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1.  Attention training for infants at familial risk of ADHD (INTERSTAARS): study protocol for a randomised controlled trial 
Trials  2016;17:608.
Background
Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder that can negatively impact on an individual’s quality of life. It is pathophysiologically complex and heterogeneous with different neuropsychological processes being impaired in different individuals. Executive function deficits, including those affecting attention, working memory and inhibitory control, are common. Cognitive training has been promoted as a treatment option, based on the notion that by strengthening the neurocognitive networks underlying these executive processes, ADHD symptoms will also be reduced. However, if implemented in childhood or later, when the full disorder has become well-established, cognitive training has only limited value. INTERSTAARS is a trial designed to test a novel approach to intervention, in which cognitive training is implemented early in development, before the emergence of the disorder. The aim of INTERSTAARS is to train early executive skills, thereby increasing resilience and reducing later ADHD symptoms and associated impairment.
Methods/design
Fifty 10–14-month-old infants at familial risk of ADHD will participate in INTERSTAARS. Infants will be randomised to an intervention or a control group. The intervention aims to train early attention skills by using novel eye-tracking technology and gaze-contingent training paradigms. Infants view animated games on a screen and different events take place contingent on where on the screen the infant is looking. Infants allocated to the intervention will receive nine weekly home-based attention training sessions. Control group infants will also receive nine weekly home visits, but instead of viewing the training games during these visits they will view non-gaze-contingent age-appropriate videos. At baseline and post treatment, infant attention control will be assessed using a range of eye-tracking, observational, parent-report and neurophysiological measures. The primary outcome will be a composite of eye-tracking tasks used to assess infant attention skills. Follow-up data will be collected on emerging ADHD symptoms when the infants are 2 and 3 years old.
Discussion
This is the first randomised controlled trial to assess the potential efficacy of cognitive training as a prevention measure for infants at familial risk of ADHD. If successful, INTERSTAARS could offer a promising new approach for developing early interventions for ADHD.
Trial registration
International Standard Randomised Controlled Trial registry: ISRCTN37683928. Registered on 22 June 2015.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1727-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-016-1727-0
PMCID: PMC5192597  PMID: 28031039
ADHD; Attention; Infancy; Cognitive training; Early intervention; Familial risk
2.  A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation 
Nature Communications  2016;7:13916.
Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization and there remains no pediatric vaccine. RSV live-attenuated vaccines (LAVs) have a history of safe testing in infants; however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we seek to engineer an RSV LAV with enhanced immunogenicity. Genetic mapping identifies strain line 19 fusion (F) protein residues that correlate with pre-fusion antigen maintenance by ELISA and thermal stability of infectivity in live RSV. We generate a LAV candidate named OE4 which expresses line 19F and is attenuated by codon-deoptimization of non-structural (NS1 and NS2) genes, deletion of the small hydrophobic (SH) gene, codon-deoptimization of the attachment (G) gene and ablation of the secreted form of G. OE4 (RSV-A2-dNS1-dNS2-ΔSH-dGm-Gsnull-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats.
Development of a safe and efficacious vaccine for respiratory syncytial virus (RSV) has been challenging. Here the authors generate a live-attenuated RSV vaccine that shows increased thermostability and immunogenicity, and protects cotton rats from RSV challenge.
doi:10.1038/ncomms13916
PMCID: PMC5187593  PMID: 28000669
3.  Doctors' perspectives on PSA testing illuminate established differences in prostate cancer screening rates between Australia and the UK: a qualitative study 
BMJ Open  2016;6(12):e011932.
Objectives
To examine how general practitioners (GPs) in the UK and GPs in Australia explain their prostate-specific antigen (PSA) testing practices and to illuminate how these explanations are similar and how they are different.
Design
A grounded theory study.
Setting
Primary care practices in Australia and the UK.
Participants
69 GPs in Australia (n=40) and the UK (n=29). We included GPs of varying ages, sex, clinical experience and patient populations. All GPs interested in participating in the study were included.
Results
GPs' accounts revealed fundamental differences in whether and how prostate cancer screening occurred in their practice and in the broader context within which they operate. The history of prostate screening policy, organisational structures and funding models appeared to drive more prostate screening in Australia and less in the UK. In Australia, screening processes and decisions were mostly at the discretion of individual clinicians, and varied considerably, whereas the accounts of UK GPs clearly reflected a consistent, organisationally embedded approach based on local evidence-based recommendations to discourage screening.
Conclusions
The GP accounts suggested that healthcare systems, including historical and current organisational and funding structures and rules, collectively contribute to how and why clinicians use the PSA test and play a significant role in creating the mindlines that GPs employ in their clinic. Australia's recently released consensus guidelines may support more streamlined and consistent care. However, if GP mindlines and thus routine practice in Australia are to shift, to ultimately reduce unnecessary or harmful prostate screening, it is likely that other important drivers at all levels of the screening process will need to be addressed.
doi:10.1136/bmjopen-2016-011932
PMCID: PMC5168698  PMID: 27920082
prostate cancer screening; mindlines; prostate-specific antigen test; australia; united kingdom
4.  Multidimensional influences on autism symptom measures: Implications for use in etiological research 
Objective
Growing awareness that symptoms of autism spectrum disorder (ASD) transcend multiple diagnostic categories, and major advances in the identification of genetic syndromes associated with ASD, has led to widespread use of ASD symptom measures in etiological studies of neurodevelopmental disorders. Insufficient consideration of potentially confounding factors such as cognitive ability or behavior problems can have important negative consequences in interpretation of findings, including erroneous estimation of associations between ASD and etiological factors.
Method
Participants were 388 children aged 2–13 years with diagnoses of ASD or another neurodevelopmental disorder without ASD. Receiver operating characteristics methods were used to assess the influence of IQ and emotional/behavioral problems on the discriminative ability of three widely used ASD symptom measures; the Social Responsiveness Scale (SRS), the Autism Diagnostic Interview-Revised (ADI-R), and the Autism Diagnostic Observation Schedule (ADOS).
Results
IQ influenced the discriminative thresholds of the SRS and ADI-R, and emotional/behavioral problems affected the discriminative thresholds of the SRS, ADI-R, and ADOS. This resulted in low specificity of ASD cut-offs on the SRS and ADI-R for children with intellectual disability without ASD (27–42%), and low specificity across all three instruments for children without ASD with elevated emotional/behavioral problems (36–59%). Adjustment for these characteristics resulted in improved discriminative ability for all three ASD measures.
Conclusion
The findings indicate that scores on ASD symptom measures reflect far more than ASD symptoms. Valid interpretation of these measures requires steps to account for the influences of IQ and emotional/behavioral problems.
doi:10.1016/j.jaac.2016.09.490
PMCID: PMC5131801  PMID: 27871640
measurement; discriminative ability; autism diagnostic observation schedule; autism diagnostic interview-revised; social responsiveness scale
5.  CD4 cell dynamics in untreated HIV-1 infection: overall rates, and effects of age, viral load, gender and calendar time 
AIDS (London, England)  2015;29(18):2435-2446.
Background
CD4 cell count is a key measure of HIV disease progression, and the basis of successive international guidelines for treatment initiation. CD4 cell dynamics are used in mathematical and econometric models for evaluating public health need and interventions. Here, we estimate rates of CD4 decline, stratified by relevant covariates, in a form that is clinically transparent and can be directly used in such models.
Methods
We analyse the ATHENA cohort, including individuals with date of seroconversion estimated to within one year and with intensive clinical follow-up prior to treatment initiation. Because CD4 counts are intrinsically noisy, we separate the analysis into long-term trends of smoothed CD4 counts, and an observation model relating actual CD4 measurements to the underlying smoothed counts. We use a monotonic spline smoothing model to describe the decline of smoothed CD4 counts through categories CD4 >500, 350–500, 200–350 and ≤200 cells/mm3. We estimate the proportion of individuals starting in each category after seroconversion and the average time spent in each category. We examine individual-level co-factors which influence these parameters.
Results
Amongst untreated individuals, the time spent in each compartment was 3.32, 2.70, 5.50 and 5.06 years. Only 76% started in the CD4>500 cells/mm3 compartment after seroconversion. Set-point viral load (SPVL) was an important factor: individuals with ≥5 log10 copies/ml took 5.37 years to reach CD4<200 cells/mm3 compared to 15.76 years for SPVL <4 log10 copies/ml.
Conclusions
Many individuals already have CD4<500 cells/mm3 after seroconversion. SPVL strongly influences the rate of CD4 decline. Treatment guidelines should consider measuring SPVL, while mathematical models should incorporate SPVL stratification.
doi:10.1097/QAD.0000000000000854
PMCID: PMC4645962  PMID: 26558543
6.  Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial 
Lancet (London, England)  2016;388(10059):2501-2509.
Summary
Background
It is not known whether early intervention can improve long-term autism symptom outcomes. We aimed to follow-up the Preschool Autism Communication Trial (PACT), to investigate whether the PACT intervention had a long-term effect on autism symptoms and continued effects on parent and child social interaction.
Methods
PACT was a randomised controlled trial of a parent-mediated social communication intervention for children aged 2–4 years with core autism. Follow-up ascertainment was done at three specialised clinical services centres in the UK (London, Manchester, and Newcastle) at a median of 5·75 years (IQR 5·42–5·92) from the original trial endpoint. The main blinded outcomes were the comparative severity score (CSS) from the Autism Diagnostic Observation Schedule (ADOS), the Dyadic Communication Assessment Measure (DCMA) of the proportion of child initiatiations when interacting with the parent, and an expressive-receptive language composite. All analyses followed the intention-to-treat principle. PACT is registered with the ISRCTN registry, number ISRCTN58133827.
Findings
121 (80%) of the 152 trial participants (59 [77%] of 77 assigned to PACT intervention vs 62 [83%] of 75 assigned to treatment as usual) were traced and consented to be assessed between July, 2013, and September, 2014. Mean age at follow-up was 10·5 years (SD 0·8). Group difference in favour of the PACT intervention based on ADOS CSS of log-odds effect size (ES) was 0·64 (95% CI 0·07 to 1·20) at treatment endpoint and ES 0·70 (95% CI −0·05 to 1·47) at follow-up, giving an overall reduction in symptom severity over the course of the whole trial and follow-up period (ES 0·55, 95% CI 0·14 to 0·91, p=0·004). Group difference in DCMA child initiations at follow-up showed a Cohen's d ES of 0·29 (95% CI −0.02 to 0.57) and was significant over the course of the study (ES 0·33, 95% CI 0·11 to 0·57, p=0·004). There were no group differences in the language composite at follow-up (ES 0·15, 95% CI −0·23 to 0·53).
Interpretation
The results are the first to show long-term symptom reduction after a randomised controlled trial of early intervention in autism spectrum disorder. They support the clinical value of the PACT intervention and have implications for developmental theory.
Funding
Medical Research Council.
doi:10.1016/S0140-6736(16)31229-6
PMCID: PMC5121131  PMID: 27793431
7.  Oral fumaric acid esters for psoriasis: abridged Cochrane systematic review including GRADE assessments 
The British Journal of Dermatology  2016;175(5):873-881.
Summary
Fumaric acid esters (FAEs) are licensed for the treatment of moderate‐to‐severe psoriasis in Germany but are also used off‐label in many other countries. We conducted this systematic review to synthesize the highest‐quality evidence for the benefits and risks of FAEs for psoriasis. Our primary outcomes were change in Psoriasis Area and Severity Index score and dropout rates due to adverse effects. Randomized controlled trials (RCTs) of FAEs or dimethylfumarate were included, with no restriction on age or psoriasis subtype. We searched the Cochrane Skin Group Specialised Register, CENTRAL in the Cochrane Library, Medline, Embase, LILACS and five trials registers, and hand searched six conference proceedings. Six RCTs with a total of 544 participants were included, four of which were published only as abstracts or brief reports, limiting study reporting. Five RCTs compared FAEs with placebo, and all demonstrated benefit in favour of FAEs. However, meta‐analysis was possible only for PASI 50 response after 12–16 weeks, which was achieved by 64% of participants on FAEs compared with 14% on placebo: risk ratio (RR) 4·55, 95% confidence interval (CI) 2·80–7·40; two studies; 247 participants; low‐quality evidence). There was no difference in dropout rates due to adverse effects (RR 5·36, 95% CI 0·28–102·12; one study; 27 participants; very low‐quality evidence and wide CI). More participants experienced nuisance adverse effects with FAEs (76%) than with placebo (16%) (RR 4·72, 95% CI 2·45–9·08; one study; 99 participants; moderate‐quality evidence), mainly abdominal pain, diarrhoea and flushing. One head‐to‐head study of very low‐quality evidence comparing FAEs with methotrexate reported comparable efficacy and dropout rates, although FAEs caused more flushing. The evidence in this review was limited and must be interpreted with caution; studies with better design and outcome reporting are needed.
What's already known about this topic?
Fumaric acid esters (FAEs) are licensed for the treatment of moderate‐to‐severe psoriasis in Germany, and are used off‐label in many other countries.Non‐Cochrane systematic reviews previously examined the effect of FAEs in psoriasis, but have not rigorously assessed the quality of the evidence.
What does this study add?
Six randomized controlled trials with 544 participants were included, four of which were published only as abstracts or brief reports, resulting in low‐ or very low‐quality evidence.Results suggest that FAEs are superior to placebo, but their efficacy in comparison with methotrexate is uncertain due to very low‐quality evidence.The relative risk of nuisance adverse effects with FAEs is about five times greater than with placebo; however, there is insufficient evidence available to give an accurate figure for dropout rates due to adverse effects.
Linked Comment: Egeberg. Br J Dermatol 2016; 175:857.
Audio Commentary
doi:10.1111/bjd.14676
PMCID: PMC5095877  PMID: 27087044
8.  Emotional health, support, and self‐efficacy in young adults with a history of language impairment 
Children and adolescents with language impairment (LI) are at risk of emotional health difficulties. However, less is known about whether these difficulties continue into adulthood for this group, or about the potential role of environmental resources (e.g., social support) or internal resources (e.g., self‐efficacy). This study investigates emotional health in 81 adults with a history of developmental LI (aged 24) compared with 87 age‐matched peers (AMPs) using Beck Inventories. Social support and self‐efficacy measures were examined as predictors. The results were fourfold: (1) adults with LI had higher levels of emotional health problems; (2) whilst the availability of social support was similar across groups, people with LI received more help from others compared to peers; (3) social support was not significantly related to emotional health in those with LI – in contrast, for AMPs, uptake of support indicated poorer emotional health; (4) self‐efficacy was the strongest predictor of emotional health in both groups and fully mediated the relationship between language and emotional health (no moderation by group). This cross‐sectional study has implications for concurrent factors that might affect emotional health outcomes for children and young people with and without LI.
doi:10.1111/bjdp.12148
PMCID: PMC5082521  PMID: 27226087
developmental disorder; language impairment; depression; anxiety; support; self‐efficacy
9.  The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study 
Background
Diagnosis of ‘specific’ language impairment traditionally required nonverbal IQ to be within normal limits, often resulting in restricted access to clinical services for children with lower NVIQ. Changes to DSM‐5 criteria for language disorder removed this NVIQ requirement. This study sought to delineate the impact of varying NVIQ criteria on prevalence, clinical presentation and functional impact of language disorder in the first UK population study of language impairment at school entry.
Methods
A population‐based survey design with sample weighting procedures was used to estimate population prevalence. We surveyed state‐maintained reception classrooms (n = 161 or 61% of eligible schools) in Surrey, England. From a total population of 12,398 children (ages 4–5 years), 7,267 (59%) were screened. A stratified subsample (n = 529) received comprehensive assessment of language, NVIQ, social, emotional and behavioural problems, and academic attainment.
Results
The total population prevalence estimate of language disorder was 9.92% (95% CI 7.38, 13.20). The prevalence of language disorder of unknown origin was estimated to be 7.58% (95% CI 5.33, 10.66), while the prevalence of language impairment associated with intellectual disability and/or existing medical diagnosis was 2.34% (95% CI 1.40, 3.91). Children with language disorder displayed elevated symptoms of social, emotional and behavioural problems relative to peers, F(1, 466) = 7.88, p = .05, and 88% did not make expected academic progress. There were no differences between those with average and low‐average NVIQ scores in severity of language deficit, social, emotional and behavioural problems, or educational attainment. In contrast, children with language impairments associated with known medical diagnosis and/or intellectual disability displayed more severe deficits on multiple measures.
Conclusions
At school entry, approximately two children in every class of 30 pupils will experience language disorder severe enough to hinder academic progress. Access to specialist clinical services should not depend on NVIQ.
doi:10.1111/jcpp.12573
PMCID: PMC5082564  PMID: 27184709
Developmental language disorder; NVIQ discrepancy; prevalence; functional impairment
10.  Depression: an exploratory parallel-group randomised controlled trial of Antenatal guided self help for WomeN (DAWN): study protocol for a randomised controlled trial 
Trials  2016;17:503.
Background
Depression is a common antenatal mental disorder and is associated with an increased risk of adverse effects on the fetus and significant morbidity for the mother; if untreated it can also continue into the post-natal period and affect mother-infant interactions. There has been little research evaluating the effectiveness or cost-effectiveness of antenatal psychological interventions for antenatal depression, particularly for mild to moderate disorders. International guidelines recommend a stepped care approach starting with Guided Self Help, and the aim of this exploratory trial is to investigate Guided Self Help modified for pregnancy.
Methods
The DAWN trial is an exploratory randomised controlled trial of the effectiveness and cost-effectiveness of antenatal Guided Self Help, modified for pregnancy and delivered by National Health Service Psychological Wellbeing Practitioners. Antenatal Guided Self Help, in addition to usual care, is compared with usual care for pregnant women diagnosed with mild to moderate depression and mixed anxiety and depression, using the Structured Clinical Interview for DSM-IV Disorders. Modifications for pregnancy include perinatal mental health training, addressing pregnancy-specific worries and including sections on health issues in pregnancy and planning for parenthood. Women allocated to Guided Self Help will be seen for up to eight sessions by a Psychological Wellbeing Practitioner (including an initial assessment session); there will also be an appointment at 12 weeks after delivery. Research measures including the Edinburgh Postnatal Depression Scale (primary outcome) and other measures of depression, anxiety, quality of life and service use will be collected from women before random allocation, 14 weeks after random allocation and at 12 weeks after delivery. Potential psychological mechanisms of the intervention will be explored using the Pregnancy-Related Thoughts Questionnaire and the Metacognitive Awareness Questionnaire.
Discussion
The DAWN trial is the first exploratory trial to investigate the efficacy of antenatal Guided Self Help for pregnant women with mild to moderate depression meeting DSM-IV diagnostic criteria. Recruitment started January 2015 and is expected to be completed by July 2016.
Trial registration
ISRCTN registry: ISRCTN83768230. Registered on 8 August 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1632-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-016-1632-6
PMCID: PMC5070149  PMID: 27756349
Depression; Pregnancy; Guided Self-Help; Randomised controlled trial
11.  Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1 
Human molecular genetics  2013;22(19):3947-3959.
Mutant superoxide dismutase 1 (SOD1) selectively associates with spinal cord mitochondria in rodent models of SOD1-mediated amyotrophic lateral sclerosis. A portion of mutant SOD1 exists in a non-native/misfolded conformation that is selectively recognized by conformational antibodies. Misfolded SOD1 is common to all mutant SOD1 models, is uniquely found in areas affected by the disease and is considered to mediate toxicity. We report that misfolded SOD1 recognized by the antibody B8H10 is present in greater abundance in mitochondrial fractions of SOD1G93A rat spinal cords compared with oxidized SOD1, as recognized by the C4F6 antibody. Using a novel flow cytometric assay, we detect an age-dependent deposition of B8H10-reactive SOD1 on spinal cord mitochondria from both SOD1G93A rats and SOD1G37R mice. Mitochondrial damage, including increased mitochondrial volume, excess superoxide production and increased exposure of the toxic BH3 domain of Bcl-2, tracks positively with the presence of misfolded SOD1. Lastly, B8H10 reactive misfolded SOD1 is present in the lysates and mitochondrial fractions of lymphoblasts derived from ALS patients carrying SOD1 mutations, but not in controls. Together, these results highlight misfolded SOD1 as common to two ALS rodent animal models and familial ALS patient lymphoblasts with four different SOD1 mutations. Studies in the animal models point to a role for misfolded SOD1 in mitochondrial dysfunction in ALS pathogenesis.
doi:10.1093/hmg/ddt249
PMCID: PMC5052069  PMID: 23736301 CAMSID: cams4906
12.  Learning to drive in young adults with language impairment 
Highlights
•First study of entry into driving by young people with language impairment (LI).•Individuals with LI are less likely than peers to have acquired a licence by age 24.•Language and independence at 17 contribute to the prediction of holding a licence.•Individuals with LI are at no greater risk of traffic violations/accidents.•Individuals with LI may benefit from support during the preparation and test phases.
Language impairment (LI) is a common developmental disorder which affects many aspects of young people’s functional skills and engagement with society. Little is known of early driving behaviour in those with this disability. This longitudinal study examines early driving experience in a sample of young adults with LI, compared with a sample of typically developing age-matched peers (AMPs). At age 24 years, significantly fewer participants with LI had acquired a driving licence. A crucial hurdle for those with LI appeared to be the Theory part of the (UK) test. Logistic regression analysis indicated that language ability and a measure of independence at age 17 contributed to the prediction of licence possession at age 24. There was no evidence of differences in traffic violations or accident rates between those with and without LI. There is little evidence that young people with LI are at greater risk on the roads than peers without LI, but some individuals with LI might benefit from support in the course of preparation for driving and in the driving test.
doi:10.1016/j.trf.2016.07.015
PMCID: PMC5139688  PMID: 27974878
Driving; Young adults; Language impairment
13.  Early gross motor skills predict the subsequent development of language in children with autism spectrum disorder 
Autism Research  2015;9(9):993-1001.
Background: Motor milestones such as the onset of walking are important developmental markers, not only for later motor skills but also for more widespread social‐cognitive development. The aim of the current study was to test whether gross motor abilities, specifically the onset of walking, predicted the subsequent rate of language development in a large cohort of children with autism spectrum disorder (ASD). Methods: We ran growth curve models for expressive and receptive language measured at 2, 3, 5 and 9 years in 209 autistic children. Measures of gross motor, visual reception and autism symptoms were collected at the 2 year visit. In Model 1, walking onset was included as a predictor of the slope of language development. Model 2 included a measure of non‐verbal IQ and autism symptom severity as covariates. The final model, Model 3, additionally covaried for gross motor ability. Results: In the first model, parent‐reported age of walking onset significantly predicted the subsequent rate of language development although the relationship became non‐significant when gross motor skill, non‐verbal ability and autism severity scores were included (Models 2 & 3). Gross motor score, however, did remain a significant predictor of both expressive and receptive language development. Conclusions: Taken together, the model results provide some evidence that early motor abilities in young children with ASD can have longitudinal cross‐domain influences, potentially contributing, in part, to the linguistic difficulties that characterise ASD. Autism Res 2016, 9: 993–1001. © 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research
doi:10.1002/aur.1587
PMCID: PMC5031219  PMID: 26692550
walking; language development; autism spectrum disorder
14.  Depression and Anxiety Change from Adolescence to Adulthood in Individuals with and without Language Impairment 
PLoS ONE  2016;11(7):e0156678.
This prospective longitudinal study aims to determine patterns and predictors of change in depression and anxiety from adolescence to adulthood in individuals with language impairment (LI). Individuals with LI originally recruited at age 7 years and a comparison group of age-matched peers (AMPs) were followed from adolescence (16 years) to adulthood (24 years). We determine patterns of change in depression and anxiety using the Child Manifest Anxiety Scale-Revised (CMAS-R) and Short Moods and Feelings Questionnaire (SMFQ). In addition to examining associations with gender, verbal and nonverbal skills, we use a time-varying variable to investigate relationships between depression and anxiety symptoms and transitions in educational/employment circumstances. The results show that anxiety was higher in participants with LI than age matched peers and remained so from adolescence to adulthood. Individuals with LI had higher levels of depression symptoms than did AMPs at 16 years. Levels in those with LI decreased post-compulsory schooling but rose again by 24 years of age. Those who left compulsory school provision (regardless of school type) for more choice-driven college but who were not in full-time employment or study by 24 years of age were more likely to show this depression pathway. Verbal and nonverbal skills were not predictive of this pattern of depression over time. The typical female vulnerability for depression and anxiety was observed for AMPs but not for individuals with LI. These findings have implications for service provision, career/employment advice and support for individuals with a history of LI during different transitions from adolescence to adulthood.
doi:10.1371/journal.pone.0156678
PMCID: PMC4942141  PMID: 27404489
15.  Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa 
PLoS ONE  2016;11(7):e0158303.
Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC) CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs) were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3%) of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.
doi:10.1371/journal.pone.0158303
PMCID: PMC4938542  PMID: 27391129
17.  How interview questions are placed in time influences caregiver description of social communication symptoms on the ADI-R 
Background
Caregiver report is crucial for the diagnosis of childhood onset psychiatric disorders, particularly autism. Three experiments were conducted to determine whether caregiver reports of past and current behaviors are affected by question timing and ordering.
Methods
Using the Autism Diagnostic Interview – Revised (ADI-R), two studies systematically varied the order in which caregivers were asked about behaviors. In a third study, descriptions of children's current behaviors at age 5 were compared to retrospective descriptions of behaviors at age 5 collected at age 10.
Results
Caregivers who were first asked about a history of symptoms, described less severe past and present behavior than caregivers reporting current behaviors as well as caregivers reporting current and history of symptoms together. Caregivers retrospectively reported more severe behaviors for age 5 when their children were age 10 than they had when their children were age 5.
Conclusions
Caregivers describe past behaviors differently depending on whether they are asked about current symptoms first. Methods of caregiver reporting can influence interpretations of symptom severity with effects on diagnoses and research findings.
doi:10.1111/jcpp.12325
PMCID: PMC4369461  PMID: 25243378
Autism spectrum disorders; ADI-R; parent report; longitudinal; diagnosis
18.  A mechanistic evaluation of the Syrian hamster embryo cell transformation assay (pH 6.7) and molecular events leading to senescence bypass in SHE cells 
Highlights
•Mechanistic evaluation of SHE CTA, specific to B(a)P.•Applicability of the Syrian hamster as a relevant model of carcinogenesis.•Molecular analysis of immortal lines derived from benzo(a)pyrene-induced MT clones.•Morphological transformation (MT) does not guarantee senescence bypass.•Secondary events to MT are necessary for cellular immortalisation.
The implementation of the Syrian hamster embryo cell transformation assay (SHE CTA) into test batteries and its relevance in predicting carcinogenicity has been long debated. Despite prevalidation studies to ensure reproducibility and minimise the subjective nature of the assay’s endpoint, an underlying mechanistic and molecular basis supporting morphological transformation (MT) as an indicator of carcinogenesis is still missing. We found that only 20% of benzo(a)pyrene-induced MT clones immortalised suggesting that, alone, the MT phenotype is insufficient for senescence bypass. From a total of 12 B(a)P- immortalised MT lines, inactivating p53 mutations were identified in 30% of clones, and the majority of these were consistent with the potent carcinogen’s mode of action. Expression of p16 was commonly silenced or markedly reduced with extensive promoter methylation observed in 45% of MT clones, while Bmi1 was strongly upregulated in 25% of clones. In instances where secondary events to MT appeared necessary for senescence bypass, as evidenced by a transient cellular crisis, clonal growth correlated with monoallelic deletion of the CDKN2A/B locus. The findings further implicate the importance of p16 and p53 pathways in regulating senescence while providing a molecular evaluation of SHE CTA −derived variant MT clones induced by benzo(a)pyrene.
doi:10.1016/j.mrgentox.2016.04.002
PMCID: PMC4877681  PMID: 27169376
SH, syrian hamster; SHE, syrian hamster embryo; CTA, cell transformation assay; Cell transformation assay; Morphological transformation; Senescence bypass; Syrian hamster; p16/CDKN2A
19.  ALS-linked misfolded SOD1 species have divergent impacts on mitochondria 
Approximately 20 % of familial Amyotrophic Lateral Sclerosis (ALS) is caused by mutations in superoxide dismutase (SOD1), which leads to misfolding of the SOD1 protein, resulting in a toxic gain of function. Several conformation-restricted antibodies have been generated that specifically recognize misfolded SOD1 protein, and have been used as therapeutics in pre-clinical models. Misfolded SOD1 selectively associates with spinal cord mitochondria in SOD1 rodent models. Using the SOD1G93A rat model, we find that SOD1 conformational specific antibodies AMF7-63 and DSE2-3H1 labeled a fibrillar network concentrated in the anterior horn; while A5C3, B8H10, C4F6 and D3H5 labeled motor neurons as well as puncta in the neuropil. There is a time-dependent accumulation of misfolded SOD1 at the surface of spinal cord mitochondria with AMF7-63-labeled mitochondria having increased volume in contrast to a mitochondrial subset labeled with B8H10. In spinal cord homogenates and isolated mitochondria, AMF7-63, DSE2-3H1 and B8H10 detect misfolded SOD1 aggregates. SOD1 that lacks its metal cofactors has an increased affinity for naïve mitochondria and misfolded SOD1 antibodies B8H10 and DSE2-3H1 readily detect demetalated mutant and wild-type SOD1. Together, these data suggest that multiple non-native species of misfolded SOD1 may exist, some of which are associated with mitochondrial damage. Conformational antibodies are invaluable tools to identify and characterize the variation in misfolded SOD1 species with regards to biochemical characteristics and toxicity. This information is highly relevant to the further development of these reagents as therapeutics.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-016-0313-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-016-0313-8
PMCID: PMC4847257  PMID: 27121871
Amyotrophic Lateral Sclerosis; Mitochondria; Superoxide dismutase; Flow cytometry
20.  General Practitioners’ Experiences of, and Responses to, Uncertainty in Prostate Cancer Screening: Insights from a Qualitative Study 
PLoS ONE  2016;11(4):e0153299.
Background
Prostate-specific antigen (PSA) testing for prostate cancer is controversial. There are unresolved tensions and disagreements amongst experts, and clinical guidelines conflict. This both reflects and generates significant uncertainty about the appropriateness of screening. Little is known about general practitioners’ (GPs’) perspectives and experiences in relation to PSA testing of asymptomatic men. In this paper we asked the following questions: (1) What are the primary sources of uncertainty as described by GPs in the context of PSA testing? (2) How do GPs experience and respond to different sources of uncertainty?
Methods
This was a qualitative study that explored general practitioners’ current approaches to, and reasoning about, PSA testing of asymptomatic men. We draw on accounts generated from interviews with 69 general practitioners located in Australia (n = 40) and the United Kingdom (n = 29). The interviews were conducted in 2013–2014. Data were analysed using grounded theory methods. Uncertainty in PSA testing was identified as a core issue.
Findings
Australian GPs reported experiencing substantially more uncertainty than UK GPs. This seemed partly explainable by notable differences in conditions of practice between the two countries. Using Han et al’s taxonomy of uncertainty as an initial framework, we first outline the different sources of uncertainty GPs (mostly Australian) described encountering in relation to prostate cancer screening and what the uncertainty was about. We then suggest an extension to Han et al’s taxonomy based on our analysis of data relating to the varied ways that GPs manage uncertainties in the context of PSA testing. We outline three broad strategies: (1) taking charge of uncertainty; (2) engaging others in managing uncertainty; and (3) transferring the responsibility for reducing or managing some uncertainties to other parties.
Conclusion
Our analysis suggests some GPs experienced uncertainties associated with ambiguous guidance and the complexities of their situation as professionals with responsibilities to patients as considerably burdensome. This raises important questions about responsibility for uncertainty. In Australia in particular they feel insufficiently supported by the health care system to practice in ways that are recognisably consistent with ‘evidence based’ professional standards and appropriate for patients. More work is needed to clarify under what circumstances and how uncertainty should be communicated. Closer attention to different types and aspects of the uncertainty construct could be useful.
doi:10.1371/journal.pone.0153299
PMCID: PMC4839572  PMID: 27100402
21.  Younger children experience lower levels of language competence and academic progress in the first year of school: evidence from a population study 
Background
The youngest children in an academic year are reported to be educationally disadvantaged and overrepresented in referrals to clinical services. In this study we investigate for the first time whether these disadvantages are indicative of a mismatch between language competence at school entry and the academic demands of the classroom.
Methods
We recruited a population sample of 7,267 children aged 4 years 9 months to 5 years 10 months attending state‐maintained reception classrooms in Surrey, England. Teacher ratings on the Children's Communication Checklist‐Short (CCC‐S), a measure of language competence, the Strengths and Difficulties Questionnaire‐Total Difficulties Score (SDQ), a measure of behavioural problems, and the Early Years Foundation Stage Profile (EYFSP), a measure of academic attainment, were obtained at the end of the reception year.
Results
The youngest children were rated by teachers as having more language deficits, behaviour problems, and poorer academic progress at the end of the school year. Language deficits were highly associated with behaviour problems; adjusted odds ratio 8.70, 95% CI [7.25–10.45]. Only 4.8% of children with teacher‐rated language deficits and 1.3% of those with co‐occurring language and behaviour difficulties obtained a ‘Good Level of Development’ on the EYFSP. While age predicted unique variance in academic attainment (1%), language competence was the largest associate of academic achievement (19%).
Conclusion
The youngest children starting school have relatively immature language and behaviour skills and many are not yet ready to meet the academic and social demands of the classroom. At a population level, developing oral language skills and/or ensuring academic targets reflect developmental capacity could substantially reduce the numbers of children requiring specialist clinical services in later years.
doi:10.1111/jcpp.12431
PMCID: PMC4832322  PMID: 26041601
Relative age; language impairment; behaviour problems; academic achievement
22.  Childhood urinary tract infection in primary care: a prospective observational study of prevalence, diagnosis, treatment, and recovery 
The British Journal of General Practice  2015;65(633):e217-e223.
Background
The prevalence of targeted and serendipitous treatment for, and associated recovery from, urinary tract infection (UTI) in pre-school children is unknown.
Aim
To determine the frequency and suspicion of UTI in children who are acutely ill, along with details of antibiotic prescribing, its appropriateness, and whether that appropriateness impacted on symptom improvement and recovery.
Design and setting
Prospective observational cohort study in primary care sites in urban and rural areas in England and Wales.
Method
Systematic urine sampling from children aged <5years presenting in primary care with acute illness with culture in NHS laboratories.
Results
Of 6079 children’s urine samples, 339 (5.6%) met laboratory criteria for UTI and 162 (47.9%) were prescribed antibiotics at the initial consultation. In total, 576/7101 (8.1%) children were suspected of having a UTI prior to urine sampling, including 107 of the 338 with a UTI (clinician sensitivity 31.7%). Children with a laboratory-diagnosed UTI were more likely to be prescribed antibiotics when UTI was clinically suspected than when it was not (86.0% versus 30.3%, P<0.001). Of 231 children with unsuspected UTI, 70 (30.3%) received serendipitous antibiotics (that is, antibiotics prescribed for a different reason). Overall, 176 (52.1%) children with confirmed UTI did not receive any initial antibiotic. Organism sensitivity to the prescribed antibiotic was higher when UTI was suspected than when treated serendipitously (77.1% versus 26.0%; P<0.001). Children with UTI prescribed appropriate antibiotics at the initial consultation improved a little sooner than those with a UTI who were not prescribed appropriate antibiotics initially (3.5 days versus 4.0 days; P = 0.005).
Conclusion
Over half of children with UTI on culture were not prescribed antibiotics at first presentation. Serendipitous UTI treatment was relatively common, but often inappropriate to the organism’s sensitivity. Methods for improved targeting of antibiotic treatment in children who are acutely unwell are urgently needed.
doi:10.3399/bjgp15X684361
PMCID: PMC4377600  PMID: 25824181
antibacterial agents; child; diagnosis; primary health care; urinary tract infections
23.  Active surveillance for prostate cancer: A systematic review of clinico-pathologic variables and biomarkers for risk stratification 
European urology  2014;67(4):619-626.
CONTEXT
Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated.
OBJECTIVE
To review primary data on markers, genetic factors and risk stratification for patient selection and predictors of progression during AS.
EVIDENCE ACQUISITION
Electronic searches were conducted in PubMed, Embase and CENTRAL from inception to April 2014 for original articles on biomarkers and risk stratification for AS.
EVIDENCE SYNTHESIS
Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that lower percent free PSA, higher Prostate Health Index (phi), higher PSA density and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of phi, PSA density, and repeat biopsy results predict later biopsy progression. While some studies have suggested a univariate relationship between urinary PCA3 and TMPRSS2:ERG with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. At this point, there is no conclusive data to support the use of genetic tests in AS Limitations of these studies include heterogeneous definitions of progression and limited follow-up.
CONCLUSIONS
There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long term outcomes, to further improve AS in the future.
PATIENT SUMMARY
Several PSA-based tests (free PSA, Prostate Health Index, PSA density) and the extent of cancer on biopsy can help to stratify the risk of progression during AS. Investigation into several other markers is underway.
doi:10.1016/j.eururo.2014.10.010
PMCID: PMC4483277  PMID: 25457014
24.  Accuracy of self-reported nevus and pigmentation phenotype compared to clinical assessment in a population-based study of young Australian adults 
Background
Awareness of individual risk may encourage improved prevention and early detection of melanoma.
Methods
We evaluated the accuracy of self-reported pigmentation and nevus phenotype compared to clinical assessment, and examined agreement between nevus counts from selected anatomical regions. The sample included 456 cases with invasive cutaneous melanoma diagnosed between ages 18-39 years and 538 controls from the population-based Australian Melanoma Family Study. Participants completed a questionnaire regarding their pigmentation and nevus phenotype, and attended a dermatologic skin examination.
Results
There was strong agreement between self-reported and clinical assessment of eye color (kappa, κ, =0.78, 95% confidence interval (CI) 0.74-0.81); and moderate agreement for hair color (κ =0.46, 95% CI 0.42-0.50). Agreement between self-reported skin color and spectrophotometer-derived measurements was poor (κ =0.12, 95% CI 0.08-0.16) to moderate (Spearman correlation rs=-0.37, 95% CI -0.32- to -0.42). Participants tended to under-estimate their nevus counts and pigmentation; men were more likely to under-report their skin color. The rs was 0.43 (95% CI 0.38-0.49) comparing clinical total body nevus counts with self-reported nevus categories. There was good agreement of quartile distributions of total body nevus counts with site-specific nevus counts, particularly on both arms.
Conclusions
Young adults have sub-optimal accuracy when assessing important risk characteristics including nevus numbers and pigmentation. Measuring nevus count on the arms is a good predictor of full body nevus count.
Impact
These results have implications for the likely success of targeted public health programs that rely on self-assessment of these factors.
doi:10.1158/1055-9965.EPI-14-1203
PMCID: PMC4698346  PMID: 25628333
skin color; pigmentation; nevi; melanoma; phenotype; accuracy; validity
25.  Sex differences in the association between infant markers and later autistic traits 
Molecular Autism  2016;7:21.
Background
Although it is well established that the prevalence of autism spectrum disorder (ASD) is higher in males than females, there is relatively little understanding of the underlying mechanisms and their developmental time course. Sex-specific protective or risk factors have often been invoked to explain these differences, but such factors are yet to be identified.
Methods
We take a developmental approach, using a prospective sample of 104 infants at high and low familial risk for ASD, to characterise sex differences in infant markers known to predict emerging autism symptoms. We examine three markers previously shown to be associated with later autistic social-communication symptoms: the Autism Observation Scale for Infants (AOSI) total score, attention disengagement speed and gaze following behaviour. Our aim was to test whether sex differences were already present in these markers at 1 year of age, which would suggest sex-specific mechanisms of risk or protection.
Results
While no sex differences were found in any of the three markers investigated, we found sex differences in their relationship to 3-year autism traits; all three markers significantly predicted later autism traits only in the boys.
Conclusions
Previously identified ‘early autism markers’ were associated with later autism symptoms only in boys. This suggests that there may be additional moderating risk or protective factors which remain to be identified. Our findings have important implications for prospective studies in terms of directly testing for the moderating effect of sex on emerging autistic traits.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-016-0081-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13229-016-0081-0
PMCID: PMC4815081  PMID: 27034768
Sex difference; Infants; Autism; High risk; Differential liability

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