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Abstract Background Indigenous Australians experience significant socioeconomic disadvantage and healthcare disparity compared to non-Indigenous Australians. A retrospective cohort study to describe the association between rates of self-discharge in Indigenous orthopaedic patients and the introduction of routine Aboriginal Liaison Officers (ALO) within the Orthopaedic multi-disciplinary team (MDT) was performed. Methods ALO were introduced within our routine Orthopaedic MDT on the 22nd of February 2021. Two patient cohorts were analysed, Group 1; patients admitted in the 9-months prior to inclusion of ALO, and Group 2; patients admitted within 9-months thereafter. The primary outcome of interest was the rate of self-discharge among Indigenous patients. Secondary outcomes of interest were the stage of treatment when patients self-discharged, recurrent self-discharge, risk factors for self-discharge and association between self-discharge and length of hospital stay. Results Introduction of ALO within routine Orthopaedic MDT was associated with a significant 37% reduced risk of self-discharge among Indigenous patients (p = 0·009), and significantly fewer self-discharges before their definitive surgical and medical treatment (p = 0·0024), or before completion of postoperative intravenous antibiotic treatment (p = 0·030). There was no significant change in the risk of recurrent self-discharge (p = 0·557). Risk factors for self-discharge were younger age; pensioners or unemployed; residents of Alice Springs Town-Camps or of communities within 51 to 100 km of Alice Springs; and those diagnosed with lacerations of the upper limb, but without tendon injury, wound and soft tissue infections or osteomyelitis. In Group 2, the odds of self-discharge decreased with increased length of hospital stay (p = 0·040). Conclusions Routine inclusion of ALO within the Orthopaedic MDT reduced the risk of self-discharge in Indigenous patients. Those who self-discharged did so only after critical aspects of their care were met.

Background: Fused hips with spine stiffness in ankylosing spondylitis (AS) reduce spinopelvic mobility. We aimed to assess spinopelvic mobility pattern and acetabular anteversion in AS after total hip arthroplasty (THA). Material and methods: Ninety-four stiff hips in 58 AS individuals (mean age: 37.05) who underwent THA between 2012 and 2018 with a modified lateral approach were included. Twenty-three hips were fused, and 71 hips had mean flexion of 37.67°. Pelvic tilt, pelvic inclination, sacral slope (SS), and lumbar lordosis were correlated with THA, and functional outcomes were assessed at 34.6-month mean follow-up. Results: Thirty-seven had a stuck sitting pattern with stuck standing seen in 4 individuals. SS standing before and after THA were 25.08° and 27.30°. SS sitting was 8.99° compared to 16.80°. SS from sitting to standing was reduced (17.7°) in 17 individuals. Spine stiffness in extension was seen in 4 out of 37. Mean acetabular inclination after THA was 42.67°, and acetabular anteversion was 17.48°. Flexion after THA improved to mean 98.47°. Changes in SS from sitting to standing were correlated with THA (r-value: 0.93, P-value: .0001). The Harris Hip Score improved from 25.31 to 82.39 (P-value

Background Aggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain tumors are limited, and 5-year survival rates remain poor. Immune checkpoint inhibitor therapy has transformed treatment of some other cancers but has yet to significantly benefit patients with glioblastoma. Early phase trials of chimeric antigen receptor (CAR) T-cell therapy in patients with glioblastoma have demonstrated that this approach is safe and feasible, but with limited evidence of its effectiveness. The choices of appropriate target antigens for CAR-T-cell therapy also remain limited.Methods We profiled an extensive biobank of patients’ biopsy tissues and patient-derived early passage glioma neural stem cell lines for GD2 expression using immunomicroscopy and flow cytometry. We then employed an approved clinical manufacturing process to make CAR- T cells from patients with peripheral blood of glioblastoma and diffuse midline glioma and characterized their phenotype and function in vitro. Finally, we tested intravenously administered CAR-T cells in an aggressive intracranial xenograft model of glioblastoma and used multicolor flow cytometry, multicolor whole-tissue immunofluorescence and next-generation RNA sequencing to uncover markers associated with effective tumor control.Results Here we show that the tumor-associated antigen GD2 is highly and consistently expressed in primary glioblastoma tissue removed at surgery. Moreover, despite patients with glioblastoma having perturbations in their immune system, highly functional GD2-specific CAR-T cells can be produced from their peripheral T cells using an approved clinical manufacturing process. Finally, after intravenous administration, GD2-CAR-T cells effectively infiltrated the brain and controlled tumor growth in an aggressive orthotopic xenograft model of glioblastoma. Tumor control was further improved using CAR-T cells manufactured with a clinical retroviral vector encoding an interleukin-15 transgene alongside the GD2-specific CAR. These CAR-T cells achieved a striking 50% complete response rate by bioluminescence imaging in established intracranial tumors.Conclusions Targeting GD2 using a clinically deployed CAR-T-cell therapy has a sound scientific and clinical rationale as a treatment for glioblastoma and other aggressive primary brain tumors.

Abstract Background Organoids are a reliable model used in the study of human brain development and under pathological conditions. However, current methods for brain organoid culture generate tissues that range from 0.5 to 2 mm of size, which need to be constantly agitated to allow proper oxygenation. The culture conditions are, therefore, not suitable for whole-brain organoid live imaging, required to study developmental processes and disease progression within physiologically relevant time frames (i.e. days, weeks, months). Results Here we designed 3D-printed microplate inserts adaptable to standard 24 multi-well plates, which allow the growth of multiple organoids in pre-defined and fixed XYZ coordinates. This innovation facilitates high-resolution imaging of whole-cerebral organoids, allowing precise assessment of organoid growth and morphology, as well as cell tracking within the organoids, over long periods. We applied this technology to track neocortex development through neuronal progenitors in brain organoids, as well as the movement of patient-derived glioblastoma stem cells within healthy brain organoids. Conclusions This new bioengineering platform constitutes a significant advance that permits long term detailed analysis of whole-brain organoids using multimodal inverted fluorescence microscopy.

Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.

Abstract Introduction For persons with hemophilia, optimization of joint outcomes is an important unmet need. The aim of this initiative was to determine use of ultrasound in evaluating arthropathy in persons with hemophilia, and to move toward consensus among hemophilia care providers regarding the preferred ultrasound protocols for global adaptation. Methods A global survey of hemophilia treatment centers was conducted that focused on understanding how and why ultrasound was being used and endeavored to move toward consensus definitions of both point‐of‐care musculoskeletal ultrasound (POC‐MSKUS) and full diagnostic ultrasound, terminology to describe structures being assessed by ultrasound, and how these assessments should be interpreted. Next, an in‐person meeting of an international group of hemophilia health care professionals and patient representatives was held, with the objective of achieving consensus regarding the acquisition and interpretation of POC‐MSKUS and full diagnostic ultrasound for use in the assessment of musculoskeletal (MSK) pathologies in persons with hemophilia. Results The recommendations were that clear definitions of the types of ultrasound examinations should be adopted and that a standardized ultrasound scoring/measurement system should be developed, tested, and implemented. The scoring/measurement system should be tiered to allow for a range of complexity yet maintain the ability for comparison across levels. Conclusion Ultrasound is an evolving technology increasingly used for the assessment of MSK outcomes in persons with hemophilia. As adoption increases globally for clinical care and research, it will become increasingly important to establish clear guidelines for image acquisition, interpretation, and reporting to ensure accuracy, consistency, and comparability across groups.

Abstract Objectives Targeted immunotherapies such as chimeric antigen receptor (CAR)‐T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples. Methods Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets. Short‐term cultures of glioma neural stem (GNS) cells were compared to cultures of healthy astrocytes and neurons using flow cytometry. Glioblastoma tissues were dissociated and analysed by high‐parameter flow cytometry and single‐cell transcriptomics (scRNAseq). Results Compared to normal brain, FAP was overexpressed at the gene and protein level in a large percentage of glioblastoma tissues, with highest levels of expression associated with poorer prognosis. FAP was also overexpressed in several paediatric brain cancers. FAP was commonly expressed by cultured GNS cells but absent from normal neurons and astrocytes. Within glioblastoma tissues, the strongest expression of FAP was around blood vessels. In fact, almost every tumor vessel was highlighted by FAP expression, whereas normal tissue vessels and cultured endothelial cells (ECs) lacked expression. Single‐cell analyses of dissociated tumors facilitated a detailed characterisation of the main cellular components of the glioblastoma microenvironment and revealed that vessel‐localised FAP is because of expression on both ECs and pericytes. Conclusion Fibroblast activation protein is expressed by multiple cell types within glioblastoma, highlighting it as an ideal immunotherapy antigen to target destruction of both tumor cells and their supporting vascular network.

Tumour induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting and hypophosphatemic osteomalacia, caused by FGF-23 (Fibroblast growth factor-23) producing mesenchymal tumours. Here, we report the case of a 40 year old lady referred by her family physician for multiple joint pains of 2 years duration. There was no evidence of inflammatory arthritis. Biochemical investigations revealed low phosphorus, with raised alkaline phosphatase and high levels of FGF-23. As a TIO was considered likely, functional imaging with a DOTATATE PET scan was done, which revealed a DOTA avid lesion in the right foot. Following surgical excision of the tumour, there was significant relief in symptoms and gradual recovery of phosphate to normal levels. It is relevant and important for family physicians as in subjects with symptom like polyarthralgia, a simple measurement of analytes like phosphate, calcium and alkaline phosphatase in primary care setting will help to arrive at a cause and referral for further evaluation as this condition is potentially treatable.

High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines have synergized to identify an expansive repertoire of unique circular RNAs (circRNAs), exceeding 100,000 variants. While the vast majority of these circRNAs comprise canonical exonic and intronic sequences, microexons (MEs)—which occur in 30% of functional mRNA transcripts—have been entirely overlooked. CircRNAs which contain these known MEs (ME-circRNAs) could be identified with commonly utilized circRNA prediction pipelines, CIRCexplorer2 and CIRI2, but were not previously recognized as ME-circRNAs. In addition, when employing a bespoke bioinformatics pipeline for identifying RNA chimeras, called Hyb, we could also identify over 2000 ME-circRNAs which contain novel MEs at their backsplice junctions, that are uncalled by either CIRCexplorer2 or CIRI2. Analysis of circRNA-seq datasets from gliomas of varying clinical grades compared with matched control tissue has shown circRNAs have potential as prognostic markers for stratifying tumor from healthy tissue. Furthermore, the abundance of microexon-containing circRNAs (ME-circRNAs) between tumor and normal tissues is correlated with the expression of a splicing associated factor, Serine/arginine repetitive matrix 4 (SRRM4). Overexpressing SRRM4, known for regulating ME inclusion in mRNAs critical for neural differentiation, in human HEK293 cells resulted in the biogenesis of over 2000 novel ME-circRNAs, including ME-circEIF4G3, and changes in the abundance of many canonical circRNAs, including circSETDB2 and circLRBA. This shows SRRM4, in which its expression is correlated with poor prognosis in gliomas, acts as a bona fide circRNA biogenesis factor. Given the known roles of MEs and circRNAs in oncogenesis, the identification of these previously unrecognized ME-circRNAs further increases the complexity and functional purview of this non-coding RNA family.

A survey of the American Association of Hip and Knee Surgeons (AAHKS) reported that 95% of respondents attempted to modify risk factors prior to arthroplasty. This study investigated Indian arthroplasty surgeons' approach to patients who have modifiable risk factors. The AAHKS survey tool was adapted for Indian surgeons and distributed to the membership of the Indian Society of Hip and Knee Surgeons and Indian Arthroplasty Association via a Survey Monkey. A total of 92 survey responses were received, representing a response rate of 12%. Overall, 87% of respondents restricted access to arthroplasty surgery for patients who have modifiable risk factors, but only 51% of respondents reported delays or restricted treatment because of risk factors. Respondents reported that financial implications were more likely to delay or restrict treatment in 97% and social/family reasons in 66%. Poor diabetic control (81%), previous infection (57%), and malnutrition/hypoalbuminemia (47%) were the most frequent modifiable risk factors. There were 82% of surgeons reporting that the patient's socioeconomic status influenced treatment including: 71% of patients who have low socioeconomic status, 57% who do not have insurance, and 45% who have limited social supports. Most surgeons (92%) reported that funding influenced the type of care provided and the choice of implants. Over 97% of Indian arthroplasty surgeons thought socioeconomic factors impaired access to orthopaedic treatment. Only half the surgeons restricted access for comorbidities and these were more often related to infection risks and diabetes. These findings contrast dramatically to the practice patterns of American AAHKS members. [ABSTRACT FROM AUTHOR]

• Cutibacterium acnes is a common cause of cranial wound infections. • Prophylatic antibiotics and surgical skin preparation are effective at eradicating Cutibacterium acnes from the skin surface but not from the underlying dermis. • Cutibacterium acnes in the untreated dermis may be a target for reducing Cutibacterium acnes cranial wound infections. Cutibacterium acnes , formerly known as Propionibacterium acnes , is increasingly recognized as a cause of surgical site infection and implant failure despite the use of prophylactic antibiotics and antiseptic surgical preparations. The aim of this study was to investigate whether C. acnes persists in the dermal layer of the skin after standard perioperative antibiotics and skin prepping with alcoholic betadine solution in consecutive patients undergoing a craniotomy. A single centre prospective observational study was performed at Flinders Medical Centre. Adult patients undergoing a cranial neurosurgical intervention between October 2019 to March 2021 were eligible for inclusion. After administration of standard preoperative antibiotics (Cefazolin), three swabs were taken for each patient: one before prepping the skin with alcoholic betadine, one after prepping the skin and a dermal swab once the skin was incised. 73 patients were included. Cutibacterium acnes cultures were positive in 61 patients of the "pre-prep" group (83.6%), 12 (16.4%) in the "post-prep" group, and 53 (72.6%) were from dermal swabs There was a significant reduction of positive cultures of the skin after surgical preparation was applied (p < 0.00001). There was a non-significant reduction of positive cultures in the dermal swabs after skin preparation (p = 0.068) Cutibacterium acnes persists within the dermis of the scalp despite standard prophylactic measures using alcoholic betadine solution and cefazolin. [ABSTRACT FROM AUTHOR]

• Continued improvements were seen for all mobility and cognitive tests out to 48 h post high-volume CSF removal. • 30% of patients proceeded to insertion of a ventriculoperitoneal shunt on the basis of delayed reassessment. • This cohort of patients demonstrated benefit from shunt insertion based on outcome measure questionnaires. • Delayed reassessment post CSF removal is important in order to capture all possible shunt responders. The principle aim of the study was to demonstrate the value of performing delayed reassessment in the diagnosis of idiopathic normal-pressure hydrocephalus (iNPH) and selection of suitable candidates for ventriculoperitoneal shunting (VPS). Thirty-one consecutive patients underwent the NPH protocol at the Flinders Medical Centre between March 2017 and November 2018. The protocol involved mobility and cognitive testing with reassessment post high-volume cerebrospinal fluid (CSF) removal at 24 h and 48 h. The Assessment of Quality of Life 6D (AQoL-6D) questionnaire and International Consultation on Incontinence Questionnaire – Urinary Incontinence Short Form (ICIQ-UI SF) were completed and repeated again at 6 weeks and 6 months post shunting. Results were analysed to determine the significance of delayed reassessment. Twenty patients (64.5%) underwent insertion of a VPS on the basis of objective improvements and specific criteria. Of these, 6 patients (30%) were shunted based on delayed reassessment at 48 h post CSF removal. Continued improvements were seen for all mobility and cognitive tests from baseline to 48 h post CSF removal. At 6 weeks and 6 months post shunting, there was an overall mean improvement in AQoL-6D and ICIQ-UI SF for the cohort and the improvement was also observed in the subgroup of patients who met shunt criteria at 48 h post CSF removal. In the diagnosis of shunt-responsive idiopathic normal-pressure hydrocephalus, delayed reassessment post CSF removal improves sensitivity and is therefore important. [ABSTRACT FROM AUTHOR]

Tunnel widening after Anterior cruciate ligament (ACL) reconstruction using a hamstring graft is known to occur at follow-up. Our study aimed to investigate the effect of suspensory fixation augmentation using an interference screw on tunnel widening in single-bundle hamstring ACL reconstruction. 48 patients who had single bundle ACL reconstruction with femoral fixed loop fixation technique in 15 knees, and, fixed loop with augmented aperture (bio screw) fixation in 33 knees were analyzed. The width of the tunnel was measured using radiographs immediate post-op and at follow-up within 1 year. Computerized Tomogram (CT) measurements of the tunnels and functional scores were also done with overall follow-up for the fixed loop group being 21.33 months (Standard Deviation (SD)11.14) and the Augmentation group 9.12 months (SD 3.83) Midpoint femur tunnel widening was reduced in the augmentation group, with measurements of 0.74 (SD 1.05) mm Antero Posterior (AP) and 1.01 (SD 1.04) mm in the Lateral view, compared to 1.54 (SD 1.48) mm AP and 1.79 (SD1.47 mm) in the Lateral for the fixed button group. The radiological widening was considerably less in the augmentation group with a p-value of 0.07. AP aperture widening in the augmentation group was 1.25(SD 1.10 mm), and 1.09(SD0.98) mm in the lateral view. The fixed button-only group measured 1.53 (SD1.30) mm in the AP, and 1.65 (SD 1.29) mm in the lateral view, both of which were not statistically significant. The follow-up Lysholm and International Knee Documentation Committee (IKDC) scores were similar for the 2 groups. Femoral tunnel midpoint and aperture widening were reduced with the fixed loop with aperture (bio screw) augmentation technique for hamstring grafts in single bundle ACL fixation within 1 year with comparable functional scores. 4. [ABSTRACT FROM AUTHOR]

• In clinical practice antiepileptic medications other than phenytoin are prescribed for post traumatic seizure prophylaxis. • This was a retrospective case not review of all traumatic intracranial haematomas that presented to a single institution over a 4 year period. • 16% of patients were prescribed an antiepileptic drug. • Rate of early PTSs for patients prescribed antiepileptic drugs was 2.9% compared with 3.5% for patients not prescribed antiepileptic drugs. • The routine administration of prophylactic antiepileptic medications that occurs in clinical practice should be re-examined. Current international guidelines for traumatic brain injury (TBI) recommend the use of phenytoin for the prevention of early post traumatic seizures (PTS) when the benefits are thought to outweigh the risks. In practice however, alternative antiepileptic drugs (AEDs) such as levetiracetam and valproate are being used as they are believed to have a more favourable risk profile. This is despite there being insufficient evidence to support their efficacy. The purpose of this study was to identify which AED was prescribed to patients presenting with a TBI at a single institution, and to determine the rate of early PTSs. This was a retrospective case-note review study done at the Flinders Medical Centre including patients admitted from May 2013 to June 2017. All patients with traumatic intracranial haematomas were included. Patients were excluded if they had seizures prior to presentation to hospital or died within 24 h of injury. The primary outcomes were rate of early PTSs and the type of prophylactic AED prescribed. During this study period, 610 patients presented with a mild, moderate or severe traumatic brain injury. Overall, 16% of patients were prescribed an AED, with more than 90% of these patients being prescribed levetiracetam. Overall, the rate of early PTSs for patients prescribed AEDs was 2.9% compared with 3.5% for patients not prescribed AEDs (OR 0.83 CI 0.24–2.85 p = 1). This study showed that levetiracetam was the most commonly prescribed AED. It also demonstrated no statistically significant difference in the rate of early PTSs in patients with TBI, with or without prophylactic AEDs. This is in keeping with other contemporary studies, and therefore the routine administration of prophylactic AEDs may need to be re-examined. [ABSTRACT FROM AUTHOR]

The aim of the study was to compare the efficacy of periarticular injection of a cocktail of analgesic drugs (PIC) with epidural infiltration (EA), in providing postoperative pain relief and early functional improvement following Total Hip Arthroplasty (THA). 50 patients undergoing unilateral THA were randomized to receive either EA or PIC for postoperative pain control. Postoperative pain relief, as determined by the visual analogue scale (VAS), functional recovery and side effects related to EA and PIC were assessed. PIC resulted in significantly lower VAS scores [0.48(0.71) vs 3.04(2.07)] in the first 24 h after surgery [mean (SD)], when compared to EA. The pain relief continued to be significantly lower even on the 10th postoperative day. Functional recovery was significantly better in the PIC group, with patients being able to walk longer distances and climb steps more quickly following THA. EA, unlike PIC was associated with side effects like nausea, vomiting, motor weakness, back pain and urinary retention. The overall satisfaction rate with treatment was significantly better in PIC group (9.04/10) than those who received EA (7.76/10). PIC provides significantly better pain control and functional recovery in the early postoperative period, with less side effects when compared with EA. PIC should be the choice for pain control following THA. [ABSTRACT FROM AUTHOR]