Optimising total knee replacement imaging: a novel 3D printed PET/CT anthropomorphic phantom for metal artefact simulation.

PURPOSE: Arthroplasty phantoms, including total knee replacement (TKR) phantoms, have been frequently used to test metal artefact reduction methods applied to positron emission tomography/computed tomography (PET/CT) images. These phantoms generally simulate either simple anatomical features or simple activity distribution around the metal inserts in the PET/CT scans. 3D printing has been used recently to fabricate fillable anthropomorphic phantoms that accurately simulate volume and geometry. This study aims to describe the process of image segmentation, phantom modelling, 3D printing and validation of a population-based fillable TKR phantom that simulates human TKR PET/CT metal artefacts. METHODS: 10 participants (5 male and 5 female) were scanned using 3T MRI and the images were segmented to create average male and average female 3D knee models, inversely with void cortical and porous trabecular compartments for 3D printing and contrast media. Virtual total knee replacement (TKR) surgery was implemented on these models to prepare the insertion locations for knee prosthetic implants. Subsequently, TKR models were printed using a 3D photopolymer resin printer and then injected with normal saline to test the phantoms for any leaks. Subsequently, diluted iodinated contrast media was injected into the cortical compartment and saline with 18F-FDG was injected into the trabecular compartment and the phantom was scanned with PET/CT. The images were then evaluated and compared to the human knee radiographic features reported in the literature. RESULTS: Phantoms were shown to be fluid-tight with distinct compartments. They showed comparable volume and geometry to the segmented human MRI knees. The phantoms demonstrated similar values for x-ray attenuation and Hounsfield units (HU) to the literature for both cortical and trabecular compartments. The phantoms displayed a uniform distribution for the radioactive tracer, resembling that seen in human trabecular bone PET. TKR phantom PET/CT images with metal inserts replicated the clinical metal artefacts seen clinically in the periprosthetic area. CONCLUSION: This novel, 3D-printed, and customisable phantom effectively mimics the geometric, radiographic and radiotracer distribution features of real TKRs. Importantly, it simulates TKR image metal artefacts, making it suitable for repeatable and comprehensive evaluation of various metal artefact reduction methods in future research.

A novel KNL1 intronic splicing variant likely destabilizes the KMN complex, causing primary microcephaly.

Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by head circumference of at least two standard deviations below the mean. Biallelic variants in the kinetochore gene KNL1 is a known cause of MCPH4. KNL1 is the central component of the KNL1-MIS12-NSL1 (KMN) network, which acts as the signaling hub of the kinetochore and is required for correct chromosomal segregation during mitosis. We identified biallelic KNL1 variants in two siblings from a non-consanguineous family with microcephaly and intellectual disability. The two siblings carry a frameshift variant predicted to prematurely truncate the transcript and undergo nonsense mediated decay, and an intronic single nucleotide variant (SNV) predicted to disrupt splicing. An in vitro splicing assay and qPCR from blood-derived RNA confirmed that the intronic variant skips exon 23, significantly reducing levels of the canonical transcript. Protein modeling confirmed that absence of exon 23, an inframe exon, would disrupt a key interaction within the KMN network and likely destabilize the kinetochore signaling hub, disrupting mitosis. Therefore, this splicing variant is pathogenic and, in trans with a frameshift variant, causes the MCPH phenotype associated with KLN1. This finding furthers the association of splicing variants as a common pathogenic variant class for KNL1.

Ultrasound Directed Reduction of Colles' type distal radial fractures in ED (UDiReCT): a feasibility randomised controlled trial.

BACKGROUND: There is a high rate of surgical fixation of displaced Colles' type distal radial wrist fractures despite fracture manipulation in the ED. Point-of-care ultrasound has been used to guide ED manipulations but its effect on the quality of fracture reduction or subsequent need for surgical fixation is unknown. This study aims to assess the feasibility of conducting a definitive randomised controlled trial to assess the use of ultrasound to guide these fracture manipulations. METHODS: We conducted a pragmatic randomised controlled feasibility trial in two EDs in England over a 6-month period (7 October 2019 to 6 April 2020). Adult patients with wrist fractures undergoing manipulation in the ED were randomised 1:1 to ultrasound-guided distal radial fracture manipulation or manipulation with sham ultrasound. The primary outcome for this study was trial recruitment rate. Other measures were recorded to assess potential future definitive trial outcomes and feasibility. RESULTS: Of 120 patients meeting inclusion criteria, 48 (40%) were recruited and randomised in the two centres, giving overall recruitment rates of 0.3 and 1.8 participants per week at each site, respectively, and 1 participant per week overall. The most common reason that patients were not included was research staff availability. After 6 weeks, six patients in each group (26% intervention, 24% control) had undergone surgical fixation, with 98% data completeness for this potential definitive trial primary outcome. Randomisation, blinding and data collection processes were effective but there were data limitations in the X-ray assessment of fracture positions. CONCLUSION: A definitive study of a similar design would be feasible within UK ED practice but organisational factors and research staff availability should be considered when estimating the predicted recruitment rate and required sites. 6-week surgical fixation rate was the most reliable outcome measure. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03868696).

Hemochromatosis Genetic Variants and Musculoskeletal Outcomes: 11.5-Year Follow-Up in the UK Biobank Cohort Study.

The iron overload disorder hemochromatosis is primarily caused by the homozygous HFE p.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain. We estimated hemochromatosis-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. A total of 451,143 European ancestry participants (40 to 70 years at baseline) were followed in hospital records (mean 11.5-years). Cox proportional hazards models estimated HFE p.C282Y and p.H63D associations with incident outcomes. Male p.C282Y homozygotes (n = 1294) had increased incidence of osteoarthritis (n = 52, hazard ratio [HR]: 2.12 [95% confidence interval, CI: 1.61 to 2.80]; p = 8.8 × 10-8), hip replacement (n = 88, HR: 1.84 [95% CI: 1.49 to 2.27]; p = 1.6 × 10-8), knee replacement (n = 61, HR: 1.54 [95% CI: 1.20 to 1.98]; p = 8.4 × 10-4), and ankle and shoulder replacement, compared to males with no HFE mutations. Cumulative incidence analysis, using Kaplan-Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n = 15, HR: 1.72 [95% CI: 1.03 to 2.87]; p = 0.04) and osteoporosis (n = 21, HR: 1.71 [95% CI: 1.11 to 2.64]; p = 0.02), although the latter association was limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n = 57, HR: 1.46, [95% CI: 1.12 to 1.89]; p = 0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n = 234, HR: 1.17 [95% CI: 1.02 to 1.33], p = 0.02), but this did not pass multiple testing corrections. In this large community cohort, the p.C282Y homozygote genotype was associated with substantial excess musculoskeletal morbidity in males. Wider HFE genotype testing may be justified, including in orthopedic clinics serving higher HFE variant prevalence populations. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Vegan and Omnivorous High Protein Diets Support Comparable Daily Myofibrillar Protein Synthesis Rates and Skeletal Muscle Hypertrophy in Young Adults.

BACKGROUND: It remains unclear whether non-animal-derived dietary protein sources (and therefore vegan diets) can support resistance training-induced skeletal muscle remodeling to the same extent as animal-derived protein sources. METHODS: In Phase 1, 16 healthy young adults (m = 8, f = 8; age: 23 ± 1 y; BMI: 23 ± 1 kg/m2) completed a 3-d dietary intervention (high protein, 1.8 g·kg bm-1·d-1) where protein was derived from omnivorous (OMNI1; n = 8) or exclusively non-animal (VEG1; n = 8) sources, alongside daily unilateral leg resistance exercise. Resting and exercised daily myofibrillar protein synthesis (MyoPS) rates were assessed using deuterium oxide. In Phase 2, 22 healthy young adults (m = 11, f = 11; age: 24 ± 1 y; BMI: 23 ± 0 kg/m2) completed a 10 wk, high-volume (5 d/wk), progressive resistance exercise program while consuming an omnivorous (OMNI2; n = 12) or non-animal-derived (VEG2; n = 10) high-protein diet (∼2 g·kg bm-1·d-1). Muscle fiber cross-sectional area (CSA), whole-body lean mass (via DXA), thigh muscle volume (via MRI), muscle strength, and muscle function were determined pre, after 2 and 5 wk, and postintervention. OBJECTIVES: To investigate whether a high-protein, mycoprotein-rich, non-animal-derived diet can support resistance training-induced skeletal muscle remodeling to the same extent as an isonitrogenous omnivorous diet. RESULTS: Daily MyoPS rates were ∼12% higher in the exercised than in the rested leg (2.46 ± 0.27%·d-1 compared with 2.20 ± 0.33%·d-1 and 2.62 ± 0.56%·d-1 compared with 2.36 ± 0.53%·d-1 in OMNI1 and VEG1, respectively; P < 0.001) and not different between groups (P > 0.05). Resistance training increased lean mass in both groups by a similar magnitude (OMNI2 2.6 ± 1.1 kg, VEG2 3.1 ± 2.5 kg; P > 0.05). Likewise, training comparably increased thigh muscle volume (OMNI2 8.3 ± 3.6%, VEG2 8.3 ± 4.1%; P > 0.05), and muscle fiber CSA (OMNI2 33 ± 24%, VEG2 32 ± 48%; P > 0.05). Both groups increased strength (1 repetition maximum) of multiple muscle groups, to comparable degrees. CONCLUSIONS: Omnivorous and vegan diets can support comparable rested and exercised daily MyoPS rates in healthy young adults consuming a high-protein diet. This translates to similar skeletal muscle adaptive responses during prolonged high-volume resistance training, irrespective of dietary protein provenance. This trial was registered at clinicaltrials.gov as NCT03572127.

Histones: coming of age in Mendelian genetic disorders.

Histones hold significant interest in development and genetic disorders due to their critical roles in chromatin dynamics, influencing gene expression and genome integrity. These roles are linked to alterations of post-translational marks, which are generally concentrated in the histone tails. The machinery modifying or interpreting these marks, known as chromatin writers, erasers or readers, have been associated with many Mendelian disorders; however, it has been only recently that the histone proteins themselves have been directly implicated in Mendelian conditions. High throughput sequencing has recently identified mutations in genes encoding histone H1, H3 and H4, all causing neurodevelopmental disorders with clinical variability. Notably, many of the mutations lie outside of recognised post-translational modification-associated residues, suggesting disrupting the core functions of histones is a primary molecular mechanism underpinning these neurodevelopmental phenotypes. In this review, we describe the clinical and genetic features of histone-related disorders, focusing on the unique aspects associated with each histone gene family, while noting the commonalities which provide insight into the required roles for histone fidelity in brain development and functioning.

The principles and effectiveness of X-ray scatter correction software for diagnostic X-ray imaging: A scoping review.

PURPOSE: An anti-scatter grid is often used in X-ray radiography to reduce the scattered X-rays generated from the patient. However, the presence of a grid means the patient dose subsequently increases. Recently,severalmanufacturers have developedsoftwarethat is capable of correctingfor scattered X-rays withouttheuse ofa conventional grid. This scoping review aims to systematically map the research assessing scattering correction software and to identify any existing knowledge gaps. METHODS: This scoping review involved conducting a systematic search in PubMed, Scopus, and Web of science to reveal studies that were relevant to the research question. Articles published between 01.01.2000 and 31.12.2021 examining X-ray scatter correction software for X-ray imaging were included. A part of the PRISMA model and PICO framework were utilised to establish eligibility criteria. A structured summary table was utilised to extract data from the selected articles. RESULTS: In this scoping review, 20 years of literature in X-ray conventional radiography. 11 articles were included in the data synthesis. The study populations of the included studies were varied: patients, image quality phantoms and anatomical phantoms. The clinical applications of X-ray scatter correction software were found to be limited to specific body parts (cervical spine, chest, shoulder, lumbar spine, hip and pelvis). The scatter correction software appears to be effective in terms of image quality and in reducing the radiation dose. However, the conventional grid still provides a higher image quality. CONCLUSIONS: X-ray scatter correction software can be effective and provides potentialbenefits for some circumstances or clinical scenarios.

The biomechanics of metaphyseal cone augmentation in revision knee replacement.

The demand for revision knee replacement (RKR) has increased dramatically with rising patient life expectancy and younger recipients for primary TKR. However, significant challenges to RKR arise from osseous defects, reduced bone quality, potential bone volume loss from implant removal and the need to achieve implant stability. This study utilizes the outcomes of an ongoing RKR clinical trial using porous metaphyseal cones 3D-printed of titanium, to investigate 1) bone mineral density (BMD) changes in three fixation zones (epiphysis, metaphysis, and diaphysis) over a year and 2) the biomechanical effects of the cones at 6 months post-surgery. It combines dual-energy x-ray absorptiometry (DXA), computed tomography (CT) with patient-specific based finite element (FE) modelling. Bone loss (-0.086 ± 0.05 g/cm2) was found in most patients over the first year. The biomechanical assessment considered four different loading scenarios from standing, walking on a flat surface, and walking downstairs, to a simulated impact of the knee. The patient-specific FE models showed that the cones marginally improved the strain distribution in the bone and shared the induced load but played a limited role in reducing the risks of bone fracture or cement debonding. This technique of obtaining real live data from a randomized clinical trial and inserting it into an in-silico FE model is unique and innovative in RKR research. The tibia RKR biomechanics examined open up further possibilities, allowing the in-silico testing of prototypes and implant combinations without putting patients at risk as per the recommended IDEAL framework standards. This process with further improvements could allow rapid innovation, optimization of implant design, and improve surgical planning.

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Imaging patients with obesity.

Obesity is a major global health issue, which directly impacts on health and is associated with multiple comorbidities. This editorial explores the challenges and clinical decision making relating to imaging patients with obesity.

Correlation of the quantitative methods for the measurement of bone uptake and plasma clearance of 18F-NaF using positron emission tomography. Systematic review and meta-analysis.

PURPOSE: 18F-NaF PET is valuable for detecting bone metabolism through osteoblastic activity in the assessment of bone disease. Hawkins, Patlak, and standardised uptake value (SUV) are the most common quantitative measurements used to evaluate bone metabolism. This systematic review evaluates the correlation between quantitative positron emission tomography (PET) methods and to compare their precision. METHODS: A systematic search in Medline, PubMed, SCOPUS, and Web of Science was undertaken to find relevant papers published from 2000. All studies with human adults undergoing 18F-NaF PET, PET/CT, or PET/MRI were included except for subjects diagnosed with non-diffuse metabolic bone disease or malignancy. Quality Assessment Tool for Studies of Diverse Designs (QATSDD) was used to assess risk of bias. A qualitative review and meta-analysis using Hedges random-effect model was used producing summary size effects of the correlation between methods in healthy and unhealthy bone sites and assessing study heterogeneity. RESULTS: 228 healthy and unhealthy participants were included across 12 studies resulted from the systematic search. One-third of studies had a moderate quality percentage while the rest had relatively high quality. The pooled correlation coefficient in meta-analysis showed a high correlation of more than 0.88 (0.71-1.05. 95 %CI) between SUV and Hawkins and more than 0.96 (0.88-1.03. 95 %CI) between Patlak and Hawkins within all subgroups, suggesting all methods yield similar results in healthy and unhealthy bone sites. SUV has the lowest precision error followed by Patlak while Hawkins method showed the highest precision error. CONCLUSION: Patlak is the best within research and SUV is better within clinical practice.

In vivo Measurement of Intraosseous Vascular Haemodynamic Markers in Human Bone Tissue Utilising Near Infrared Spectroscopy.

Objective: Poor vascular health is associated with reduced bone strength and increased risk of fragility fracture. However, direct measurement of intraosseous vascular health is difficult due to the density and mineral content of bone. We investigated the feasibility of using a commercially available continuous wave near infrared spectroscopy (NIRS) system for the investigation of vascular haemodynamics in human bone in vivo. Approach: An arterial occlusion (AO) protocol was developed for obtaining haemodynamic measurements of the proximal tibia and lateral calf, including assessment of the protocol's intra operator reproducibility. For 36 participants, intraosseous haemodynamics derived by NIRS were compared to alternative tests of bone health based on dual x-ray absorptiometry (DXA) testing and MRI. Main Results: Near infrared spectroscopy markers of haemodynamics of the proximal tibia demonstrated acceptable reproducibility, comparable with reproducibility assessments of alternative modalities measuring intraosseous haemodynamics, and the use of NIRS for measuring muscle. Novel associations have been demonstrated between haemodynamic markers of bone measured with NIRS and body composition and bone mineral density (BMD) measurements obtained with both DXA and MRI. Significance: Near infrared spectroscopy provides inexpensive, non-invasive, safe, and real time data on changes in oxygenated and deoxygenated haemoglobin concentration in bone at the proximal tibia. This study has demonstrated the potential for NIRS to contribute to research investigating the pathophysiological role of vascular dysfunction within bone tissue, but also the limitations and need for further development of NIRS technology.

MCM complex members MCM3 and MCM7 are associated with a phenotypic spectrum from Meier-Gorlin syndrome to lipodystrophy and adrenal insufficiency.

The MCM2-7 helicase is a heterohexameric complex with essential roles as part of both the pre-replication and pre-initiation complexes in the early stages of DNA replication. Meier-Gorlin syndrome, a rare primordial dwarfism, is strongly associated with disruption to the pre-replication complex, including a single case described with variants in MCM5. Conversely, a biallelic pathogenic variant in MCM4 underlies immune deficiency with growth retardation, features also seen in individuals with pathogenic variants in other pre-initiation complex encoding genes such as GINS1, MCM10, and POLE. Through exome and chromium genome sequencing, supported by functional studies, we identify biallelic pathogenic variants in MCM7 and a strong candidate biallelic pathogenic variant in MCM3. We confirm variants in MCM7 are deleterious and through interfering with MCM complex formation, impact efficiency of S phase progression. The associated phenotypes are striking; one patient has typical Meier-Gorlin syndrome, whereas the second case has a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. We provide further insight into the developmental complexity of disrupted MCM function, highlighted by two patients with a similar variant profile in MCM7 but disparate clinical features. Our results build on other genetic findings linked to disruption of the pre-replication and pre-initiation complexes, and the replisome, and expand the complex clinical genetics landscape emerging due to disruption of DNA replication.

A synonymous variant in a non-canonical exon of CDC45 disrupts splicing in two affected sibs with Meier-Gorlin syndrome with craniosynostosis.

Disruption of the initiation of DNA replication is significantly associated with Meier-Gorlin syndrome (MGORS), an autosomal recessive condition of reduced growth, microtia and patellar a/hypoplasia. Biallelic mutations in CDC45, a member of the pre-initiation complex in DNA replication, cause a spectrum of phenotypes ranging from MGORS with craniosynostosis, through to isolated short stature and craniosynostosis. Here we report two affected sibs with MGORS and craniosynostosis, with biallelic variants in CDC45 identified by 10X Chromium whole genome sequencing. One variant is a frameshift mutation, predicted to be pathogenic, and is inherited in trans with a synonymous variant in a non-canonical exon (exon 7) of CDC45. An in vitro splicing assay showed that while the canonical CDC45 exon 6-exon 8 transcript (with skipping of exon 7; numbering as per NM001178010.2) remained as the predominant transcript, the variant allele induced the use of novel splice acceptor sites in intron 6, all of which produced transcripts harbouring premature stop codons. This perturbation of canonical splicing provides evidence that this synonymous variant is indeed a deleterious alteration in this family. This report adds to the initial patient cohort in which several synonymous variants were also described, further highlighting the contribution of this variant type in CDC45. It also reiterates the true potential pathogenicity of synonymous variants, which is a mutation type that is commonly ignored in variant prioritization strategies.

Successful pregnancies in an adult with Meier-Gorlin syndrome harboring biallelic CDT1 variants.

Meier-Gorlin syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10× Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in Intron 8. Splicing defects arising from this variant were confirmed through in vitro analysis. At 49 years, she represents the oldest patient with a molecular diagnosis described in the literature and is the first reported patient with Meier-Gorlin syndrome to have carried a successful pregnancy to term. Both of her pregnancies were complicated by postpartum hemorrhage and upon subsequent necessary hysterectomy, revealed uterine abnormalities. There is scant knowledge on reproductive ability and success in patients with Meier-Gorlin syndrome. Successful pregnancies among other clinically recognizable forms of primordial dwarfism have also not been described previously. This case is therefore of clinical interest for many forms of inherited growth retardation, and will assist in providing more information and clinical guidance for females of reproductive age.

An evaluation of MRI lumbar spine scans within a community-based diagnostic setting.

BACKGROUND: With an ongoing move towards more management of patients within the community setting, demand for magnetic resonance imaging (MRI) is increasing and commonly used in lower back conditions. There is well recorded overuse of MRI in this scenario which goes against evidence-based practice and adds to rising healthcare costs. METHODS: The study was a retrospective review of lumbar spine MRI scans performed within a community-based setting over an 18-month period. The review took a randomised purposive sample of patients (n = 450); looking at adherence to, and relevance of, guidelines in managing lower back conditions. Data extracted provided information on demographics and prevalence of clinical presentation and report observations. RESULTS: There is variation in practice and utlisation of MRI with this patient group which warrants further exploration. Results support inappropriate use, lacking adherence to guidelines and pathways, leading to unnecessary imaging. 46% of referrals were considered clinically justified with 38% of report findings considered abnormal and of clinical relevance. Chi-square and binomial logistic regression were used to assess the significance and relationship of any factors on referral justification and report outcome. No difference was found between type of referrer, with patient age and leg symptoms being significant factors. CONCLUSION: The study highlights the opportunity to integrate better referral criteria to improve referral quality, its suitability and the relevance of final reports. In the current climate this would help manage appropriate use of imaging resources during the post COVID-19 pandemic recovery phase, as well as support recommendations regarding diagnostic reform and a move towards more community-based diagnostics.

Pathogenic variants causing ABL1 malformation syndrome cluster in a myristoyl-binding pocket and increase tyrosine kinase activity.

ABL1 is a proto-oncogene encoding a nonreceptor tyrosine kinase, best known in the somatic BCR-ABL fusion gene associated with chronic myeloid leukaemia. Recently, germline missense variants in ABL1 have been found to cause an autosomal dominant developmental syndrome with congenital heart disease, skeletal malformations and characteristic facies. Here, we describe a series of six new unrelated individuals with heterozygous missense variants in ABL1 (including four novel variants) identified via whole exome sequencing. All the affected individuals in this series recapitulate the phenotype of the ABL1 developmental syndrome and additionally we affirm that hearing impairment is a common feature of the condition. Four of the variants cluster in the myristoyl-binding pocket of ABL1, a region critical for auto-inhibitory regulation of the kinase domain. Bio-informatic analysis of transcript-wide conservation and germline/somatic variation reveals that this pocket region is subject to high missense constraint and evolutionary conservation. Functional work to investigate ABL1 kinase activity in vitro by transient transfection of HEK293T cells with variant ABL1 plasmid constructs revealed increased phosphorylation of ABL1-specific substrates compared to wild-type. The increased tyrosine kinase activity was suppressed by imatinib treatment. This case series of six new patients with germline heterozygous ABL1 missense variants further delineates the phenotypic spectrum of this condition and recognises microcephaly as a common finding. Our analysis supports an ABL1 gain-of-function mechanism due to loss of auto-inhibition, and demonstrates the potential for pharmacological inhibition using imatinib.

Geometric semi-automatic analysis of radiographs of Colles' fractures.

Fractures of the wrist are common in Emergency Departments, where some patients are treated with a procedure called Manipulation under Anaesthesia. In some cases, this procedure is unsuccessful and patients need to revisit the hospital where they undergo surgery to treat the fracture. This work describes a geometric semi-automatic image analysis algorithm to analyse and compare the x-rays of healthy controls and patients with dorsally displaced wrist fractures (Colles' fractures) who were treated with Manipulation under Anaesthesia. A series of 161 posterior-anterior radiographs from healthy controls and patients with Colles' fractures were acquired and analysed. The patients' group was further subdivided according to the outcome of the procedure (successful/unsuccessful) and pre- or post-intervention creating five groups in total (healthy, pre-successful, pre-unsuccessful, post-successful, post-unsuccessful). The semi-automatic analysis consisted of manual location of three landmarks (finger, lunate and radial styloid) and automatic processing to generate 32 geometric and texture measurements, which may be related to conditions such as osteoporosis and swelling of the wrist. Statistical differences were found between patients and controls, as well as between pre- and post-intervention, but not between the procedures. The most distinct measurements were those of texture. Although the study includes a relatively low number of cases and measurements, the statistical differences are encouraging.

What Medical Imaging Professionals Talk About When They Talk About Compassion.

BACKGROUND: Compassion is a poorly understood concept in medical Imaging research, but an increase in its focus was recommended in the Francis Report (2013). Little research has been conducted in this area to date. METHODS: The project was conducted from within a constructivist paradigm with appropriate ethical approval. As part of a wider doctoral study, data were harvested from a Twitter journal club discussion between medical imaging professionals of the author's published literature review and one focus group of post-graduate radiographers. Data were transcribed and analysed thematically. RESULTS: Compassion in DI is conceptualised according to three themes constructed from the data: 1) Perceptible elements of the procedure; 2) Underlying qualities, skills and abilities of radiographers; 3) Moral and ethical foundations. When medical imaging professionals talk about compassion they talk about its importance in professional practice, the challenges faced in giving compassionate care and the strategies they employ to cope with the emotional as well as physical demands they face. Contradictory organisational values and an over-emphasis on individuals' responsibility for providing compassionate care were also highlighted. Ethical professional practice need not necessarily include in every interaction expressions of compassion, or feelings in a medical imaging professional of caring about their patient. CONCLUSION: The concept of compassion has depth, with surface appearances underpinned by moral values and behaviour-motivating drivers. These findings offer a clearer understanding of compassion that could inform radiographic practice and education.