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author:("brenner, S")
1.  Two- to eight-month-old infants’ perception of dynamic auditory-visual spatial co-location 
Child development  2011;82(4):1210-1223.
From birth, infants detect associations between the locations of static visual objects and sounds they emit, but there is limited evidence regarding their sensitivity to the dynamic equivalent when a sound-emitting object moves. In four experiments involving 36 2-month-olds, 48 5-month-olds and 48 8-month-olds, we investigated infants’ ability to process this form of spatial co-location. Whereas there was no evidence of spontaneous sensitivity, all age groups detected a dynamic co-location during habituation, and looked longer at test trials in which sound and sight were dislocated. Only 2-month-olds showed clear sensitivity to the dislocation relation, although 8-month-olds did so following additional habituation. These results are discussed relative to the intersensory redundancy hypothesis and work suggesting increasing specificity in processing with age.
PMCID: PMC3134617  PMID: 21545580
2.  Training Compliance Control Yields Improvements in Drawing as a Function of Beery Scores 
PLoS ONE  2014;9(3):e92464.
Many children have difficulty producing movements well enough to improve in sensori-motor learning. Previously, we developed a training method that supports active movement generation to allow improvement at a 3D tracing task requiring good compliance control. Here, we tested 7–8 year old children from several 2nd grade classrooms to determine whether 3D tracing performance could be predicted using the Beery VMI. We also examined whether 3D tracing training lead to improvements in drawing. Baseline testing included Beery, a drawing task on a tablet computer, and 3D tracing. We found that baseline performance in 3D tracing and drawing co-varied with the visual perception (VP) component of the Beery. Differences in 3D tracing between children scoring low versus high on the Beery VP replicated differences previously found between children with and without motor impairments, as did post-training performance that eliminated these differences. Drawing improved as a result of training in the 3D tracing task. The training method improved drawing and reduced differences predicted by Beery scores.
PMCID: PMC3961363  PMID: 24651280
3.  Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease 
Medici, Marco | Porcu, Eleonora | Pistis, Giorgio | Teumer, Alexander | Brown, Suzanne J. | Jensen, Richard A. | Rawal, Rajesh | Roef, Greet L. | Plantinga, Theo S. | Vermeulen, Sita H. | Lahti, Jari | Simmonds, Matthew J. | Husemoen, Lise Lotte N. | Freathy, Rachel M. | Shields, Beverley M. | Pietzner, Diana | Nagy, Rebecca | Broer, Linda | Chaker, Layal | Korevaar, Tim I. M. | Plia, Maria Grazia | Sala, Cinzia | Völker, Uwe | Richards, J. Brent | Sweep, Fred C. | Gieger, Christian | Corre, Tanguy | Kajantie, Eero | Thuesen, Betina | Taes, Youri E. | Visser, W. Edward | Hattersley, Andrew T. | Kratzsch, Jürgen | Hamilton, Alexander | Li, Wei | Homuth, Georg | Lobina, Monia | Mariotti, Stefano | Soranzo, Nicole | Cocca, Massimiliano | Nauck, Matthias | Spielhagen, Christin | Ross, Alec | Arnold, Alice | van de Bunt, Martijn | Liyanarachchi, Sandya | Heier, Margit | Grabe, Hans Jörgen | Masciullo, Corrado | Galesloot, Tessel E. | Lim, Ee M. | Reischl, Eva | Leedman, Peter J. | Lai, Sandra | Delitala, Alessandro | Bremner, Alexandra P. | Philips, David I. W. | Beilby, John P. | Mulas, Antonella | Vocale, Matteo | Abecasis, Goncalo | Forsen, Tom | James, Alan | Widen, Elisabeth | Hui, Jennie | Prokisch, Holger | Rietzschel, Ernst E. | Palotie, Aarno | Feddema, Peter | Fletcher, Stephen J. | Schramm, Katharina | Rotter, Jerome I. | Kluttig, Alexander | Radke, Dörte | Traglia, Michela | Surdulescu, Gabriela L. | He, Huiling | Franklyn, Jayne A. | Tiller, Daniel | Vaidya, Bijay | de Meyer, Tim | Jørgensen, Torben | Eriksson, Johan G. | O'Leary, Peter C. | Wichmann, Eric | Hermus, Ad R. | Psaty, Bruce M. | Ittermann, Till | Hofman, Albert | Bosi, Emanuele | Schlessinger, David | Wallaschofski, Henri | Pirastu, Nicola | Aulchenko, Yurii S. | de la Chapelle, Albert | Netea-Maier, Romana T. | Gough, Stephen C. L. | Meyer zu Schwabedissen, Henriette | Frayling, Timothy M. | Kaufman, Jean-Marc | Linneberg, Allan | Räikkönen, Katri | Smit, Johannes W. A. | Kiemeney, Lambertus A. | Rivadeneira, Fernando | Uitterlinden, André G. | Walsh, John P. | Meisinger, Christa | den Heijer, Martin | Visser, Theo J. | Spector, Timothy D. | Wilson, Scott G. | Völzke, Henry | Cappola, Anne | Toniolo, Daniela | Sanna, Serena | Naitza, Silvia | Peeters, Robin P. | Cotsapas, Chris
PLoS Genetics  2014;10(2):e1004123.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
Author Summary
Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.
PMCID: PMC3937134  PMID: 24586183
4.  Cross-Modal Matching of Audio-Visual German and French Fluent Speech in Infancy 
PLoS ONE  2014;9(2):e89275.
The present study examined when and how the ability to cross-modally match audio-visual fluent speech develops in 4.5-, 6- and 12-month-old German-learning infants. In Experiment 1, 4.5- and 6-month-old infants’ audio-visual matching ability of native (German) and non-native (French) fluent speech was assessed by presenting auditory and visual speech information sequentially, that is, in the absence of temporal synchrony cues. The results showed that 4.5-month-old infants were capable of matching native as well as non-native audio and visual speech stimuli, whereas 6-month-olds perceived the audio-visual correspondence of native language stimuli only. This suggests that intersensory matching narrows for fluent speech between 4.5 and 6 months of age. In Experiment 2, auditory and visual speech information was presented simultaneously, therefore, providing temporal synchrony cues. Here, 6-month-olds were found to match native as well as non-native speech indicating facilitation of temporal synchrony cues on the intersensory perception of non-native fluent speech. Intriguingly, despite the fact that audio and visual stimuli cohered temporally, 12-month-olds matched the non-native language only. Results were discussed with regard to multisensory perceptual narrowing during the first year of life.
PMCID: PMC3930698  PMID: 24586651
5.  Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS): statistical analysis plan for a randomised controlled trial 
Trials  2014;15:59.
The Coping with Persistent Pain, Effectiveness Research into Self-management (COPERS) trial assessed whether a group-based self-management course is effective in reducing pain-related disability in participants with chronic musculoskeletal pain. This article describes the statistical analysis plan for the COPERS trial.
Methods and design
COPERS was a pragmatic, multicentre, unmasked, parallel group, randomised controlled trial. This article describes (a) the overall analysis principles (including which participants will be included in each analysis, how results will be presented, which covariates will be adjusted for, and how we will account for clustering in the intervention group); (b) the primary and secondary outcomes, and how each outcome will be analysed; (c) sensitivity analyses; (d) subgroup analyses; and (e) adherence-adjusted analyses.
Trial registration
PMCID: PMC3930300  PMID: 24528484
Statistical analysis plan; Randomised controlled trial; Self-management; Chronic musculoskeletal pain; Complex intervention
6.  Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality 
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.
Data Sources and Study Selection
The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.
Data Extraction
Individual data on 55 287 participants with 542 494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25 977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.
Among 55 287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51 837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86–1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96–1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28–2.80) for a TSH level of 10 to 19.9 mIU/L (n=70 events/235; 38.4/1000 person-years; P<.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91–1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03–1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10–2.27, n=28 deaths/333; 7.7/1000 person-years; P=.005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.
Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.
PMCID: PMC3923470  PMID: 20858880
7.  Association Between Ideal Cardiovascular Health and Carotid Intima‐Media Thickness: A Twin Study 
The American Heart Association (AHA) recently developed the Cardiovascular Health Index (CVHI), a health metric consisting of 7 modifiable risk factors. The relationship of the CVHI with preclinical markers, such as carotid intima‐media thickness (CIMT) has not been assessed.
We examined 490 male monozygotic and dizygotic twins without overt cardiovascular disease. CIMT was measured using B‐mode ultrasonography. Each of the 7 CVHI components (blood pressure, fasting glucose, total cholesterol, body mass index, physical activity, healthy diet, and smoking) was given a point score of 0, 1, or 2 to represent poor, intermediate, or ideal health, respectively. A CVHI summation score was computed (range 0 to 14) and categorized as inadequate (0 to 4), average (5 to 9), or optimum (10 to 14) cardiovascular health. Mixed‐model regression was used to examine the association of the CVHI with CIMT.
The mean age of the twins was 55.4 years, and 61% were monozygotic. The mean CIMT was 0.75 (±0.11) mm and the mean CVHI score was 7.7 (±2.1). There was an inverse correlation between CVHI and CIMT (Spearman r=−0.22, P<0.01). For every 5‐unit increase in overall CVHI score (indicating better cardiovascular health category), CIMT decreased by 0.045 mm (P<0.001) after adjusting for demographic variables and other confounders. Within monozygotic twin pairs, a 5‐unit increment in CVHI score was associated with a 0.05 mm lower CIMT (P<0.001).
The CVHI is independently associated with CIMT and the association is not confounded by shared genetic and other familial factors.
PMCID: PMC3959690  PMID: 24385450
epidemiology; prevention; risk factors
8.  Serum INSL3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose hCG: a randomized-controlled trial 
Fertility and sterility  2012;99(1):132-139.
To study the potential role for using serum biomarkers including insulin-like factor 3 (INSL3), 17-hydroxyprogesterone (17-OHP), anti-Müllerian hormone (AMH) and inhibin B (INHB) as correlates of intratesticular testosterone (IT-T) concentrations in men.
Prospective, randomized-controlled trial
University-based medical center
37 healthy men ages 18–50
All men received the gonadotropin-releasing hormone antagonist, acyline, plus very low doses of human chorionic gonadotropin (hCG) (0 IU, 15 IU, 60 IU or 125 IU) subcutaneously every other day or 7.5 grams testosterone gel daily (7.5 mg delivered). IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment.
Main Outcome Measures
Intratesticular and serum hormone and gonadotropin concentrations
Following 10 days of gonadotropin suppression, serum INSL3 decreased by over 90% and correlated highly with IT-T concentrations. In contrast, serum INHB, AMH and 17-OHP did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment.
Serum INSL3 correlates highly with IT-T and serum testosterone concentrations during acute gonadotropin suppression in men. HCG stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings. NCT# 00839319
PMCID: PMC3534941  PMID: 23040523
Androgens; INSL3; Male Infertility; Gonadotropins; Intratesticular Testosterone
9.  Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality 
Archives of internal medicine  2012;172(10):10.1001/archinternmed.2012.402.
Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.
Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.
Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age-and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06–1.46), CHD mortality (HR, 1.29; 95% CI, 1.02–1.62), CHD events (HR, 1.21; 95% CI, 0.99–1.46), and AF (HR, 1.68; 95% CI, 1.16–2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03).
Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.
PMCID: PMC3872478  PMID: 22529182
10.  Where is the patient in models of patient-centred care: a grounded theory study of total joint replacement patients 
Patient-centered care ideally considers patient preferences, values and needs. However, it is unclear if policies such as wait time strategies for hip and knee replacement surgery (TJR) are patient-centred as they focus on an isolated episode of care. This paper describes the accounts of people scheduled to undergo TJR, focusing on their experience of (OA) as a chronic disease that has considerable impact on their everyday lives.
Semi-structured qualitative interviews were conducted with participants scheduled to undergo TJR who were recruited from the practices of two orthopaedic surgeons. We first used maximum variation and then theoretical sampling based on age, sex and joint replaced. 33 participants (age 38-79 years; 17 female) were included in the analysis. 20 were scheduled for hip replacement and 13 for knee replacement. A constructivist approach to grounded theory guided sampling, data collection and analysis.
While a specific hip or knee was the target for surgery, individuals experienced multiple-joint symptoms and comorbidities. Management of their health and daily lives was impacted by these combined experiences. Over time, they struggled to manage symptoms with varying degrees of access to and acceptance of pain medication, which was a source of constant concern. This was a multi-faceted issue with physicians reluctant to prescribe and many patients reluctant to take prescription pain medications due to their side effects.
For patients, TJR surgery is an acute intervention in the experience of chronic disease, OA and other comorbidities. While policy has focused on wait time as patient/surgeon decision for surgery to surgery date, the patient’s experience does not begin or end with surgery as they struggle to manage their pain. Our findings suggest that further work is needed to align the medical treatment of OA with the current policy emphasis on patient-centeredness. Patient-centred care may require a paradigm shift that is not always evident in current policy and strategies.
PMCID: PMC3883472  PMID: 24359110
Osteoarthritis; Hip and knee replacement; Models of care; Qualitative methods; Patient experiences of care; Patient-centered care
11.  Association Between Promoter Methylation of Serotonin Transporter Gene and Depressive Symptoms: A Monozygotic Twin Study 
Psychosomatic medicine  2013;75(6):10.1097/PSY.0b013e3182924cf4.
Epigenetic mechanisms have been implicated in the pathogenesis of psychiatric disorders. The serotonin transporter gene (SLC6A4) is a key candidate gene for depression. We examined the association between SLC6A4 promoter methylation variation and depressive symptoms using 84 monozygotic twin pairs.
DNA methylation level in the SLC6A4 promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The number of current depressive symptoms was assessed using the Beck Depressive Inventory II (BDI-II). The association between methylation variation and depressive symptoms was examined using matched twin-pair analyses, adjusting for body mass index, smoking, physical activity, and alcohol consumption. Multiple testing was controlled by adjusted false discovery rate (q value).
Intrapair difference in DNA methylation variation at 10 of the 20 studied CpG sites is significantly correlated with intrapair difference in BDI scores. Linear regression using intrapair differences demonstrates that intrapair difference in BDI score was significantly associated with intrapair differences in DNA methylation variation after adjusting for potential confounders and correction for multiple testing. On average, a 10% increase in the difference in mean DNA methylation level was associated with 4.4 increase in the difference in BDI score (95% confidence interval = 0.9–7.9, p = .01).
This study provides evidence that variation in methylation level within the promoter region of the serotonin transporter gene is associated with variation in depressive symptoms in a large sample of monozygotic twin pairs. This relationship is not confounded by genetic and shared environment. The 5-HTTLPR genotype also does not modulate this association.
PMCID: PMC3848698  PMID: 23766378
DNA methylation; SLC6A4; depressive symptoms; monozygotic twins
12.  Cross vascular risk for first and recurrent hospitalised atherothrombosis determined retrospectively from linked data 
BMJ Open  2013;3(11):e003813.
To determine the sex-specific and age-specific risk ratios for the first-ever and recurrent hospitalisation for cerebrovascular, coronary and peripheral arterial disease in persons with other vascular history versus without other vascular history in Western Australia from 2005to 2007.
Cross-sectional linkage study.
Hospitalised population in a representative Australian State.
All persons aged 34–85 years between 1 January 2005 and 31 December 2007 were hospitalised with a principal diagnosis of atherothrombosis.
Data sources
Person-linked file of statutory-collected administrative morbidity and mortality records.
Main outcome measures
Sex-specific and age-specific risk ratios for the first-ever and recurrent hospitalisations for symptomatic atherothrombosis of the brain, coronary and periphery using a 15-year look-back period lead to the determining of prior events.
Over 3 years, 40 877 (66% men; 55% first-ever) were hospitalised for atherothrombosis. For each arterial territory, age-specific recurrent rates were higher than the corresponding first-ever rates, with the biggest difference seen in the youngest age groups. For all types of first-ever atherothrombosis, the rates were higher in those with other vascular history and the risk ratios declined with an advancing age (trend: all p<0.0001) and remained significantly >1 even for 75–84 years old. However, for recurrent events, the rates were marginally higher in those with other vascular history and no risk ratio age trend was apparent with several not significantly >1 (trend: all p>0.13).
This study of hospitalised atherothrombosis suggests first-events predominate and that the risk of further events in the same or other arterial territory is very high for all ages and both sexes, accentuating the necessity for an early and sustained active prevention.
PMCID: PMC3840350  PMID: 24259391
13.  Joint Attention without Gaze Following: Human Infants and Their Parents Coordinate Visual Attention to Objects through Eye-Hand Coordination 
PLoS ONE  2013;8(11):e79659.
The coordination of visual attention among social partners is central to many components of human behavior and human development. Previous research has focused on one pathway to the coordination of looking behavior by social partners, gaze following. The extant evidence shows that even very young infants follow the direction of another's gaze but they do so only in highly constrained spatial contexts because gaze direction is not a spatially precise cue as to the visual target and not easily used in spatially complex social interactions. Our findings, derived from the moment-to-moment tracking of eye gaze of one-year-olds and their parents as they actively played with toys, provide evidence for an alternative pathway, through the coordination of hands and eyes in goal-directed action. In goal-directed actions, the hands and eyes of the actor are tightly coordinated both temporally and spatially, and thus, in contexts including manual engagement with objects, hand movements and eye movements provide redundant information about where the eyes are looking. Our findings show that one-year-olds rarely look to the parent's face and eyes in these contexts but rather infants and parents coordinate looking behavior without gaze following by attending to objects held by the self or the social partner. This pathway, through eye-hand coupling, leads to coordinated joint switches in visual attention and to an overall high rate of looking at the same object at the same time, and may be the dominant pathway through which physically active toddlers align their looking behavior with a social partner.
PMCID: PMC3827436  PMID: 24236151
14.  Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial 
Objective To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics.
Design Cluster randomised controlled trial.
Setting Community mental health teams in secondary psychiatric care in the United Kingdom.
Participants Patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, who were prescribed long acting antipsychotic (depot) injections but had received 75% or less of the prescribed injections. We randomly allocated 73 teams with a total of 141 patients. Primary outcome data were available for 35 intervention teams with 75 patients (96% of randomised) and for 31 control teams with 56 patients (89% of randomised).
Interventions Participants in the intervention group were offered £15 (€17; $22) for each depot injection over a 12 month period. Participants in the control condition received treatment as usual.
Main outcome measure The primary outcome was the percentage of prescribed depot injections given during the 12 month intervention period.
Results 73 teams with 141 consenting patients were randomised, and outcomes were assessed for 131 patients (93%). Average baseline adherence was 69% in the intervention group and 67% in the control group. During the 12 month trial period adherence was 85% in the intervention group and 71% in the control group. The adjusted effect estimate was 11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an adherence of ≥95%, which was achieved in 28% of the intervention group and 5% of the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67, P=0.003). Although differences in clinician rated clinical improvement between the groups failed to reach statistical significance, patients in the intervention group had more favourable subjective quality of life ratings (β=0.71, 95% confidence interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse events were low in both groups and did not show substantial differences.
Conclusion Offering modest financial incentives to patients with psychotic disorders is an effective method for improving adherence to maintenance treatment with antipsychotics.
Trial registration Current Controlled Trials ISRCTN77769281.
PMCID: PMC3805491  PMID: 24100934
15.  Evaluation of paediatric nursing-sensitive outcomes in an Australian population using linked administrative hospital data 
Research into nursing-sensitive outcomes using administrative health data has focussed on hospitalised adults. However, we developed algorithms for the identification of 13 paediatric nursing-sensitive outcomes, which we seek to examine for clinical utility. The aims were to determine the rates of paediatric nursing-sensitive outcomes in a Western Australian hospital and ascertain sociodemographic and clinical characteristics associated with a greater risk of developing nursing-sensitive outcomes in hospitalised children.
A retrospective cohort study used linked administrative data of all Western Australian children ≤18 years admitted to the only tertiary paediatric hospital in Perth between 1999 and 2009. Rates per 1,000 hospital separations and per 10,000 patient days were calculated for the following nursing-sensitive outcomes: lower respiratory tract infection (LRTI), gastrointestinal (GI) infection, pneumonia, sepsis, arrest/shock/respiratory failure, central nervous system complication, central venous line infection, infectious disease, pressure ulcer, failure to rescue, surgical wound infection, physiologic/metabolic derangement, and postoperative cardiopulmonary complications. Poisson multiple regression models were fitted to estimate rate ratios (RR) and 95% confidence intervals (CI) for suspected risk factors.
Linked records of 129,719 hospital separations were analysed. Rates ranged from 0.5/1,000 for pressure ulcer to 14.0/1,000 hospital separations for GI infections. Age was significantly associated with the risk of a nursing-sensitive outcome: compared with adolescents, toddlers had greater risk of GI infection (RR 9.89; 95% CI 6.24, 15.69); infants had 7.74 times greater risk of LRTI (95% CI 5.11, 11.75), while neonates had lower risks for sepsis (RR 0.26; 95% CI 0.08, 0.90) and physiologic/metabolic derangement (RR 0.12; 95% CI 0.04, 0.35). The risk of surgical wound infection was 7.78 times greater (95% CI 5.10, 11.86) for emergency admissions than elective admissions.
Seven of the 13 defined nursing-sensitive outcomes occurred with sufficient frequency (>100 events over the 10 year study period) to be potentially useful for monitoring the quality of nursing care. These nursing-sensitive outcomes are: LRTI, GI infection, pneumonia, surgical wound infection, physiologic/metabolic derangement, sepsis and postoperative cardiopulmonary complications. When used for quality improvement or to benchmark with other agencies, data need to be adjusted for, or stratified by age and admission type, to ensure equitable comparisons.
PMCID: PMC3852600  PMID: 24103062
16.  Self-management support for moderate-to-severe chronic obstructive pulmonary disease: a pilot randomised controlled trial 
The British Journal of General Practice  2012;62(603):e687-e695.
Better self management could improve quality of life (QoL) and reduce hospital admissions in chronic obstructive pulmonary disease (COPD), but the best way to promote it remains unclear.
To explore the feasibility, effectiveness and cost effectiveness of a novel, layperson-led, theoretically driven COPD self-management support programme.
Design and setting
Pilot randomised controlled trial in one UK primary care trust area.
Patients with moderate to severe COPD were identified through primary care and randomised 2:1 to the 7-week-long, group intervention or usual care. Outcomes at baseline, 2, and 6 months included self-reported health, St George’s Respiratory Questionnaire (SGRQ), EuroQol, and exercise.
Forty-four per cent responded to GP invitation, 116 were randomised: mean (standard deviation [SD]) age 69.5 (9.8) years, 46% male, 78% had unscheduled COPD care in the previous year. Forty per cent of intervention patients completed the course; 35% attended no sessions; and 78% participants completed the 6-month follow-up questionnaire. Results suggest that the intervention may increase both QoL (mean EQ-5D change 0.12 (95% confidence interval [CI] = –0.02 to 0.26) higher, intervention versus control) and exercise levels, but not SGRQ score. Economic analyses suggested that with thresholds of £20 000 per quality-adjusted life-year gained, the intervention is likely to be cost-effective.
This intervention has good potential to meet the UK National Institute for Health and Clinical Excellence criteria for cost effectiveness, and further research is warranted. However, to make a substantial impact on COPD self-management, it will also be necessary to explore other ways to enable patients to access self-management education.
PMCID: PMC3459776  PMID: 23265228
pilot projects; pulmonary disease, chronic obstructive; randomised controlled trial; self-care; self-management; patient education as topic; primary health care
17.  A bioturbation classification of European marine infaunal invertebrates 
Ecology and Evolution  2013;3(11):3958-3985.
Bioturbation, the biogenic modification of sediments through particle reworking and burrow ventilation, is a key mediator of many important geochemical processes in marine systems. In situ quantification of bioturbation can be achieved in a myriad of ways, requiring expert knowledge, technology, and resources not always available, and not feasible in some settings. Where dedicated research programmes do not exist, a practical alternative is the adoption of a trait-based approach to estimate community bioturbation potential (BPc). This index can be calculated from inventories of species, abundance and biomass data (routinely available for many systems), and a functional classification of organism traits associated with sediment mixing (less available). Presently, however, there is no agreed standard categorization for the reworking mode and mobility of benthic species. Based on information from the literature and expert opinion, we provide a functional classification for 1033 benthic invertebrate species from the northwest European continental shelf, as a tool to enable the standardized calculation of BPc in the region. Future uses of this classification table will increase the comparability and utility of large-scale assessments of ecosystem processes and functioning influenced by bioturbation (e.g., to support legislation). The key strengths, assumptions, and limitations of BPc as a metric are critically reviewed, offering guidelines for its calculation and application.
PMCID: PMC3810888  PMID: 24198953
Biodiversity; biogeochemical; ecosystem function; functional group; good environmental status; Marine Strategy Framework Directive; process; trait
18.  Myocardial Ischemia During Mental Stress: Role of Coronary Artery Disease Burden and Vasomotion 
Mental stress–induced myocardial ischemia (MSIMI) is associated with adverse prognosis in patients with coronary artery disease (CAD), yet the mechanisms underlying this phenomenon remain unclear. We hypothesized that compared with exercise/pharmacological stress–induced myocardial ischemia (PSIMI) that is secondary to the atherosclerotic burden of CAD, MSIMI is primarily due to vasomotor changes.
Methods and Results
Patients with angiographically documented CAD underwent 99mTc‐sestamibi myocardial perfusion imaging at rest and following both mental and physical stress testing, performed on separate days. The severity and extent of CAD were quantified using the Gensini and Sullivan scores. Peripheral arterial tonometry (Itamar Inc) was used to assess the digital microvascular tone during mental stress as a ratio of pulse wave amplitude during speech compared with baseline. Measurements were made in a discovery sample (n=225) and verified in a replication sample (n=159). In the pooled (n=384) sample, CAD severity and extent scores were not significantly different between those with and without MSIMI, whereas they were greater in those with compared with those without PSIMI (P<0.04 for all). The peripheral arterial tonometry ratio was lower in those with compared with those without MSIMI (0.55±0.36 versus 0.76±0.52, P=0.009). In a multivariable analysis, the peripheral arterial tonometry ratio was the only independent predictor of MSIMI (P=0.009), whereas angiographic severity and extent of CAD independently predicted PSIMI.
The degree of digital microvascular constriction, and not the angiographic burden of CAD, is associated with MSIMI. Varying causes of MSIMI compared with PSIMI may require different therapeutic interventions that require further study.
PMCID: PMC3835239  PMID: 24145741
coronary disease; ischemia; mental stress; vasoconstriction
19.  Infants Help a Non-Human Agent 
PLoS ONE  2013;8(9):e75130.
Young children can be motivated to help adults by sympathetic concern based upon empathy, but the underlying mechanisms are unknown. One account of empathy-based sympathetic helping in adults states that it arises due to direct-matching mirror-system mechanisms which allow the observer to vicariously experience the situation of the individual in need of help. This mechanism could not account for helping of a geometric-shape agent lacking human-isomorphic body-parts. Here 17-month-olds observed a ball-shaped non-human agent trying to reach a goal but failing because it was blocked by a barrier. Infants helped the agent by lifting it over the barrier. They performed this action less frequently in a control condition in which the barrier could not be construed as blocking the agent. Direct matching is therefore not required for motivating helping in infants, indicating that at least some of our early helpful tendencies do not depend on human-specific mechanisms. Empathy-based mechanisms that do not require direct-matching provide one plausible basis for the observed helping. A second possibility is that rather than being based on empathy, the observed helping occurred as a result of a goal-contagion process in which the infants were primed with the unfulfilled goal.
PMCID: PMC3776733  PMID: 24058657
20.  Young infants’ perception of the trajectories of two- and three-dimensional objects 
We investigated oculomotor anticipations in 4-month-old infants as they viewed center-occluded object trajectories. In two experiments, we examined performance in two-dimensional (2D) and three-dimensional (3D) dynamic occlusion displays and in an additional 3D condition with a smiley face as the moving target stimulus. Rates of anticipatory eye movements were not facilitated by 3D displays or by the (presumably) more salient smiley face relative to the 2D condition. However, latencies of anticipations were reduced, implying that 3D visual information may have supported formation of more robust mental representations of the moving object. Results are interpreted in a context of perceptual constraints on developing cognitive capacities during early infancy.
PMCID: PMC3567617  PMID: 22704037
Infant perception; Depth perception; Visual development; Eye movements; Object knowledge
21.  Coding of the reach vector in parietal area 5d 
Neuron  2012;75(2):342-351.
Competing models of sensorimotor computation predict different topological constraints in the brain. Some models propose population coding of particular reference frames in anatomically distinct nodes, whereas others require no such dedicated subpopulations and instead predict that regions will simultaneously code in multiple, intermediate, reference frames. Current empirical evidence is conflicting, partly due to difficulties involved in identifying underlying reference frames. Here, we independently varied the locations of hand, gaze and target over many positions while recording from the dorsal aspect of parietal area 5. We find that the target is represented in a predominantly hand-centered reference frame here, contrasting with the relative code seen in dorsal premotor cortex and the mostly gaze-centered reference frame in the parietal reach region. This supports the hypothesis that different nodes of the sensorimotor circuit contain distinct and systematic representations, and this constrains the types of computational model that are neurobiologically relevant.
PMCID: PMC3408621  PMID: 22841318
Monkey; macaque; parietal; reaching; reference frame
22.  Evidence-based paramedic models of care to reduce unnecessary emergency department attendance – feasibility and safety 
As demand for Emergency Department (ED) services continues to exceed increases explained by population growth, strategies to reduce ED presentations are being explored. The concept of ambulance paramedics providing an alternative model of care to the current default ‘see and transport to ED’ has intuitive appeal and has been implemented in several locations around the world. The premise is that for certain non-critically ill patients, the Extended Care Paramedic (ECP) can either ‘see and treat’ or ‘see and refer’ to another primary or community care practitioner, rather than transport to hospital. However, there has been little rigorous investigation of which types of patients can be safely identified and managed in the community, or the impact of ECPs on ED attendance.
St John Ambulance Western Australia paramedics will indicate on the electronic patient care record (e-PCR) of patients attended in the Perth metropolitan area if they consider them to be suitable to be managed in the community. ‘Follow-up’ will examine these patients using ED data to determine the patient’s disposition from the ED. A clinical panel will then develop a protocol to identify those patients who can be safely managed in the community. Paramedics will then assess patients against the derived ECP protocols and identify those deemed suitable to ‘see and treat’ or ‘see and refer’. The ED disposition (and other clinical outcomes) of these ‘ECP protocol identified’ patients will enable us to assess whether it would have been appropriate to manage these patients in the community. We will also ‘track’ re-presentations to EDs within seven days of the initial presentation. This is a ‘virtual experiment’ with no direct involvement of patients or changes in clinical practice. A systems modelling approach will be used to assess the likely impact on ED crowding.
To date the efficacy, cost-effectiveness and safety of alternative community-based models of emergency care have not been rigorously investigated. This study will inform the development of ECP protocols through the identification of types of patient presentation that can be considered both safe and appropriate for paramedics to manage in the community.
PMCID: PMC3724748  PMID: 23855265
Pre-hospital; Extended care paramedics; Ambulance; Emergency department demand; Community care; Patient safety; Economic evaluation
23.  Exercise for depression in elderly residents of care homes: a cluster-randomised controlled trial 
Lancet  2013;382(9886):41-49.
Depression is common and is associated with poor outcomes among elderly care-home residents. Exercise is a promising low-risk intervention for depression in this population. We tested the hypothesis that a moderate intensity exercise programme would reduce the burden of depressive symptoms in residents of care homes.
We did a cluster-randomised controlled trial in care homes in two regions in England; northeast London, and Coventry and Warwickshire. Residents aged 65 years or older were eligible for inclusion. A statistician independent of the study randomised each home (1 to 1·5 ratio, stratified by location, minimised by type of home provider [local authority, voluntary, private and care home, private and nursing home] and size of home [<32 or ≥32 residents]) into intervention and control groups. The intervention package included depression awareness training for care-home staff, 45 min physiotherapist-led group exercise sessions for residents (delivered twice weekly), and a whole home component designed to encourage more physical activity in daily life. The control consisted of only the depression awareness training. Researchers collecting follow-up data from individual participants and the participants themselves were inevitably aware of home randomisation because of the physiotherapists' activities within the home. A researcher masked to study allocation coded NHS routine data. The primary outcome was number of depressive symptoms on the geriatric depression scale-15 (GDS-15). Follow-up was for 12 months. This trial is registered with ISRCTN Register, number ISRCTN43769277.
Care homes were randomised between Dec 15, 2008, and April 9, 2010. At randomisation, 891 individuals in 78 care homes (35 intervention, 43 control) had provided baseline data. We delivered 3191 group exercise sessions attended on average by five study participants and five non-study residents. Of residents with a GDS-15 score, 374 of 765 (49%) were depressed at baseline; 484 of 765 (63%) provided 12 month follow-up scores. Overall the GDS-15 score was 0·13 (95% CI −0·33 to 0·60) points higher (worse) at 12 months for the intervention group compared with the control group. Among residents depressed at baseline, GDS-15 score was 0·22 (95% CI −0·52 to 0·95) points higher at 6 months in the intervention group than in the control group. In an end of study cross-sectional analysis, including 132 additional residents joining after randomisation, the odds of being depressed were 0·76 (95% CI 0·53 to 1·09) for the intervention group compared with the control group.
This moderately intense exercise programme did not reduce depressive symptoms in residents of care homes. In this frail population, alternative strategies to manage psychological symptoms are required.
National Institute for Health Research Health Technology Assessment.
PMCID: PMC3919159  PMID: 23643112
24.  Rudimentary Sympathy in Preverbal Infants: Preference for Others in Distress 
PLoS ONE  2013;8(6):e65292.
Despite its essential role in human coexistence, the developmental origins and progression of sympathy in infancy are not yet fully understood. We show that preverbal 10-month-olds manifest sympathetic responses, evinced in their preference for attacked others according to their evaluations of the respective roles of victim, aggressor, and neutral party. In Experiment 1, infants viewing an aggressive social interaction between a victim and an aggressor exhibited preference for the victim. In Experiment 2, when comparing the victim and the aggressor to a neutral object, infants preferred the victim and avoided the aggressor. These findings indicate that 10-month-olds not only evaluate the roles of victims and aggressors in interactions but also show rudimentary sympathy toward others in distress based on that evaluation. This simple preference may function as a foundation for full-fledged sympathetic behavior later on.
PMCID: PMC3680456  PMID: 23776467
25.  Impact of Short Term Consumption of Diets High in Either Non-Starch Polysaccharides or Resistant Starch in Comparison with Moderate Weight Loss on Indices of Insulin Sensitivity in Subjects with Metabolic Syndrome 
Nutrients  2013;5(6):2144-2172.
This study investigated if additional non-starch polysaccharide (NSP) or resistant starch (RS), above that currently recommended, leads to better improvement in insulin sensitivity (IS) than observed with modest weight loss (WL). Obese male volunteers (n = 14) were given an energy-maintenance (M) diet containing 27 g NSP and 5 g RS daily for one week. They then received, in a cross-over design, energy-maintenance intakes of either an NSP-enriched diet (42 g NSP, 2.5 g RS) or an RS-enriched diet (16 g NSP, 25 g RS), each for three weeks. Finally, a high protein (30% calories) WL diet was provided at 8 MJ/day for three weeks. During each dietary intervention, endogenous glucose production (EGP) and IS were assessed. Fasting glycaemia was unaltered by diet, but plasma insulin and C-peptide both decreased with the WL diet (p < 0.001), as did EGP (−11%, p = 0.006). Homeostatis model assessment of insulin resistance improved following both WL (p < 0.001) and RS (p < 0.05) diets. Peripheral tissue IS improved only with WL (57%–83%, p < 0.005). Inclusion of additional RS or NSP above amounts currently recommended resulted in little or no improvement in glycaemic control, whereas moderate WL (approximately 3 kg fat) improved IS.
PMCID: PMC3725498  PMID: 23752495
insulin sensitivity; stable isotope kinetics; non-starch polysaccharides; resistant starch; weight loss; Minimal Models; metabolic syndrome

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