Quantifying changes in shoulder orientation between the prone and supine positions from magnetic resonance imaging.

BACKGROUND: Predicting breast tissue motion using biomechanical models can provide navigational guidance during breast cancer treatment procedures. These models typically do not account for changes in posture between procedures. Difference in shoulder position can alter the shape of the pectoral muscles and breast. A greater understanding of the differences in the shoulder orientation between prone and supine could improve the accuracy of breast biomechanical models. METHODS: 19 landmarks were placed on the sternum, clavicle, scapula, and humerus of the shoulder girdle in prone and supine breast MRIs (N = 10). These landmarks were used in an optimization framework to fit subject-specific skeletal models and compare joint angles of the shoulder girdle between these positions. FINDINGS: The mean Euclidean distance between joint locations from the fitted skeletal model and the manually identified joint locations was 15.7 mm ± 2.7 mm. Significant differences were observed between prone and supine. Compared to supine position, the shoulder girdle in the prone position had the lateral end of the clavicle in more anterior translation (i.e., scapula more protracted) (P < 0.05), the scapula in more protraction (P < 0.01), the scapula in more upward rotation (associated with humerus elevation) (P < 0.05); and the humerus more elevated (P < 0.05) for both the left and right sides. INTERPRETATION: Shoulder girdle orientation was found to be different between prone and supine. These differences would affect the shape of multiple pectoral muscles, which would affect breast shape and the accuracy of biomechanical models.

Vision for the 12 LABOURS Digital Twin Platform.

Clinical translation of personalised computational physiology workflows and digital twins can revolutionise healthcare by providing a better understanding of an individual's physiological processes and any changes that could lead to serious health consequences. However, the lack of common infrastructure for developing these workflows and digital twins has hampered the realisation of this vision. The Auckland Bioengineering Institute's 12 LABOURS project aims to address these challenges by developing a Digital Twin Platform to enable researchers to develop and personalise computational physiology models to an individual's health data in clinical workflows. This will allow clinical trials to be more efficiently conducted to demonstrate the efficacy of these personalised clinical workflows. We present a demonstration of the platform's capabilities using publicly available data and an existing automated computational physiology workflow developed to assist clinicians with diagnosing and treating breast cancer. We also demonstrate how the platform facilitates the discovery and exploration of data and the presentation of workflow results as part of clinical reports through a web portal. Future developments will involve integrating the platform with health systems and remote-monitoring devices such as wearables and implantables to support home-based healthcare. Integrating outputs from multiple workflows that are applied to the same individual's health data will also enable the generation of their personalised digital twin.Clinical Relevance- The proposed 12 LABOURS Digital Twin Platform will enable researchers to 1) more efficiently conduct clinical trials to assess the efficacy of their computational physiology workflows and support the clinical translation of their research; 2) reuse primary and derived data from these workflows to generate novel workflows; and 3) generate personalised digital twins by integrating the outputs of different computational physiology workflows.

The statistical challenge of analysing changes in dual energy computed tomography (DECT) urate volumes in people with gout.

BACKGROUND: Dual energy computed tomography (DECT) allows direct visualization of monosodium urate crystal deposition in gout. However, DECT urate volume data are often highly skewed (mostly small volumes with the remainder considerably larger), making statistical analyses challenging in longitudinal research. The aim of this study was to explore the ability of various analysis methods to normalise DECT urate volume data and determine change in DECT urate volumes over time. METHODS: Simulated datasets containing baseline and year 1 DECT urate volumes for 100 people with gout were created from two randomised controlled trials. Five methods were used to transform the DECT urate volume data prior to analysis: log-transformation, Box-Cox transformation, log(X-(min(X)-1)) transformation; inverse hyperbolic sine transformation, and rank order. Linear regression analyses were undertaken to determine the change in DECT urate volume between baseline and year 1. Cohen's d were calculated as a measure of effect size for each data treatment method. These analyses were then tested in a validation clinical trial dataset containing baseline and year 1 DECT urate volumes from 91 people with gout. RESULTS: No data treatment method successfully normalised the distribution of DECT urate volumes. For both simulated and validation data sets, significant reductions in DECT urate volumes were observed between baseline and Year 1 across all data treatment methods and there were no significant differences in Cohen's d effect sizes. CONCLUSIONS: Normalising highly skewed DECT urate volume data is challenging. Adopting commonly used transformation techniques may not significantly improve the ability to determine differences in measures of central tendency when comparing the change in DECT urate volumes over time.

Changes in Tophus Composition During Urate-Lowering Therapy: A Dual-Energy Computed Tomography Study.

OBJECTIVE: The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. METHODS: Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. RESULTS: The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). CONCLUSION: The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.

Intensive Serum Urate Lowering With Oral Urate-Lowering Therapy for Erosive Gout: A Randomized Double-Blind Controlled Trial.

OBJECTIVE: To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout. METHODS: We undertook a 2-year, double-blind randomized controlled trial of 104 participants with erosive gout who were receiving serum urate-lowering therapy orally and who had serum urate levels of ≥0.30 mmoles/liter at baseline. Participants were randomly assigned to either an intensive serum urate target of <0.20 mmoles/liter or a standard target of <0.30 mmoles/liter (considered the standard according to rheumatology guidelines). Oral serum urate-lowering therapy was titrated to target using a standardized protocol (with the maximum approved doses of allopurinol, probenecid, febuxostat, and benzbromarone). The primary end point was the total computed tomography (CT) bone erosion score. Outcome Measures in Rheumatology (OMERACT) gout core outcome domains were secondary end points. RESULTS: Although the serum urate levels were significantly lower in the intensive target group compared to the standard target group over the study period (P = 0.002), fewer participants in the intensive target group achieved the randomized serum urate target level by year 2 (62% versus 83% of patients in the standard target group; P < 0.05). The intensive target group required higher doses of allopurinol (mean ± SD 746 ± 210 mg/day versus 497 ± 186 mg/day; P < 0.001) and received more combination therapy (P = 0.0004) compared to the standard target group. We observed small increases in CT bone erosion scores in both serum urate target groups over 2 years, with no between-group difference (P = 0.20). OMERACT core outcome domains (gout flares, tophi, pain, patient's global assessment of disease activity, health-related quality of life, and activity limitation) improved in both groups over 2 years, with no between-group differences. Adverse event and serious adverse event rates were similar between the groups. CONCLUSION: Compared to a serum urate target of <0.30 mmoles/liter, more intensive serum urate lowering is difficult to achieve with an oral urate-lowering therapy. Intensive serum urate lowering leads to a high medication burden and does not improve bone erosion scores in patients with erosive gout.

Denosumab did not improve computerized tomography erosion scores when added to intensive urate-lowering therapy in gout: Results from a pilot randomized controlled trial.

BACKGROUND/PURPOSE: Disordered osteoclast activity has been implicated in the pathogenesis of gouty bone erosion. We sought to determine if the addition of denosumab (a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand - RANKL) to intensive urate-lowering therapy (ULT) improves gouty bone erosion. METHODS: Open-label, parallel-group pilot randomized controlled trial in which 20 participants with gout with at least one confirmed conventional radiographic foot bone erosion were assigned in a 1:1 allocation to receive denosumab (60 mg subcutaneous every 6 months) added to intensive ULT (serum urate ≤5 mg/dL or 300 µmol/L at the time of randomization and continued for the duration of the study), or intensive ULT alone. The primary outcome was the change in the bilateral foot and ankle computed tomography (CT) bone erosion score from baseline to 12 months, assessed by an experienced musculoskeletal radiologist blinded to study assignment. Secondary outcomes included change in serum C-terminal telopeptide (CTX), and patient reported outcomes of pain and function. RESULTS: Although serum CTX declined markedly in the denosumab/ULT group compared with the ULT alone group, there was no interval change in CT erosion score in either the denosumab/ULT or ULT alone group after one year of follow-up. Other secondary outcomes did not differ between groups. There were two severe adverse events: One patient developed atrial fibrillation (on denosumab/ULT) and another atrial flutter (on ULT alone). CONCLUSIONS: In this pilot study, denosumab did not offer additional benefit to intensive urate lowering therapy for gouty bone erosion.

MRI imaging of soft tissue tumours of the foot and ankle.

The majority of soft tissue lesions in the foot and ankle are benign. The aim of this review is to provide the reader with a comprehensive overview of the magnetic resonance imaging (MRI) characteristics of the most common benign and malignant soft tissue neoplasms which occur around the foot and ankle. This should enable the reader to formulate a reasonable differential diagnosis and, most importantly, to recognise those rare aggressive lesions that require further assessment and tissue biopsy.

Aneurysmal bone cyst treated with percutaneous doxycycline: is a single treatment sufficient?

OBJECTIVE: The purpose of this case series is to report on the effectiveness of a single percutaneous injection of doxycycline as a primary treatment for aneurysmal bone cyst (ABC). MATERIALS AND METHODS: A retrospective cohort study was conducted on seven patients diagnosed with ABC at various anatomical sites, with the intention to treat by a single percutaneous injection of doxycycline. Mean patient age was 14 years. RESULTS: Signs of treatment response were seen in six of seven patients after one injection. Three of the seven received a second treatment, despite signs of response. Another had expansion of the lesion after treatment, requiring excision. In total, three patients had a single injection of doxycycline as their sole treatment and another three showed signs of response after a single injection. CONCLUSIONS: A single percutaneous injection of doxycycline should be considered a viable primary treatment option for ABC.

Predictors of activity limitation in people with gout: a prospective study.

The objective of the study was to determine clinical factors associated with activity limitation and predictors of a change in activity limitation after 1 year in people with gout. Two hundred ninety-five participants with gout (disease duration < 10 years) attended a baseline assessment which included medical and disease-specific history, pain visual analog score and plain radiographs scored for erosion and narrowing. Activity limitation was assessed using the Health Assessment Questionnaire-II (HAQ-II). After 1 year, participants were invited to complete a further HAQ-II; follow-up questionnaires were available for 182 participants. Fully saturated and stepwise regression analyses were used to determine associations between baseline characteristics and HAQ-II at baseline and 1 year, and to determine predictors of worsening HAQ-II in those with normal baseline scores. Median (range) baseline HAQ-II was 0.20 (0-2.50) and 0.20 (0-2.80) after 1 year of follow-up. Pain score was the strongest independent predictor of baseline HAQ-II, followed by radiographic narrowing score, type 2 diabetes, swollen joint count, BMI, age and urate (model R2 = 0.51, P < 0.001). Baseline HAQ-II was the strongest predictor of change in HAQ-II at 1 year, followed by tender joint count (model R2 = 0.19, P < 0.001). Of those with HAQ-II scores of 0 at baseline (n = 59, 32% of those with follow-up data), most did not progress (n = 52, 88%); however, baseline pain score, type 2 diabetes and flare frequency were significant predictors of worsening HAQ-II in this group (R2 = 0.34, P < 0.001). People with gout experience a wide range of activity limitation, and levels of activity limitation are, on average, stable over a 1-year period. Baseline pain scores are strongly associated with activity limitation and predict development of activity limitation in those with normal HAQ-II scores at baseline.

The patient experience of musculoskeletal imaging tests for investigation of inflammatory arthritis: a mixed-methods study.

The objective of this study was to understand the patient experience of musculoskeletal imaging tests for investigation of inflammatory arthritis and factors that contribute to this experience. We conducted a thematic analysis of semi-structured interviews with 33 patients who had a recent peripheral joint musculoskeletal imaging test for investigation of inflammatory arthritis. Data from these interviews were used to generate an 18-item questionnaire which was posted to rheumatology clinic patients within 6 weeks of peripheral joint imaging. Variables associated with the overall experience of the test were analysed using stepwise linear regression. Analysis of the interviews identified six themes: knowledge about the test, awareness of potential harm, the role of imaging in clinical care, discomfort, experience of waiting and 'seeing is believing'. Completed questionnaires were available from 132 patients. In regression analysis, a strong negative association was observed between the 'discomfort during the test' item and the overall experience of the test (standardised beta -0.35, p < 0.001). 'Staff made the experience better' (0.26, p < 0.001) and 'information provided' (0.28, p < 0.001) were positively associated with the overall experience of the test. For those who viewed their images, 'looking at the images with my doctor made me feel more involved in my care' (0.24, p = 0.022) was also associated positively with overall experience. Factors before, during and after a musculoskeletal imaging test contribute to the patient experience. The overall experience is most influenced by patient discomfort and interactions with staff during the test, information provided and viewing images to improve patient involvement in clinical care.

Imaging tools to measure treatment response in gout.

Imaging tests are in clinical use for diagnosis, assessment of disease severity and as a marker of treatment response in people with gout. Various imaging tests have differing properties for assessing the three key disease domains in gout: urate deposition (including tophus burden), joint inflammation and structural joint damage. Dual-energy CT allows measurement of urate deposition and bone damage, and ultrasonography allows assessment of all three domains. Scoring systems have been described that allow radiological quantification of disease severity and these scoring systems may play a role in assessing the response to treatment in gout. This article reviews the properties of imaging tests, describes the available scoring systems for quantification of disease severity and discusses the challenges and controversies regarding the use of imaging tools to measure treatment response in gout.

Relationship of bone erosion with the urate and soft tissue components of the tophus in gout: a dual energy computed tomography study.

OBJECTIVES: Imaging and pathology studies have established a close relationship between tophus and bone erosion in gout. The tophus is an organized structure consisting of urate crystals and chronic inflammatory tissue. The aim of this work was to examine the relationship between bone erosion and each component of the tophus. METHODS: Plain radiographs and dual energy CT scans of the feet were prospectively obtained from 92 people with tophaceous gout. The 10 MTP joints were scored for erosion score, tophus urate and soft tissue volume. Data were analysed using generalized estimating equations and mediation analysis. RESULTS: Tophus was visualized in 80.2% of all joints with radiographic (XR) erosion [odds ratio (OR) = 7.1 (95% CI: 4.8, 10.6)] and urate was visualized in 78.6% of all joints with XR erosion [OR = 6.6 (95% CI: 4.7, 9.3)]. In mediation analysis, tophus urate volume and soft tissue volume were directly associated with XR erosion score. About a third of the association of the tophus urate volume with XR erosion score was indirectly mediated through the strong association between tophus urate volume and tophus soft tissue volume. CONCLUSION: Urate and soft tissue components of the tophus are strongly and independently associated with bone erosion in gout.

Urate crystal deposition and bone erosion in gout: 'inside-out' or 'outside-in'? A dual-energy computed tomography study.

BACKGROUND: It is currently unknown whether bone erosion in gout occurs through an 'inside-out' mechanism due to direct intra-osseous crystal deposition or through an 'outside-in' mechanism from the surface of bone. The aim of this study was to examine the mechanism ('outside-in' vs. 'inside-out') of monosodium urate (MSU) crystal deposition in bone erosion in gout. Specifically, we used three-dimensional dual-energy computed tomography (DECT) to analyse the positional relationship between bone and MSU crystal deposition in tophaceous gout, and to determine whether intra-osseous crystal deposition occurs in the absence of erosion. METHODS: One hundred forty-four participants with gout and at least one palpable tophus had a DECT scan of both feet. Two readers independently scored all metatarsal heads (1433 bones available for scoring). For bones in contact with urate, the bone was scored for whether urate was present within an erosion, on the surface of bone or within bone only (true intra-osseous deposit). Data were analysed using generalised estimating equations. RESULTS: Urate in contact with bone was present in 370 (54.3 %) of 681 joints with urate deposition. For those bones in contact with urate, deposition was present on the surface of bone in 143 (38.6 %) of 370 joints and within erosion in 227 (61.4 %) of 370. True intra-osseous urate deposition was not observed at any site (p < 0.0001). For all bones with apparent intra-osseous deposition in one plane, examination in other planes revealed urate deposition within an en face erosion. CONCLUSIONS: In tophaceous gout, MSU crystal deposition is present within the joint, on the bone surface and within bone erosion, but it is not observed within bone in the absence of a cortical break. These data support the concept that MSU crystals deposit outside bone and contribute to bone erosion through an 'outside-in' mechanism.

Dual-Energy CT of Urate Deposits in Costal Cartilage and Intervertebral Disks of Patients With Tophaceous Gout and Age-Matched Controls.

OBJECTIVE: The purpose of this study was to investigate whether monosodium urate (MSU) deposits could be identified within the abdomen and axial skeleton of patients with tophaceous gout using dual-energy CT (DECT). CONCLUSION: DECT of the abdomen, chest wall, and spine revealed extensive MSU deposits in costal cartilages and, to a lesser extent, intervertebral disks in the male patients with gout in our study. These were quantified volumetrically. However, age-matched control subjects showed similar deposits, indicating this was not a disease-specific finding. Thus, MSU deposition in the axial skeleton may be physiologic in middle-aged men.

Factors associated with change in radiographic damage scores in gout: a prospective observational study.

BACKGROUND/AIMS: Radiographic damage is frequently observed in patients with longstanding gout. The aim of this prospective observational study was to determine factors associated with change in radiographic damage scores in gout. METHODS: People with gout and disease duration <10 years were recruited into this prospective observational study. At the baseline visit, structured assessment was undertaken in 290 participants including detailed clinical examination and plain radiographs (XR) of the hands and feet. Participants were invited to attend a further study visit with repeat XR 3 years after the baseline visit. XR were scored for erosion and joint space narrowing according to the gout-modified Sharp/van der Heijde XR damage score. RESULTS: Age, subcutaneous tophus count and tender joint count were independently associated with XR damage score at the baseline visit. Paired serial XR were available for 140 participants. In stepwise linear regression analysis, change in total damage score over 3 years was positively associated with change in subcutaneous tophus count and baseline XR damage score, and inversely associated with baseline subcutaneous tophus count (model R2=0.39, p<0.001). Change in subcutaneous tophus count contributed most to the change in erosion score (partial R2 change=0.31, p<0.001), and baseline XR damage score contributed most to the change in narrowing score (partial R2 change=0.31, p<0.001). CONCLUSIONS: Development of new subcutaneous tophi and baseline radiographic damage are associated with progressive joint damage scores in people with gout. These data provide further evidence that the tophus plays a central role in bone erosion in gout.

Path Analysis Identifies Receptor Activator of Nuclear Factor-κB Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout.

OBJECTIVE: To determine the relationship between tophus, erosion and bone remodeling factors in gout. METHODS: Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion. RESULTS: Tophus number, Maori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin. CONCLUSION: Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion.

Gout on CT of the feet: A symmetric arthropathy.

INTRODUCTION: The aim of this study was to assess the distribution of bone erosions in the feet of patients with gout using CT and thereby to test the hypothesis that gout is an asymmetric arthropathy. METHODS: CT scans of both feet were obtained from 25 patients with chronic gout. CT scans were scored for bone erosion using a semi-quantitative method based on the rheumatoid arthritis MRI scoring system (RAMRIS). CT bone erosion was assessed at 22 bones in each foot (total 1,100 bones) by two independent radiologists. Symmetry was assessed by two methods: (i) comparing right and left foot scores for each patient; and (ii) calculating the proportion of paired joints with or without erosions. RESULTS: Observer agreement was excellent (intra-class correlation coefficient 0.92). In the group overall, the difference in scores between the feet was not significant (Student's t-test P = 0.8). In 17 of 25 patients, the difference in erosion scores between the two feet was less than the inter-observer difference. In 24 of 25 patients, the proportion of paired joints was greater than 0.5, indicating symmetric disease. CONCLUSIONS: Erosive disease from gout is, in fact, a symmetric process in our patient group. This finding is contrary to the established view of gout as an asymmetric arthritis and lends new insight into the behaviour of this common disease.

Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study.

BACKGROUND: The aim of this study was to compare the frequency and volume of dual energy CT (DECT) urate deposits in people with asymptomatic hyperuricaemia and symptomatic gout. METHODS: We analysed DECT scans of the feet from asymptomatic individuals with serum urate ≥540 µmol/L (n=25) and those with crystal proven gout without clinically apparent tophi (n=33). RESULTS: DECT urate deposits were observed in 6/25 (24%) participants with asymptomatic hyperuricaemia, 11/14 (79%) with early gout (predefined as disease duration ≤3 years) and 16/19 (84%) with late gout (p<0.001). DECT urate deposition was observed in both joints and tendons in the asymptomatic hyperuricaemia group, but significantly less frequently than in those with gout (p≤0.001 for both joint and tendon sites). The volume of urate deposition was also significantly lower in those with asymptomatic hyperuricaemia, compared with the early and the late gout groups (p<0.01 for both comparisons). Similar urate volumes were observed in the early and late gout groups. CONCLUSIONS: Although subclinical urate deposition can occur in people with asymptomatic hyperuricaemia, these deposits occur more frequently and at higher volumes in those with symptomatic gout. These data suggest that a threshold of urate crystal volume may be required before symptomatic disease occurs.

Relationship between structural joint damage and urate deposition in gout: a plain radiography and dual-energy CT study.

OBJECTIVES: The aim of this work was to examine the relationship between joint damage and monosodium urate (MSU) crystal deposition in gout. METHODS: Plain radiographs and dual-energy CT (DECT) scans of the feet were prospectively obtained from 92 people with tophaceous gout. Subcutaneous tophus count was recorded. The ten metatarsophalangeal joints were scored on plain radiography for Sharp-van der Heijde erosion and joint space narrowing (JSN) scores, and presence of spur, osteophyte, periosteal new bone and sclerosis (920 total joints). DECT scans were analysed for the presence of MSU crystal deposition at the same joints. RESULTS: DECT MSU crystal deposition was more frequently observed in joints with erosion (OR (95% CI) 8.5 (5.5 to 13.1)), JSN (4.2 (2.7 to 6.7%)), spur (7.9 (4.9 to 12.8)), osteophyte (3.9 (2.5 to 6.0)), periosteal new bone (7.0 (4.0 to 12.2)) and sclerosis (6.9 (4.6 to 10.2)), p<0.0001 for all. A strong linear relationship was observed in the frequency of joints affected by MSU crystals with radiographic erosion score (p<0.0001). The number of joints at each site with MSU crystal deposition correlated with all features of radiographic joint damage (r>0.88, p<0.05 for all). In linear regression models, the relationship between MSU crystal deposition and all radiographic changes except JSN and osteophytes persisted after adjusting for subcutaneous tophus count, serum urate concentration and disease duration. CONCLUSIONS: MSU crystals are frequently present in joints affected by radiographic damage in gout. These findings support the concept that MSU crystals interact with articular tissues to influence the development of structural joint damage in this disease.