Mouse Models of Syndromic Craniosynostosis

Craniosynostosis is a common craniofacial birth defect. This review focusses on the advances that have been achieved through studying the pathogenesis of craniosynostosis using mouse models. Classic methods of gene targeting which generate individual gene knockout models have successfully identified numerous genes required for normal development of the skull bones and sutures. However, the study of syndromic craniosynostosis has largely benefited from the production of knockin models that precisely mimic human mutations. These have allowed the detailed investigation of downstream events at the cellular and molecular level following otherwise unpredictable gain-of-function effects. This has greatly enhanced our understanding of the pathogenesis of this disease and has the potential to translate into improvement of the clinical management of this condition in the future

Assessing the quality and communicative aspects of patient decision aids for early-stage breast cancer treatment: a systematic review

Purpose: Decision aids (DAs) support patients in shared decision-making by providing balanced evidence-based treatment information and eliciting patients’ preferences. The purpose of this systematic review was to assess the quality and communicative aspects of DAs for women diagnosed with early-stage breast cancer. Methods: Twenty-one currently available patient DAs were identified through both published literature (MEDLINE, Embase, CINAHL, CENTRAL, and PsycINFO) and online sources. The DAs were reviewed for their quality by using the International Patient Decision Aid Standards (IPDAS) checklist, and subsequently assessed to what extent they paid attention to various communicative aspects, including (i) information presentation, (ii) personalization, (iii) interaction, (iv) information control, (v) accessibility, (vi) suitability, and (vii) source of information. Results: The quality of the DAs varied substantially, with many failing to comply with all components of the IPDAS criteria (mean IPDAS score = 64%, range 31–92%). Five aids (24%) did not include any probability information, 10 (48%) presented multimodal descriptions of outcome probabilities (combining words, numbers, and visual aids), and only 2 (10%) provided personalized treatment outcomes based on patients and tumor characteristics. About half (12; 57%) used interaction methods for eliciting patients’ preferences, 16 (76%) were too lengthy, and 5 (24%) were not fully accessible. Conclusions: In addition to the limited adherence to the IPDAS checklist, our findings suggest that communicative aspects receive even less attention. Future patient DA developments for breast cancer treatment should include communicative aspects that could influence the uptake of DAs in daily clinical practice

Predicting calvarial growth in normal and craniosynostotic mice using a computational approach

During postnatal calvarial growth the brain grows gradually and the overlying bones and sutures accommodate that growth until the later juvenile stages. The whole process is coordinated through a complex series of biological, chemical and perhaps mechanical signals between various elements of the craniofacial system. The aim of this study was to investigate to what extent a computational model can accurately predict the calvarial growth in wild-type (WT) and mutant type (MT) Fgfr2C342Y/+ mice displaying bicoronal suture fusion. A series of morphological studies were carried out to quantify the calvarial growth at P3, P10 and P20 in both mouse types. MicroCT images of a P3 specimen were used to develop a finite element model of skull growth to predict the calvarial shape of WT and MT mice at P10. Sensitivity tests were performed and the results compared with ex vivo P10 data. Although the models were sensitive to the choice of input parameters, they predicted the overall skull growth in the WT and MT mice. The models also captured the difference between the ex vivoWT and MT mice. This modelling approach has the potential to be translated to human skull growth and to enhance our understanding of the different reconstruction methods used to manage clinically the different forms of craniosynostosis, and in the long term possibly reduce the number of re-operations in children displaying this condition and thereby enhance their quality of life

What does it take to make integrated care work? A ‘cookbook’ for large-scale deployment of coordinated care and telehealth

The Advancing Care Coordination & Telehealth Deployment (ACT) Programme is the first to explore the organisational and structural processes needed to successfully implement care coordination and telehealth (CC&TH) services on a large scale. A number of insights and conclusions were identified by the ACT programme. These will prove useful and valuable in supporting the large-scale deployment of CC&TH. Targeted at populations of chronic patients and elderly people, these insights and conclusions are a useful benchmark for implementing and exchanging best practices across the EU. Examples are: Perceptions between managers, frontline staff and patients do not always match; Organisational structure does influence the views and experiences of patients: a dedicated contact person is considered both important and helpful; Successful patient adherence happens when staff are engaged; There is a willingness by patients to participate in healthcare programmes; Patients overestimate their level of knowledge and adherence behaviour; The responsibility for adherence must be shared between patients and health care providers; Awareness of the adherence concept is an important factor for adherence promotion; The ability to track the use of resources is a useful feature of a stratification strategy, however, current regional case finding tools are difficult to benchmark and evaluate; Data availability and homogeneity are the biggest challenges when evaluating the performance of the programmes

The effect of a smaller target range on the compliance in targeting and distribution of oxygen saturation in perterm infants

BACKGROUND: Following recent recommendations, the oxygen saturation (SpO2) target range for preterm infants in our nursery was narrowed towards the higher end from 85%-95% to 90%-95%. We determined the effect of narrowing the SpO2 target range on the compliance in target range and distribution of SpO2 in preterm infants. METHODS: Before and after changing the target range from 85%-95% to 90%-95%, infants <30 weeks of gestation receiving oxygen were compared during their admission on the neonatal intensive care unit. For each infant, distribution of SpO2 was noted by collecting SpO2 samples each minute, and the percentage of time spent with SpO2 within 90%-95% was calculated. Oxygen was manually adjusted. Hypoxaemic events (SpO2 <80%) where oxygen was titrated were analysed. RESULTS: Data were analysed for 104 infants (57 before and 47 after the range was narrowed). The narrower range was associated with an increase in the median (IQR) SpO2 (93% (91%-96%) vs 94% (92%-97%), p=0.01), but no increase in median time SpO2 within 90%-95% (49.2% (39.6%-59.7%) vs (46.9% (27.1%-57.9%), p=0.72). The distribution of SpO2 shifted to the right with a significant decrease in SpO2 <90%, but not <80%. The count of minute values for Sp02 <80% decreased, while the frequency and duration of hypoxaemic events and oxygen titration were not different. CONCLUSION: Narrowing the target range from 85%-95% to 90%-95% in preterm infants was associated with an increase in median SpO2 and a rightward shift in the distribution, but no change in time spent between 90% and 95%

Characterizing the skull base in craniofacial microsomia using principal component analysis

The aim of this study was to compare the anatomical differences in the skull base between the affected and non-affected side in patients with craniofacial microsomia (CFM), and to compare the affected and non-affected sides with measurements from a normal population. Three-dimensional computed tomography scans of 13 patients with unilateral CFM and 19 normal patients (age range 7–12 years) were marked manually with reliable homologous landmarks. Principal component analysis (PCA), as part of a point distribution model (PDM), was used to analyse the variability within the normal and preoperative CFM patient groups. Through analysis of the differences in the principal components calculated for the two groups, a model was created to describe the differences between CFM patients and normal age-matched controls. The PDMs were also used to describe the shape changes in the skull base between the cohorts and validated this model. Using thin-plate splines as a means of interpolation, videos were created to visualize the transformation from CFM skull to normal skull, and to display the variability in shape changes within the groups themselves. In CFM cases, the skull base showed significant asymmetry. Anatomical areas around the glenoid fossa and mastoid process showed the most asymmetry and restriction of growth, suggesting a pathology involving the first and second pharyngeal arches

Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations

X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip

Gain-of-Function Mutations in ZIC1 Are Associated with Coronal Craniosynostosis and Learning Disability

Human ZIC1 (zinc finger protein of cerebellum 1), one of five homologs of the Drosophila pair-rule gene odd-paired, encodes a transcription factor previously implicated in vertebrate brain development. Heterozygous deletions of ZIC1 and its nearby paralog ZIC4 on chromosome 3q25.1 are associated with Dandy-Walker malformation of the cerebellum, and loss of the orthologous Zic1 gene in the mouse causes cerebellar hypoplasia and vertebral defects. We describe individuals from five families with heterozygous mutations located in the final (third) exon of ZIC1 (encoding four nonsense and one missense change) who have a distinct phenotype in which severe craniosynostosis, specifically involving the coronal sutures, and variable learning disability are the most characteristic features. The location of the nonsense mutations predicts escape of mutant ZIC1 transcripts from nonsense-mediated decay, which was confirmed in a cell line from an affected individual. Both nonsense and missense mutations are associated with altered and/or enhanced expression of a target gene, engrailed-2, in a Xenopus embryo assay. Analysis of mouse embryos revealed a localized domain of Zic1 expression at embryonic days 11.5-12.5 in a region overlapping the supraorbital regulatory center, which patterns the coronal suture. We conclude that the human mutations uncover a previously unsuspected role for Zic1 in early cranial suture development, potentially by regulating engrailed 1, which was previously shown to be critical for positioning of the murine coronal suture. The diagnosis of a ZIC1 mutation has significant implications for prognosis and we recommend genetic testing when common causes of coronal synostosis have been excluded