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Axial spondyloarthritis (axSpA) encompasses both radiographic and non-radiographic axSpA. It is a chronic inflammatory disease with a predilection for involving the axial skeleton. The most common presenting symptoms are chronic back pain and spinal stiffness but peripheral and extra-musculoskeletal manifestations occur also frequently. The diagnosis of axSpA relies on the recognition of a clinical pattern of the disease, based on clinical, laboratory and imaging features. The Assessment in SpondyloArthritis international Society classification criteria for axSpA are valid and well implemented for research purposes. Sustained disease activity, measured by validated tools such as the Ankylosing Spondylitis Disease Activity Score, leads to irreversible structural damage and poor functioning and therefore should be abrogated. As part of the management algorithm, non-steroidal anti-inflammatory drugs remain as the first line of pharmacological treatment besides physiotherapy. As a second line, tumour necrosis factor inhibitor and interleukin-17 inhibitor are available but recently Janus kinase inhibitors have also shown efficacy in improving symptoms of the disease.

PurposesOur purpose was to use computed tomography (CT) Hounsfield unit (HU) values to identify the undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases.MethodsA total of 334 patients with lumbar degenerative diseases were retrospectively reviewed and divided into two groups according to the degree of lumbar degenerative changes in preoperative lumbar CT images. Patients who had at least three vertebrae with severe degeneration at L1–L4 were placed in the degenerative group, and others were placed in the control group. HU value of trabecular bone in middle axial CT image of vertebral body, T-score and bone mineral density (BMD) at L1–L4 and hips were measured. CT HU thresholds for osteoporosis were obtained from control group and then applied to identify undiagnosed spinal osteoporosis.ResultsThere were 182 patients in the degenerative group and 152 patients in the control group. CT HU value had a positive correlation with T-score and BMD of lumbar spine in both groups (P < 0.001), while the correlation coefficients at L1–L4 were higher in the control group (> 0.7) than in the degenerative group (< 0.7). T-score and BMD of lumbar spine were higher in the degenerative group (P < 0.05), while CT HU value, T-score and BMD of hips had no significant difference between two groups. According to the linear regression equations of vertebral T-score and CT HU value in the control group, the thresholds matching T-score of − 2.5 were 110, 100, 85 and 80HU for L1, L2, L3 and L4, respectively. Defining CT osteoporosis as L1 ≤ 110HU or L2 ≤ 100HU or L3 ≤ 85HU or L4 ≤ 80HU was 88.5% (69/78) specific and 60.8% (45/74) sensitive for distinguishing DXA osteoporosis of lumbar spine in the control group. The rate of undiagnosed spinal osteoporosis was higher in the degenerative group than in the control group according to CT HU thresholds (38.7% vs. 11.5%, P < 0.05).ConclusionsDegenerative changes in the lumbar spine can increase BMD and T-score provided by lumbar DXA, leading to an underestimation of vertebral osteoporosis. Thresholds for osteoporosis based on CT HU values can be used as a complementary method to identify undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.

Dilophosaurus wetherilli was the largest animal known to have lived on land in North America during the Early Jurassic. Despite its charismatic presence in pop culture and dinosaurian phylogenetic analyses, major aspects of the skeletal anatomy, taxonomy, ontogeny, and evolutionary relationships of this dinosaur remain unknown. Skeletons of this species were collected from the middle and lower part of the Kayenta Formation in the Navajo Nation in northern Arizona. Redescription of the holotype, referred, and previously undescribed specimens of Dilophosaurus wetherilli supports the existence of a single species of crested, large-bodied theropod in the Kayenta Formation. The parasagittal nasolacrimal crests are uniquely constructed by a small ridge on the nasal process of the premaxilla, dorsoventrally expanded nasal, and tall lacrimal that includes a posterior process behind the eye. The cervical vertebrae exhibit serial variation within the posterior centrodiapophyseal lamina, which bifurcates and reunites down the neck. Iterative specimen-based phylogenetic analyses result in each of the additional specimens recovered as the sister taxon to the holotype. When all five specimens are included in an analysis, they form a monophyletic clade that supports the monotypy of the genus. Dilophosaurus wetherilli is not recovered as a ceratosaur or coelophysoid, but is instead a non-averostran neotheropod in a grade with other stem-averostrans such as Cryolophosaurus ellioti and Zupaysaurus rougieri. We did not recover a monophyletic ‘Dilophosauridae.’ Instead of being apomorphic for a small clade of early theropods, it is more likely that elaboration of the nasals and lacrimals of stem-averostrans is plesiomorphically present in early ceratosaurs and tetanurans that share those features. Many characters of the axial skeleton of Dilophosaurus wetherilli are derived compared to Late Triassic theropods and may be associated with macropredation and an increase in body size in Theropoda across the Triassic-Jurassic boundary.

Axial spondyloarthritis manifests as a chronic inflammatory disease primarily affecting the sacroiliac joints and spine. Although chronic back pain and spinal stiffness are typical initial symptoms, peripheral (ie, enthesitis, arthritis, and dactylitis) and extra-musculoskeletal (ie, uveitis, inflammatory bowel disease, and psoriasis) manifestations are also common. Timely and accurate diagnosis is challenging and relies on identifying a clinical pattern with a combination of clinical, laboratory (HLA-B27 positivity), and imaging findings (eg, structural damage on pelvic radiographs and bone marrow oedema on MRI of the sacroiliac joints). The Assessment in SpondyloArthritis international Society classification criteria for axial spondyloarthritis are widely used for research and have contributed to a better understanding of the gestalt of axial spondyloarthritis. Persistent disease activity, assessed mainly by the Axial Spondyloarthritis Disease Activity Score, leads to irreversible structural damage and functional impairment. Management involves non-pharmacological (eg, education, smoking cessation, exercise, physiotherapy) and pharmacological therapy. Non-steroidal anti-inflammatory drugs remain first line pharmacotherapy, while tumour necrosis factor, IL-17, and Janus kinase inhibitors are considered second-line therapies. Future advances are expected to increase disease awareness, facilitate early and accurate diagnosis, optimise disease management, and enhance overall quality of life in patients with axial spondyloarthritis.

Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial. Key Points• It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS).• The exact mechanisms of AS are complex and multifactorial which will require much future research• Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies

The body plan of the mammalian embryo is shaped through the process of gastrulation, an early developmental event that transforms an isotropic group of cells into an ensemble of tissues that is ordered with reference to three orthogonal axes 1 . Although model organisms have provided much insight into this process, we know very little about gastrulation in humans, owing to the difficulty of obtaining embryos at such early stages of development and the ethical and technical restrictions that limit the feasibility of observing gastrulation ex vivo 2 . Here we show that human embryonic stem cells can be used to generate gastruloids—three-dimensional multicellular aggregates that differentiate to form derivatives of the three germ layers organized spatiotemporally, without additional extra-embryonic tissues. Human gastruloids undergo elongation along an anteroposterior axis, and we use spatial transcriptomics to show that they exhibit patterned gene expression. This includes a signature of somitogenesis that suggests that 72-h human gastruloids show some features of Carnegie-stage-9 embryos 3 . Our study represents an experimentally tractable model system to reveal and examine human-specific regulatory processes that occur during axial organization in early development. Human gastruloids—three-dimensional aggregates derived from human embryonic stem cells—show features of human embryos at around 19–21 days, and provide a model for the study of early human development.

ObjectiveTo investigate the frequency of bone marrow oedema (BME) and fatty lesions (FL) suggestive of axial spondyloarthritis (axSpA) on MRI of the spine and sacroiliac joints (SIJ) in a general population sample.MethodsAs part of a community-based cohort project (Study of Health in Pomerania), volunteers underwent spinal (sagittal T1/T2) and SIJ (semicoronal short tau inversion recovery) MRI examinations. Two calibrated readers evaluated the images to detect BME in SIJ and vertebral corners (VC) and FL in VC suggestive of axSpA using Assessment of SpondyloArthritis international Society definitions.ResultsMRIs of 793 volunteers (49.4% males, mean age 37.3±6.3 years, 8.4% human leucocyte antigen-B27+) aged <45 years were evaluated. SIJ BME was seen in 136 (17.2%), VC BME in 218 (27.5%) and FL in 645 (81.4%) volunteers. SIJ BME in ≥1, ≥3 and ≥5 SIJ quadrants was seen in 136 (17.2%), 7 (0.9%) and 1 (0.1%) volunteers, respectively. In VC, BME≥1, ≥3 and ≥5 lesions were seen in 218 (27.5%), 38 (4.8%) and 6 (0.8%) volunteers, respectively, while FL≥1, ≥3 and ≥5 were seen in 645 (81.3%), 351 (44.3%) and 185 (23.3%) volunteers, respectively. Logistic regression analysis showed that BME and FL in VC were related to increasing age: OR 1.33, 95% CI 1.02 to 1.72, and OR 1.73, 95% CI 1.32 to 2.27, per decade increase, respectively.ConclusionsIn this large population-based study, a high frequency of inflammatory and fatty MRI lesions suggestive of axSpA was found, especially in the spine. This indicates a limited value of such MRI findings for diagnosis and classification of axSpA. The increasing frequency with age suggests that mechanical factors could play a role.

Background Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. Methods The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. Results The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. Conclusions The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.

AbstractAxial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton associated with significant pain and disability. Previously, the diagnosis of ankylosing spondylitis required advanced changes on plain radiographs of the sacroiliac joints. Classification criteria released in 2009, however, identified a subset of patients, under the age of 45, with back pain for more than three months in the absence of radiographic sacroiliitis who were classified as axSpA based on a positive magnetic resonance imaging or HLAB27 positivity and specific clinical features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, compared with those identified by the older New York criteria, contained a larger percentage of women and demonstrated less structural damage. However, their clinical manifestations and response to biologics were similar to radiographic axSpA. The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules involved in the pathophysiology of axSpA. This discovery propelled the generation of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA.

ObjectivesOsteosarcoma is the most common primary bone malignancy.1 Due to its vague presenting features and rarity, osteosarcoma diagnosis is challenging. Evidence is mixed regarding whether time to diagnosis of osteosarcoma impacts patient outcome. The COVID-19 pandemic has been associated with paediatric malignancy diagnostic delay2 and prolonged diagnostic time has been associated with poor outcomes.3 The aims of this study were to identify:Does time to diagnosis impact patient outcome?Did the COVID-19 pandemic impact time to diagnosis?Are there any identifiable causes of delayed diagnosis?Can diagnosis be improved?MethodsA retrospective study of paediatric patients (<18 years) diagnosed with osteosarcoma at a tertiary centre between 2015–2022 focussing on time to diagnosis. We define time to diagnosis as time from first symptom onset to biopsy result. Patient data were collected from electronic records.ResultsThis cohort comprised 24 patients – 22 patients with primary tumours, 2 patients with secondary tumours. 21 patients had appendicular skeletal involvement, vs 3 patients with axial skeletal involvement.Average age at diagnosis was 11.3 years and average time to diagnosis was 72.4 days.Average time to diagnosis of patients in remission vs deceased patients did not significantly differ (77.4 days vs 65.9 days). Prolonged time to diagnosis was seen during and following the COVID-19 pandemic (109.6 days vs 52.9 days).Increased time to diagnosis was seen in tumours affecting the axial skeleton compared to the appendicular skeleton (133.7 days vs 59.0 days). Patients referred via 2-week wait had higher mortality rates compared to patients presenting via other pathways.4/24 patients had x-rays completed early in their diagnostic journey, but osteosarcoma was not considered at this stage.ConclusionProlonged time to diagnosis did not appear to influence mortality in this patient cohort. However, diagnostic delay is undoubtedly a major cause of emotional turmoil to the patient and their families.The COVID-19 pandemic appears to have negatively impacted osteosarcoma diagnostic pathways. Due to small sample size, results should be interpreted with caution. Review of current 2-week wait criteria, with more emphasis on atypical presentations, should occur.A normal x-ray does not exclude pathology. MRI should be considered in patients with persistent bony pain or swelling.Future work should investigate mortality rates before and after the COVID-19 pandemic, to determine if disruptions to diagnosis impacted mortality.ReferencesBeird, et al. Nature Reviews Disease Primers, 2022.Quarello, et al. Journal of Adolescent and Young Adult Oncology, 2022.Yoshida, et al. Journal of Bone Oncology, 2021.