accumulation and clearance of bubbles within a model vasculature.
Analysis of Doppler ultrasound recordings revealed a minimum of 371 and maximum of 6476 bubbles entering the middle cerebral artery territories during surgery. This was estimated to correspond to a total volume of air ranging between 0.003 and 0.12 mL. Based on analysis of a total of 18667 embolic signals, the median diameter of bubbles entering the cerebral arteries was 33 μm (IQR: 18 to 69 μm). Although bubble diameters ranged from ~5 μm to 3.5 mm, the majority (85%) were less than 100 μm. Numerous small bubbles detected during cardiopulmonary bypass were estimated by Monte-Carlo simulation to be benign. However, during weaning from bypass, showers containing large macro-bubbles were observed, which were estimated to transiently affect up to 2.2% of arterioles.
Detailed analysis of Doppler ultrasound data can be used to provide an estimate of bubble diameter, total volume of air, and the likely impact of embolic showers on cerebral blood flow. Although bubbles are alarmingly numerous during surgery, our simulations suggest that the majority of bubbles are too small to be harmful.
PMCID: PMC4383554  PMID: 25837519
18.  Shared Genetic Influences Between Attention-Deficit/Hyperactivity Disorder (ADHD) Traits in Children and Clinical ADHD 
Twin studies and genome-wide complex trait analysis (GCTA) are not in agreement regarding heritability estimates for behavioral traits in children from the general population. This has sparked a debate on the possible difference in genetic architecture between behavioral traits and psychiatric disorders. In this study, we test whether polygenic risk scores associated with variation in attention-deficit/hyperactivity disorder (ADHD) trait levels in children from the general population predict ADHD diagnostic status and severity in an independent clinical sample.
Single nucleotide polymorphisms (SNPs) with p < .5 from a genome-wide association study of ADHD traits in 4,546 children (mean age, 7 years 7 months) from the Avon Longitudinal Study of Parents and Children (ALSPAC; general population sample) were selected to calculate polygenic risk scores in 508 children with an ADHD diagnosis (independent clinical sample) and 5,081 control participants. Polygenic scores were tested for association with case-control status and severity of disorder in the clinical sample.
Increased polygenic score for ADHD traits predicted ADHD case-control status (odds ratio = 1.17 [95% CI = 1.08–1.28], p = .0003), higher ADHD symptom severity (β = 0.29 [95% CI = 0.04–0.54], p = 0.02), and symptom domain severity in the clinical sample.
This study highlights the relevance of additive genetic variance in ADHD, and provides evidence that shared genetic factors contribute to both behavioral traits in the general population and psychiatric disorders at least in the case of ADHD.
PMCID: PMC4382052  PMID: 25791149
attention-deficit/hyperactivity disorder (ADHD); polygenic risk scores; Avon Longitudinal Study of Parents and Children (ALSPAC); common variants; genetics
19.  Dynamic behavior of venous collapsibility and central venous pressure during standardized crystalloid bolus: A prospective, observational, pilot study 
Measurement of intravascular volume status is an ongoing challenge for physicians in the surgical intensive care unit (SICU). Most surrogates for volume status, including central venous pressure (CVP) and pulmonary artery wedge pressure, require invasive lines associated with a number of potential complications. Sonographic assessment of the collapsibility of the inferior vena cava (IVC) has been described as a noninvasive method for determining volume status. The purpose of this study was to analyze the dynamic response in IVC collapsibility index (IVC-CI) to changes in CVP in SICU patients receiving fluid boluses for volume resuscitation.
Materials and Methods:
A prospective pilot study was conducted on a sample of SICU patients who met clinical indications for intravenous (IV) fluid bolus and who had preexisting central venous access. Boluses were standardized to crystalloid administration of either 500 mL over 30 min or 1,000 mL over 60 min, as clinically indicated. Concurrent measurements of venous CI (VCI) and CVP were conducted right before initiation of IV bolus (i.e. time 0) and then at 30 and 60 min (as applicable) after bolus initiation. Patient demographics, ventilatory parameters, and vital sign assessments were recorded, with descriptive outcomes reported due to the limited sample size.
Twenty patients received a total of 24 IV fluid boluses. There were five recorded 500 mL boluses given over 30 min and 19 recorded 1,000 mL boluses given over 60 min. Mean (median) CVP measured at 0, 30, and 60 minutes post-bolus were 6.04 ± 3.32 (6.5), 9.00 ± 3.41 (8.0), and 11.1 ± 3.91 (12.0) mmHg, respectively. Mean (median) IVC-CI values at 0, 30, and 60 min were 44.4 ± 25.2 (36.5), 26.5 ± 22.8 (15.6), and 25.2 ± 21.2 (14.8), respectively.
Observable changes in both VCI and CVP are apparent during an infusion of a standardized fluid bolus. Dynamic changes in VCI as a measurement of responsiveness to fluid bolus are inversely related to changes seen in CVP. Moreover, an IV bolus tends to produce an early response in VCI, while the CVP response is more gradual. Given the noninvasive nature of the measurement technique, VCI shows promise as a method of dynamically measuring patient response to fluid resuscitation. Further studies with larger sample sizes are warranted.
PMCID: PMC4477400  PMID: 26157649
Central venous pressure; inferior vena cava collapsibility index; intravascular volume status assessment; intravenous fluid bolus; Point-of-care ultrasound
20.  The Pathogenesis of Contact Lens-Associated Microbial Keratitis 
Sight-threatening microbial keratitis associated with contact lens wear remains a serious concern for patients, eye-care practitioners, and the contact lens industry. Several decades of research and some major advances in lens and solution technology have not resulted in a decline in disease incidence. Here, we offer a perspective on the complex pathogenesis of microbial keratitis, the factors that have prevented a better understanding of this disease, and new approaches being used to tacke this important clinical problem.
PMCID: PMC4379041  PMID: 20190671
microbial keratitis; Pseudomonas aeruginosa; cornea; epithelium; innate immunity; contact lenses; hygiene; biofilms
21.  An unrecognised case of metabolic acidosis following neobladder augmentation cystoplasty 
•Hyperchloraemic metabolic acidosis is a well established complication following urinary diversion.•Patients with orthotopic neobladder with high residual urine and large capacity are at particular risks.•A delay in the diagnosis can lead to significant morbidity.•The risks of metabolic acidosis should be clearly documented on discharge to ensure early recognition by non-specialists.
We present a case where there was a delay in the diagnosis of severe metabolic acidosis in a patient with an orthotopic neobladder. There are a growing number of patients with orthotopic neobladders and a wider range of clinicians are encountering these patients. A delay in the diagnosis can lead to significant morbidity but if identified early it can be easily treated.
Presentation of case
A 59-year old patient with a recent neobladder augmentation cystoplasty was admitted under the medical team with a metabolic acidosis which was incorrectly presumed to be secondary to urosepsis. His condition rapidly deteriorated until a surgical review identified hyperchloremic metabolic acidosis secondary to neobladder augmentation. The patient required admission to the intensive care unit where he was treated with intravenous alkalising therapy which produced rapid metabolic improvement. Following a full recovery, he underwent neo-bladder excision and ileal conduit formation.
Hyperchloraemic metabolic acidosis develops due to the bowel segment absorbing urinary constituents including ammonium, hydrogen ions and chloride in exchange for sodium and bicarbonate. It can be diagnosed by careful interpretation of the arterial blood gas and calculation of the anion gap. This hyperchloraemic metabolic acidosis can be corrected with alkalizing agents combined with catheterisation.
Hyperchloremic metabolic acidosis is a well-established complication of urinary diversion. Patient with orthotopic neobladder with high residual urine and large capacity are at even higher risk of metabolic acidosis. This information should be clearly documented in the post-operative discharge documentation to ensure early recognition by non-specialists.
PMCID: PMC4446673  PMID: 25979515
Metabolic acidosis; Urinary diversion; Neobladder
22.  Common variation near ROBO2 is associated with expressive vocabulary in infancy 
Nature communications  2014;5:4831.
Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, analysing an early (15-18 months, ‘one-word stage’, NTotal=8,889) and a later (24-30 months, ‘two-word stage’, NTotal=10,819) phase of language acquisition. For the early phase, one SNP (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon binding receptor, reaches the genome-wide significance level (p=1.3×10−8) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by Genome-wide Complex Trait Analysis (meta-GCTA h215-18-months=0.13, meta-GCTA h224-30-months=0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h224-months=0.20).
PMCID: PMC4175587  PMID: 25226531
23.  Intentional ingestions of foreign objects among prisoners: A review 
The intentional ingestion of foreign objects (IIFO) is described more commonly in prison populations than in the general population, with an estimated annual incidence of 1 in 1900 inmates in our state correctional facilities. Incidents often involve ingestion of small metal objects (e.g., paperclips, razor blades) or other commonly available items like pens or eating utensils. Despite ingestion of relatively sharp objects, most episodes can be clinically managed with either observation or endoscopy. Surgery should be reserved for those with signs or symptoms of gastrointestinal perforation or obstruction. For those with a history of IIFO, efforts should focus on prevention of recurrence as subsequent episodes are associated with higher morbidity, significant healthcare and security costs. The pattern of IIFO is often repetitive, with escalation both in frequency of ingestions and in number of items ingested. Little is known about successful prevention strategies, but efforts to monitor patients and provide psychiatric care are potential best-practice strategies. This article aims to provide state-of-the art review on the topic, followed by a set of basic recommendations.
PMCID: PMC4360434  PMID: 25789086
Ingestion; Foreign body; Endoscopy; Prisoner; Swallower; Prevention; Recurrence
24.  Ireland’s medical brain drain: migration intentions of Irish medical students 
To provide the optimum level of healthcare, it is important that the supply of well-trained doctors meets the demand. However, despite many initiatives, Ireland continues to have a shortfall of physicians, which has been projected to persist. Our study aimed to investigate the migration intentions of Irish medical students and identify the factors that influence their decisions in order to design appropriate interventions to sustain the supply of trained doctors in order to maintain a viable medical system.
An online cross-sectional survey was undertaken of all Irish medical students studying in the Republic of Ireland. The survey included nominal, ordinal, and scale items to determine migration intentions, factors influencing their decisions, and understanding of the Irish healthcare system.
A total of 2 273 medical students responded (37% response rate), of whom 1 519 were classified as Irish medical students (having completed secondary school in Ireland). Of these, 88% indicated they were either definitely migrating or contemplating migrating following graduation or completion of the pre-registration intern year. Forty percent expressed an intention of returning to Ireland within 5 years. The factors most influencing their decision to leave were career opportunities (85%), working conditions (83%), and lifestyle (80%).
The migration intentions expressed in this study predict an immediate and severe threat to the sustainability of the Irish healthcare service. Urgent interventions such as providing information about career options and specialty training pathways are required. These must begin in the undergraduate phase and continue in postgraduate training and are needed to retain medical school graduates.
PMCID: PMC4363465  PMID: 25889783
Medical students; Emigration and immigration; Human resources

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