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1.  MACROD2 gene associated with autistic-like traits in a general population sample 
Psychiatric genetics  2014;24(6):241-248.
There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.
PMCID: PMC4320645  PMID: 25360606
association; autistic-like traits; MACROD2; Raine study; single nucleotide polymorphism
2.  Breast milk donation after neonatal death in Australia: a report 
Lactation and breast milk can hold great value and meaning for grieving mothers who have experienced a recent death of an infant. Donation to a human milk bank (HMB) as an alternative to discarding breast milk is one means of respecting the value of breast milk. There is little research, national policy discussion, or organizational representation in Australia on the subject of breast milk donation after infant death. On 29 November 2013 the Mercy Hospital for Women in Melbourne, Australia hosted Australia’s first National Stakeholder Meeting (NSM) on the topic of milk donation after neonatal death. The NSM drew together representatives from Australian HMBs, neonatal intensive care units (NICUs) currently using donor human milk, and Australia’s chief NICU parent support organization. The NSM was video-recorded and transcribed, and analyzed thematically by researchers. This article reports the seven dominant themes discussed by stakeholders during the NSM: the spectrum of women’s lactation and donation experiences after infant death; the roles of the HMB and NICU in meeting the needs of the bereaved donor; how bereaved mothers’ lactation autonomy may interface with a HMB’s donation guidelines; how milk donation may be discussed with bereaved mothers; the variation between four categories of milk donation after neonatal death; the impact of limited resources and few HMBs on providing donation programs for bereaved mothers in Australia. This article provides evidence from researchers and practitioners that can assist HMB staff in refining their bank’s policy on milk donation after infant death, and provides national policy makers with key considerations to support lactation, human milk banking, and bereavement services nation-wide.
PMCID: PMC4271333  PMID: 25530794
Breast milk donation; Infant death; Bereavement; Human milk bank; Neonatal intensive care
3.  Glia Talk Back 
PLoS Biology  2014;12(11):e1001990.
PMCID: PMC4227634  PMID: 25386988
6.  The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease 
Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia.
We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated.
Median rituximab dose was 6 g (1–20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after ≥ 6 g rituximab. 45/115 (39%) with IgG ≥6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p = 0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection.
In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring.
PMCID: PMC4038057  PMID: 24884562
Rituximab; Hypogammaglobulinaemia; B cell; Vasculitis; Systemic lupus erythematosus (SLE); IgG; Infection; Autoimmune
7.  A Novel Investigation of a Blister-Like Syndrome in Aquarium Echinopora lamellosa 
PLoS ONE  2014;9(5):e97018.
This study investigates potential causes of a novel blister-like syndrome in the plating coral Echinopora lamellosa. Visual inspections of this novel coral syndrome showed no obvious signs of macroparasites and the blisters themselves manifested as fluid-filled sacs on the surface of the coral, which rose from the coenosarc between the coral polyps. Histological analysis of the blisters showed that there was no associated necrosis with the epidermal or gastrodermal tissues. The only difference between blistered areas and apparently healthy tissues was the presence of proliferated growth (possible mucosal cell hyperplasia) directly at the blister interface (area between where the edge of the blister joined apparently healthy tissue). No bacterial aggregates were identified in any histological samples, nor any sign of tissue necrosis identified. We conclude, that the blister formations are not apparently caused by a specific microbial infection, but instead may be the result of irritation following growth anomalies of the epidermis. However, future work should be conducted to search for other potential casual agents, including viruses.
PMCID: PMC4020768  PMID: 24827734
8.  Correction: Predictive Validity and Classification Accuracy of ActiGraph Energy Expenditure Equations and Cut-Points in Young Children 
PLoS ONE  2014;9(1):10.1371/annotation/c26dd8e7-d512-4255-a80c-f3bf56c1ac0d.
PMCID: PMC3898872
9.  Predictive Validity and Classification Accuracy of ActiGraph Energy Expenditure Equations and Cut-Points in Young Children 
PLoS ONE  2013;8(11):e79124.
Evaluate the predictive validity of ActiGraph energy expenditure equations and the classification accuracy of physical activity intensity cut-points in preschoolers.
Forty children aged 4–6 years (5.3±1.0 years) completed a ∼150-min room calorimeter protocol involving age-appropriate sedentary, light and moderate-to vigorous-intensity physical activities. Children wore an ActiGraph GT3X on the right mid-axillary line of the hip. Energy expenditure measured by room calorimetry and physical activity intensity classified using direct observation were the criterion methods. Energy expenditure was predicted using Pate and Puyau equations. Physical activity intensity was classified using Evenson, Sirard, Van Cauwenberghe, Pate, Puyau, and Reilly, ActiGraph cut-points.
The Pate equation significantly overestimated VO2 during sedentary behaviors, light physical activities and total VO2 (P<0.001). No difference was found between measured and predicted VO2 during moderate-to vigorous-intensity physical activities (P = 0.072). The Puyau equation significantly underestimated activity energy expenditure during moderate-to vigorous-intensity physical activities, light-intensity physical activities and total activity energy expenditure (P<0.0125). However, no overestimation of activity energy expenditure during sedentary behavior was found. The Evenson cut-point demonstrated significantly higher accuracy for classifying sedentary behaviors and light-intensity physical activities than others. Classification accuracy for moderate-to vigorous-intensity physical activities was significantly higher for Pate than others.
Available ActiGraph equations do not provide accurate estimates of energy expenditure across physical activity intensities in preschoolers. Cut-points of ≤25counts⋅15 s−1 and ≥420 counts⋅15 s−1 for classifying sedentary behaviors and moderate-to vigorous-intensity physical activities, respectively, are recommended.
PMCID: PMC3823763  PMID: 24244433
10.  Handheld Computers to Run ACASI to Assess HIV Risk and Deliver Tailored Soap Opera Video Feedback: Acceptability Among Young Adult Urban Women 
PMCID: PMC3191252  PMID: 21664834
ACASI; handheld computers; HIV prevention in urban women; soap opera videos for health promotion
11.  ‘You can’t just hit a button’: an ethnographic study of strategies to repurpose data from advanced clinical information systems for clinical process improvement 
BMC Medicine  2013;11:103.
Current policies encourage healthcare institutions to acquire clinical information systems (CIS) so that captured data can be used for secondary purposes, including clinical process improvement. Such policies do not account for the extra work required to repurpose data for uses other than direct clinical care, making their implementation problematic. This paper aims to analyze the strategies employed by clinical units to use data effectively for both direct clinical care and clinical process improvement.
Ethnographic methods were employed. A total of 54 contextual interviews with health professionals spanning various disciplines and 18 hours of observation were carried out in 5 intensive care units in England using an advanced CIS. Case studies of how the extra work was achieved in each unit were derived from the data and then compared.
We found that extra work is required to repurpose CIS data for clinical process improvement. Health professionals must enter data not required for clinical care and manipulation of this data into a machine-readable form is often necessary. Ambiguity over who should be responsible for this extra work hindered CIS data usage for clinical process improvement. We describe 11 strategies employed by units to accommodate this extra work, distributing it across roles. Seven of these motivated data entry by health professionals and four addressed the machine readability of data. Many of the strategies relied heavily on the skill and leadership of local clinical customizers.
To realize the expected clinical process improvements by the use of CIS data, clinical leaders and policy makers need to recognize and support the redistribution of the extra work that is involved in data repurposing. Adequate time, funding, and appropriate motivation are needed to enable units to acquire and deliver the necessary skills in CIS customization.
PMCID: PMC3635898  PMID: 23574920
Clinical information system; Clinical process improvement; Computerized medical records systems; Intensive care; Qualitative research; Secondary use of data; User-customization
12.  Genome-Wide Association Study of Autistic-Like Traits in a General Population Study of Young Adults 
Lay abstract: It has been proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD), representing the extreme end of this distribution. The current study undertook a genome-wide association (GWA) scan of 965 young Western Australian adults to identify novel risk variants associated with autistic-like traits. No associations reached genome-wide significance; however, a review of nominally associated single nucleotide polymorphisms (SNPs) indicated two positional candidate loci that have been previously implicated in autistic-like trait etiology.
Scientific abstract: Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A GWA study using 2,462,046 SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine) Study. No SNP associations reached genome-wide significance (p < 5.0 × 10−8). However, investigations into nominal observed SNP associations (p < 1.0 × 10−5) add support to two positional candidate genes previously implicated in ASD etiology, PRKCB1, and CBLN1. The rs198198 SNP (p = 9.587 × 10−6), is located within an intron of the protein kinase C, beta 1 (PRKCB1) gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 × 10−6) is located in a region flanking the Cerebellin 1 (CBLN1) gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.
PMCID: PMC3795398  PMID: 24133439
autistic-like traits; genome-wide association; PRKCB1; autism spectrum disorder; autism spectrum quotient; CBLN1
13.  Patterns of physical activity and sedentary behaviour in preschool children 
Little is known about patterns of sedentary behavior (SB) and physical activity among preschoolers. Therefore, in this observational study patterns of SB and moderate-to-vigorous physical activity (MVPA) were examined in detail throughout the week in preschool-aged boys and girls.
A sample of 703 Melbourne preschool children (387 boys; 4.6 ± 0.7 y) were included in data analysis. SB and MVPA data were collected using accelerometry over an eight-day period. Percentage of time per hour in SB and in MVPA between 08:00 h and 20:00 h was calculated. Multi-level logistic regression models were created to examine the hour-by-hour variability in SB and MVPA for boys and girls across weekdays and weekend days. Odds ratios (OR) were calculated to interpret differences in hour-by-hour SB and MVPA levels between boys and girls, and between weekdays and weekend days.
The highest SB levels co-occurred with the lowest MVPA levels from the morning till the early afternoon on weekdays, and during the morning and around midday on weekends. Besides, participation in SB was the lowest and participation in MVPA was the highest from the mid afternoon till the evening on weekdays and weekend days. The variability across the hours in SB and, especially, in MVPA was rather small throughout weekdays and weekends. These patterns were found in both boys and girls. During some hours, girls were found to be more likely than boys to demonstrate higher SB levels (OR from 1.08 to 1.16; all p < 0.05) and lower MVPA levels (OR from 0.75 to 0.88; all p < 0.05), but differences were small. During weekends, hour-by-hour SB levels were more likely to be lower (OR from 0.74 to 0.98; all p < 0.05) and hour-by-hour MVPA levels were more likely to be higher (OR from 1.15 to 1.50; all p < 0.05), than during weekdays, in boys and girls.
Entire weekdays, especially from the morning till the early afternoon, and entire weekend days are opportunities to reduce SB and to promote MVPA in preschool-aged boys and girls. Particularly weekdays hold the greatest promise for improving SB and MVPA. No particular time of the week was found where one sex should be targeted.
PMCID: PMC3544605  PMID: 23186232
Accelerometry; Physical activity; Sedentary behavior; Variability; Hour-by-hour; Young children
14.  Brief intervention for alcohol misuse in people attending sexual health clinics: study protocol for a randomized controlled trial 
Trials  2012;13:149.
Over the last 30 years the number of people who drink alcohol at harmful levels has increased in many countries. There have also been large increases in rates of sexually transmitted infections. Available evidence suggests that excessive alcohol consumption and poor sexual health may be linked. The prevalence of harmful alcohol use is higher among people attending sexual health clinics than in the general population, and a third of those attending clinics state that alcohol use affects whether they have unprotected sex. Previous research has demonstrated that brief intervention for alcohol misuse in other medical settings can lead to behavioral change, but the clinical- and cost-effectiveness of this intervention on sexual behavior have not been examined.
We will conduct a two parallel-arm, randomized trial. A consecutive sample of people attending three sexual health clinics in London and willing to participate in the study will be screened for excessive alcohol consumption. Participants identified as drinking excessively will then be allocated to either active treatment (Brief Advice and referral for Brief Intervention) or control treatment (a leaflet on healthy living). Randomization will be via an independent and remote telephone randomization service and will be stratified by study clinic. Brief Advice will comprise feedback on the possible health consequences of excessive alcohol consumption, written information about alcohol and the offer of an appointment for further assessment and Brief Intervention. Follow-up data on alcohol use, sexual behavior, health related quality of life and service use will be collected by a researcher masked to allocation status six months later. The primary outcome for the study is mean weekly alcohol consumption during the previous three months, and the main secondary outcome is the proportion of participants who report unprotected sex during this period.
Opportunistic intervention for excessive alcohol use has been shown to be effective in a range of medical settings. The SHEAR study will examine whether delivering such interventions in sexual health clinics results in reductions in alcohol consumption and will explore whether this is associated with changes in sexual behavior.
PMCID: PMC3482149  PMID: 22920408
Alcohol misuse; Intervention; Randomized controlled trial; Sexual health; Effectiveness
15.  Progress in treatment of ANCA-associated vasculitis 
Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.
PMCID: PMC3446448  PMID: 22569190
16.  Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study 
Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population.
Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data.
The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman’s rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: -.07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have ‘high’ scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females.
These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD.
PMCID: PMC3500651  PMID: 23110806
Autism; Testosterone; Prenatal; Perinatal; Autistic-like traits
17.  Validating the prediction of lower urinary tract infection in primary care: sensitivity and specificity of urinary dipsticks and clinical scores in women 
Dipsticks are one of the most commonly used near-patient tests in primary care, but few clinical or dipstick algorithms have been rigorously developed.
To confirm whether previously documented clinical and dipstick variables and algorithms predict laboratory diagnosis of urinary tract infection (UTI).
Design of study
Validation study.
Primary care.
A total of 434 adult females with suspected lower UTI had bacteriuria assessed using the European Urinalysis Guidelines.
Sixty-six per cent of patients had confirmed UTI. The predictive values of nitrite, leucocyte esterase (+ or greater), and blood (haemolysed trace or greater) were confirmed (independent multivariate odds ratios = 5.6, 3.5, and 2.1 respectively). The previously developed dipstick rule — based on presence of nitrite, or both leucocytes and blood — was moderately sensitive (75%) but less specific (66%; positive predictive value [PPV] 81%, negative predictive value [NPV] 57%). Predictive values were improved by varying the cut-off point: NPV was 76% for all three dipstick results being negative; the PPV was 92% for having nitrite and either blood or leucocyte esterase. Urine offensive smell was not found to be predictive in this sample; for a clinical score using the remaining three predictive clinical features (urine cloudiness, dysuria, and nocturia), NPV was 67% for none of the features, and PPV was 82% for three features.
A clinical score is of limited value in increasing diagnostic precision. Dipstick results can modestly improve diagnostic precision but poorly rule out infection. Clinicians need strategies to take account of poor NPVs.
PMCID: PMC2894378  PMID: 20594439
algorithms, clinical scoring; diagnosis, urinary tract infection; primary care; urinalysis
18.  Tuning into Places 
PLoS Biology  2011;9(4):e1001042.
PMCID: PMC3071365  PMID: 21494324
19.  Npn-1 Primes Limbs for Motion 
PLoS Biology  2011;9(2):e1001023.
PMCID: PMC3043088  PMID: 21364946
20.  Stress Brings Memories to the Fore 
PLoS Biology  2010;8(12):e1001007.
PMCID: PMC3006348  PMID: 21203582
21.  There Goes the (Gene Expression) Neighbourhood Theory 
PLoS Biology  2010;8(11):e1001002.
PMCID: PMC2994654  PMID: 21151338
22.  Day and Night: Circadian Rhythms in Worms 
PLoS Biology  2010;8(10):e1000511.
PMCID: PMC2953526  PMID: 20967233
23.  Protein Aggregation Increases with Age 
PLoS Biology  2010;8(8):e1000449.
PMCID: PMC2919422  PMID: 20711479
24.  Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure 
Psychopharmacology  2004;179(2):470-478.
Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability.
This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure.
Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an “inappropriate” phase when conditioning stimuli were absent and reward presentation would be delayed.
Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase.
Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.
PMCID: PMC2893398  PMID: 15565431
Schizophrenia; Dual diagnosis; Substance use disorders; Addiction; Impulsivity; Prefrontal cortex; Nucleus accumbens; Hippocampus; Conditioned learning
25.  Memory Is Enhanced at Behaviorally Relevant Times 
PLoS Biology  2010;8(3):e1000338.
PMCID: PMC2838749  PMID: 20305718

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