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1.  Primary care and youth mental health in Ireland: qualitative study in deprived urban areas 
BMC Family Practice  2013;14:194.
Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15–24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people’s unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals’ experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16–25 years) in primary care in deprived urban settings in Ireland.
The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres.
We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care’s longitudinal nature as a key asset in promoting treatment engagement.
Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people’s experience and developing complex interventions that promote early intervention are priorities. (350 words)
PMCID: PMC3880165  PMID: 24341616
Young people; Urban deprivation; Mental health; Substance use; Primary care; General practice
2.  Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse 
The Journal of Clinical Investigation  2013;123(10):4344-4358.
Escape of prostate cancer (PCa) cells from ionizing radiation–induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
PMCID: PMC3784522  PMID: 24091326
3.  Conditional-ready mouse embryonic stem cell derived macrophages enable the study of essential genes in macrophage function 
Scientific Reports  2015;5:8908.
The ability to differentiate genetically modified mouse embryonic stem (ES) cells into functional macrophages provides a potentially attractive resource to study host-pathogen interactions without the need for animal experimentation. This is particularly useful in instances where the gene of interest is essential and a knockout mouse is not available. Here we differentiated mouse ES cells into macrophages in vitro and showed, through a combination of flow cytometry, microscopic imaging, and RNA-Seq, that ES cell-derived macrophages responded to S. Typhimurium, in a comparable manner to mouse bone marrow derived macrophages. We constructed a homozygous mutant mouse ES cell line in the Traf2 gene that is known to play a role in tumour necrosis factor-α signalling but has not been studied for its role in infections or response to Toll-like receptor agonists. Interestingly, traf2-deficient macrophages produced reduced levels of inflammatory cytokines in response to lipopolysaccharide (LPS) or flagellin stimulation and exhibited increased susceptibility to S. Typhimurium infection.
PMCID: PMC4354151  PMID: 25752829
4.  Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury 
The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.
PMCID: PMC3948131  PMID: 24398940
brain injury; caspase-1; IL-1; inflammasome; spinal cord injury; stroke
5.  Variations in Ischemic Heart Disease Burden by Age, Country, and Income: The Global Burden of Diseases, Injuries and Risk Factors 2010 Study 
Global heart  2014;9(1):91-99.
Ischemic Heart Disease (IHD) was the leading cause of disease burden worldwide in 2010. The majority of IHD burden affected middle income regions. We hypothesized that IHD burden may vary among countries, even within the same broad geographic region.
Disability-adjusted life years (DALYs) due to IHD were estimated at the region level for seven “super-regions”, 21 regions, and 187 countries using geographically nested models for IHD mortality and prevalent non-fatal IHD(nonfatal acute myocardial infarction, angina pectoris, or ischemic heart failure). Acute myocardial infarction, angina, and heart failure disability weights were applied to prevalent cases. Absolute numbers of DALYs and age-standardized DALYs per 100,000 persons were estimated for each region and country in 1990 and 2010. IHD burden for world regions was analyzed by country, income, and age.
About two-thirds of 2010 IHD DALYs affected middle income countries. In the North Africa/Middle East and South Asia regions—regions with high IHD burden—more than 29% of males and 24% of females struck by IHD were <50 years old. Age-standardized IHD DALYs decreased in most countries between 1990 and 2010, but increased in a number of countries in the Eastern Europe/Central Asia region (>1,000 per 100,000 increase) and South Asia region (>175 per 100,000). Age-standardized DALYs varied by up to eight fold among countries, by about 9,000 per 100,000 among middle income countries, about 7,400 among low income countries, and about 4,300 among high income countries.
The majority of IHD burden in 2010 impacted middle income regions, where younger adults were more likely to develop IHD in regions like South Asia and North Africa/Middle East. However, IHD burden varied substantially by country within regions, especially among middle income countries. A global or regional approach to IHD prevention will not be sufficient; research and policy should focus on the highest burden countries within regions.
PMCID: PMC4071302  PMID: 24977114
ischemic heart disease; national income; mortality; burden of disease; global health
6.  A Transactional Analysis of the Relation between Maternal Sensitivity and Child Vagal Regulation 
Developmental psychology  2013;50(3):784-793.
A transactional model examining the longitudinal association between vagal regulation (as indexed by vagal withdrawal) and maternal sensitivity from age 2.5 to age 5.5 was assessed. The sample included 356 children (171 male, 185 female) and their mothers who participated in the 2.5, 4.5, and 5.5 year laboratory visits. Cardiac vagal tone was obtained during a baseline task and during emotional frustration tasks. Maternal sensitivity was assessed via direct observation during a pretend play and cleanup task. To test for transactional associations, a path model estimating stability paths for vagal withdrawal and maternal sensitivity was compared to a full reciprocal model that included all cross-lagged pathways. A chi-square difference test was used to evaluate if the cross-lagged model explained the data above and beyond the stability model. The vagal withdrawal cross-lagged model was found to fit significantly better than the stability model and revealed that maternal sensitivity at 2.5 years was associated positively with vagal withdrawal at 4.5 years, and vagal withdrawal at 4.5 years was associated positively with maternal sensitivity at 5.5 years. These results suggest that early sensitive responding by mothers was associated with increases in vagal withdrawal, which in turn was associated with higher levels of sensitive parenting.
PMCID: PMC4165529  PMID: 23895168
early childhood; maternal sensitivity; parenting; physiological regulation; RSA; self-regulation; vagal tone; vagal withdrawal
7.  Breed differences in humoral and cellular responses of lambs to experimental infection with the gastrointestinal nematode Teladorsagia circumcincta 
Veterinary Research  2015;46:8.
While Texel lambs have increased resistance to infection with the gastrointestinal nematode Teladorsagia circumcincta compared to Suffolk lambs, the underlying resistance mechanisms are still unknown. The aim of this study was to compare parasitological, humoral and cellular responses of Texel and Suffolk lambs over time following a single experimental infection with T. circumcincta. Gastrointestinal nematode free (but not naïve) lambs received a single oral dose of 3 × 104 infective T. circumcincta larvae. The variables examined included worm burden, mucosal and serum IgA, abomasal mast cells and eosinophils, haematological parameters and plasma pepsinogen. Texel lambs had significantly lower worm burden on day 14 and lower plasma pepsinogen concentration from day 14 onwards than Suffolks and their response in mucosal IgA to infection occurred earlier. The results from the study suggest that an earlier local IgA response in the Texel contributes to the resistant characteristics of the breed, while the increased level of plasma pepsinogen in the Suffolk lambs implies greater abomasal tissue damage arising from the nematode infection.
PMCID: PMC4329660  PMID: 25827901
8.  Vasoactivity of Rucaparib, a PARP-1 Inhibitor, is a Complex Process that Involves Myosin Light Chain Kinase, P2 Receptors, and PARP Itself 
PLoS ONE  2015;10(2):e0118187.
Therapeutic inhibition of poly(ADP-ribose) polymerase (PARP), as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699), induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK) 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib’s activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.
PMCID: PMC4331495  PMID: 25689628
9.  Strategies for improving early detection and diagnosis of neovascular age-related macular degeneration 
Treatment of the neovascular form of age-related macular degeneration (AMD) has been revolutionized by the introduction of such agents as ranibizumab, bevacizumab, and aflibercept. As a result, the incidence of legal blindness occurring secondary to AMD has fallen dramatically in recent years in many countries. While these agents have undoubtedly been successful in reducing visual impairment and blindness, patients with neovascular AMD typically lose some vision over time, and often lose the ability to read, drive, or perform other important activities of daily living. Efforts are therefore under way to develop strategies that allow for earlier detection and treatment of this disease. In this review, we begin by providing an overview of the rationale for, and the benefits of, early detection and treatment of neovascular AMD. To achieve this, we begin by providing an overview of the pathophysiology and natural history of choroidal neovascularization, before reviewing the evidence from both clinical trials and “real-world” outcome studies. We continue by highlighting an area that is often overlooked: the importance of patient education and awareness for early AMD detection. We conclude the review by reviewing an array of both established and emerging technologies for early detection of choroidal neovascularization, ranging from Amsler chart testing, to hyperacuity testing, to advanced imaging techniques, such as optical coherence tomography.
PMCID: PMC4337735  PMID: 25733802
Amsler; detection; choroidal neovascularization; hyperacuity; optical coherence tomography
10.  Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals 
PLoS ONE  2015;10(2):e0117160.
Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.
To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.
Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.
We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.
PMCID: PMC4326126  PMID: 25674793
11.  Vision in schizophrenia: why it matters 
PMCID: PMC4318337  PMID: 25698992
schizophrenia; vision; perception; risk; cognition; blindness; brain
12.  An Evaluation of Welding Processes to Reduce Hexavalent Chromium Exposures and Reduce Costs by Using Better Welding Techniques 
Environmental Health Insights  2014;8(Suppl 1):47-50.
A group of stainless steel arc welding processes was compared for emission rates of fume and hexavalent chromium, and costs per meter length of weld. The objective was to identify those with minimal emissions and also compare relative labor and consumables costs. The selection included flux-cored arc welding (FCAW), shielded-metal arc welding (SMAW), and multiple gas metal arc welding (GMAW) processes. Using a conical chamber, fumes were collected, and fume generation rates and hexavalent chromium (Cr6+) were measured. GMAW processes used were short-circuit (SC) and pulsed-spray modes. Flux-cored welding used gas shielding. Costs were estimated per meter of a 6.3-mm thick horizontal butt weld. Emission rates of Cr6+ were lowest for GMAW processes and highest for SMAW; several GMAW processes had less than 2% of the SMAW generation rate. Labor and consumable costs for the processes studied were again highest for SMAW, with those of several GMAW types about half that cost. The results show that use of any of the GMAW processes (and flux-cored welding) could substantially reduce fume and Cr6+ emissions, and greatly reduce costs relative to SMAW.
PMCID: PMC4270263  PMID: 25574138
welding; hexavalent chromium; welding fume
13.  POT1 loss-of-function variants predispose to familial melanoma 
Nature genetics  2014;46(5):478-481.
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.
PMCID: PMC4266105  PMID: 24686849
14.  Oropharyngeal Aspiration of Burkholderia mallei and Burkholderia pseudomallei in BALB/c Mice 
PLoS ONE  2014;9(12):e115066.
Burkholderia mallei and Burkholderia pseudomallei are potentially lethal pathogens categorized as biothreat agents due, in part, to their ability to be disseminated via aerosol. There are no protective vaccines against these pathogens and treatment options are limited and cumbersome. Since disease severity is greatest when these agents are inhaled, efforts to develop pre- or post-exposure prophylaxis focus largely on inhalation models of infection. Here, we demonstrate a non-invasive and technically simple method for affecting the inhalational challenge of BALB/c mice with B. pseudomallei and B. mallei. In this model, two investigators utilized common laboratory tools such as forceps and a micropipette to conduct and characterize an effective and reproducible inhalational challenge of BALB/c mice with B. mallei and B. pseudomallei. Challenge by oropharyngeal aspiration resulted in acute disease. Additionally, 50% endpoints for B. pseudomallei K96243 and B. mallei ATCC 23344 were nearly identical to published aerosol challenge methods. Furthermore, the pathogens disseminated to all major organs typically targeted by these agents where they proliferated. The pro-inflammatory cytokine production in the proximal and peripheral fluids demonstrated a rapid and robust immune response comparable to previously described murine and human studies. These observations demonstrate that OA is a viable alternative to aerosol exposure.
PMCID: PMC4263729  PMID: 25503969
15.  Processing of Spatial-Frequency Altered Faces in Schizophrenia: Effects of Illness Phase and Duration 
PLoS ONE  2014;9(12):e114642.
Low spatial frequency (SF) processing has been shown to be impaired in people with schizophrenia, but it is not clear how this varies with clinical state or illness chronicity. We compared schizophrenia patients (SCZ, n = 34), first episode psychosis patients (FEP, n = 22), and healthy controls (CON, n = 35) on a gender/facial discrimination task. Images were either unaltered (broadband spatial frequency, BSF), or had high or low SF information removed (LSF and HSF conditions, respectively). The task was performed at hospital admission and discharge for patients, and at corresponding time points for controls. Groups were matched on visual acuity. At admission, compared to their BSF performance, each group was significantly worse with low SF stimuli, and most impaired with high SF stimuli. The level of impairment at each SF did not depend on group. At discharge, the SCZ group performed more poorly in the LSF condition than the other groups, and showed the greatest degree of performance decline collapsed over HSF and LSF conditions, although the latter finding was not significant when controlling for visual acuity. Performance did not change significantly over time for any group. HSF processing was strongly related to visual acuity at both time points for all groups. We conclude the following: 1) SF processing abilities in schizophrenia are relatively stable across clinical state; 2) face processing abnormalities in SCZ are not secondary to problems processing specific SFs, but are due to other known difficulties constructing visual representations from degraded information; and 3) the relationship between HSF processing and visual acuity, along with known SCZ- and medication-related acuity reductions, and the elimination of a SCZ-related impairment after controlling for visual acuity in this study, all raise the possibility that some prior findings of impaired perception in SCZ may be secondary to acuity reductions.
PMCID: PMC4259337  PMID: 25485784
16.  The Interactive Roles of Parenting, Emotion Regulation and Executive Functioning in Moral Reasoning during Middle Childhood 
Cognition & emotion  2013;27(8):10.1080/02699931.2013.789792.
We examined mother-child cooperative behavior, children’s emotion regulation and executive function, as well as combinations of these factors, as predictors of moral reasoning in 89 10-year-old children. Dyadic cooperation was coded from videotaped observations of laboratory puzzle and speech tasks. Emotion regulation was derived from maternal report, and executive functioning was assessed with the Tower of London task. Moral reasoning was coded during mother-child conversations about morally ambiguous, peer-conflict situations. Two significant interactions indicated that children from more cooperative dyads who also had higher executive function skills had higher moral reasoning scores than other children, and children lower in both emotion regulation and executive function had lower moral reasoning scores than other children. The results contribute to the literature on the multiple and interactive levels of influence on moral reasoning in childhood.
PMCID: PMC3751970  PMID: 23650955
parent-child; cooperative behavior; executive functioning; emotion regulation; moral reasoning
17.  Impact of prostate cancer on sexual relationships: a longitudinal perspective on intimate partners’ experiences 
The journal of sexual medicine  2013;10(12):10.1111/jsm.12295.
In this prospective study of localized prostate cancer patients and their partners, we analyzed how partner issues evolve over time, focusing on satisfaction with care, influence of cancer treatment and its impact on relationship with patient, cancer worry, and personal activities.
Our study aims were twofold: 1) to determine whether the impact of treatment on patients and partners moderate over time and (2) if receiving surgery (i.e., radical prostatectomy) influences partner issues more than other treatments.
Patients newly diagnosed with localized prostate cancer and their female partners were recruited from 3 states to complete surveys by mail at 3 time points over 12 months.
Main Outcome Measures
The four primary outcomes assessed in the partner analysis included satisfaction with treatment, cancer worry, and the influence of cancer and its treatment on their relationship (both general relationship and sexual relationship).
This analysis included 88 patient-partner pairs. At 6 months, partners reported that cancer had a negative impact on their sexual relationship (39% - somewhat negative and 12% - very negative). At 12 months, this proportion increased substantially (42% – somewhat negative and 29% - very negative). Partners were significantly more likely to report that their sexual relationship was worse when the patient reported having surgery (p=0.0045, OR=9.8025, 95% CI 2.076–46.296). A minority of partners reported significant negative impacts in other areas involving their personal activities (16% at 6 months and 25% at 12 months) or work life (6% at 6 months, which increased to 12% at 12 months).
From partners’ perspectives, prostate cancer therapy has negative impact on sexual relationships, and appears to worsen over time.
PMCID: PMC3855071  PMID: 24118980
prostate cancer; partner; sexual function
18.  Mothers' and Fathers' Negative Responsibility Attributions and Perceptions of Children's Problem Behavior 
Personal Relationships  2013;20(4):10.1111/pere.12010.
Parents' negative responsibility attributions about their child's misbehavior are related to a perception that the child has more behavior problems. The current study used a dyadic framework to explore how mothers' and fathers' attributions relate to their own perceptions and to their partner's perceptions of the child's externalizing problems. Participants included 102 couples interviewed when children were 7 years old. Results confirmed that mothers reported more externalizing behavior problems in their children than did fathers, and fathers of boys reported more child behavior problems than fathers of girls. Dyadic analyses suggested that parents' negative responsibility attributions of the child's behavior were associated with greater perceptions of child externalizing problems on behalf of parents and their partners.
PMCID: PMC3859456  PMID: 24348082
Parental attributions; children's problem behavior; dyadic data analysis
19.  Automatic Feature-Based Grouping During Multiple Object Tracking 
Contour interpolation automatically binds targets with distractors to impair multiple object tracking (Keane, Mettler, Tsoi, & Kellman, 2011). Is interpolation special in this regard, or can other features produce the same effect? To address this question, we examined the influence of eight features on tracking: color, contrast polarity, orientation, size, shape, depth, interpolation and a combination (shape, color, size). In each case, subjects tracked 4 of 8 objects that began as undifferentiated shapes, changed features as motion began (to enable grouping), and returned to their undifferentiated states before halting. The features were always irrelevant to the task instructions. We found that inter-target grouping improved performance for all feature types, except orientation and interpolation (Experiment 1 and Experiment 2). Most importantly, target-distractor grouping impaired performance for color, size, shape, combination, and interpolation. The impairments were at times large (>15% decrement in ac curacy) and occurred relative to a homogeneous condition in which all objects had the same features at each moment of a trial (Experiment 2) and relative to a “diversity” condition in which targets and distractors had different features at each moment (Experiment 3). We conclude that feature-based grouping occurs for a variety of features besides interpolation, even when irrelevant to task instructions and contrary to the task demands, suggesting that interpolation is not unique in promoting automatic grouping in tracking tasks. Our results also imply that various kinds of features are encoded automatically and in parallel during tracking.
PMCID: PMC3901520  PMID: 23458095
multiple object tracking; attention; perceptual grouping; perceptual organization
20.  Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins 
Nucleic Acids Research  2014;43(3):e15.
The emergence of new sequencing technologies has facilitated the use of bacterial whole genome alignments for evolutionary studies and outbreak analyses. These datasets, of increasing size, often include examples of multiple different mechanisms of horizontal sequence transfer resulting in substantial alterations to prokaryotic chromosomes. The impact of these processes demands rapid and flexible approaches able to account for recombination when reconstructing isolates’ recent diversification. Gubbins is an iterative algorithm that uses spatial scanning statistics to identify loci containing elevated densities of base substitutions suggestive of horizontal sequence transfer while concurrently constructing a maximum likelihood phylogeny based on the putative point mutations outside these regions of high sequence diversity. Simulations demonstrate the algorithm generates highly accurate reconstructions under realistically parameterized models of bacterial evolution, and achieves convergence in only a few hours on alignments of hundreds of bacterial genome sequences. Gubbins is appropriate for reconstructing the recent evolutionary history of a variety of haploid genotype alignments, as it makes no assumptions about the underlying mechanism of recombination. The software is freely available for download at, implemented in Python and C and supported on Linux and Mac OS X.
PMCID: PMC4330336  PMID: 25414349
21.  A case–control study comparing the incidence of early symptoms in pancreatic and biliary tract cancer 
BMJ Open  2014;4(11):e005720.
Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTC) are often diagnosed late and at an advanced stage. Population-based screening programmes do not exist and diagnosis is primarily dependent on symptom recognition. Recently symptom-based cancer decision support tools (CDSTs) have been introduced into primary care practices throughout the UK to support general practitioners (GPs) in identifying patients with suspected PDAC. However, future refinement of these tools to improve their diagnostic accuracy is likely to be necessary.
The Health Improvement Network (THIN) is a primary care database, which includes more than 11 million electronic patient records, from 562 GP practices in the UK.
All patients with a diagnosis of PDAC or BTC between 2000 and 2010 were included in the study along with six matched controls; 2773 patients with PDAC, 848 patients with BTC and 15 395 controls.
Primary and secondary outcome measures
The primary aim of this study was to determine the early symptom profiles of PDAC and BTC. Secondary aims included comparing early symptom trends between BTC and PDAC, defining symptom onset in PDAC and evaluating trends in routine blood tests nearest to the time of diagnosis.
In the year prior to diagnosis, patients with PDAC visited their GP on a median of 18 (IQR 11–27) occasions. PDAC was associated with 11 alarm symptoms and BTC with 8. Back pain (OR 1.33 (95% CI 1.18 to 1.49) p<0.001), lethargy (1.42 (95% CI 1.25 to 1.62) p<0.001) and new onset diabetes (OR 2.46 (95% CI 2.16 to 2.80)) were identified as unique features of PDAC.
PDAC and BTC are associated with numerous early alarm symptoms. CDSTs are therefore likely to be useful in identifying these tumours at an early stage. Inclusion of unique symptoms, symptoms with an early onset and routinely performed blood tests is likely to further improve the sensitivity of these tools.
PMCID: PMC4244441  PMID: 25410605
22.  Web-Based Intervention for Returning Veterans with Symptoms of Posttraumatic Stress Disorder and Risky Alcohol Use 
A substantial number of military personnel who have served in Iraq (Operation Iraqi Freedom; OIF) and Afghanistan (Operating Enduring Freedom; OEF) develop symptoms of posttraumatic stress disorder (PTSD) in response to their military experiences and many of these same individuals will drink in a risky or problematic manner following deployment. If left untreated, PTSD symptoms and alcohol problems can become chronic and have a significant, negative impact on the lives of veterans, their families and communities. Further, OIF and OEF service members are often reluctant to seek treatment for mental health symptoms or alcohol problems secondary to stigma. In order to reach this population it is essential that new strategies and venues for delivering evidence-based care are explored. Web-based interventions are uniquely suited to this cohort of veterans in that they have the potential to reach a significant number of veterans who commonly use the Web and who might not otherwise receive care. This article will review the prevalence of PTSD and alcohol problems among OIF and OEF veterans, common barriers they experience with accessing care in traditional mental health settings, and what is known about the effectiveness of Web-based approaches for PTSD and alcohol problems. It also describes the components of a new Web-based intervention, developed by the authors, that uses motivational enhancement and cognitive-behavioral strategies to intervene with returning veterans who report PTSD symptoms and problem drinking. Recommendations for future directions in working with returning veterans with PTSD and alcohol problems will be offered.
PMCID: PMC4219624  PMID: 25378713
Veterans; PTSD; Alcohol; Web intervention
23.  The impact of Oncotype DX testing on breast cancer management and chemotherapy prescribing patterns in a tertiary referral centre 
European Journal of Cancer  2014;50(16):2763-2770.
The use of chemotherapy in node-negative, (O)Estrogen Receptor (ER)-positive breast cancer has changed significantly since the introduction of Oncotype DX to determine systemic recurrence risk based on tumour genomic signature.
This study aims to1.Document longitudinal changes in chemotherapy use,2.Assess the impact of new evidence on local protocol.
A cohort study was undertaken, including consecutive patients with early node-negative, ER-positive breast cancer diagnosed between 2006 and May 2013, including a period of prospective clinical trial (Trial Assigning Individualised Options for Treatment (TAILORx)) recruitment. Data were collected regarding patient demographics, tumour clinico-pathological features, Oncotype DX use and recurrence score and chemotherapy use. All therapeutic decisions were made following multidisciplinary discussion, with adherence to guidelines and consideration of trial protocol and Oncotype DX recurrence scores.
479 consecutive patients were included in the study, of whom 241 (50%) underwent Oncotype DX testing, 97 as part of the TAILORx clinical trial. Oncotype DX testing began on a trial basis in 2007 and until October 2011, only patients enrolled on TAILORx availed of genomic profiling. From October 2011, Oncotype DX was used in all eligible patients as per National Cancer Control Programme (NCCP) guidelines. A total of 216 (45%) patients received chemotherapy. The use of chemotherapy changed in inverse proportion to the availability of the genomic assay. Of those patients in whom Oncotype DX was utilised, 138 (57%) were spared chemotherapy.
This study validates the use of molecular testing in the rationalisation of systemic therapy.
PMCID: PMC4204201  PMID: 25240289
Breast cancer; Oncotype DX; Oncotype; Genomic profiling; Genomic assay; Recurrence score; Adjuvant chemotherapy; Chemotherapy; Individualised therapy
24.  Reduced Heme Levels Underlie the Exponential Growth Defect of the Shewanella oneidensis hfq Mutant 
PLoS ONE  2014;9(10):e109879.
The RNA chaperone Hfq fulfills important roles in small regulatory RNA (sRNA) function in many bacteria. Loss of Hfq in the dissimilatory metal reducing bacterium Shewanella oneidensis strain MR-1 results in slow exponential phase growth and a reduced terminal cell density at stationary phase. We have found that the exponential phase growth defect of the hfq mutant in LB is the result of reduced heme levels. Both heme levels and exponential phase growth of the hfq mutant can be completely restored by supplementing LB medium with 5-aminolevulinic acid (5-ALA), the first committed intermediate synthesized during heme synthesis. Increasing expression of gtrA, which encodes the enzyme that catalyzes the first step in heme biosynthesis, also restores heme levels and exponential phase growth of the hfq mutant. Taken together, our data indicate that reduced heme levels are responsible for the exponential growth defect of the S. oneidensis hfq mutant in LB medium and suggest that the S. oneidensis hfq mutant is deficient in heme production at the 5-ALA synthesis step.
PMCID: PMC4214671  PMID: 25356668
25.  Aspergillus Colonization of the Lung Allograft is a Risk Factor for Bronchiolitis Obliterans Syndrome 
Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between 1/2000 and 6/2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87 to 520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS.
PMCID: PMC4214373  PMID: 19459819

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