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This study uses NHS waiting times and osteoporosis medication community prescription datasets to assess the impact of COVID-19 on DXA waits and osteoporosis medication patterns in England. Results show significant increases in DXA waiting list times and variation in prescription rates. Investment is needed to improve waiting list times., Purpose: This study investigates the impact of COVID-19 on DXA scan waiting lists, service recovery and osteoporosis medication prescriptions in the NHS following the March 2020 national lockdowns and staff redeployment., Methods: Data from March 2019 to June 2023, including NHS digital diagnostics waiting times (DM01) and osteoporosis medication prescriptions from the English Prescribing Dataset (EPD), were analysed. This encompassed total waiting list data across England's seven regions and prescribing patterns for various osteoporosis medications. Analyses included total activity figures and regression analysis to estimate expected activity without COVID-19, using R for all data analysis., Results: In England, DXA waiting lists have grown significantly, with the yearly mean waiting list length increasing from 31,851 in 2019 to 65,757 in 2023. The percentage of patients waiting over 6 weeks for DXA scans rose from 0.9% in 2019 to 40% in 2020, and those waiting over 13 weeks increased from 0.1% in 2019 to 16.7% in 2020. Prescription trends varied, with increases in denosumab, ibandronic acid and risedronate sodium and decreases in alendronic acid, raloxifene hydrochloride and teriparatide. A notable overall prescription decrease occurred in the second quarter of 2020., Conclusion: COVID-19 has significantly increased DXA scan waiting lists with ongoing recovery challenges. There is a noticeable disparity in DXA service access across England. Osteoporosis care, indicated by medication prescriptions, also declined during the pandemic. Addressing these issues requires focused investment and effort to improve DXA scan waiting times and overall access to osteoporosis care in England., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Introduction: The conventional anti-scatter grid is widely used in X-ray radiography to reduce scattered X-rays, but it increases patient dose. Scatter-correction software offers a dose-reducing alternative by correcting for scattered X-rays without a physical grid. Grids and software correction are necessary to reduce scatter radiation and improve image quality especially for the large body parts. The scatter correction can be beneficial in situations where the use of grid is challenging. The implementation of grids and advanced software correction techniques is imperative to ensure that radiographic images maintain high levels of clarity, contrast, and resolution, and ultimately facilitating more accurate diagnoses. This study compares image quality and radiation dose for abdomen exams using scatter correction software and physical grids., Methods: An anthropomorphic phantom (abdomen) underwent imaging with varying fat and lean tissue layers and body mass index (BMI) configurations. Imaging parameters included 70 kVp tube voltage, 110 cm SID, and Automatic Exposure Control (AEC) both lateral and central chambers. AP abdomen X-ray projections were acquired with and without an anti-scatter grid, and scatter correction software was applied. Image quality was assessed using contrast to noise ratio (CNR) and signal to noise ratio (SNR) metrics. The tube current mAs was considered an exposure factor that affected radiation dose and was used to compare the VG software and physical grid. Radiation dose was measured using Dose Area Products (DAP). The effective dose was estimated using Monte Carlo simulation-PCXMC software. Paired t-tests were used to investigate the image quality difference between the Gridless and VG software, Gridless and PG, and VG software and PG approaches. For the DAP and effective dose, paired t-test was used to investigate the difference between VG software and PG., Results: Images acquired with a grid had the highest mean CNR (71.3 ± 32) compared to Gridless (50 ± 33.8) and scatter correction software (59.3 ± 37.9). The mean SNR of the grid images was (82.7.3 ± 38.9), which is 18% higher than the scatter correction software images (70.4 ± 36.7) and 29% higher than in the Gridless images (62.9.3 ± 34). The mean DAP value was reduced by 81% when the scatter correction software was used compared to the grid (mean: 65.4 μGy.m 2 and 338.2 μGy.m 2 , respectively) with a significant difference (p = 0.001). Scatter correction software resulted in a lower effective dose compared to physical grid use, (mean difference± SD = -0.3 ± 0.18 mSv) with a significant difference (P = 0.02)., Conclusion: Scatter correction software reduced the radiation dose required but images employing a grid yielded higher CNR and SNR. However, the radiation dose reduction might affect the image quality to a level that impacts the diagnostic information available. Thus, further research needs to be conducted to optimise the use of the scatter correction software., Implication for Practice: Objectively, X-ray scatter correction software might be promising in conditions where a grid cannot be applied., (Copyright © 2024 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is incomplete. We reviewed all cases of mucormycosis diagnosed at a single pediatric cancer center over 5 decades to identify the clinical features of mucormycosis in pediatric oncology patients and to identify risk factors for mortality. There were 44 cases of mucormycosis diagnosed between 1970-2019. Most patients (89%) had hematological malignancies and a history of prolonged and severe neutropenia (91%). In this series, hyperglycemia and exposure to corticosteroids were common. Pulmonary (36%) and disseminated infections (32%) were most common; rhino-orbital-cerebral infections were relatively infrequent (11%). Rhizopus spp. was the most common etiological agent (40%) followed by Mucor spp. (31%), and Cunninghamella spp. (19%). Overall mortality was 44% and 51% and attributable mortality was 39% and 41% at the end of antifungal therapy and end of follow up, respectively. Attributable mortality fell to 18% in 2010-2019, from 58-60% in previous decades; adjunctive surgery was associated with decreased mortality. Mortality remains unacceptably high despite aggressive antifungal therapy and adjunctive surgery, suggesting novel therapeutic strategies are needed., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.H. reports receiving consultant fees from MiraVista and Abbott Laboratories and G.M. is the recipient of research funding from Astellas Pharma Inc. and SymBio Pharmaceuticals. No other authors have competing interests., (Copyright: © 2024 Marón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.)

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/m 2 ) 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/m 2 ) 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., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The COVID-19 pandemic created major challenges across society, healthcare provision and also for those delivering healthcare education programmes. Clinical placements were disrupted and, in many incidences cancelled. Higher education institutions were required to move completely to online delivery methods with little notice. This created significant additional workload, stress and the need to learn new skills at a time of great uncertainty. This study explored the risks of burnout in academic radiographers during the first 12 months of the pandemic., Methods: A survey was circulated using SurveyMonkey™ via personal, national and international networks, including the European Federation of Radiographer Societies (EFRS), to reach as many academic radiographers as possible. Disengagement and exhaustion were measured using the Oldenburg burnout inventory. Descriptive statistics and a one-way ANOVA were used to analyse the quantitative data using STATA V16 (Statacorp, TA)., Results: 533 academic radiographers responded to the survey from 43 different countries. Mean disengagement was in the medium range and exhaustion was high for the total dataset. In a subset of countries with 10 or more responses, there was significant variation between countries, with the UK having highest mean exhaustion score and the UK, Ireland and France sharing the highest mean disengagement score. In the total dataset, 86% agreed workload had increased during the pandemic and 35% had considered leaving academia in the last year., Conclusion: These data demonstrate the stark reality of the impact of the COVID-19 pandemic on academic radiographers' workload, wellbeing, and intention to leave their roles., Implications for Practice: COVID-19 has had a significant impact on academic radiographers and this study highlights the urgent need for remedial measures to better support academic radiographers in order to ensure a sufficient, and sustainable workforce., Competing Interests: Conflict of interest statement None., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The COVID-19 pandemic arrived in Europe in March 2020 and created major challenges across healthcare provision and for healthcare education programmes as well as having a major impact on society. Within the profession of Radiography changes in medical imaging, radiotherapy, and teaching practices have been reported along with the negative impact on radiographers and students. The aim of this study was to investigate key challenges relating to academic practice during the COIVD-19 pandemic; how radiography academics have coped and to identify recommendations for further support required to facilitate recovery of the academic faculty as the pandemic ebbs., Methods: A survey was circulated using SurveyMonkey™ via personal, national and international networks, including the European Federation of Radiographer Societies (EFRS), to reach as many academic radiographers as possible. Open questions relating to the challenges of providing radiography education during the COVID-19 pandemic and the and coping strategies used were included. Thematic analysis was conducted using NVivo (QSR International, MA)., Results: 533 academic radiographers responded to the whole survey from 43 different countries, with 340 responses relating to challenges and 327 for coping strategies. The main themes for the challenges were clinical practice, communication with colleagues, lack of face to face, managing change, students (support), and staff support. The coping strategy themes were communication with colleagues, physical exercise, self-care and wellbeing., Conclusion: These data demonstrate a multitude of challenges for academic radiographers and the pressure they worked under during the first year of the COVID-19 pandemic was clear. However, the majority employed healthy coping strategies to help them deal with the pressure, uncertainty and trauma of the situation., Implications for Practice: COVID-19 had a significant impact on academic radiographers and while many reported good strategies for coping, the level of pressure is unsustainable. This study highlights the need to support academic radiographers to ensure a sustainable workforce., Competing Interests: Conflict of interest statement None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The COVID-19 pandemic caused an unprecedented health crisis resulting in over 6 million deaths worldwide, a figure, which continues to grow. In addition to the excess mortality, there are individuals who recovered from the acute stages, but suffered long-term changes in their health post COVID-19, commonly referred to as long COVID. It is estimated there are currently 1.8 million long COVID sufferers by May 2022 in the UK alone. The aim of this narrative literature review is to explore the signs, symptoms and diagnosis of long COVID and the potential impact on imaging services., Key Findings: Long COVID is estimated to occur in 9.5% of those with two doses of vaccination and 14.6% if those with a single dose or no vaccination. Long COVID is defined by ongoing symptoms lasting for 12 or more weeks post acute infection. Symptoms are associated with reductions in the quality of daily life and may involve multisystem manifestations or present as a single symptom., Conclusion: The full impact of long COVID on imaging services is yet to be realised, but there is likely to be significant increased demand for imaging, particularly in CT for the assessment of lung disease. Educators will need to include aspects related to long COVID pathophysiology and imaging presentations in curricula, underpinned by the rapidly evolving evidence base., Implications for Practice: Symptoms relating to long COVID are likely to become a common reason for imaging, with a particular burden on Computed Tomography services. Planning, education and updating protocols in line with a rapidly emerging evidence base is going to be essential., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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/cm 2 ) 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., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The first pediatric AIDS cases were reported in 1982. A decade later, the World Health Organization estimated there were more than 500,000 pediatric AIDS cases resulting from mother-to-child transmission, 90% of which were in sub-Saharan Africa. Although the rate of new infections globally has been cut in half since the peak of the pandemic, human immunodeficiency virus (HIV) remains a public health threat, and rates of new infections continue to increase in some regions. Mother-to-child transmission of HIV has now been virtually eliminated in many parts of the world but remains an issue in resource-limited countries., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This paper will outline the status and basic principles of artificial intelligence (AI) in radiography along with some thoughts and suggestions on what the future might hold. While the authors are not always able to separate the current status from future developments in this field, given the speed of innovation in AI, every effort has been made to give a view to the present with projections to the future., Key Findings: AI is increasingly being integrated within radiography and radiographers will increasingly be working with AI based tools in the future. As new AI tools are developed it is essential that robust validation is undertaken in unseen data, supported by more prospective interdisciplinary research. A framework of stronger, more comprehensive approvals are recommended and the involvement of service users, including practitioners, patients and their carers in the design and implementation of AI tools is essential. Clearer accountability and medicolegal frameworks are required in cases of erroneous results from the use of AI-powered software and hardware. Clearer career pathways and role extension provision for healthcare practitioners, including radiographers, are required along with education in this field where AI will be central., Conclusion: With the current growth rate of AI tools it is expected that many of the applications in medical imaging will continue to develop to more accurate, less expensive and more readily available versions moving from the bench to the bedside. The hope is that, alongside efficiency and increased patient throughput, patient centred care and precision medicine will find their way in, so we will not only deliver a faster, safer, seamless clinical service but also one that will have the patients at its heart., Impact for Practice: AI is already reaching clinical practice in many forms and its presence will continue to increase over the short and long-term future. Radiographers must learn to work with AI, embracing it and maximising the positive outcomes from this new technology., Competing Interests: Conflict of interest statement Dr. Nick Woznitza wishes to declare his consultancy work for InHealth Reporting Dr. Melissa Pergola is employed by the American Society of Radiologic Technologists (ASRT) as Executive Vice President of Governance and Public Policy. Dr. Karen Knapp is supported by the National Institute for Health Research Applied Research Collaboration South West Peninsula. The views expressed in this publication are those of the author and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. Dr. Christina Malamateniou is the programme director of the AI module that is mentioned in this publication., (Copyright © 2021 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meertens, Knapp, Strain, Casanova, Ball, Fulford and Thorn.)

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., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

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., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

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.

Background: Guidelines for the use of antiretroviral agents in adults and adolescents with HIV recommend that antiretroviral therapy (ART) be started as soon as possible. While rapid initiation of ART in adults with HIV has been well-described, there is relatively little information describing this approach for youth., Methods: On April 1, 2018, St. Jude Children's Research Hospital began offering ART to youth with HIV infection at their first clinic visit. We report the results of a quality improvement initiative that compared patients who offered ART at their first visit to a historical cohort of patients who initiated ART at a subsequent visit. Demographic, HIV biomarker, and visit information were abstracted from medical records, described and compared using univariate statistical methods., Results: There were 124 ART-naive youth (median age 19 years, 91% male, 94% black) first seen during the indicated time period. A total of 54 patients were in the baseline cohort and 70 patients were in the rapid start cohort. 90% of youth in the rapid start cohort started ART on their first clinic visit. Time from first clinic visit to undetectable viral load was significantly higher in the baseline cohort compared with the rapid start cohort (median 54 vs. 41 days; P = 0.01). Retention in care 12 months following the first clinic visit was comparable and overall high (>80%)., Conclusions: Starting ART-naïve youth with HIV infection on ART at their first clinic visit is feasible, has high acceptance, leads to faster viral load suppression, and is associated with high retention in care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors have declared that no competing interests exist.

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&#95;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.

Introduction: Diagnostic student radiographer attrition is reported at 14%, 6% higher than the average for higher education, however, little research has been undertaken on this subject. This study explored risk factors for attrition and strategies that enabled these to be overcome., Methods: A two-phase study was undertaken. Phase one: data for 579 former student diagnostic radiographers (468 completers and 111 non-completers) from 3 English universities were analysed. Logistic regression was used to estimate odds ratios and 95% confidence intervals for completion based on individual characteristics. Phase two: content analysis of data from an online survey of 186 current UK student diagnostic radiographers exploring their experiences was undertaken., Results: Phase one: Attrition was 19%. Increased age, non A-level entry qualifications and poor academic performance were predictors of attrition (p < 0.005). Phase two: Challenges reported by groups identified as 'at risk' showed that for mature students and those with non-traditional entry qualifications, external responsibilities/pressures and financial pressures were likely to be the greatest cause of attrition and for younger students with traditional qualifications, academic difficulty and excessive workload were most significant. Scientific learning and academic writing were identified as the most common academic difficulties by all groups. Poor mental health may also be a risk factor., Conclusion: Although characteristics were identified that increased the chance of attrition, the study concluded that attrition is most likely to be multi-factorial. Academic and personal support were identified as key in students continuing their studies when they considered leaving. Clinical placement experience is likely to influence continuation decisions., Implications for Practice: Transparency around course expectations and academic requirements together with ensuring high quality clinical placements may assist in reducing attrition., Competing Interests: Conflict of interest statement None., (Copyright © 2019 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 μg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC 0-12 ) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [ P  < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [ P  < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC 0-12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [ P  = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [ P  = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [ P  = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [ P  = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations ( C min ) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC 50 ) of 0.146 μg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression., (Copyright © 2020 American Society for Microbiology.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: HIV-infected, postpartum women on antiretroviral therapy (ART) have high rates of viremia. We examined predictors of postpartum viremia in the PROMISE study., Methods: Women with pre-ART CD4 T-cell counts ≥400 cells/mm who started ART during pregnancy were randomized postpartum to continue ART (CTART) or discontinue ART (DCART). Viral load and self-reported adherence were collected every 12 weeks, up to 144 weeks. Women in DCART reinitiated therapy when clinically indicated. Viremia was defined as 2 consecutive viral loads >1000 copies/mL after 24 weeks on ART. Adherence was dichotomized as missing versus not missing ART doses in the past 4 weeks. Predictors of viremia were examined using Cox proportional hazards regression with adherence as a time-varying covariate., Results: Among 802 women in the CTART arm, median age at entry was 27 years and median CD4 T-cell count 696 cells/mm. Of 175 women in CTART with viremia (22%), 141 had resistance data, and 12% had resistance to their current regimen. There was an estimated 0.12 probability of viremia by week 48 and 0.25 by week 144. Predictors of viremia included missed ART doses within the past 4 weeks, younger age, shorter duration of pre-entry ART, and being from the South American/Caribbean region. Of 137 women in DCART who reinitiated therapy, probability of viremia was similar to CTART (0.24 by week 96; 0.27 by week 144)., Conclusions: Rates of postpartum viremia are high and viremia is more likely in younger postpartum women who start ART later in pregnancy. Interventions should target these higher-risk women.

Introduction: We evaluated the reporting competency of radiographers providing preliminary clinical evaluations (PCE) for intraluminal pathology of computed tomography colonography (CTC)., Method: Following validation of a suitable tool, audit was undertaken to compare radiographer PCE against radiology reports. A database was designed to capture radiographer and radiologist report data. The radiographer's PCE of intraluminal pathology was given a score, the "pathology discrepancy and significance" (PDS) score based on the pathology present, any discrepancy between the PCE and the final report, and the significance of that discrepancy on the management of the patient. Agreement was assessed using percentage agreement and Kappa coefficient. Significant discrepancies between findings were compared against endoscopy and pathology reports., Results: There was agreement or insignificant discrepancy between the radiographer PCE and the radiology report for 1736 patients, representing 97.0% of cases. There was a significant discrepancy between findings in 2.8% of cases and a major discrepancy recorded for 0.2% of cases. There was a 98.4% agreement in the 229 cases where significant pathologies were present., Conclusion: From a database of 1815 studies acquired over three years and representing work done in a clinical environment, this study indicates a potential for trained radiographers to provide a PCE of intraluminal pathology., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Novel therapeutic regulators of uterine contractility are needed to manage preterm labor, induce labor and control postpartum hemorrhage. Therefore, we previously developed a high-throughput assay for large-scale screening of small molecular compounds to regulate calcium-mobilization in primary mouse uterine myometrial cells. The goal of this study was to select the optimal myometrial cells for our high-throughput drug discovery assay, as well as determine the similarity or differences of myometrial cells to vascular smooth muscle cells (VSMCs)-the most common off-target of current myometrial therapeutics. Molecular and pharmacological assays were used to compare myometrial cells from four sources: primary cells isolated from term pregnant human and murine myometrium, immortalized pregnant human myometrial (PHM-1) cells and immortalized non-pregnant human myometrial (hTERT-HM) cells. In addition, myometrial cells were compared to vascular SMCs. We found that the transcriptome profiles of hTERT-HM and PHM1 cells were most similar (r = 0.93 and 0.90, respectively) to human primary myometrial cells. Comparative transcriptome profiling of primary human myometrial transcriptome and VSMCs revealed 498 upregulated (p ≤ 0.01, log2FC≥1) genes, of which 142 can serve as uterine-selective druggable targets. In the high-throughput Ca 2+ -assay, PHM1 cells had the most similar response to primary human myometrial cells in OT-induced Ca 2+ -release (E max  = 195% and 143%, EC 50  = 30 nM and 120 nM, respectively), while all sources of myometrial cells showed excellent and similar robustness and reproducibility (Z' = 0.52 to 0.77). After testing a panel of 61 compounds, we found that the stimulatory and inhibitory responses of hTERT-HM cells were highly-correlated (r = 0.94 and 0.95, respectively) to human primary cells. Moreover, ten compounds were identified that displayed uterine-selectivity (≥5-fold E max or EC 50 compared to VSMCs). Collectively, this study found that hTERT-HM cells exhibited the most similarity to primary human myometrial cells and, therefore, is an optimal substitute for large-scale screening to identify novel therapeutic regulators of myometrial contractility. Moreover, VSMCs can serve as an important counter-screening tool to assess uterine-selectivity of targets and drugs given the similarity observed in the transcriptome and response to compounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© 2019 Wiley Periodicals, Inc.)

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.

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 cm 2 ) compared to the NDRL (2.5 and 4 Gy cm 2 ). 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.

Introduction: The Francis Report recommended an increased focus on compassion in healthcare, and recognition and non-judgmental acceptance of diversity is fundamental in compassionate patient care. The aim of this study was to achieve a wider understanding of diversity that includes individual patient needs, expectations, perceptions and feelings during diagnostic imaging., Methods: Using thirty-four semi-structured interviews with individual patients, this qualitative study explored their experiences of undergoing diagnostic radiography examinations and asked what compassionate care meant to them and how it is perceived and manifested in the brief, task-focussed and highly technical diagnostic projection imaging encounter. Data were analysed using Thematic Analysis., Results: Four key themes were identified from the analysis; these were: feelings and vulnerability; hidden emotions; professionalism and valued qualities and communication., Conclusion: Diversity is defined not only in terms of socio-cultural differences but also psychological ones, i.e. individual emotional and attitudinal characteristics, some of which may be consciously or unconsciously concealed. In order that patients are treated equitably and all of their care needs met, recommendations include a broader focus in education and training to include adapting communication skills and techniques in perception and expression of non-verbal cues. Further research into the pressures specific to the time-pressured, task-focussed, highly technical and rapid turnover environment of projection imaging radiography and how this impacts upon compassionate patient care would make a useful contribution to the field., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

A range of technologies using near infrared (NIR) light have shown promise at providing real time measurements of hemodynamic markers in bone tissue in vivo, an exciting prospect given existing difficulties in measuring hemodynamics in bone tissue. This systematic review aimed to evaluate the evidence for this potential use of NIR systems, establishing their potential as a research tool in this field. Major electronic databases including MEDLINE and EMBASE were searched using pre-planned search strategies with broad scope for any in vivo use of NIR technologies in human bone tissue. Following identification of studies by title and abstract screening, full text inclusion was determined by double blind assessment using predefined criteria. Full text studies for inclusion were data extracted using a predesigned proforma and quality assessed. Narrative synthesis was appropriate given the wide heterogeneity of included studies. Eighty-eight full text studies fulfilled the inclusion criteria, 57 addressing laser Doppler flowmetry (56 intra-operatively), 21 near infrared spectroscopy, and 10 photoplethysmography. The heterogeneity of the methodologies included differing hemodynamic markers, measurement protocols, anatomical locations, and research applications, making meaningful direct comparisons impossible. Further, studies were often limited by small sample sizes with potential selection biases, detection biases, and wide variability in results between participants. Despite promising potential in the use of NIR light to interrogate bone circulation, the application of NIR systems in bone requires rigorous assessment of the reproducibility of potential hemodynamic markers and further validation of these markers against alternative physiologically relevant reference standards. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2595-2603, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

We sought to define the genomic landscape of diffuse large B-cell lymphoma (DLBCL) by using formalin-fixed paraffin-embedded (FFPE) biopsy specimens. We used targeted sequencing of genes altered in hematologic malignancies, including DNA coding sequence for 405 genes, noncoding sequence for 31 genes, and RNA coding sequence for 265 genes (FoundationOne-Heme). Short variants, rearrangements, and copy number alterations were determined. We studied 198 samples (114 de novo, 58 previously treated, and 26 large-cell transformation from follicular lymphoma). Median number of GAs per case was 6, with 97% of patients harboring at least one alteration. Recurrent GAs were detected in genes with established roles in DLBCL pathogenesis (e.g. MYD88, CREBBP, CD79B, EZH2), as well as notable differences compared to prior studies such as inactivating mutations in TET2 (5%). Less common GAs identified potential targets for approved or investigational therapies, including BRAF, CD274 (PD-L1), IDH2, and JAK1/2. TP53 mutations were more frequently observed in relapsed/refractory DLBCL, and predicted for lack of response to first-line chemotherapy, identifying a subset of patients that could be prioritized for novel therapies. Overall, 90% (n = 169) of the patients harbored a GA which could be explored for therapeutic intervention, with 54% (n = 107) harboring more than one putative target.

In mouse models used to study parturition or pre-clinical therapeutic testing, measurement of uterine contractions is limited to either ex vivo isometric tension or operative intrauterine pressure (IUP). The goal of this study was to: (1) develop a method for transcervical insertion of a pressure catheter to measure in vivo intrauterine contractile pressure during mouse pregnancy, (2) determine whether this method can be utilized numerous times in a single mouse pregnancy without affecting the timing of delivery or fetal outcome and (3) compare the in vivo contractile activity between mouse models of term and preterm labor (PTL). Visualization of the cervix allowed intrauterine pressure catheter (IUPC) placement into anesthetized pregnant mice (plug = day 1, delivery = day 19.5). The amplitude, frequency, duration and area under the curve (AUC) of IUP was lowest on days 16-18, increased significantly ( P  < 0.05) on the morning of day 19 and reached maximal levels during by the afternoon of day 19 and into the intrapartum period. An AUC threshold of 2.77 mmHg discriminated between inactive labor (day 19 am) and active labor (day 19 pm and intrapartum period). Mice examined on a single vs every experimental timepoint did not have significantly different IUP, timing of delivery, offspring number or fetal/neonatal weight. The IUP was significantly greater in LPS-treated and RU486-treated mouse models of PTL compared to time-matched vehicle control mice. Intrapartum IUP was not significantly different between term and preterm mice. We conclude that utilization of a transcervical IUPC allows sensitive assessment of in vivo uterine contractile activity and labor progression in mouse models without the need for operative approaches., (© 2018 Society for Reproduction and Fertility.)

Introduction: Disuse osteopenia is a known consequence of reduced weight-bearing and has been demonstrated at the hip following leg injury but has not been specifically studied in postmenopausal women., Method: Bilateral DXA (GE Lunar Prodigy) bone mineral density (BMD) measurements were taken at the neck of femur (NOF), total hip region (TH) and lumbar spine in postmenopausal female groups comprising controls (N = 43), new leg fractures (#<3wks) (N = 9), and participants who had sustained a leg fracture more than one year previously (#>1yr) (N = 24). #>1yr were assessed at a single visit and the remaining groups at intervals over twelve months. Weight-bearing, function, 3-day pedometer readings, and pain levels were also recorded., Results: The #<3wks demonstrated significant (p < 0.05) losses in ipsilateral TH BMD at 6 weeks from baseline 0.927 ± 0.137 g/cm 2 , to 0.916 ± 0.151 g/cm 2 improving to 0.946 ± 0.135 g/cm 2 (n.s) at 12 months following gradual return to normal function and weight-bearing activity. The #>1yr scored significantly below controls in almost all key physical and functional outcomes demonstrating a long-term deficit in hip bone density on the ipsilateral side., Conclusion: The clinical significance of post-fracture reduction in hip BMD is a potential increased risk of hip fracture for a variable period that may be mitigated after return to normal function and weight-bearing. Improvement at 12 months in #<3wks is not consistent with #>1yr results indicating that long-term impairment in function and bone health may persist for some leg fracture patients. Unilateral bone loss could have implications for Fracture Liaison Services when assessing the requirement for medication post fracture., (Copyright © 2017 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Objectives: Research investigating the longitudinal effects of the most popular sports on bone development in adolescent males is scarce. The aim is to investigate the effect of 12-month participation in osteogenic and non-osteogenic sports on bone development., Design: A 12-month study was conducted in adolescent males involved in football, swimming and cycling and compared with an active control group., Methods: 116 adolescent males (13.1±0.1years at baseline): 37 footballers, 37 swimmers, 28 cyclists and 14 active controls were followed for 12 months. Bone mineral content (BMC) was measured by dual-energy X-ray absorptiometry, and bone stiffness was measured by quantitative ultrasound. Bone outcomes at 12 months were adjusted for baseline bone status, age, height, lean mass and moderate to vigorous physical activity., Results: Footballers had higher improvement in adjusted BMC at the total body, total hip, shaft, Ward's triangle, legs and bone stiffness compared to cyclists (6.3-8.0%). Footballers had significantly higher adjusted BMC at total body, shaft and legs compared to swimmers (5.4-5.6%). There was no significant difference between swimmers and cyclists for any bone outcomes. Swimming and cycling participation resulted in non-significant lower bone development at most sites of the skeleton compared to controls (-4.3 to -0.6%)., Conclusions: Football participation induces significantly greater improvements in BMC and bone stiffness over 12 months compared to cycling and swimming., Clinical Trial Registration: ISRCTN17982776., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Background: Physical inactivity is a highly modifiable risk factor for the development of osteoporosis but, due to a lack of research that has precisely and objectively meaured physical activity (PA) relevant to bone, the specific contribution that PA can make to bone health is poorly understood. This study examined whether a more precise measure of PA relelvant to bone was associated with meaures of bone health in pre- and post-menopausal women in UK Biobank., Methods: Time spent at intensities specific to bone health [≥750 milli-gravitational units (mg) and ≥1000 mg] were analysed from raw tri-axial acceleration data averaged over 1-second epochs from 7-day monitoring of habitual PA using accelerometry-based activity monitors (100 Hz; AX3, Axivity, UK) of 1218 pre- and 1316 post-menopausal healthy women. In a cross-sectional analysis, associations between categories of time (<1, 1-2 and ≥2 minutes) spent above the intensity thresholds and calcaneal quantitative ultrasound measures of bone health (bone mineral density T-score, BMDT-score; speed of sound, SOS; and broadband ultrasound attenuation, BUA) were examined., Results: Compared with <1 minute, spending 1-2 or ≥2 minutes/day at intensities ≥1000 mg in pre-menopausal and ≥750 mg in post-menopausal women was positively associated with BMDT-score, SOS and BUA., Conclusion: Brief bursts of high-intensity PA relevant to bone health can be captured by applying bone-specific thresholds of intensity to raw tri-axial accelerations averaged over 1-second epochs. Accumulating 1-2 minutes/day of high-intensity PA, equivalent to running in pre-menopausal women and slow jogging in post-menopausal women, is associated with better bone health., (© The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Adolescence is a crucial period for bone development, and exercise can enhance bone acquisition during this period of life. However, it is not known how the different loading sports practiced can affect bone acquisition in adolescent male athletes. Therefore, the purpose of the present study was to determine the 1-year longitudinal bone acquisition among adolescent males involved in osteogenic (football) and non-osteogenic (swimming and cycling) sports and to compare with active controls. A total of 116 adolescent males aged 12 to 14 years at baseline were followed for 1 year: 37 swimmers, 37 footballers, 28 cyclists, and 14 active controls. Bone mineral content (BMC) was assessed using dual-energy X-ray absorptiometry (DXA); cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), and section modulus (Z) at the femoral neck was assessed using hip structural analysis (HSA); and bone texture of the lumbar spine was assessed using trabecular bone score (TBS). Serum N-terminal propeptide of procollagen type I (PINP), isomer of the Carboxi-terminal telopeptide of type 1 collagen (CTX-I), total serum calcium, and 25 hydroxyvitamin D [25(OH)D] were analyzed. Footballers had significantly higher adjusted BMC at the lumbar spine (7.0%) and femoral neck (5.0%) compared with cyclists, and significantly greater BMC at the lumbar spine (6.9%) compared with swimmers. Footballers presented significantly greater TBS (4.3%) compared with swimmers, and greater CSMI (10.2%), CSA (7.1%), Z (8.9%) and TBS (4.2%) compared with cyclists. No differences were noted between cyclists and swimmers, both groups had similar bone acquisition compared with controls. PINP was significantly higher in footballers and controls compared with cyclists and swimmers (3.3% to 6.0%), and 25(OH)D was significantly higher in footballers and cyclists compared with swimmers and controls (9.9% to 13.1%). These findings suggest that bone acquisition is higher in adolescent male footballers compared with swimmers and cyclists at the femoral neck and lumbar spine sites of the skeleton. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Introduction: Academia is one area of practice in which radiographers can specialise; they compile approximately 2% of the total radiography profession in the UK, but are highly influential and essential for the education and development of the workforce in addition to undertaking research. However, the academic environment is very different to clinical practice and a period of transition is required., Methods: Data were collated to explore the age and retirement profile of the academic radiography workforce in the UK; to understand the research time allocated to this workforce; the time required to develop a clinical radiographer into an academic and the mentorship and succession planning provisions nationally. An online UK wide survey was conducted and sent to all 24 Universities delivering radiography education within the UK., Results: Eighteen out of 24 Universities in the UK responded to the survey. Approximately 30% of radiography academics are due to retire over the next 10 years, with over 25% of radiographers who currently hold a doctorate qualification included within this figure. Those entering academia have notably lower qualifications as a group than those who are due to retire. Developing clinical radiographers into academics was thought to take 1-3 years on average, or longer if they are required to undertake research., Conclusion: There is vulnerability in the academic radiography workforce. Higher education institutions need to invest in developing the academic workforce to maintain research and educational expertise, which is underpinned by master's and doctorate level qualifications., (Copyright © 2017 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

Purpose: The determinants of areal bone mineral density (aBMD) and hip geometry estimates in adolescent athletes are poorly understood. This study aimed to identify the determinants of aBMD and hip geometry estimates in adolescent male athletes., Methods: One hundred twenty-one men (13.1 ± 0.1 yr) were measured: 41 swimmers, 37 footballers, 29 cyclists, and 14 controls. Dual energy X-ray absorptiometry measured aBMD at lumbar spine, femoral neck and total body. Hip structural analysis evaluated hip geometry estimates at the femoral neck. Multiple linear regression examined the contribution of the sports practised, stature, lean and fat mass, serum calcium and vitamin D, moderate to vigorous physical activity, vertical jump and cardiorespiratory fitness with aBMD and hip geometry estimates., Results: Region-specific lean mass was the strongest positive predictor of aBMD (β = 0.614-0.931) and football participation was the next strongest predictor (β = 0.304-0.579). Stature (β = 0.235-0.380), fat mass (β = 0.189), serum calcium (β = 0.103), serum vitamin D (β = 0.104-0.139), and vertical jump (β = 0.146-0.203) were associated with aBMD across various specific sites. All hip geometry estimates were associated with lean mass (β = 0.370 - 0.568) and stature (β = 0.338-0.430). Football participation was associated with hip cross-sectional area (β = 0.322) and moderate to vigorous physical activity (β = 0.140-0.142). Cardiorespiratory fitness (β = 0.183-0.207) was associated with section modulus and cross-sectional moment of inertia., Conclusions: Region-specific lean mass is the strongest determinant of aBMD and hip geometry estimates in adolescent male athletes. Football participation and stature were important determinants for aBMD and hip geometry estimates, whereas the contribution of the other predictors was site specific.