Royal Perth Hospital

Background There are various diagnostic manoeuvres to distinguish between atrial tachycardia (AT), atrio-ventricular nodal re-entrant tachycardia (AVNRT) and orthodromic re-entrant tachycardia (ORT) when assessing a narrow complex supraventricular tachycardia (SVT) in the electrophysiology (EP) laboratory. These manoeuvres are commonly used in combination to come to a diagnosis due to the inability of a single test to be able to reliably differentiate between the arrhythmias. Objective To determine whether a single captured His-synchronous simultaneous extra-stimulus in the atrium and ventricle (“Double Capture”) can reliably distinguish the mechanism of a narrow complex SVT. Methods At a single institution, we reviewed the data on patients in whom this maneuver was performed as part of their routine electrophysiology study and analyzed the intracardiac recordings. There were 44 patients who underwent routine electrophysiology studies for narrow complex SVTs and the maneuver was attempted. If the simultaneous extra-stimuli was delivered when the His was refractory and captured both the atrium (A) and ventricle (V), the earliest signal was assessed to attempt to differentiate the mechanism. Results Double Capture was attempted in 44 patients of which six were excluded due to incorrect timing or inadequate electrogram recordings. Of the 38 remaining patients who either had AVNRT or ORT (no atrial tachycardias were included), “Double Capture” was achieved in 29 patients (76%). In patients in whom “Double Capture” occurred, reproducible termination of the tachyarrhythmia with “Double Capture” corresponded with ORT (n = 7). In patients with “Double Capture” with a His signal as the first signal post, and ongoing tachycardia, this typically corresponded with a diagnosis of AVNRT (n = 20), though there were two exceptions with ORT (n = 2). Conclusion In this small study, “Double Capture” of the A and V during a sustained narrow complex SVT without change to the tachycardia or His interval timings was able to confirm AVNRT with a specificity of 78% and ORT with a specificity of 100%. This maneuver may be especially helpful to confirm bystander pathways or assess septal pathways. Graphical Abstract

Objective Intraoperative radiotherapy (IORT) is a specialised radiotherapy technique that delivers a precise, single high-dose fraction to the tumour bed after surgical removal of the tumour, aiming to eliminate residual cancer cells. This study investigates the incorporation of novel applicators into an existing intraoperative radiotherapy (IORT) system to enable dose modulation, performing Monte Carlo simulations, 3D printing, and experimental validation. The Zeiss Intrabeam IORT device, a low-kV IORT system capable of delivering X-rays nearly isotropically, with energies up to 50 kV, was used in this study. Approach Applicators were modified to alter dose distributions, incorporating features such as shielding or changes to an ellipsoid shape. The EGSnrc Monte Carlo (MC) code was employed to simulate the dose distributions of each applicator design, generating data such as dose maps, percentage depth dose (PDD) curves, percent difference maps between shielded and unshielded regions, and energy spectra to characterise each applicator. Gafchromic EBT3 film measurements were performed on select 3D printed applicators, to verify the MC simulations, with dose distribution data extracted for comparison. Main Results Visual comparisons of dose and percentage different maps indicate a high correlation between the MC simulations and film measurements. Most PDD points for spherical applicators showed deviations within 4%, while ellipsoid applicators had deviations of 14% for the unshielded and 5% for the shielded applicators. All RMSEs were below 0.05 for spherical and 0.18 for ellipsoid designs. Based on film data, shielded ellipsoid applicators reduced the dose by ~99%, 48%, 22%, and 8% at 0.3, 1, 2, and 3 cm, respectively, while shielded spherical applicators achieved ~83%, 35%, 14%, and 7% reductions at the same distances. Energy spectra for photons exiting shielded regions were also generated. Significance Results of this study may be used in the development of patient-specific IORT techniques, or the development of a treatment planning system involving mIORT.

OBJECTIVES The impact of conotruncal anomalies (CTAs), including tetralogy of Fallot, truncus arteriosus, ventriculo-arterial discordance, double outlet right ventricle (DORV), and interrupted aortic arch type B, on long-term outcomes remains poorly described in the Fontan cohort. We sought to review the outcomes of Fontan patients with conotruncal anomalies in Australia and New Zealand. METHODS We reviewed the data from 1835 patients who underwent a Fontan operation between 1975 and 2023 from the Australia and New Zealand Fontan Registry. RESULTS Conotruncal anomalies occurred in 895 patients (49%), including D-TGA (n = 476), DORV (n = 360), and L-TGA (n = 170). Patients with CTAs had more heterotaxy syndrome (11.3% vs 6.8%, p < 0.001) and less left-ventricular dominance (53% vs 60% p = 0.011). Median follow-up was 11.7 years (IQR: 5.3–20.3 years).). Overall transplant-free survival and freedom from Fontan failure was 84% (95% CI: 81–87%) and 72% (95% CI: 68–75%) at 20 years, respectively. No difference was demonstrated in survival or freedom from Fontan failure between patients with or without CTAs (p = 0.50 and p = 0.83). Pacemaker implantation was more common in patients with CTAs (11.2% vs 8.3%, p = 0.038). Overall, 45 patients underwent outflow tract reinterventions, including semilunar valves, after Fontan operation. Freedom from these reinterventions was 95% (95% CI: 93–96%) at 30 years and was higher in patients with CTAs (p < 0.001). CONCLUSIONS Patients with conotruncal anomalies did not have a demonstrable difference in long-term survival and freedom from Fontan failure to other patients undergoing Fontan operation. Patients with conotruncal anomalies have higher incidence of outflow tract reinterventions, including semilunar valves, and higher rate of pacemaker implantation.

Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with increasing incidence rates in Australia. As most treatments are performed in metropolitan centres, we hypothesised that rural patients may be adversely affected. Aims To investigate survival outcomes and treatment access between rural and metropolitan HCC patients within a single tertiary hospital network. Methods Retrospective cohort study of HCC patients treated at Royal Perth Hospital from May 2012 to May 2023. Analysed variables included clinical and demographic factors, HCC characteristics (including staging), treatment outcomes and adherence to post-intervention surveillance. Overall survival was compared using Kaplan–Meier analysis and multivariable Cox regression to assess potential confounders. Results Among 400 patients, 305 were from metropolitan (76.2%) and 95 were from rural (23.8%) areas. Baseline characteristics, including demographics, comorbidities, performance status, HCC stage and alpha-fetoprotein levels at diagnosis, were similar between the two groups. Median overall survival was significantly lower for rural patients compared to metropolitan patients (2.53 vs 4.70 years; P = 0.035). Multivariable analysis indicated that rural residence was an independent predictor of poorer survival (adjusted hazard ratio 1.45, P = 0.026). There was no difference in time to treatment or treatment allocation between groups. Surveillance adherence post-curative intervention was lower in rural patients (63% vs 96%, P < 0.001). Conclusions This study highlights a significant survival disadvantage for rural HCC patients, emphasising geographical disparities in healthcare outcomes. While our patients had equal access to treatment, disparities may emerge from challenges in post-treatment care and surveillance adherence. Strategies targeting rural healthcare delivery and patient follow-up are necessary to mitigate these disparities.

IMPORTANCE: Evidence suggests that trauma-related mortality and morbidities may follow a multiphasic pattern, with outcomes extending beyond hospital discharge. OBJECTIVES: To determine the incidence of having new mental health conditions after the first (or index) trauma admission and their association with long-term health outcomes. DESIGN, SETTING, AND PARTICIPANTS: This population-based, linked-data cohort study was conducted between January 1994 and September 2020, with data analyzed in April 2024. Participants were adult patients with trauma admitted to 1 of the 5 adult trauma hospitals in Western Australia. All patients with major trauma with an Injury Severity Score (ISS) greater than 15were included. For each patient with major trauma, 2 patients with trauma with a lower ISS (<16)were randomly selected. EXPOSURE: A new mental health condition recorded in either subsequent public or private hospitalizations after trauma admission. MAIN OUTCOMES AND MEASURES: The primary outcomes were the associations between new mental health conditions after trauma and subsequent risks of trauma readmission, suicide, and all-cause mortality, as determined by Cox proportional hazards regression. Logistic regression was used to determine which factors were associated with developing a new mental health condition after trauma. RESULTS: Of 29 191 patients (median [IQR] age, 42 [27-65] years; 19 383 male [66.4%]; median [IQR] ISS, 9 [5-16]; 9405 with ISS >15 and 19 786 with ISS <16) considered, 2233 (7.6%) had a mental health condition before their trauma admissions. The median (IQR) follow-up time after the index trauma admission was 99.8 (61.2-148.5) months. Of 26 958 patients without a prior mental health condition, 3299 (11.3%) developed a mental health condition subsequently, including drug dependence (2391 patients [8.2%], with 419 patients [1.4%] experiencing opioid dependence) and neurotic disorders (1574 patients [5.4%]), including posttraumatic stress disorder. Developing a new mental health condition after trauma was associated with subsequent trauma readmissions (adjusted hazard ratio [aHR], 1.30; 95%CI, 1.23-1.37; P < .001), suicides (aHR, 3.14; 95%CI, 2.00-4.91; P < .001), and all-cause mortality (aHR, 1.24; 95%CI, 1.12-1.38; P < .001). Younger age, unemployment, being single or divorced (vs married), Indigenous ethnicity, and a lower socioeconomic status were all associated with developing a new mental health condition after the first trauma admission. CONCLUSIONS AND RELEVANCE: This cohort study of 29 191 patients with trauma found that mental health conditions after trauma were common and associated with an increased risk of adverse long-term outcomes, indicating that mental health follow-up of patients with trauma, particularly those from vulnerable subgroups, may be warranted.

Promptly recognising changes in an acutely unwell child’s condition is fundamental to prevent tragic outcomes. Western Australian (WA) healthcare facilities used inconsistent and varied paediatric early warning systems. To improve care consistency, a standardised ESCALATION system, inclusive of family involvement and sepsis recognition, was developed. Post-implementation audits offered limited insight into system fidelity, adoption, and integration. Furthermore, evaluation identified a need to tailor the ESCALATION system for Aboriginal families. WA Country Health Service (WACHS) provides healthcare to people who live in regional, rural and remote WA. Perth Children’s hospital (PCH) is the States specialist facility. This study will evaluate the scale-up and sustainability of the ESCALATION system into WACHS paediatric facilities and PCH, with a focus on strengthening Aboriginal family involvement. A pre-post, intervention study using implementation science methods, with two sub-studies. Sub-study one evaluates the ESCALATION system fidelity and adoption at six WACHS hospitals using audits, surveys, and focus groups with health professionals. Normalisation Process Theory will be used to understand practice integration and to develop and test solutions. Sub-study two uses participatory action approach at three WACHS sites and at PCH using surveys, interviews/focus groups with health professionals and Aboriginal families to co-design and test solutions to enhance Aboriginal family involvement in the ESCALATION system. Study findings will provide a comprehensive understanding of factors impacting the sustainability of the ESCALATION system ensuring it is used as intended in WA’s paediatric healthcare settings and meets the needs of all users including families, particularly Aboriginal families.

Background and Aims Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome (ACS). Recent data suggest a harmful association of dual antiplatelet therapy compared with single antiplatelet therapy following SCAD. This study investigated independent predictors of major adverse cardiovascular events (MACEs) and recurrence in patients with SCAD. Methods This multicentre cohort study involving 23 Australian and New Zealand sites included patients aged ≥18 years with an ACS due to SCAD confirmed on core laboratory adjudication. Multivariable Cox proportional hazard models analysed predictors for the primary MACE outcome. Results Among 586 patients, 505 (150 prospective, 355 retrospective) with SCAD confirmed by core laboratory adjudication, mean age was 52.2 ± 10.6 years, 88.6% were female, and 74.5% were Caucasian. At long-term follow-up (median 21 months), MACE and SCAD recurrence occurred in 8.6% and 3.6% of patients, respectively. Oral anticoagulation on discharge [adjusted hazard ratio (aHR) 3.8, 95% confidence interval (CI) 1.6–9.3, P = .003], ticagrelor combined with aspirin (aHR 1.8, 95% CI 1.04–3.2, P = .037), fibromuscular dysplasia (aHR 2.2, 95% CI 1.05–4.5, P = .037), and history of stroke (aHR 3.8, 95% CI 1.2–12.2, P = .03) were independently associated with higher MACE. Fibromuscular dysplasia (aHR 3.9, 95% CI 1.5–26.5, P = .01), ticagrelor combined with aspirin (aHR 2.6, 95% CI 2.1–5.3, P = .01), and history of stroke (aHR 6.2, 95% CI 1.8–9.5, P = .01) were also associated with higher SCAD recurrence. Conclusions The findings support the hypothesis that SCAD is primarily caused by intramural bleeding, with a harmful association of more potent antiplatelet therapy and anticoagulation with adverse cardiovascular outcomes.

Background Viral infections are associated with significant morbidity and mortality in neonates. The COVID-19 pandemic led to changes in viral epidemiology in Western Australia. The impact on patients in neonatal intensive care is uncertain. Methods A retrospective cohort study of all infants admitted to King Edward Memorial Hospital and Perth Children’s Hospital Neonatal Intensive Care Units with laboratory-confirmed viral infections between January 2016 and June 2021 was performed. Demographic, clinical, polymerase chain reaction virus type, management, and outcomes data were collected. Groups were compared by χ ⁻² and comparison of means as appropriate. P values <0.05 were considered significant. Results A total of 14,935 infants were admitted during the study period. There were 267 positive polymerase chain reaction tests in 140 infants (0.8%). Viruses detected included rhinovirus (60/140, 43%), respiratory syncytial virus (48/140, 34%), enterovirus (15/140, 11%) and cytomegalovirus (8/140, 6%). Respiratory viral infections (RVIs) were more common than nonrespiratory viral infections (110/140 [79%] vs. 30/140 [21%]; P < 0.001). A majority of RVI and nonrespiratory viral infections were community-acquired (75/110 [68%] and 19/30 [63%], respectively) and in preterm infants (75/110 [68%] and 19/30 [63%], respectively). A higher proportion of infants with NRVIs compared to RVIs had long-term sequelae (13/30 [43%] vs. 17/110 [15%]; P < 0.001). RVIs decreased during COVID-19 in WA but remained similar for NRVIs. Conclusions The incidence of viral infection in our study was 0.8% of all admissions. Respiratory viruses were most common, more likely to be community–acquired, and in infants born preterm. COVID-19 and community control measures had an impact on NICU viral incidence.

Background Anterior cruciate ligament (ACL) ruptures are a potent risk factor for post-traumatic knee osteoarthritis (PTOA). Annually, in Aotearoa New Zealand, approximately 2,500 people under the age of 30 undergo ACL reconstruction surgery. Due to the young age of injury and surgery, many develop osteoarthritis before age 50 and have a higher likelihood of requiring total knee replacement compared to the general population. This study aimed to gain insight into the medium- to long-term impacts of ACL rupture on people's well-being in Aotearoa New Zealand, by exploring their lived experiences five or more years post-injury. Method In this Interpretive Description observational study, we conducted semi-structured interviews with people who had ruptured their ACL and had or were at risk of developing PTOA. Analysis was conducted guided by Braun and Clarke’s Reflexive Thematic Analysis. Findings Twelve people (7 women, median age 49.5 [25–62] years) were interviewed. Three themes were generated from the data: 1) Nobody Ever Told Me…, 2) The Post-Rehabilitation Void, and 3) The Elephant in the Room: The Psychosocial Impact. Participants commonly described fear, grief and long-term psychological impacts, and most reported wanting to know more about the long-term management of their knees. Conclusion and impact The study highlights opportunities to provide better long-term support and management, improve outcomes, and reduce the burden on these individuals. ACL injury can profoundly impact people's lives in the long term. Better education, support services, and consideration of psychosocial factors are needed. Addressing identified barriers could reduce the individual and socioeconomic burden of PTOA for New Zealanders. Future research involving stakeholders must establish acceptable long-term management programmes tailored to ensure they meet the population's needs and address the unique socioeconomic context and ethnic disparities in Aotearoa New Zealand.

Purpose Radiographic measurements have gained wide acceptance in anticipating the risk of inappropriate glenoid component positioning in reverse shoulder arthroplasty (RSA). This study aims to investigate whether the RSA angle overcorrects the base plate inclination, tilting it inferiorly, compared to the base plate correction angle (BCA), which provides neutral inclination and lateralization. Methods One hundred normal anteroposterior shoulder radiographs were evaluated to determine the average values of the RSA angle, BCA, base plate orientation angle (BOA), and the base plate shoulder angle (BSA), which represents the amount of overcorrection accomplished via the RSA angle beyond the BCA’s scope. The interobserver reliability among two independent testers was assessed by the intraclass correlation coefficient. A t-test was applied to compare the mean values of the BCA and RSA angle. Results The mean BOA and BCA values were 118° ± 5.7° and 17° ± 4.6°, respectively. The RSA angle value was 23° ± 6°. Compared to the BCA, the RSA angle overcorrected the base plate inclination by 15° ± 5° (BSA). The Student’s t-test showed a statistically significant difference between the values of the BCA and RSA angle (p-value = 0.000). The interobserver reliability was excellent for all angle measurements among two independent testers. Conclusion The RSA angle and the BOA/BCA are reliable radiographic measurements to determine the inclination of the inferior glenoid segment prior to RSA. However, surgeons need to consider the inherent inferior inclination associated with positioning the base plate according to the RSA angle (15° ± 5°).

Blepharocheilodontic syndrome (BCD syndrome) is an autosomal dominant condition characterized by cleft lip/palate, distinct eyelid abnormalities, and ectodermal changes affecting hair and teeth. This report presents a novel case of CTNND1 ‐related BCD syndrome in a 3‐year‐old female. In addition to the typical features, including unilateral cleft lip/palate and eyelid malformations, the patient exhibited a duplex kidney, ureterocele, and a bicornuate uterus—phenotypic traits not previously associated with BCD syndrome. Whole exome sequencing identified a de novo heterozygous pathogenic splice site variant in CTNND1 , confirming the diagnosis. The presence of these additional urogenital anomalies suggests a potential expansion of the BCD syndrome phenotype. This case highlights the need for further investigation into the spectrum of anomalies associated with BCD syndrome, recommending ultrasound evaluation of the urinary tract in newly diagnosed individuals.

Introduction Familial hypercholesterolaemia (FH) is a common genetic condition causing elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease. Little is currently known about how persons with FH are counselled by their healthcare professionals regarding pregnancy and breastfeeding, and how FH impacts the partner relationship and family planning. Current guidelines advise interrupting most cholesterol-lowering medication during conception, pregnancy, and breastfeeding. The guidelines, however, do not provide guidance on how healthcare professionals should address family planning, pregnancy, and breastfeeding with persons with FH and their partners in their day-to-day practice. Therefore, whether and how these topics are communicated in clinical practice remains unclear. This study aims to investigate FH awareness, knowledge, and current practices of care concerning family planning, pregnancy, and breastfeeding among persons with FH, their partners, and healthcare professionals. Methods and analysis This is the protocol of a global, mixed-methods study conducted in the Netherlands, Norway, and Australia in persons with FH, their partners, and their treating healthcare professionals. Persons with FH are interviewed about their current experiences with FH care related to family planning until inductive thematic saturation is achieved. A minimum of 120 partners of persons with FH will participate in an anonymous survey about the impact of FH on their relationship and family planning. In addition, a minimum of 120 healthcare professionals will be surveyed about their current practices and counselling of persons with FH on family planning, pregnancy, and breastfeeding. Ethics and dissemination All applicable ethics committees (Erasmus University Medical Center (MEC-2023-0070), Royal Perth Hospital human research ethics committee (RGS0000005951), and Oslo University Hospital (23/28008)) approved this study prior to its commencement. The results of this study will be disseminated via peer-reviewed journal articles, research seminars, conference presentations, and relevant media. Community dissemination is envisaged through FH patient and advocacy groups involved in community engagement in each study country.

To investigate the surgical impact of preoperative breast MRI in patients diagnosed with invasive lobular breast cancer (ILC) in a prospective observational study. The prospective MIPA observational study database was queried for patients aged 18–80 with newly diagnosed unilateral ILC at needle biopsy referred for primary surgery. Patients who underwent preoperative MRI (MRI group) were matched (1:1) with those who did not (noMRI group) according to nine confounding covariates. Surgical outcomes were compared between the matched groups with nonparametric statistics after calculating odds ratios (ORs). A total of 547 women with unilateral needle biopsy-diagnosed ILC were identified (158 noMRI group, 389 MRI group). After patient matching, each group retained 103 patients, for a total of 206 matched patients. For the rate of women having a first-line mastectomy, there was no significant difference between the MRI group (21.4%, 22/103; p = 0.727; OR 1.20, 95% CI: 0.61–2.38) and the noMRI group (18.4%, 19/103). Conversely, the reoperation rate in the MRI group (1.9%, 2/103) was significantly lower (p = 0.007; OR of avoiding reoperation 7.29, 95% CI: 1.60–33.21) than in the noMRI group (12.6%, 13/103 patients). Overall mastectomy rates (first plus second-line) did not significantly differ between the MRI group (23.3%, 24/103; p = 0.867, OR 1.12, 95% CI: 0.58–2.16) and the noMRI group (21.4%, 22/103). Women who had preoperative MRI after a needle biopsy diagnosis of ILC had a significant six-fold reduction in reoperations compared to those who did not have an MRI examination, with similar overall mastectomy rates. Question No randomized controlled trials investigating the impact of preoperative MRI on surgical outcomes (mastectomy rates and reoperation) of needle-biopsy-diagnosed ILC have been conducted. Findings In a patient-matched analysis of 103 vs 103 women, preoperative MRI led to a greater than six-fold reduction of reoperations, without significant differences in first-line and overall mastectomy rates. Clinical relevance In the absence of randomized controlled trials, patient matching can be applied to mitigate confounding factors that drive the referral to preoperative MRI, showing that preoperative MRI has beneficial effects on surgical outcomes in patients with needle biopsy-diagnosed unilateral ILC.

Background/Objectives: Determining whether dietary fatty acids and the use of fat spreads are associated with cardiovascular risk factors is difficult due to the multicollinearity of fatty acids and the consumption of multiple spread types. Methods: We applied clustering methodologies using data on 31 different fatty acids and 5 different types of fat spreads (high fat: butter, blended butters, and margarines; lower fat: polyunsaturated and monounsaturated) and investigated associations with blood pressure, serum lipid patterns and insulin resistance in the Raine Study Gen2 participants in Western Australia, at 20 and 22 years of age. Results: Amongst n = 785 participants, there were eight distinct clusters formed from the fatty acid data and ten distinct clusters formed from the fat spread data. Male participants had higher systolic blood pressure than females (122.2 ± 11.6 mmHg versus 111.7 ± 10.3, p < 0.001 at age 20 and 123.4 ± 10.6 versus 113.9 ± 9.8, p < 0.001 at age 22). Males consuming exclusively butter as a fat spread had significantly higher SBP (+4.3 mmHg) compared with males not using spreads. Males consuming a high intake of margarine had significantly higher SBP (+6.6 mmHg), higher DBP (+3.4 mmHg) and higher triglycerides (+30.5%). Amongst females, four patterns of fatty acid intake were associated with lower levels of HDL cholesterol compared with the low-saturated-fat/high n-3 reference group (p = 0.017 after adjustment for relevant confounders, range = −10.1% to −16.0%, p = 0.017). There were no associations between clusters and HOMA-IR or other serum lipids for males or females. Conclusions: Compared to using no fat spreads, amongst males, a high intake of margarine was characterised by higher systolic and diastolic blood pressure and higher serum triglycerides, whilst the use of butter also was associated with higher SBP. Diets low in n-3s or high in trans fats were associated with sub-optimal HDL levels amongst females.

Purpose of Review High-density lipoprotein (HDL) is integral to reverse cholesterol transport (RCT), a process considered to protect against atherosclerotic cardiovascular disease (ASCVD). We summarise findings from the recent AEGIS-II trial and discuss new opportunities for HDL therapeutics targeted at RCT. Recent Findings Mendelian randomisation studies have suggested a causal association between the functional properties of HDL and ASCVD. However, the AEGIS-II trial of CSL112, an apolipoprotein A-I therapy that enhances cholesterol efflux, did not meet its primary endpoint. Exploratory analyses demonstrated that CSL112 significantly reduced ASCVD events among participants with a baseline low-density lipoprotein (LDL)-cholesterol ≥ 100 mg/dL, suggesting that RCT may depend on LDL-cholesterol levels. Summary The role of HDL therapeutics in patients with familial hypercholesterolaemia, inherited low HDL-cholesterol and impaired HDL function, especially with inadequately controlled LDL-cholesterol, merits further investigation. The treatment of patients with monogenic defects in HDL metabolism remains a significant gap in care that needs further research.

Cancer cells are addicted to polyamines, polycations essential for cellular function. While dual targeting of cellular polyamine biosynthesis and polyamine uptake is under clinical investigation in solid cancers, preclinical and clinical studies into its potential in haematological malignancies are lacking. Here we investigated the preclinical efficacy of polyamine depletion in acute leukaemia. The polyamine biosynthesis inhibitor difluoromethylornithine (DFMO) inhibited growth of a molecularly diverse panel of acute leukaemia cell lines, while non‐malignant cells were unaffected. Responsiveness to DFMO was linked to decreased levels of its molecular target, the rate‐limiting polyamine biosynthesis enzyme ODC1, and of the polyamine transporters ATP13A2 and ATP13A3. DFMO increased polyamine uptake and upregulated expression of polyamine transporters in acute leukaemia cells, a compensatory effect abolished by treatment with the polyamine transport inhibitor AMXT 1501. This drug, currently in a phase 1 clinical trial in solid tumours in combination with DFMO, potentiated the inhibitory effects of DFMO, and their combination synergistically inhibited the growth of acute leukaemia cell lines by inducing apoptosis. DFMO and AMXT 1501 limited disease progression in highly aggressive xenograft models of infant KMT2A‐rearranged leukaemia, even when treatment was initiated at high disease burden. Increased expression of c‐MYC was associated with enhanced sensitivity to the combination of DFMO and AMXT 1501, suggesting this oncoprotein as a potential predictive marker of response to the drug combination. In conclusion, targeting polyamine biosynthesis and polyamine uptake limits disease progression in models of acute leukaemia, supporting further preclinical and clinical investigation into this approach for acute leukaemia.

To determine whether the discharge diagnosis codes used within tertiary hospitals accurately identified patients with Giant Cell Arteritis (GCA), as determined by expert opinion at 6 months. The study was performed across three major hospitals within Perth, Western Australia. Patients with an International Classification of Diseases (ICD) code for GCA (M31.5 and M31.6) at discharge on first inpatient presentation were identified. Review of case notes, discharge summaries, letters, pathology, and imaging results were undertaken. The percentage of patients with an ICD code for GCA at initial discharge with confirmed GCA by expert opinion at 6 months (as the anchor diagnosis) was calculated. As validation of the anchor diagnosis, the percentage who fulfilled the 2022 ACR/EULAR criteria was also calculated, the number of hospital discharges per patient with an ICD code for GCA was calculated, to determine if multiple discharges with an ICD code for GCA increased the specificity of the ICD coding. 93 out of 157 admissions with an ICD for GCA were identified as a first inpatient presentation. At 6 months follow up, 65.6%, 95 CI [55.0%, 75.1%] had confirmed GCA by expert opinion. 88.2%, 95 CI [79.8%, 93.9%] met the 2022 ACR/EULAR criteria for GCA. The specificity of the ICD coding increased with increasing number of discharges– 67.4% with single episode, 80% with two episodes, and 100% with three or more episodes (p = 0.1373). Only 43.8%, 95 CI [26.4%, 62.3%] of patients who did not have GCA had an alternative diagnosis provided. 31.3%, 95 CI [16.1%, 50.0%] of patients who did not have GCA still have the GCA diagnosis listed in their subsequent clinical records and discharge summaries. Only 2/3rds of those patients with an initial discharge ICD code for GCA were found to have confirmed GCA at follow-up. This poor correlation between the ICD coding and confirmed diagnosis of GCA will impact the quality of data extracted from administrative health datasets for epidemiological and longitudinal studies. Selecting patients with two or more GCA coded episodes could improve the homogeneity of the cohort for recruitment into GCA studies, but a larger sample size study is required.