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.

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.

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.

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.

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).

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.

Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome.

MATERIAL: Linked-read whole genome sequencing (WGS) presents a new opportunity for cost-efficient singleton sequencing in place of traditional trio-based designs while generating informative-phased variants, effective for recessive disorders when parental DNA is unavailable. METHODS: We have applied linked-read WGS to identify novel causes of Meier-Gorlin syndrome (MGORS), a condition recognised by short stature, microtia and patella hypo/aplasia. There are eight genes associated with MGORS to date, all encoding essential components involved in establishing and initiating DNA replication. RESULTS: Our successful phasing of linked-read data led to the identification of biallelic rare variants in four individuals (24% of our cohort) in DONSON, a recently established DNA replication fork surveillance factor. The variants include five novel missense and one deep intronic variant. All were demonstrated to be deleterious to function; the missense variants all disrupted the nuclear localisation of DONSON, while the intronic variant created a novel splice site that generated an out-of-frame transcript with no residual canonical transcript produced. CONCLUSION: Variants in DONSON have previously been associated with extreme microcephaly, short stature and limb anomalies and perinatal lethal microcephaly-micromelia syndrome. Our novel genetic findings extend the complicated spectrum of phenotypes associated with DONSON variants and promote novel hypotheses for the role of DONSON in DNA replication. While our findings reiterate that MGORS is a disorder of DNA replication, the pathophysiology is obviously complex. This successful identification of a novel disease gene for MGORS highlights the utility of linked-read WGS as a successful technology to be considered in the genetic studies of recessive conditions.

Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability.

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

Impact of a novel home-based exercise intervention on health indicators in inactive premenopausal women: a 12-week randomised controlled trial.

PURPOSE: This study tested the hypothesis that a novel, audio-visual-directed, home-based exercise training intervention would be effective at improving cardiometabolic health and mental well-being in inactive premenopausal women. METHODS: Twenty-four inactive premenopausal women (39 ± 10 years) were randomly assigned to an audio-visual-directed exercise training group (DVD; n = 12) or control group (CON; n = 12). During the 12-week intervention period, the DVD group performed thrice-weekly training sessions of 15 min. Training sessions comprised varying-intensity movements involving multiplanar whole-body accelerations and decelerations (average heart rate (HR) = 76 ± 3% HRmax). CON continued their habitual lifestyle with no physical exercise. A series of health markers were assessed prior to and following the intervention. RESULTS: Following the DVD intervention, HDL cholesterol (pre: 1.83 ± 0.45, post: 1.94 ± 0.46 mmol/L) and mental well-being, assessed via the Warwick Edinburgh Mental Well-Being Scale, improved (P < 0.05). Conversely, [LDL cholesterol], [triglycerides], fasting [glucose], body composition and resting blood pressure and HR were unchanged following the DVD intervention (P > 0.05). There were no pre-post intervention changes in any of the outcome variables in the CON group (P > 0.05). CONCLUSION: The present study suggests that a novel, audio-visual-directed exercise training intervention, consisting of varied-intensity movements interspersed with spinal and lower limb mobility and balance tasks, can improve [HDL cholesterol] and mental well-being in premenopausal women. Therefore, home-based, audio-visual-directed exercise training (45 min/week) appears to be a useful tool to initiate physical activity and improve aspects of health in previously inactive premenopausal women.

Expanding the phenotypic spectrum associated with DPF2: A new case report.

Coffin-Siris syndrome (CSS) is a clinically and genetically heterogeneous developmental disorder, linked to disruption of the BAF chromatin-remodeling complex. Recently, de novo missense and truncating variants have been reported in DPF2 in patients sharing some of the common features of CSS. Here we report a further individual harboring a novel de novo missense DPF2 variant, c.1066T>G, p.Cys356Gly. Structural modeling indicated that the predicted amino acid substitution affects a core residue required for zinc ion coordination and would likely alter the PHD2 domain structure of DPF2. The clinical presentation of Pierre Robin sequence and diaphragmatic hernia did not immediately suggest CSS, with the more common CSS features of hypoplastic toenails and characteristic facial features very subtle. This individual further broadens the phenotypic features of DPF2-related CSS, as well as CSS more generally.

Investigation of changes in bone density and chemical composition associated with bone marrow oedema-type appearances in magnetic resonance images of the equine forelimb.

BACKGROUND: The aetiology of bone marrow oedema-like abnormalities (BMOA) seen on magnetic resonance imaging (MRI) is as yet not fully understood. The current study aimed to investigate the potential of projection radiography and Raman microspectroscopy to provide information regarding the underlying physiological changes associated with BMOA in equine bone samples. METHODS: MRI was used to assess 65 limbs from 43 horses. A subset of 13 limbs provided 25 samples, 8 with BMOA present and 17 as controls; these were examined with projection radiography to assess bone mineral density and Raman spectroscopy to assess bone composition. Statistical analysis was conducted using SPSS, the relationship between BMOA and age was tested using binary logistic regression, other outcome measures via unpaired t-tests. RESULTS: Overall BMOA was found to be associated with locally increased bone density (p = 0.011), suggesting increased bone formation; however, no measurable changes relating to bone remodelling were found, and there were no detectable changes in the chemical composition of bone. CONCLUSIONS: BMOA is associated with locally increased bone density, without an associated change in the chemical composition of bone, suggesting this is not linked to BMOA. The presence of increased bone density associated with BMOA does appear to suggest that an increased amount of bone formation is occurring in these regions, but as Raman microspectroscopy data do not demonstrate any significant changes in bone chemical composition associated with BMOA, it would appear that the increased bone volume is due to a greater amount of bone being formed rather than an imbalance in relation to bone remodelling. The study provides a proof of principle for the use of Raman microspectroscopy and projection radiography in in vitro studies of BMOA.

Increased radiation dose and projected radiation-related lifetime cancer risk in patients with obesity due to projection radiography.

PURPOSE: Primarily to evaluate the radiation dose delivered to patients with obesity in projection radiography and its relationship to the patient's size. A secondary purpose is to estimate the subsequent projected radiation-related lifetime cancer risk to patients with obesity compared to normal-weight patients. METHOD AND MATERIAL: Data from 1964 patients from a bariatric clinic in the UK were reviewed with the relevant permission. 630 patients were identified to have a projection radiography history and were included in the study. Patients' dose area product (DAP) data were collected for all projection radiography. Multiple exams in one day including a single DAP reading and exams with no records of DAP and exposure factors were excluded. Correlations were calculated and data analysed to yield the third quartile for each examination using STATA 14. Absorbed doses were generated from PCXMC simulation, utilising DAP data from this study and the UK national diagnostic reference level (NDRL), to calculate the effective risk for patients with obesity compared to patients with normal-weight. RESULTS: Patients with obesity received higher DAPs for all examinations included in this study compared to NDRL. Abdominal and lumbar spine radiographs DAPs were the highest (17.6 and 30.31 Gy cm2) compared to the NDRL (2.5 and 4 Gy cm2). Only moderate to low correlations were found between patient's size and DAPs in the abdomen and chest radiographs. The projected radiation-related lifetime cancer risk for patients with obesity is up to 153% higher than for adult patients with normal weight. CONCLUSION: Patients with obesity receive higher DAPs than normal-weight adults which may be in excess of that expected due to their size. Therefore, radiation-related lifetime cancer risk is increased in patients with obesity as a result of medical radiation exposures. This indicates more dose optimisation research is needed in this group of patients to reduce dose rate and variation.

A mutated dph3 gene causes sensitivity of Schizosaccharomyces pombe cells to cytotoxic agents.

Dph3 is involved in diphthamide modification of the eukaryotic translation elongation factor eEF2 and in Elongator-mediated modifications of tRNAs, where a 5-methoxycarbonyl-methyl moiety is added to wobble uridines. Lack of such modifications affects protein synthesis due to inaccurate translation of mRNAs at ribosomes. We have discovered that integration of markers at the msh3 locus of Schizosaccharomyces pombe impaired the function of the nearby located dph3 gene. Such integrations rendered cells sensitive to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. We constructed dph3 and msh3 strains with mutated ATG start codons (ATGmut), which allowed investigating drug sensitivity without potential interference by marker insertions. The dph3-ATGmut and a dph3::loxP-ura4-loxM gene disruption strain, but not msh3-ATGmut, turned out to be sensitive to hydroxyurea and methyl methanesulfonate, likewise the strains with cassettes integrated at the msh3 locus. The fungicide sordarin, which inhibits diphthamide modified eEF2 of Saccharomyces cerevisiae, barely affected survival of wild type and msh3Δ S. pombe cells, while the dph3Δ mutant was sensitive. The msh3-ATG mutation, but not dph3Δ or the dph3-ATG mutation caused a defect in mating-type switching, indicating that the ura4 marker at the dph3 locus did not interfere with Msh3 function. We conclude that Dph3 is required for cellular resistance to the fungicide sordarin and to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. This is likely mediated by efficient translation of proteins in response to DNA damage and replication stress.

Obesity increases precision errors in total body dual-energy x-ray absorptiometry measurements.

Total body (TB) dual-energy X-ray absorptiometry (DXA) is increasingly being used to measure body composition in research and clinical settings. This study investigated the effect of body mass index (BMI) and body fat on precision errors for total and regional TB DXA measurements of bone mineral density, fat tissue, and lean tissue using the GE Lunar Prodigy (GE Healthcare, Bedford, UK). One hundred forty-four women with BMI's ranging from 18.5 to 45.9 kg/m(2) were recruited. Participants had duplicate DXA scans of the TB with repositioning between examinations. Participants were divided into 3 groups based on their BMI, and the root mean square standard deviation and the percentage coefficient of variation were calculated for each group. The root mean square standard deviation (percentage coefficient of variation) for the normal (<25 kg/m²; n = 76), overweight (25-30 kg/m²; n = 36), and obese (>30 kg/m²; n = 32) BMI groups, respectively, were total BMD (g/cm(2)): 0.009 (0.77%), 0.009 (0.69%), 0.011 (0.91%); total fat (g): 545 (2.98%), 486 (1.72%), 677 (1.55%); total lean (g): 551 (1.42%), 540 (1.34%), and 781 (1.68%). These results suggest that serial measurements in obese subjects should be treated with caution because the least significant change may be larger than anticipated.

Effect of a program of short bouts of exercise on bone health in adolescents involved in different sports: the PRO-BONE study protocol.

BACKGROUND: Osteoporosis is a skeletal disease associated with high morbidity, mortality and increased economic costs. Early prevention during adolescence appears to be one of the most beneficial practices. Exercise is an effective approach for developing bone mass during puberty, but some sports may have a positive or negative impact on bone mass accrual. Plyometric jump training has been suggested as a type of exercise that can augment bone, but its effects on adolescent bone mass have not been rigorously assessed. The aims of the PRO-BONE study are to: 1) longitudinally assess bone health and its metabolism in adolescents engaged in osteogenic (football), non-osteogenic (cycling and swimming) sports and in a control group, and 2) examine the effect of a 9 month plyometric jump training programme on bone related outcomes in the sport groups. METHODS/DESIGN: This study will recruit 105 males aged 12-14 years who have participated in sport specific training for at least 3 hours per week during the last 3 years in the following sports groups: football (n = 30), cycling (n = 30) and swimming (n = 30). An age-matched control group (n = 15) that does not engage in these sports more than 3 hours per week will also be recruited. Participants will be measured on 5 occasions: 1) at baseline; 2) after 12 months of sport specific training where each sport group will be randomly allocated into two sub-groups: intervention group (sport + plyometric jump training) and sport group (sport only); 3) exactly after the 9 months of intervention; 4) 6 months following the intervention; 5) 12 months following the intervention. Body composition (dual energy X-ray absorptiometry, air displacement plethysmography and bioelectrical impedance), bone stiffness index (ultrasounds), physical activity (accelerometers), diet (24 h recall questionnaire), pubertal maturation (Tanner stage), physical fitness (cardiorespiratory and muscular), bone turnover markers and vitamin D will be measured at each visit. DISCUSSION: The PRO-BONE study is designed to investigate the impact of osteogenic and non-osteogenic sports on bone development in adolescent males during puberty, and how a plyometric jump training programme is associated with body composition parameters.

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.

The relationship between sagittal curvature and extensor muscle volume in the lumbar spine.

A previous modelling study predicted that the forces applied by the extensor muscles to stabilise the lumbar spine would be greater in spines that have a larger sagittal curvature (lordosis). Because the force-generating capacity of a muscle is related to its size, it was hypothesised that the size of the extensor muscles in a subject would be related to the size of their lumbar lordosis. Magnetic resonance imaging (MRI) data were obtained, together with age, height, body mass and back pain status, from 42 female subjects. The volume of the extensor muscles (multifidus and erector spinae) caudal to the mid-lumbar level was estimated from cross-sectional area measurements in axial T1-weighted MRIs spanning the lumbar spine. Lower lumbar curvature was determined from sagittal T1-weighted images. A stepwise linear regression model was used to determine the best predictors of muscle volume. The mean lower lumbar extensor muscle volume was 281 cm(3) (SD = 49 cm(3)). The mean lower lumbar curvature was 30 ° (SD = 7 °). Five subjects reported current back pain and were excluded from the regression analysis. Nearly half the variation in muscle volume was accounted for by the variables age (standardised coefficient, B = -3.2, P = 0.03) and lower lumbar curvature (B = 0.47, P = 0.002). The results support the hypothesis that extensor muscle volume in the lower lumbar spine is related to the magnitude of the sagittal curvature; this has implications for assessing muscle size as an indicator of muscle strength.

Visual expertise in detecting and diagnosing skeletal fractures.

OBJECTIVE: Failure to identify fractures is the most common error in accident and emergency departments. Therefore, the current research aimed to understand more about the processes underlying perceptual expertise when interpreting skeletal radiographs. MATERIALS AND METHODS: Thirty participants, consisting of ten novices, ten intermediates, and ten experts were presented with ten clinical cases of normal and abnormal skeletal radiographs of varying difficulty (obvious or subtle) while wearing eye tracking equipment. RESULTS: Experts were significantly more accurate, more confident, and faster in their diagnoses than intermediates or novices and this performance advantage was more pronounced for the subtle cases. Experts were also faster to fixate the site of the fracture and spent more relative time fixating the fracture than intermediates or novices and this was again most pronounced for subtle cases. Finally, a multiple linear regression analysis found that time to fixate the fracture was inversely related to diagnostic accuracy and explained 34 % of the variance in this variable. CONCLUSIONS: The results suggest that the performance advantage of expert radiologists is underpinned by superior pattern recognition skills, as evidenced by a quicker time to first fixate the pathology, and less time spent searching the image.

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.

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.