Publications by authors named "Paul A Thompson"

90 Publications

Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis.

Wellcome Open Res 2018 1;3:85. Epub 2021 Jun 1.

Department of Experimental Psychology, University of Oxford, Oxford, OX2 6GG, UK.

: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions.   We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, and , were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with or variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in or are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. http://dx.doi.org/10.12688/wellcomeopenres.13828.2.
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http://dx.doi.org/10.12688/wellcomeopenres.14677.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134338.4PMC
June 2021

Generalized Structured Component Analysis in candidate gene association studies: applications and limitations.

Wellcome Open Res 2019 8;4:142. Epub 2020 Oct 8.

Department of Biological and Medical Sciences, Oxford Brookes University, Headington Campus, Oxford, OX3 0BP, UK.

Generalized Structured Component Analysis (GSCA) is a component-based alternative to traditional covariance-based structural equation modelling. This method has previously been applied to test for association between candidate genes and clinical phenotypes, contrasting with traditional genetic association analyses that adopt univariate testing of many individual single nucleotide polymorphisms (SNPs) with correction for multiple testing. We first evaluate the ability of the GSCA method to replicate two previous findings from a genetics association study of developmental language disorders. We then present the results of a simulation study to test the validity of the GSCA method under more restrictive data conditions, using smaller sample sizes and larger numbers of SNPs than have previously been investigated. Finally, we compare GSCA performance against univariate association analysis conducted using PLINK v1.9. Results from simulations show that power to detect effects depends not just on sample size, but also on the ratio of SNPs with effect to number of SNPs tested within a gene. Inclusion of many SNPs in a model dilutes true effects. We propose that GSCA is a useful method for replication studies, when candidate SNPs have been identified, but should not be used for exploratory analysis.
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http://dx.doi.org/10.12688/wellcomeopenres.15396.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818107PMC
October 2020

Assessing the reliability of an online behavioural laterality battery: A pre-registered study.

Laterality 2021 Jul 15;26(4):359-397. Epub 2020 Dec 15.

Department of Experimental Psychology, University of Oxford, Oxford, UK.

Studies of cerebral lateralization often involve participants completing a series of perceptual tasks under laboratory conditions. This has constrained the number of participants recruited in such studies. Online testing can allow for much larger sample sizes but limits the amount of experimental control that is feasible. Here we considered whether online testing could give valid and reliable results on four tasks: a rhyme decision visual half-field task, a dichotic listening task, a chimeric faces task, and a finger tapping task. We recruited 392 participants, oversampling left-handers, who completed the battery twice. Three of the tasks showed evidence of both validity and reliability, insofar as they showed hemispheric advantages in the expected direction and test-retest reliability of at least  = .75. The reliability of the rhyme decision task was less satisfactory ( = .62). We also confirmed a prediction that extreme left-handers were more likely to depart from typical lateralization. Lateralization across the two language tasks (dichotic listening and rhyme judgement) was weakly correlated, but unrelated to lateralization on the chimeric faces task. We conclude that three of the tasks, dichotic listening, chimeric faces and finger tapping, show considerable promise for online evaluation of cerebral lateralization.
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http://dx.doi.org/10.1080/1357650X.2020.1859526DOI Listing
July 2021

Functional organisation for verb generation in children with developmental language disorder.

Neuroimage 2021 02 4;226:117599. Epub 2020 Dec 4.

Department of Experimental Psychology & Wellcome Trust Centre for Integrative Neuroimaging, University of Oxford, Anna Watts Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK.

Developmental language disorder (DLD) is characterised by difficulties in learning one's native language for no apparent reason. These language difficulties occur in 7% of children and are known to limit future academic and social achievement. Our understanding of the brain abnormalities associated with DLD is limited. Here, we used a simple four-minute verb generation task (children saw a picture of an object and were instructed to say an action that goes with that object) to test children between the ages of 10-15 years (DLD N = 50, typically developing N = 67). We also tested 26 children with poor language ability who did not meet our criteria for DLD. Contrary to our registered predictions, we found that children with DLD did not have (i) reduced activity in language relevant regions such as the left inferior frontal cortex; (ii) dysfunctional striatal activity during overt production; or (iii) a reduction in left-lateralised activity in frontal cortex. Indeed, performance of this simple language task evoked activity in children with DLD in the same regions and to a similar level as in typically developing children. Consistent with previous reports, we found sub-threshold group differences in the left inferior frontal gyrus and caudate nuclei, but only when analysis was limited to a subsample of the DLD group (N = 14) who had the poorest performance on the task. Additionally, we used a two-factor model to capture variation in all children studied (N = 143) on a range of neuropsychological tests and found that these language and verbal memory factors correlated with activity in different brain regions. Our findings indicate a lack of support for some neurological models of atypical language learning, such as the procedural deficit hypothesis or the atypical lateralization hypothesis, at least when using simple language tasks that children can perform. These results also emphasise the importance of controlling for and monitoring task performance.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836232PMC
February 2021

Profile of language abilities in a sample of adults with developmental disorders.

Dyslexia 2021 Feb 17;27(1):3-28. Epub 2020 Nov 17.

Department of Experimental Psychology, University of Oxford, Oxford, UK.

This study investigated the profile of language abilities in a sample of high-achieving English speaking adults with developmental disorders. Ninety-seven adult participants were recruited: 49 with a dyslexia diagnosis (dyslexic group), 16 with a diagnosis of a different developmental disorder including dyspraxia, autism and SpLD (non-dyslexic developmental disorder group) and 32 with no diagnosis (non-disordered group). Dyslexic and non-dyslexic developmental disorder groups demonstrated similar impairments across measures of word reading, working memory, processing speed and oral language. Dyslexic participants showed the usual pattern of impaired phonological skills but spared non-verbal intelligence and vocabulary. There were also some suggestions of impaired structural oral language skills in this group. A data-driven clustering analysis found that diagnosis was not a reliable predictor of similarity between cases, with diagnostic categories split between data-driven clusters. Overall, the findings indicate that high-achieving adults with developmental disorders do demonstrate impairments that are likely to affect success in higher education, but that support needs should be assessed on a case-by-case basis, rather than according to diagnostic label.
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http://dx.doi.org/10.1002/dys.1672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894539PMC
February 2021

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study.

J Clin Oncol 2020 07 1;38(21):2427-2437. Epub 2020 Jun 1.

Sanford Cancer Center, Sanford Health, Sioux Falls, SD.

Purpose: Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC.

Patients And Methods: Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS).

Results: The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively.

Conclusion: Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.
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http://dx.doi.org/10.1200/JCO.19.03156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365766PMC
July 2020

Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy.

Am J Med Genet C Semin Med Genet 2020 06 26;184(2):256-266. Epub 2020 May 26.

Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, Oxfordshire, UK.

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)-stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss-of-function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within-group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.
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http://dx.doi.org/10.1002/ajmg.c.31791DOI Listing
June 2020

Investigation into inconsistent lateralisation of language functions as a potential risk factor for language impairment.

Eur J Neurosci 2020 02 14;51(4):1106-1121. Epub 2019 Dec 14.

Department of Experimental Psychology, Radcliffe Observatory Quarter, University of Oxford, Oxford, UK.

Disruption to language lateralisation has been proposed as a cause of developmental language impairments. In this study, we tested the idea that consistency of lateralisation across different language functions is associated with language ability. A large sample of adults with variable language abilities (N = 67 with a developmental disorder affecting language and N = 37 controls) were recruited. Lateralisation was measured using functional transcranial Doppler sonography (fTCD) for three language tasks that engage different language subprocesses (phonological decision, semantic decision and sentence generation). The whole sample was divided into those with consistent versus inconsistent lateralisation across the three tasks. Language ability (using a battery of standardised tests) was compared between the consistent and inconsistent groups. The results did not show a significant effect of lateralisation consistency on language skills. However, of the 31 individuals showing inconsistent lateralisation, the vast majority (84%) were in the disorder group with only five controls showing such a pattern, a difference that was higher than would be expected by chance. The developmental disorder group also demonstrated weaker correlations between laterality indices across pairs of tasks. In summary, although the data did not support the hypothesis that inconsistent language lateralisation is a major cause of poor language skills, the results suggested that some subtypes of language disorder are associated with inefficient distribution of language functions between hemispheres. Inconsistent lateralisation could be a causal factor in the aetiology of language disorder or may arise in some cases as the consequence of developmental disorder, possibly reflective of compensatory reorganisation.
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http://dx.doi.org/10.1111/ejn.14623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078955PMC
February 2020

The understanding of complex syntax in children with Down syndrome.

Wellcome Open Res 2018 28;3:140. Epub 2019 Feb 28.

Department of Experimental Psychology, University of Oxford, Oxford, Oxon, UK.

Down syndrome (DS) is associated with poor language skills that seem disproportionate to general nonverbal ability, but the nature and causes of this deficit are unclear. We assessed how individuals with DS understand complex linguistic constructions, and considered how cognitive ability and memory and impact the ability of those with DS to process these sentence types. There were three groups participating in the study: children with DS (n = 33) and two control groups composed of children with cognitive impairment of unknown aetiology (CI) (n = 32) and children with typical development (n = 33). The three groups did not differ on raw scores on a test of non-verbal cognitive ability. Using a newly devised animation task, we examined how well individuals with DS (n = 33) could understand relative clauses, complement clauses and adverbial clauses compared to children with CI and typically developing controls. Participants also completed the Test for the Reception of Grammar-2, three measures of memory (forward and backward digit recall, visuo-spatial memory) and a hearing screen. Results indicated that (1) with the exception of intransitive subject relative clauses, children with DS performed at floor on all other complex sentences, (2) they performed at a significantly lower level than both control groups, and (3) DS status accounted for a significant proportion of the variance over and above memory skills. Our findings suggest that children with DS have a disproportionate difficulty understanding complex sentences compared to two control groups matched on mental age. Furthermore, their understanding of syntax is not completely explained by poor cognitive or memory skills, rather it appears to be a specific deficit that may distinguish children with DS from other neurodevelopmental disorders.
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http://dx.doi.org/10.12688/wellcomeopenres.14861.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259485PMC
February 2019

The Collaborative Laborist and Midwifery Model: An Accepted and Sustainable Model.

S D Med 2018 Dec;71(12):534-537

Department of Obstetrics and Gynecology, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.

In 2010, the OB/GYN physicians at this mid-sized midwestern medical center implemented a laborist model on the obstetrics ward. A laborist is a dedicated obstetrician within the obstetric ward who oversees the management of labor and performs deliveries as both the primary physician and also when consulted by other providers, including community obstetricians, family physicians and nurse midwives. In 2014, a collaborative obstetric model was implemented with the addition of an in-house certified nurse midwife (CNM) to assist the laborist in obstetric care. This retrospective study analyzes the impact of these care models on clinical outcomes, including rates of induction of labor, total (primary and repeat) cesarean sections, and vaginal births after cesarean section. The three time periods (i.e., pre-laborist, laborist, laborist plus CNM) periods are compared. Induction rates decreased from 48.6 percent to 46.5 percent to 28.8 percent during the three time periods. Primary cesarean section rates decreased from 15.9 percent to 14.6 percent to 13.6 percent. Total cesarean section rates slightly decreased but this was not statistically significant, going from 28.9 percent to 28.4 percent, to 27.7 percent. Vaginal births after cesarean section increased from 9.2 percent to 12.9 percent to 15 percent. Staff satisfaction was also measured utilizing anonymous surveys during the first two time periods. There was improvement in seven of the eight questions from the pre-laborist to the laborist model. In conclusion, a collaborative care model on the obstetric floor at this Institution has had a positive impact on patient care outcomes and staff satisfaction.
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December 2018

Language phenotypes in children with sex chromosome trisomies.

Wellcome Open Res 2018 28;3:143. Epub 2019 Jan 28.

Department of Experimental Psychology, University of Oxford, Oxford, Oxon, OX2 6GG, UK.

Sex chromosome trisomies (47,XXX, 47,XXY and 47,XYY) are known to be a risk factor for language disorder, but it is hard to predict outcomes, because many cases are identified only when problems are found. We recruited children aged 5-16 years with all three types of trisomy, and divided them into a High Bias group, identified in the course of investigations for neurodevelopmental problems, and a Low Bias group, identified via prenatal screening or other medical investigations. Children from a twin sample were used to compare pattern and severity of language problems: they were subdivided according to parental concerns about language/history of speech-language therapy into a No Concerns group (N = 118) and a Language Concerns group (N = 57). Children were assessed on a psychometric battery and a standardized parent checklist. After excluding children with intellectual disability, autism or hearing problems, the sample included 28 XXX, 18 XXY and 14 XYY Low Bias cases and 7 XXX, 13 XXY and 17 XYY High Bias cases. Variation within each trisomy group was substantial: within the Low Bias group, overall language scores were depressed relative to normative data, but around one third had no evidence of problems. There was no effect of trisomy type, and the test profile was similar to the Language Concerns comparison group. The rate of problems was much greater in the High Bias children with trisomies. When advising parents after discovery of a trisomy, it is important to emphasise that, though there is an increased risk of language problems, there is a very wide range of outcomes. Severe language problems are more common in those identified via genetic testing for neurodevelopmental problems but these are not characteristic of children identified on prenatal screening.
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http://dx.doi.org/10.12688/wellcomeopenres.14904.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376256PMC
January 2019

Fish Oil and Perioperative Bleeding.

Circ Cardiovasc Qual Outcomes 2018 11;11(11):e004584

Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (D.M.).

Background Fish oil is among the most common natural supplements for treatment of hypertriglyceridemia or prevention of cardiovascular disease. However, concerns about theoretical bleeding risk have led to recommendations that patients should stop taking fish oil before surgery or delay in elective procedures for patients taking fish oil by some health care professionals. Methods and Results We tested the effect of fish oil supplementation on perioperative bleeding in a multinational, placebo-controlled trial involving 1516 patients who were randomized to perioperative fish oil (eicosapentaenoic acid+docosahexaenoic acid; 8-10 g for 2-5 days preoperatively, and then 2 g/d postoperatively) or placebo. Primary outcome was major perioperative bleeding as defined by the Bleeding Academic Research Consortium. Secondary outcomes include perioperative bleeding per thrombolysis in myocardial infarction and International Society on Thrombosis and Hemostasis definitions, chest tube output, and total units of blood transfused. Participants' mean (SD) age was 63 (13) years, and planned surgery included coronary artery bypass graft (52%) and valve surgery (50%). The primary outcome occurred in 92 patients (6.1%). Compared with placebo, risk of Bleeding Academic Research Consortium bleeding was not higher in the fish oil group: odds ratio, 0.81; 95% CI, 0.53-1.24; absolute risk difference, 1.1% lower (95% CI, -3.0% to 1.8%). Similar findings were seen for secondary bleeding definitions. The total units of blood transfused were significantly lower in the fish oil group compared with placebo (mean, 1.61 versus 1.92; P<0.001). Evaluating achieved plasma phospholipid omega-3 polyunsaturated fatty acids levels with supplementation (on the morning of surgery), higher levels were associated with lower risk of Bleeding Academic Research Consortium bleeding, with substantially lower risk in the third (odds ratio, 0.30 [95% CI, 0.11-0.78]) and fourth (0.36 [95% CI, 0.15-0.87]) quartiles, compared with the lowest quartile. Conclusions Fish oil supplementation did not increase perioperative bleeding and reduced the number of blood transfusions. Higher achieved n-3-PUFA levels were associated with lower risk of bleeding. These novel findings support the need for reconsideration of current recommendations to stop fish oil or delay procedures before cardiac surgery. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00970489.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.118.004584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376981PMC
November 2018

Shortened Taper Duration after Implementation of a Standardized Protocol for Iatrogenic Benzodiazepine and Opioid Withdrawal in Pediatric Patients: Results of a Cohort Study.

Pediatr Qual Saf 2018 May-Jun;3(3):e079. Epub 2018 May 18.

University of South Dakota, Sanford School of Medicine, Vermillion, S.Dak.

Introduction: Methadone and lorazepam prescribing discrepancies for the use of iatrogenic withdrawal were observed among providers. A standardized pharmacist-managed methadone and lorazepam taper protocol was implemented at a pediatric tertiary care facility with the aim to reduce the length of taper for patients with iatrogenic withdrawal.

Methods: A multidisciplinary team of nurses, pharmacists, and physicians reviewed the current literature, then developed and implemented a standardized withdrawal taper protocol. Outcomes were compared with a retrospective control group using past prescribing practices. The primary endpoint was the length of methadone and/or lorazepam taper. Secondary endpoints included evaluation for significant differences between the control and standardized protocol groups regarding additional breakthrough withdrawal medications, pediatric intensive care unit (PICU) and hospital length of stay. We also evaluated provider satisfaction with the protocol.

Results: The standardized protocol group included 25 patients who received methadone and/or lorazepam taper. A retrospective control group contained 24 patients. Median methadone taper length before protocol implementation was 9.5 days with an interquartile range (IQR) of 5.5-14.5 days; after protocol implementation, it was 6.0 (IQR, 3.0-9.0) days ( = 0.0145). Median lorazepam taper length before protocol implementation was 13.0 (IQR, 8.0-18.0) days; after protocol implementation, it was 6.0 (4.0-7.0) days ( = 0.0006). A statistical difference between PICU length of stay, hospital length of stay, or the number of additional medications for breakthrough withdrawal was not found.

Conclusions: The use of a standardized withdrawal protocol resulted in shorter taper duration for both the methadone and lorazepam groups. There was no difference in PICU or hospital length of stay.
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http://dx.doi.org/10.1097/pq9.0000000000000079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132810PMC
May 2018

Growth in syntactic complexity between four years and adulthood: evidence from a narrative task.

J Child Lang 2018 09 4;45(5):1174-1197. Epub 2018 Jun 4.

Department of Experimental Psychology,University of Oxford,Oxford,Oxon,UK.

Studies examining productive syntax have used varying elicitation methods and have tended to focus on either young children or adolescents/adults, so we lack an account of syntactic development throughout middle childhood. We describe here the results of an analysis of clause complexity in narratives produced by 354 speakers aged from four years to adulthood using the Expressive, Receptive, and Recall of Narrative Instrument (ERRNI). We show that the number of clauses per utterance increased steadily through this age range. However, the distribution of clause types depended on which of two stories was narrated, even though both stories were designed to have a similar story structure. In addition, clausal complexity was remarkably similar regardless of whether the speaker described a narrative from pictures, or whether the same narrative was recalled from memory. Finally, our findings with the youngest children showed that the task of generating a narrative from pictures may underestimate syntactic competence in those aged below five years.
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http://dx.doi.org/10.1017/S0305000918000144DOI Listing
September 2018

Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis.

Wellcome Open Res 2018 12;3:10. Epub 2018 Feb 12.

Department of Experimental Psychology, University of Oxford, Oxford, Oxfordshire, OX1 3UD, UK.

: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions.  We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, and , will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.
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http://dx.doi.org/10.12688/wellcomeopenres.13828.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904730PMC
February 2018

Clinical factors associated with physician choice of femoral versus radial access: A real-world experience from a single academic center.

J Interv Cardiol 2018 Apr 25;31(2):236-243. Epub 2017 Dec 25.

Division of Cardiology, Sanford School of Medicine, Sioux Falls, South Dakota.

Objectives: To analyze clinical factors associated with operator's preference in selection of femoral versus radial access for angiography and percutaneous intervention (PCI) procedures.

Background: There has been an increase in radial access in cardiac catheterization and PCI in the last few decades.

Methods: Data from 11 226 consecutive cardiac catheterization procedures were collected from Sanford University Medical Center (University of South Dakota, Sanford School of Medicine) from 2011 to 2015.

Results: In the overall cases, clinical factors that favored upfront femoral access include patients presenting as ST-elevation myocardial infarction (STEMI) or emergent, coronary artery bypass graft, body mass index (BMI) <30 kg/m and age ≥70 years, whereas morbidly obese patients (BMI ≥35) and age <70 favored upfront radial access. Radial access in the overall group had lower fluoroscopy time (6.5 vs 8.4 min, P < 0.0001) and lower contrast use (68.8 vs 80.6 cc, P < 0.0001). In the PCI group, efficacy of upfront radial access is less evident with radial fluoroscopy time (10.1 vs 11.0 min, P < 0.0028) and contrast use being higher in radial group (113.8 vs 108.2 cc, P < 0.037). Interventional cardiologists were more efficient in diagnostic cases than non-interventional cardiologists.

Conclusion: STEMI or emergent cases and elderly patients favor upfront femoral access. As BMI increases and age decreases, radial access is progressively favored. In diagnostic cases, radial access appears to be superior to femoral access in efficacy, but the distinction is less obvious in PCI and STEMI or emergent cases.
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http://dx.doi.org/10.1111/joic.12479DOI Listing
April 2018

Discussion of: "Pretransfer CT scans are frequently performed, but rarely helpful in rural trauma systems".

Am J Surg 2017 12 5;214(6):1065-1066. Epub 2017 Oct 5.

Sanford USD General Surgery Residency, Sioux Falls, SD, USA. Electronic address:

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http://dx.doi.org/10.1016/j.amjsurg.2017.10.007DOI Listing
December 2017

Measuring language lateralisation with different language tasks: a systematic review.

PeerJ 2017 24;5:e3929. Epub 2017 Oct 24.

Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.

Language lateralisation refers to the phenomenon in which one hemisphere (typically the left) shows greater involvement in language functions than the other. Measurement of laterality is of interest both to researchers investigating the neural organisation of the language system and to clinicians needing to establish an individual's hemispheric dominance for language prior to surgery, as in patients with intractable epilepsy. Recently, there has been increasing awareness of the possibility that different language processes may develop hemispheric lateralisation independently, and to varying degrees. However, it is not always clear whether differences in laterality across language tasks with fMRI are reflective of meaningful variation in hemispheric lateralisation, or simply of trivial methodological differences between paradigms. This systematic review aims to assess different language tasks in terms of the strength, reliability and robustness of the laterality measurements they yield with fMRI, to look at variability that is both dependent and independent of aspects of study design, such as the baseline task, region of interest, and modality of the stimuli. Recommendations are made that can be used to guide task design; however, this review predominantly highlights that the current high level of methodological variability in language paradigms prevents conclusions as to how different language functions may lateralise independently. We conclude with suggestions for future research using tasks that engage distinct aspects of language functioning, whilst being closely matched on non-linguistic aspects of task design (e.g., stimuli, task timings etc); such research could produce more reliable and conclusive insights into language lateralisation. This systematic review was registered as a protocol on Open Science Framework: https://osf.io/5vmpt/.
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http://dx.doi.org/10.7717/peerj.3929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659218PMC
October 2017

Pretransfer CT scans are frequently performed, but rarely helpful in rural trauma systems.

Am J Surg 2017 Dec 18;214(6):1061-1064. Epub 2017 Sep 18.

Sanford USD General Surgery Residency, Sioux Falls, SD, USA. Electronic address:

Background: Rural trauma patients often undergo workup prior to transfer to a trauma center. Repeat and redundant imaging at the trauma center is common.

Methods: Two hundred consecutive adult trauma patients transferred to a regional trauma center were retrospectively evaluated.

Results: 197 patients met criteria. 152 underwent CT scan prior to transfer and CT was the indication for transfer in 88 patients (44.7%). One intervention was performed as a result of CT imaging. 84 patients (55.3%) received repeat CT imaging. There were no statistically significant differences in rates of CT imaging at the outside facility based on injury severity, mechanism of injury, or age. The most common reason for repeat CT scans was incomplete initial imaging. The ability to obtain initial imaging was not a significant factor.

Conclusions: Repeat CT imaging in transferred trauma patients is very common. The majority of reimaging is done for incomplete initial imaging. Rural trauma systems may benefit from improved protocols for more efficient care.
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http://dx.doi.org/10.1016/j.amjsurg.2017.07.037DOI Listing
December 2017

Logical and Methodological Issues Affecting Genetic Studies of Humans Reported in Top Neuroscience Journals.

J Cogn Neurosci 2018 Jan 26;30(1):25-41. Epub 2017 Sep 26.

University of Oxford.

Genetics and neuroscience are two areas of science that pose particular methodological problems because they involve detecting weak signals (i.e., small effects) in noisy data. In recent years, increasing numbers of studies have attempted to bridge these disciplines by looking for genetic factors associated with individual differences in behavior, cognition, and brain structure or function. However, different methodological approaches to guarding against false positives have evolved in the two disciplines. To explore methodological issues affecting neurogenetic studies, we conducted an in-depth analysis of 30 consecutive articles in 12 top neuroscience journals that reported on genetic associations in nonclinical human samples. It was often difficult to estimate effect sizes in neuroimaging paradigms. Where effect sizes could be calculated, the studies reporting the largest effect sizes tended to have two features: (i) they had the smallest samples and were generally underpowered to detect genetic effects, and (ii) they did not fully correct for multiple comparisons. Furthermore, only a minority of studies used statistical methods for multiple comparisons that took into account correlations between phenotypes or genotypes, and only nine studies included a replication sample or explicitly set out to replicate a prior finding. Finally, presentation of methodological information was not standardized and was often distributed across Methods sections and Supplementary Material, making it challenging to assemble basic information from many studies. Space limits imposed by journals could mean that highly complex statistical methods were described in only a superficial fashion. In summary, methods that have become standard in the genetics literature-stringent statistical standards, use of large samples, and replication of findings-are not always adopted when behavioral, cognitive, or neuroimaging phenotypes are used, leading to an increased risk of false-positive findings. Studies need to correct not just for the number of phenotypes collected but also for the number of genotypes examined, genetic models tested, and subsamples investigated. The field would benefit from more widespread use of methods that take into account correlations between the factors corrected for, such as spectral decomposition, or permutation approaches. Replication should become standard practice; this, together with the need for larger sample sizes, will entail greater emphasis on collaboration between research groups. We conclude with some specific suggestions for standardized reporting in this area.
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http://dx.doi.org/10.1162/jocn_a_01192DOI Listing
January 2018

Evaluation and comparison of staining patterns of factor XIIIa (AC-1A1), adipophilin and GATA3 in sebaceous neoplasia.

J Cutan Pathol 2018 Jan 19;45(1):1-7. Epub 2017 Sep 19.

Department of Pathology, University of South Dakota, Sanford School of Medicine, Sioux Falls, South Dakota.

Background: Reliable nuclear immunohistochemical stains for sebaceous neoplasms have not been readily available. Positive nuclear staining has been reported for GATA3 and factor XIIIa (AC-1A1). We sought to determine the diagnostic utility of these nuclear stains by comparing their staining pattern to adipophilin, a consistently positive cytoplasmic stain.

Methods: Cases with the diagnosis of sebaceous hyperplasia, sebaceous adenoma, sebaceous epithelioma/sebaceoma, sebaceous carcinoma, and nonsebaceous neoplasms (basal cell carcinoma and squamous cell carcinoma) were examined. Intensity and extent of staining of the basal cells and mature sebocytes were evaluated for each stain.

Results: Factor XIIIa (AC-1A1) was 87.3% sensitive and 95.1% specific for all sebaceous neoplasms sand showed high inter-observer reliability. Adipophilin was 83.2% sensitive and 87.8% specific. GATA3 was the least sensitive (80.9%) and specific (75.6%) marker. When factor XIIIa was compared against composite staining of all three markers its staining was still uniquely significant (P = .0210).

Conclusion: Factor XIIIa (AC-1A1) is a sensitive and specific nuclear marker for sebaceous differentiation. Its diagnostic utility exceeds that of adipophilin. Factor XIIIa should be included in the expanding group of immunohistochemical and special stains which can be utilized to aid in the diagnosis of sebaceous neoplasms.
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http://dx.doi.org/10.1111/cup.13037DOI Listing
January 2018

Phase 2 of CATALISE: a multinational and multidisciplinary Delphi consensus study of problems with language development: Terminology.

J Child Psychol Psychiatry 2017 Oct 30;58(10):1068-1080. Epub 2017 Mar 30.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Background: Lack of agreement about criteria and terminology for children's language problems affects access to services as well as hindering research and practice. We report the second phase of a study using an online Delphi method to address these issues. In the first phase, we focused on criteria for language disorder. Here we consider terminology.

Methods: The Delphi method is an iterative process in which an initial set of statements is rated by a panel of experts, who then have the opportunity to view anonymised ratings from other panel members. On this basis they can either revise their views or make a case for their position. The statements are then revised based on panel feedback, and again rated by and commented on by the panel. In this study, feedback from a second round was used to prepare a final set of statements in narrative form. The panel included 57 individuals representing a range of professions and nationalities.

Results: We achieved at least 78% agreement for 19 of 21 statements within two rounds of ratings. These were collapsed into 12 statements for the final consensus reported here. The term 'Language Disorder' is recommended to refer to a profile of difficulties that causes functional impairment in everyday life and is associated with poor prognosis. The term, 'Developmental Language Disorder' (DLD) was endorsed for use when the language disorder was not associated with a known biomedical aetiology. It was also agreed that (a) presence of risk factors (neurobiological or environmental) does not preclude a diagnosis of DLD, (b) DLD can co-occur with other neurodevelopmental disorders (e.g. ADHD) and (c) DLD does not require a mismatch between verbal and nonverbal ability.

Conclusions: This Delphi exercise highlights reasons for disagreements about terminology for language disorders and proposes standard definitions and nomenclature.
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http://dx.doi.org/10.1111/jcpp.12721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638113PMC
October 2017

Analysis of Reimbursement of Genetic Counseling Services at a Single Institution in a State Requiring Licensure.

J Genet Couns 2017 Aug 8;26(4):852-858. Epub 2017 Feb 8.

Sanford Health, Sioux Falls, SD, USA.

Reimbursement for genetic counseling services was examined at a single institution. Patient encounters utilizing the 96040 CPT® code from 7/31/2009 through 7/31/2013 were reviewed. Exclusion criteria included billing records of patients seen by a physician the same day, self-pay, Medicaid, and Medicare patients. Of the 8,630 encounters with a genetic counselor, 582 encounters were eligible for review. Descriptive statistics (i.e., percentage of encounters receiving some level of reimbursement, average reimbursement rate, number of third party payors providing any level of reimbursement, and number of ICD-9 codes receiving any level of reimbursement) depicted reimbursement of the 96040 CPT® code for the encounters analyzed. Statistical analysis found a significant difference in reimbursement between third party payors that do and do not credential genetic counselors (p < .0001). There was no statistically significant difference between reimbursement rates for primary diagnostic ICD-9 codes when compared to primary diagnostic ICD-9 V codes used. Results will provide a useful baseline for local and national comparisons due to the paucity of data regarding CPT® 96040.
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http://dx.doi.org/10.1007/s10897-016-0062-7DOI Listing
August 2017

Reduction in Contrast Nephropathy From Coronary Angiography and Percutaneous Coronary Intervention With Ultra-Low Contrast Delivery Using an Automated Contrast Injector System.

J Invasive Cardiol 2016 Nov 15;28(11):446-450. Epub 2016 Jul 15.

University of South Dakota Sanford School of Medicine, 1301 West 18th Street, Route 6004, Sioux Falls, SD 57105 USA.

Objective: To evaluate the incidence of contrast-induced nephropathy (CIN) following coronary angiography and percutaneous coronary intervention (PCI) utilizing a novel ultra-low contrast delivery (ULCD) technique.

Background: Current techniques for reducing contrast volumes during angiographic and PCI procedures require the use of advanced coronary imaging methods, such as intravascular ultrasound and coronary flow wires. We propose the use of an automated contrast injector system (ACIS) with a novel programming technique that significantly reduces contrast volumes and CIN development.

Methods: From 2013 to 2014, a total of 123 patients with stage III or higher chronic kidney disease (CKD) underwent coronary angiography, PCI, or a combined procedure using the ULCD technique. A retrospective analysis was conducted to evaluate contrast volumes and rate of CIN development. Patients developing CIN were compared using tests of proportions.

Results: The median contrast volume was 17.9 mL (n = 123). The study cohorts comprised diagnostic (15.2 mL; n = 72), PCI (17.1 mL; n = 30), and PCI + diagnostic groups (27.9 mL; n = 21). The incidence of CIN observed in the entire cohort through day 7 was 3.3% (4/123). Seventy-five percent of the CIN cases occurred following diagnostic angiography alone. Longitudinal follow-up at 21 days identified an additional 5 cases of CIN. Compared to literature data, the ULCD technique delivers less contrast per case.

Conclusion: The adaptation of the ULCD technique for coronary procedures significantly reduces contrast volume delivery when compared with conventional practice or previously described low-contrast techniques. The ULCD appears to be an efficacious method of limiting CIN development in a susceptible population with CKD.
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November 2016

CATALISE: A Multinational and Multidisciplinary Delphi Consensus Study. Identifying Language Impairments in Children.

PLoS One 2016 8;11(7):e0158753. Epub 2016 Jul 8.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, Oxon, United Kingdom.

Delayed or impaired language development is a common developmental concern, yet there is little agreement about the criteria used to identify and classify language impairments in children. Children's language difficulties are at the interface between education, medicine and the allied professions, who may all adopt different approaches to conceptualising them. Our goal in this study was to use an online Delphi technique to see whether it was possible to achieve consensus among professionals on appropriate criteria for identifying children who might benefit from specialist services. We recruited a panel of 59 experts representing ten disciplines (including education, psychology, speech-language therapy/pathology, paediatrics and child psychiatry) from English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom and USA). The starting point for round 1 was a set of 46 statements based on articles and commentaries in a special issue of a journal focusing on this topic. Panel members rated each statement for both relevance and validity on a seven-point scale, and added free text comments. These responses were synthesised by the first two authors, who then removed, combined or modified items with a view to improving consensus. The resulting set of statements was returned to the panel for a second evaluation (round 2). Consensus (percentage reporting 'agree' or 'strongly agree') was at least 80 percent for 24 of 27 round 2 statements, though many respondents qualified their response with written comments. These were again synthesised by the first two authors. The resulting consensus statement is reported here, with additional summary of relevant evidence, and a concluding commentary on residual disagreements and gaps in the evidence base.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938414PMC
August 2017

Decreasing the critical value of hemoglobin required for physician notification reduces the rate of blood transfusions.

Int J Gen Med 2016 3;9:133-6. Epub 2016 Jun 3.

Department of Infectious Disease, Sanford Health, Sanford USD Medical Center, Sioux Falls, SD, USA; Department of Infectious Disease, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.

Red blood cell transfusions have been cited as one of the most overused therapeutic interventions in the USA. Excessively aggressive transfusion practices may be driven by mandatory physician notification of critical hemoglobin values that do not generally require transfusion. We examined the effect of decreasing the critical value of hemoglobin from 8 to 7 g/dL at our institution. Along with this change, mandatory provider notification for readings between 7 and 8 g/dL was rescinded. Transfusion rates were compared retrospectively during paired 5-month periods for patients presenting in three key hemoglobin ranges (6.00-6.99, 7.00-7.99, and 8.00-8.99 g/dL). A change in transfusion practices was hypothesized in the 7-8 g/dL range, which was no longer labeled critical and for which mandated physician calls were rescinded. Transfusion rates showed a statistically significant 8% decrease (P≤0.0001) during the 5-month period post change in our transfusion practices. This decrease in the 7.00-7.99 g/dL range was significantly greater than the 2% decrease observed in either the 6-6.99 g/dL (P=0.0017) or 8-8.99 g/dL (P≤0.0001) range. Cost savings of up to $700,000/year were extrapolated from our results showing 491 fewer units of red blood cells transfused during the 5-month post change. These cost savings do not take into account the additional impact of complications associated with blood transfusions.
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http://dx.doi.org/10.2147/IJGM.S96248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902242PMC
June 2016

The Asfora Bullet Cage System Shows Comparable Fusion Rate Success Versus Control Cage in Posterior Lumbar Interbody Fusion in a Randomized Clinical Trial.

S D Med 2016 Apr;69(4):157-65, 167

Background: Low back pain and degeneration of the intervertebral disc are an integrated malady that affects millions of Americans. Cage devices used in association with posterior lumbar interbody fusion (PLIF) have been shown to be an effective approach in the treatment of a number of lower spine disorders attributed to degenerative disc disease (DDD).

Objective: This study was undertaken as part of a U.S. Food and Drug Administration (FDA) Investigational Device Exemption (IDE) study and compares the effectiveness of the Asfora Bullet Cage System (ABCS) to successfully fuse vertebra at one or two levels between L2 and S1 in patients with DDD to an FDA approved comparison device, the Medtronic-Sofamor Danek Inter Fix Threaded Fusion Device (MSDIFD).

Methods: A total of 257 randomized participants were implanted with either the ABCS device (n = 132) or the MSDIFD device (n = 125) through an open posterior approach using autogenous local bone graft without the use of pedicle screws. Patients were evaluated prior to surgery and at the 24 month (24-M) visit for fusion status, deep tendon reflex status, sensory function, motor function, straight leg raise status, pain, disability, and device safety. Radiological evaluation and statistical analysis were performed by independent professionals.

Results: Evaluation of device success was performed at 24-M visit. From the original group of 257 patients, 59 were lost to follow-up. Primary measures of success at the 24-M visit involved pain and function, fusion, neurological status, and device-related adverse events measures. Pain and function improved in both (MSDIFD: 75.7 percent; ABCS: 82.6 percent). Fusion success with all radiographic points at 24-M visits was 79.4 percent MSDIFD and 88.2 percent ABCS. Neurological improvement was seen in both (MSDIFD: 77.0 percent; ABCS: 87.8 percent). One device-related grade 1 adverse event was reported in the MSDIFD group. Disc height preservation was equivalent for single level fusions (MSDIFD: 16.1 percent; ABCS: 20.0 percent) and second level fusions (MSDIFD: 10.7 percent; ABCS: 14.3 percent). General health and well-being improvement was the same (MSDIFD: 37.0 percent; ABCS: 40.0 percent). Subsequent fusion, up to 10 years, was equivalent (MSDIFD: 83.8 percent; ABCS: 91.2). Results for both devices were considered to be satisfactory, with a slight non-significant superiority for the ABCS.

Conclusion: From the ABCS device FDA IDE sanctioned study and the review of the literature, we concluded that the Asfora Bullet Cage System is safe, effective and comparable to other interbody fusion devices which are used stand-alone or in conjunction with pedicle screws, rhBMP-2, or autogenous bone harvested from the iliac crest inserted through anterior, lateral or posterior approaches.
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April 2016
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