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.

The Tophus Impact Questionnaire (TIQ-20): responsiveness to change during urate-lowering therapy.

OBJECTIVES: In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy. METHODS: We analysed data from a two-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured using Vernier calipers and the TIQ-20 was recorded at study visits. Participants at the one site were invited into a dual energy CT (DECT) sub-study. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1, and Year 2 (n = 58, 39 with DECT data). Data were analysed using mixed model approach to repeated measures. RESULTS: Improvements were observed in all tophus measures over the two-year period. The mean (SD) TIQ-20 scores reduced over two years from 3.59 (1.77)-2.46 (1.73), P< 0.0001, and the mean (95%CI) TIQ-20 change over the two years was -1.13 (-1.54, -0.71). Effect size (Cohen's d) for the change in the sum of the index tophi diameter over two years was 0.68, for DECT urate volume was 0.50, and for the TIQ-20 was 0.71. CONCLUSION: For people with tophaceous gout treated with allopurinol using a treat to target serum urate approach, improvements in TIQ-20 occur, as well as improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact.

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.

Radiology and Te Whatu Ora - Health New Zealand in 2022. Why we should all care.

Radiology is a key enabler of clinical activity and has been shown to be highly cost effective. Demand and activity have increased over time, with demand for computed tomography (CT), magnetic resource imaging (MRI) and ultrasound (US) growing faster than population growth. Complexity has also increased over time. Resources in the public sector have not kept up with demand, exacerbated by the COVID-19 pandemic. A reliance on an overseas trained workforce has resulted in critical shortages. Waiting times for CT, MRI and US across Aotearoa New Zealand remain well below targets and have not improved over 10 years. Robust links between clinical activity and radiology resourcing are needed to address the deficits and thereby maintain clinical safety.

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.

Development of a radiographic scoring system for new bone formation in gout.

BACKGROUND: Features of new bone formation (NBF) are common in tophaceous gout. The aim of this project was to develop a plain radiographic scoring system for NBF in gout. METHODS: Informed by a literature review, scoring systems were tested in 80 individual 1st and 5th metatarsophalangeal joints. Plain radiography scores were compared with computed tomography (CT) measurements of the same joints. The best-performing scoring system was then tested in paired sets of hand and foot radiographs obtained over 2 years from an additional 25 patients. Inter-reader reproducibility was assessed using intraclass correlation coefficients (ICC). NBF scores were correlated with plain radiographic erosion scores (using the gout-modified Sharp-van der Heijde system). RESULTS: Following a series of structured reviews of plain radiographs and scoring exercises, a semi-quantitative scoring system for sclerosis and spur was developed. In the individual joint analysis, the inter-observer ICC (95% CI) was 0.84 (0.76-0.89) for sclerosis and 0.81 (0.72-0.87) for spur. Plain radiographic sclerosis and spur scores correlated with CT measurements (r = 0.65-0.74, P < 0.001 for all analyses). For the hand and foot radiograph sets, the inter-observer ICC (95% CI) was 0.94 (0.90-0.98) for sclerosis score and 0.76 (0.65-0.84) for spur score. Sclerosis and spur scores correlated highly with plain radiographic erosion scores (r = 0.87 and 0.71 respectively), but not with change in erosion scores over 2 years (r = -0.04-0.15). CONCLUSION: A semi-quantitative plain radiographic scoring method for the assessment of NBF in gout is feasible, valid, and reproducible. This method may facilitate consistent measurement of NBF in 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.

The impact of antibiotic pre-treatment on diagnostic yield of CT-guided biopsy for spondylodiscitis: A multi-centre retrospective study and meta-analysis.

INTRODUCTION: Patients with suspected spondylodiscitis often undergo CT-guided biopsy to identify a causative microbiological organism. Antibiotic pre-treatment has been postulated as a cause for a negative biopsy, although previous clinical studies have been heterogenous with a meta-analysis suggesting no effect. The aim of this study was to assess the impact of antibiotic pre-treatment on microbiological yield. METHODS: Retrospective review of consecutive adult patients undergoing CT-guided biopsy for suspected spondylodiscitis in two tertiary centres between 2010 and 2016. Demographic, procedural and clinical data were collected. Antibiotic pre-treatment was ascertained from patient drug charts. RESULTS: Over the 6-year period, 104 biopsies in 104 patients were included. 51% had a positive microbiological yield at CT-guided biopsy, with the most common isolated organism being Staphylococcus aureus (10.6%). Over two thirds of patients (69.3%) were off antibiotics at time of biopsy. There was no significant difference in microbiological yield in those patients on versus off antibiotics (48.2% vs 54.2%, P = 0.55). 10.6% patients had a final diagnosis of Mycobacterium tuberculosis spondylodiscitis, and this organism was significantly associated with a positive microbiological yield (90.9% vs 46.2%, P = 0.01). There was an inverse association between the presence of fever and sepsis with positive microbiological yield. CONCLUSIONS: CT-guided biopsy in suspected spondylodiscitis obtains a positive microbiological yield in about half of patients. This was significantly higher in patients diagnosed with tuberculosis spondylodiscitis, but there was no significant difference with antibiotic pre-treatment. Therefore, antibiotic pre-treatment should not preclude clinicians from pursuing a microbiological sample through CT-guided biopsy.

Tibiotalar cartilage stress corresponds to T2 mapping: application to barefoot running in novice and marathon-experienced runners.

A 3D anatomically-based finite-element foot model was adopted for predicting von Mises stresses within tibiotalar cartilage following 5 km barefoot running. To compare this predicted stress with T2 maps, magnetic resonance scans of the right ankle and plantar pressure were obtained from ten novices and ten marathon-experienced runners before and after running. Following running, tibiotalar cartilage stress was decreased in experienced runners. This corresponded with T2 values that did not change between pre- and post-running suggesting no increase in cartilage fluid levels. In contrast, novices maintained the same level of von Mises stress and this corresponded with a significant T2 increase in tibiotalar cartilage.

An automated computational biomechanics workflow for improving breast cancer diagnosis and treatment.

Clinicians face many challenges when diagnosing and treating breast cancer. These challenges include interpreting and co-locating information between different medical imaging modalities that are used to identify tumours and predicting where these tumours move to during different treatment procedures. We have developed a novel automated breast image analysis workflow that integrates state-of-the-art image processing and machine learning techniques, personalized three-dimensional biomechanical modelling and population-based statistical analysis to assist clinicians during breast cancer detection and treatment procedures. This paper summarizes our recent research to address the various technical and implementation challenges associated with creating a fully automated system. The workflow is applied to predict the repositioning of tumours from the prone position, where diagnostic magnetic resonance imaging is performed, to the supine position where treatment procedures are performed. We discuss our recent advances towards addressing challenges in identifying the mechanical properties of the breast and evaluating the accuracy of the biomechanical models. We also describe our progress in implementing a prototype of this workflow in clinical practice. Clinical adoption of these state-of-the-art modelling techniques has significant potential for reducing the number of misdiagnosed breast cancers, while also helping to improve the treatment of patients.

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.

T2 relaxation time measurements in tibiotalar cartilage after barefoot running and its relationship to ankle biomechanics.

The influence of ankle kinematics and plantar pressure from mid-range barefoot running on T2 relaxation times of tibiotalar cartilage is unknown. This study aimed to quantitatively evaluate the T2 relaxation time of tibiotalar cartilage and ankle biomechanics following 5 km barefoot running. Twenty healthy runners (who had no 5 km barefoot running experience) underwent 3.0-Tesla magnetic resonance (MR) scans and assessment of running gait before and after 5 km barefoot running. Participants were divided into two groups consisting of marathon-experienced (n = 10) and novice (n = 10) with equal number of males and females in each group. Three musculoskeletal radiologists measured T2 relaxation times in 18 regions of the ankle cartilage: anterior zone, central zone, and posterior zone, or lateral, middle, and medial sections in the sagittal plane. Three-dimensional ankle kinetics, kinematics, and plantar pressure were all also assessed during barefoot running. In the novice group, the T2 relaxation time in the posterior zone of tibial cartilage (p = 0.001) and lateral section in both tibial (p = 0.02) and talar (p = 0.02) cartilage were significantly increased after barefoot running. Ankle kinematics exhibited significant changes in females. Plantar loading was shifted from the medial to lateral aspect after running. This included a significant reduction in the loading under the toes and the 1st, 2nd and 3rd metatarsals, with a significant increase under the 4th and 5th metatarsals and lateral midfoot. The results suggest that plantar pressure may directly lead to local increases in cartilage T2 signal, which was not associated with changes in ankle kinematics.

Effects of Allopurinol Dose Escalation on Bone Erosion and Urate Volume in Gout: A Dual-Energy Computed Tomography Imaging Study Within a Randomized, Controlled Trial.

OBJECTIVE: To examine whether allopurinol dose escalation to achieve serum urate (SU) target can influence bone erosion or monosodium urate (MSU) crystal deposition, as measured by dual-energy computed tomography (DECT) in patients with gout. METHODS: We conducted an imaging study of a 2-year randomized clinical trial that compared immediate allopurinol dose escalation to SU target with conventional dosing for 1 year followed by dose escalation to target, in gout patients who were receiving allopurinol and who had an SU level of ≥0.36 mmoles/liter. DECT scans of feet and radiographs of hands and feet were obtained at baseline, year 1, and year 2 visits. DECT scans were scored for bone erosion and urate volume. RESULTS: Paired imaging data were available for 87 patients (42 in the dose-escalation group and 45 in the control group). At year 2, the progression in the CT erosion score was higher in the control group than in the dose-escalation group (+7.8% versus +1.4%; P = 0.015). Changes in plain radiography erosion or narrowing scores did not differ between groups. Reductions in DECT urate volume were observed in both groups. At year 2, patients in the control group who had an SU level of <0.36 mmoles/liter and patients in the dose-escalation group had reduced DECT urate volume (-27.6 to -28.3%), whereas reduction in DECT urate volume was not observed in control group patients with an SU level of ≥0.36 mmoles/liter (+1.5%) (P = 0.023). CONCLUSION: These findings provide evidence that long-term urate-lowering therapy using a treat-to-SU-target strategy can influence structural damage and reduce urate crystal deposition in gout.

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.

Higher Binding Affinity and in vitro Potency of Reslizumab for Interleukin-5 Compared With Mepolizumab.

Reslizumab and mepolizumab are recently approved monoclonal antibodies for the treatment of severe (uncontrolled) eosinophilic asthma. Both are effective in neutralizing the function of interleukin-5 (IL-5). This study is the first to compare the binding affinity and in vitro potency of both antibodies in head-to-head assays. Two assays assessed binding affinity (using the equilibrium dissociation constant [KD]) of each drug for human IL-5. In the Biacore surface plasmon resonance assay, the association constant (kon) values for human IL-5 for reslizumab and mepolizumab were 3.93 × 106 and 1.83 × 105, respectively. The dissociation constant (koff) values were 4.29 × 10⁻4 and 2.14 × 10⁻4, respectively. Calculated KD values for human IL-5 for reslizumab and mepolizumab were 109 and 1,170 pM, respectively, representing an approximately 11-fold stronger binding affinity with reslizumab. In the Kinetic Exclusion Assay, the kon values for human IL-5 for reslizumab and mepolizumab were 3.17 × 106 and 1.32 × 105, respectively. The koff values were 1.36 × 10⁻5 and 1.48 × 10⁻5, respectively. Measured KD values for human IL-5 for reslizumab and mepolizumab were 4.3 and 112 pM, respectively, representing an approximately 26-fold stronger binding affinity for reslizumab. A human-IL-5-dependent cell proliferation assay was developed to assess in vitro potency, based on a human cell line selected for enhanced surface expression of IL-5 receptor-alpha and consistent proliferation response to IL-5. The concentration at which 50% inhibition occurred (IC50) was determined for both antibodies. Reslizumab and mepolizumab inhibited IL-5-dependent cell proliferation, with IC50 values of approximately 91.1 and 286.5 pM, respectively, representing on average 3.1-fold higher potency with reslizumab. In conclusion, comparative assays show that reslizumab has higher affinity binding for and in vitro potency against human IL-5 compared with mepolizumab. However, these results do not take into consideration the different methods of administration of reslizumab and mepolizumab.