Evidence-based management and intervention for autism spectrum disorders

Autism Spectrum Disorder (ASD) is diagnosed along a continuum of behavioural variants in social communication and repetitive behaviours [96]. Most individuals on the autism spectrum also experience differences in sensory perception. Some individuals on the spectrum are ‘high-functioning’ and able to cope in every day environments, while others are severely affected, non-verbal, and may have co-occurring diagnoses, such as intellectual disability, epilepsy, and/or obsessional, conduct, or mental health disorders. These individuals require substantial support, caring and careful management, and evidence-based, effective interventions.

Parent ratings of child cognition and language compared with Bayley-III in preterm 3-year-olds

Background
Parent ratings on questionnaires may provide valid and cost-effective tools for screening cognitive development of children at risk of developmental delay.

Aims
In this study, we examined the convergent validity of combining parent-based reports of non-verbal cognitive abilities (PARCA3) and verbal abilities (CDI-III) in relation to the Bayley-III cognitive scale in 3-year-olds born late pre-term.

Methods
Mothers of 185 late-preterm children were asked to complete the PARCA3 and the CDI-III shortly before children reached age three; children were then assessed using the Bayley-III close to their third birthday.

Results
The two maternal questionnaires were significantly and moderately correlated with the Bayley-III cognitive scores. Together the maternal ratings accounted for 15% of the variance in the Bayley-III cognitive scores, after controlling for other covariates in regression analysis. In particular, the PARCA3 contributed significantly to explain variance in the Bayley-III cognitive scores when controlling for the CDI-III. However, the CDI-III was also independently associated with the Bayley-III cognitive scores.

Conclusions
Parent ratings of child cognition and language together may provide cost-effective screening of development in “at risk” preschoolers.

Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents

Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Measuring non-use value of environmental goods using the contingent valuation method:problems of information and cognition and the application of cognitive questionnaire design methods

Much interest now focuses on the use of the contingent valuation method (CVM) to assess non-use value of environmental goods. The paper reviews recent literature and highlights particular problems of information provision and respondent knowledge, comprehension and cognition. These must be dealt with by economists in designing CVM surveys for eliciting non-use values. Cognitive questionnaire design methods are presented which invoke concepts from psychology and tools from cognitive survey design (focus groups and verbal reports) to reduce a complex environmnetal good into a meaningful commodity that can be valued by respondents in a contingent market. This process is illustrated with examples from the authors' own research valuing alternative afforestation programmes. -Authors

Incidence and significance of the JAK2 V617F mutation in patients with chronic myeloproliferative disorders

BACKGROUND: The chronic myeloproliferative disorders (MPD) are clonal haemopoietic stem cell disorders.

AIMS: The incidence of JAK2 V617F mutation was sought in a population of patients with MPD.

METHODS: The JAK2 V617 mutation status was determined in 79 patients with known MPD and 59 patients with features suggestive of MPD.

RESULTS: The mutation was found in patients with polycythaemia vera, essential thrombocythaemia, idiopathic myelofibrosis and in patients with other chronic myeloproliferative disorders. Eight JAK2 V617F positive cases were identified amongst those patients with features suggestive of MPD.

CONCLUSIONS: The incidence of the JAK2 V617F mutation in MPD patients is similar to that reported by other groups. The assay confirmed and refined the diagnosis of several patients with features indicative of MPD. We suggest screening for this mutation in all patients with known and suspected MPD as identification is valuable in classification and is a potential target for signal transduction therapy.

Cognition, metacognition and patient safety

This article explores the factors that contribute to patient safety incidents. It highlights the importance of human factors in influencing the clinician's performance. Rather than focusing on clinical skills, the article explores the range of non-technical skills which are seen to each contribute to patient safety, including: communication, teamworking, leadership, active followership, situational awareness, decision-making, assertiveness, and workload management. It asks how cognitive processes can influence safe decision-making.