Medicine publications
Permanent URI for this collection
Browse
Recent Submissions
Item Open Access Urine congophilia associated with preeclampsia does not persist 6-months postpartum(Elsevier BV, 2024) Hofstee, P.; Lum, J.S.; Chow, Y.Y.; Wittwer, M.R.; Arstall, M.; Dekker, G.; Clifton, V.L.; Wright, I.M.; Kelly, M.A.; Ecroyd, H.Introduction: Preeclampsia is a common hypertensive disorder of pregnancy. Several studies have demonstrated that protein aggregates, detected through urine congophilia, is associated with preeclampsia; however, it has yet to be investigated whether urine congophilia remains postpartum in these women. In this study, we aimed to augment prior studies and determine whether urine congophilia is present postpartum. Methods: Women were recruited from Lyell McEwin Hospital, South Australia. Urine samples were collected during pregnancy and 6-months postpartum from women with non-preeclampsia pregnancies (n = 48) and women with pregnancies complicated by preeclampsia (n = 42). A Congo Red Dot blot test, total protein and creatinine levels from urine, as well as serum Soluble fms-like tyrosine kinase 1 to placental growth factor ratio (sFlt-1:PlGF), were assessed and correlated. Results: Preeclamptic women exhibited increased urine congophilia (P < 0.01), sFlt-1:PlGF ratio (P < 0.0001) and total protein (P < 0.01) during pregnancy; with a positive correlation between urine congophilia and total protein across the entire cohort (P < 0.0001). Although urine congophilia was no longer detected 6-months postpartum in preeclamptic women, total protein remained elevated (P < 0.05). sFlt-1:PlGF ratio during pregnancy was positively correlated with congophilia across the cohort (P = 0.0007). Serum creatinine was also higher in preeclamptic women during pregnancy (P < 0.001). Discussion: These results support that urine congophilia is significantly elevated in pregnancies complicated with preeclampsia and show that it does not continue postpartum, although larger cohort studies are needed to determine its feasibility as a diagnostic marker.Item Open Access Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy(Nature Publishing Group, 2024) de Nys, R.; van Eyk, C.L.; Ritchie, T.; Møller, R.S.; Scheffer, I.E.; Marini, C.; Bhattacharjee, R.; Kumar, R.; Gecz, J.Clustering Epilepsy (CE) is an epileptic disorder with neurological comorbidities caused by heterozygous variants of the X chromosome gene Protocadherin 19 (PCDH19). Recent studies have implicated dysregulation of the Nuclear Hormone Receptor (NHR) pathway in CE pathogenesis. To obtain a comprehensive overview of the impact and mechanisms of loss of PCDH19 function in CE pathogenesis, we have performed epigenomic, transcriptomic and proteomic analysis of CE relevant models. Our studies identified differential regulation and expression of Androgen Receptor (AR) and its targets in CE patient skin fibroblasts. Furthermore, our cell culture assays revealed the repression of PCDH19 expression mediated through ERα and the co-regulator FOXA1. We also identified a protein-protein interaction between PCDH19 and AR, expanding upon the intrinsic link between PCDH19 and the NHR pathway. Together, these results point to a novel mechanism of NHR signaling in the pathogenesis of CE that can be explored for potential therapeutic options.Item Open Access Assessing the influence of preconception diet on male fertility: a systematic scoping review(Oxford University Press (OUP), 2024) Tully, C.A.; Alesi, S.; McPherson, N.O.; Sharkey, D.J.; Teong, X.T.; Tay, C.T.; Silva, T.R.; Puglisi, C.; Barsby, J.P.; Moran, L.J.; Grieger, J.A.; Mousa, A.BACKGROUND: The last decade has seen increased research on the relationship between diet and male fertility, but there are no clearly defined nutritional recommendations for men in the preconception period to support clinical fertility outcomes. OBJECTIVE AND RATIONALE: The purpose of this scoping review is to examine the extent and range of research undertaken to evaluate the effect(s) of diet in the preconception period on male clinical fertility and reproductive outcomes. SEARCH METHODS: Four electronic databases (MEDLINE and EMBASE via Ovid, CAB Direct, and CINAHL via EBSCO) were searched from inception to July 2023 for randomized controlled trials (RCTs) and observational studies (prospective/retrospective, case–control, and cross-sectional). Intervention studies in male participants or couples aiming to achieve dietary or nutritional change, or non-intervention studies examining dietary or nutritional components (whole diets, dietary patterns, food groups or individual foods) in the preconception period were included. Controls were defined as any comparison group for RCTs, and any/no comparison for observational studies. Primary outcomes of interest included the effect(s) of male preconception diet on clinical outcomes such as conception (natural or via ART), pregnancy rates and live birth rates. Secondary outcomes included time to conception and sperm parameters. OUTCOMES: A total of 37 studies were eligible, including one RCT and 36 observational studies (prospective, cross-sectional, and case–control studies; four studies in non-ART populations) published between 2008 and 2023. Eight reported clinical outcomes, 26 reported on secondary outcomes, and three reported on both. The RCT did not assess clinical outcomes but found that tomato juice may benefit sperm motility. In observational studies, some evidence suggested that increasing fish or reducing sugar-sweetened beverages, processed meat or total fat may improve fecundability. Evidence for other clinical outcomes, such as pregnancy rates or live birth rates, showed no relationship with cereals, soy and dairy, and inconsistent relationships with consuming red meat or a ‘healthy diet’ pattern. For improved sperm parameters, limited evidence supported increasing fish, fats/fatty acids, carbohydrates and dairy, and reducing processed meat, while the evidence for fruits, vegetables, cereals, legumes, eggs, red meat and protein was inconsistent. Healthy diet patterns in general were shown to improve sperm health. WIDER IMPLICATIONS: Specific dietary recommendations for improving male fertility are precluded by the lack of reporting on clinical pregnancy outcomes, heterogeneity of the available literature and the paucity of RCTs to determine causation or to rule out reverse causation. There may be some benefit from increasing fish, adopting a healthy dietary pattern, and reducing consumption of sugar-sweetened beverages and processed meat, but it is unclear whether these benefits extend beyond sperm parameters to improve clinical fertility. More studies exploring whole diets rather than singular foods or nutritional components in the context of male fertility are encouraged, particularly by means of RCTs where feasible. Further assessment of core fertility outcomes is warranted and requires careful planning in high-quality prospective studies and RCTs. These studies can lay the groundwork for targeted dietary guidelines and enhance the prospects of successful fertility outcomes for men in the preconception period. Systematic search of preconception diet suggests that increasing fish and reducing sugary drinks, processed meats and total fat may improve male fertility, while consuming healthy diets, fish, fats/fatty acids, carbohydrates and dairy and reducing processed meat can improve sperm health.Item Open Access The impact of maternal asthma on the fetal lung: Outcomes, mechanisms and interventions(Elsevier, 2024) Robinson, J.L.; Gatford, K.L.; Clifton, V.L.; Morrison, J.L.; Stark, M.J.Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers.Item Open Access The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer(Springer Nature, 2024) Achinger-Kawecka, J.; Stirzaker, C.; Portman, N.; Campbell, E.; Chia, K.-M.; Du, Q.; Laven-Law, G.; Nair, S.S.; Yong, A.; Wilkinson, A.; Clifton, S.; Milioli, H.H.; Alexandrou, S.; Caldon, C.E.; Song, J.; Khoury, A.; Meyer, B.; Chen, W.; Pidsley, R.; Qu, W.; et al.Three-dimensional (3D) epigenome remodeling is an important mechanism of gene deregulation in cancer. However, its potential as a target to counteract therapy resistance remains largely unaddressed. Here, we show that epigenetic therapy with decitabine (5-Aza-mC) suppresses tumor growth in xenograft models of pre-clinical metastatic estrogen receptor positive (ER+) breast tumor. Decitabine-induced genome-wide DNA hypomethylation results in large-scale 3D epigenome deregulation, including de-compaction of higher-order chromatin structure and loss of boundary insulation of topologically associated domains. Significant DNA hypomethylation associates with ectopic activation of ER-enhancers, gain in ER binding, creation of new 3D enhancer-promoter interactions and concordant up-regulation of ER-mediated transcription pathways. Importantly, long-term withdrawal of epigenetic therapy partially restores methylation at ER-enhancer elements, resulting in a loss of ectopic 3D enhancer-promoter interactions and associated gene repression. Our study illustrates the potential of epigenetic therapy to target ER+ endocrine-resistant breast cancer by DNA methylation-dependent rewiring of 3D chromatin interactions, which are associated with the suppression of tumor growth.Item Open Access Expression of PCOS candidate genes in bovine fetal and adult ovarian somatic cells(Bioscientifica, 2022) Liu, M.; Bastian, N.A.; Hartanti, M.D.; Hummitzsch, K.; Irving-Rodgers, H.F.; Anderson, R.A.; Rodgers, R.J.Polycystic ovary syndrome (PCOS) is an endocrine metabolic disorder that appears to have a genetic predisposition and a fetal origin. The fetal ovary has two major somatic cell types shown previously to be of different cellular origins and different morphologies and to differentially express 15 genes. In this study, we isolated the somatic gonadal ridge epithelial-like (GREL) cells (n = 7) and ovarian fetal fibroblasts (n = 6) by clonal expansion. Using qRT-PCR, we compared the gene expression levels of PCOS candidate genes with previous data on the expression levels in whole fetal ovaries across gestation. We also compared these levels with those in bovine adult ovarian cells including fibroblasts (n = 4), granulosa cells (n = 5) and surface epithelial cells (n = 5). Adult cell types exhibited clear differences in the expression of most genes. In fetal ovarian cells, DENND1A and ERBB3 had significantly higher expression in GREL cells. HMGA2 and TGFB1I1 tended to have higher expression in fetal fibroblasts than GREL cells. The other 19 genes did not exhibit differences between GREL cells and fetal fibroblasts and FBN3, FSHB, LHCGR, FSHR and ZBTB16 were very lowly expressed in GREL cells and fibroblasts. The culture of fetal fibroblasts in EGF-containing medium resulted in lower expression of NEIL2 but higher expression of MAPRE1 compared to culture in the absence of EGF. Thus, the two fetal ovarian somatic cell types mostly lacked differential expression of PCOS candidate genes.Item Open Access Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial(Springer Science and Business Media LLC, 2023) Agarwal, N.; Shah, K.K.; Dansie, K.; Bennett, P.N.; Greenham, L.; Brown, C.; Smyth, B.; McDonald, S.; Jesudason, S.; Viecelli, A.K.; Morton, R.L.Background: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants’ treating team, for severe or worsening symptoms as identifed by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. Methods: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. Results: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. Conclusions: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A defnitive national RCT is underway.Item Open Access Pulsed-field ablation: Computational modeling of electric fields for lesion depth analysis(Elsevier BV, 2022) Meckes, D.; Emami, M.; Fong, I.; Lau, D.H.; Sanders, P.Background: Pulsed-field ablation (PFA) is an emerging and promising nonthermal technology for cardiac ablation. The effective applied voltage to achieve adequate irreversible myocardial injury is not well studied. The pulsed-field strength remains independent of tissue contact; therefore, PFA is assumed to be an ablation technology, not mandating the need for tissue contact. Objective: Determine the effect of applied voltage and distance to surface on depth of myocardial injury using PFA. Methods: A computational model was developed and validated based on extracted data from in vivo studies to examine the effect of different applied voltages and the impact of distance between the catheter and endocardial surface on the depth of irreversible myocardial injury using PFA. Results: The depth of lesions created by PFA are dose-dependent, and there is a direct correlation between applied PFA voltages and depth of irreversible myocardial injury. The minimum applied voltage of PFA required to create a lesion deeper than 1 mm is 300 volts. The catheter-tissue contact plays a pivotal role in determining lesion depth. With optimal catheter contact in the absence of trabeculation, the minimal applied energy required to achieve a 3-mm-deep lesion is 700 volts. A minor increase in the cathetertissue distance of 1–2 mm doubles the minimum required applied voltage, increasing it to 1500 volts. Conclusion: PFA is an important new technology that is proposed to be more efficacious and safer than currently used thermal ablation. Here we demonstrate the impact of dose dependence and the need for maintaining tissue contact during ablation.Item Open Access Quantifying EGFR endosomal recycling via immunofluorescence in breast cancer cells(Elsevier BV, 2022) Lonic, A.; Onglao, W.; Khew-Goodall, Y.Previously published protocols for quantification of endosomal recycling are limited by the use of radioactive reagents, washing of cells in reducing buffers, or the requirement for large numbers of cells. Here, we describe a protocol for quantification of endosomal recycling using immunofluorescence that is optimized for EGFR in BT-549 breast cancer cells but could be applied to other RTKs and cell lines. Our protocol enables quick assessment of recycling and uses a relatively small number of cells.Item Open Access The shifting care and outcomes for patients with endangered limbs – Critical limb ischemia (SCOPE-CLI) registry overview of study design and rationale(Elsevier BV, 2022) Scierka, L.E.; Mena-Hurtado, C.; Shishehbor, M.H.; Spertus, J.A.; Nagpal, S.; Babrowski, T.; Bunte, M.C.; Politano, A.; Humphries, M.; Chung, J.; Kirksey, L.; Alabi, O.; Soukas, P.; Parikh, S.; Faizer, R.; Fitridge, R.; Provance, J.; Romain, G.; McMillan, N.; Stone, N.; et al.Background: Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is associated with pain, poor wound healing, high rates of amputation, and mortality (>20% at 1 year). Little is known about the processes of care, patients’ preferences, or outcomes, as seen from patients’ perspectives. The SCOPE-CLI study was co-designed with patients to holistically document patient characteristics, treatment preferences, patterns of care, and patient-centered outcomes for CLI. Methods: This 11-center prospective observational registry will enroll and interview 816 patients from multispecialty, interdisciplinary vascular centers in the United States and Australia. Patients will be followed up at 1, 2, 6, and 12 months regarding their psychosocial factors and health status. Hospitalizations, interventions, and outcomes will be captured for 12 months with vital status extending to 5 years. Pilot data were collected between January and July of 2021 from 3 centers. Results: A total of 70 patients have been enrolled. The mean age was 68.4 ± 11.3 years, 31.4% were female, and 20.0% were African American. Conclusions: SCOPE-CLI is uniquely co-designed with patients who have CLI to capture the care experiences, treatment preferences, and health status outcomes of this vulnerable population and will provide much needed information to understand and address gaps in the quality of CLI care and outcomes.Item Metadata only Reducing the polyp burden in serrated polyposis by serial colonoscopy: the impact of nationally coordinated community surveillance(New Zealand Medical Association, 2017) Parry, S.; Burt, R.W.; Win, A.K.; Aung, Y.K.; Woodall, S.; Arnold, J.; Clendenning, M.; Buchanan, D.D.; Price, T.J.; Rosty, C.; Young, J.P.Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC) and an evolving management approach. The aims of this study were to assess the polyp burden reduction over time, and the incidence of CRC in serrated polyposis patients undergoing community surveillance.This is an observational study based on prospectively collected data. A total of 96 SPS patients with no personal history of CRC were prospectively enrolled in a surveillance program under the guidance of a tertiary center. Patients underwent surveillance colonoscopy in multiple centres across New Zealand.Patients underwent a median of four colonoscopies with a median interval of 15 months over a median follow-up period of 4.8 years. Five of 96 patients (5%) were referred for surgery, and the remaining 91 were managed by colonoscopy alone. In patients referred for surgery, 92% of the surveillance intervals to the fourth colonoscopy had been ≤12 months compared to 33% (P<0.001) in the colonoscopy only group, and all five (100%) had ≥20 pancolonic polyps after four procedures compared with only 5/91 (5%) in those managed by colonoscopy alone. In patients successfully managed by colonoscopy, 86% had <10 pancolonic polyps, >75% no longer had polyps ≥10mm and >90% no longer had proximal serrated polyps ≥10mm after the fourth colonoscopy. No patients were found to develop CRC during the study time period.Patients with SPS were managed by proactive surveillance colonoscopy in wider hospital settings under tertiary centre guidance, with only 5% requiring surgical management. No CRC was diagnosed in any patient during surveillance.Item Open Access Relaxin elicits renoprotective actions accompanied by increasing bile acid levels in streptozotocin-induced diabetic mice(Elsevier BV, 2023) Leo, C.H.; Ou, J.L.M.; Ong, E.S.; Qin, C.X.; Ritchie, R.H.; Parry, L.J.; Ng, H.H.Background: The peptide hormone relaxin has potent anti-fibrotic and anti-inflammatory properties in various organs, including the kidneys. However, the protective effects of relaxin in the context of diabetic kidney complications remain controversial. Here, we aimed to evaluate the effects of relaxin treatment on key markers of kidney fibrosis, oxidative stress, and inflammation and their subsequent impact on bile acid metabolism in the streptozotocin-induced diabetes mouse model. Methods and results: Male mice were randomly allocated to placebo-treated control, placebo-treated diabetes or relaxin-treated diabetes groups (0.5 mg/kg/d, final 2 weeks of diabetes). After 12 weeks of diabetes or sham, the kidney cortex was harvested for metabolomic and gene expression analyses. Diabetic mice exhibited significant hyperglycaemia and increased circulating levels of creatine, hypoxanthine and trimethylamine N-oxide in the plasma. This was accompanied by increased expression of key markers of oxidative stress (Txnip), inflammation (Ccl2 and Il6) and fibrosis (Col1a1, Mmp2 and Fn1) in the diabetic kidney cortex. Relaxin treatment for the final 2 weeks of diabetes significantly reduced these key markers of renal fibrosis, inflammation, and oxidative stress in diabetic mice. Furthermore, relaxin treatment significantly increased the levels of bile acid metabolites, deoxycholic acid and sodium glycodeoxycholic acid, which may in part contribute to the renoprotective action of relaxin in diabetes. Conclusion: In summary, this study shows the therapeutic potential of relaxin and that it may be used as an adjunctive treatment for diabetic kidney complications.Item Open Access The effect of inlet flow profile and nozzle diameter on drug delivery to the maxillary sinus(Springer, 2022) Pourmehran, O.; Cazzolato, B.; Tian, Z.; Arjomandi, M.In this paper, the effect of the turbulence and swirling of the inlet flow and the diameter of the nozzle on the flow characteristics and the particles' transport/deposition patterns in a realistic combination of the nasal cavity (NC) and the maxillary sinus (MS) were examined. A computational fluid dynamics (CFD) model was developed in ANSYS® Fluent using a hybrid Reynolds averaged Navier-Stokes-large-eddy simulation algorithm. For the validation of the CFD model, the pressure distribution in the NC was compared with the experimental data available in the literature. An Eulerian-Lagrangian approach was employed for the prediction of the particle trajectories using a discrete phase model. Different inlet flow conditions were investigated, with turbulence intensities of 0.15 and 0.3, and swirl numbers of 0.6 and 0.9 applied to the inlet flow at a flow rate of 7 L/min. Monodispersed particles with a diameter of 5 µm were released into the nostril for various nozzle diameters. The results demonstrate that the nasal valve plays a key role in nasal resistance, which damps the turbulence and swirl intensities of the inlet flow. Moreover, it was found that the effect of turbulence at the inlet of the NC on drug delivery to the MS is negligible. It was also demonstrated that increasing the flow swirl at the inlet and decreasing the nozzle diameter improves the total particle deposition more than threefold due to the generation of the centrifugal force, which acts on the particles in the nostril and vestibule. The results also suggest that the drug delivery efficiency to the MS can be increased by using a swirling flow with a moderate swirl number of 0.6. It was found that decreasing the nozzle diameter can increase drug delivery to the proximity of the ostium in the middle meatus by more than 45%, which subsequently increases the drug delivery to the MS. The results can help engineers design a nebulizer to improve the efficiency of drug delivery to the maxillary sinuses.Item Open Access Current advances in imaging spectroscopy and its state-of-the-art applications(Elsevier, 2024) Zahra, A.; Qureshi, R.; Sajjad, M.; Sadak, F.; Nawaz, M.; Khan, H.A.; Uzair, M.Imaging spectroscopy integrates traditional computer vision and spectroscopy into a single system and has gained widespread acceptance as a non-destructive scientific instrument for a wide range of applications. The current state of imaging spectroscopy spans diverse applications including but not limited to air-borne and ground-based computer vision systems. This paper presents the current state of research and industrial applications including precision agriculture, material classification, medical science, forensic science, face recognition and document image analysis, environment monitoring, and remote sensing, which can be aided through imaging spectroscopy. In this regard, we further discuss a comprehensive list of applications of imaging spectroscopy, pre-processing techniques, and spectral image acquisition systems. Likewise, publicly available databases and current software tools for spectral data analysis are also documented in this review. This review paper, therefore, could potentially serve as a reference and roadmap for people looking for literature, databases, applications, and tools to undertake additional research in imaging spectroscopy.Item Open Access FAST-IT: Find A Simple Test - In TIA (Transient Ischaemic Attack) - a prospective cohort study to develop a multivariable prediction model for diagnosis of TIA through proteomic discovery and candidate lipid mass-spectrometry, neuroimaging and machine learning - study protocol(BMJ Journals, 2022) Milton, A.G.; Lau, S.; Kremer, K.L.; Rao, S.R.; MAS, E.; Snel, M.F.; Trim, P.J.; Sharma, D.; Edwards, S.; Jenkinson, M.; Kleinig, T.J.; Noschka, E.; Hamilton-Bruce, M.A.; Koblar, S.A.Introduction Transient ischaemic attack (TIA) may be a warning sign of stroke and difficult to differentiate from minor stroke and TIA-mimics. Urgent evaluation and diagnosis is important as treating TIA early can prevent subsequent strokes. Recent improvements in mass spectrometer technology allow quantification of hundreds of plasma proteins and lipids, yielding large datasets that would benefit from different approaches including machine learning. Using plasma protein, lipid and radiological biomarkers, our study will develop predictive algorithms to distinguish TIA from minor stroke (positive control) and TIA-mimics (negative control). Analysis including machine learning employs more sophisticated modelling, allowing non-linear interactions, adapting to datasets and enabling development of multiple specialised test-panels for identification and differentiation. Methods and analysis Patients attending the Emergency Department, Stroke Ward or TIA Clinic at the Royal Adelaide Hospital with TIA, minor stroke or TIA-like symptoms will be recruited consecutively by staff-alert for this prospective cohort study. Advanced neuroimaging will be performed for each participant, with images assessed independently by up to three expert neurologists. Venous blood samples will be collected within 48 hours of symptom onset. Plasma proteomic and lipid analysis will use advanced mass spectrometry (MS) techniques. Principal component analysis and hierarchical cluster analysis will be performed using MS software. Output files will be analysed for relative biomarker quantitative differences between the three groups. Differences will be assessed by linear regression, one-way analysis of variance, Kruskal-Wallis H-test, χ2 test or Fisher’s exact test. Machine learning methods will also be applied including deep learning using neural networks.Item Open Access Transvenous phrenic nerve stimulation for treating central sleep apnea may regulate sleep microstructure(Elsevier BV, 2024) Hartmann, S.; Immanuel, S.; McKane, S.; Linz, D.; Parrino, L.; Baumert, M.Study objectives: To assess the impact of transvenous phrenic nerve stimulation (TPNS) on non-rapid eye movement sleep microstructure quantified by cyclic alternating pattern (CAP) in individuals with central sleep apnea (CSA). Methods: We analyzed baseline and 6-month follow-up overnight polysomnograms (PSG) in 134 CSA patients enrolled in the remed¯e System Pivotal Trial implanted with TPNS randomized (1:1) to neurostimulation (treatment group) or no stimulation (control group). Differences in CAP rate, A1 index, and A2+A3 index between study arms at follow-up were assessed using Analysis of Covariance adjusted for baseline values. Results: On follow-up PSG, the treatment group showed a decrease in the frequency of A2+A3 phases compared to controls (− 5.86 ± 11.82 vs. 0.67 ± 15.25, p = 0.006), while the frequency of A1 phases increased more in the treatment group (2.57 ± 11.67 vs. − 2.47 ± 10.60, p = 0.011). The change in CAP rate at follow-up was comparable between study arms. Conclusions: TPNS treatment for central sleep apnea may affect sleep microstructure. Brief phases of rapid cortical activity appear to be replaced by short phases of slower cortical activity, which may promote sleep continuity. Further investigations are warranted to elucidate the mechanisms underlying the effect of TPNS on CAP.Item Metadata only Reporting quality and risk of bias in JBI systematic reviews evaluating the effectiveness of interventions: a methodological review protocol.(Wolters Kluwer, 2023) Grammatopoulos, T.; Hunter, J.W.S.; Munn, Z.; Stone, J.C.; Barker, T.H.Objective: The objective of this methodological review is to evaluate the adherence of systematic reviews of effectiveness published in JBI Evidence Synthesis to reporting guidelines and methodological quality. Introduction: Systematic reviews of effectiveness are essential tools for health practitioners and policy-makers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and the Risk of Bias in Systematic Reviews (ROBIS) tool are used to ensure maintenance of high reporting standards and methodological quality, respectively. This review will utilize these tools to identify strengths and shortfalls in the reporting quality of JBI systematic reviews of effectiveness. Inclusion criteria: This review will include the 20 most recent systematic reviews of effectiveness published in JBI Evidence Synthesis. Methods: This review will search MEDLINE (PubMed) for effectiveness reviews published in JBI Evidence Synthesis. Abstract and full-text screening will be performed by 2 independent reviewers, and the most recent 20 studies will be selected for inclusion. Data regarding adherence to PRISMA 2020 and ROBIS will be extracted by 2 independent reviewers. Data will be presented descriptively with tables and synthesized narratively.Item Open Access REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol(BMJ, 2023) Deane, A.M.; Alhazzani, W.; Guyatt, G.; Finfer, S.; Marshall, J.C.; Myburgh, J.; Zytaruk, N.; Hardie, M.; Saunders, L.; Knowles, S.; Lauzier, F.; Chapman, M.J.; English, S.; Muscedere, J.; Arabi, Y.; Ostermann, M.; Venkatesh, B.; Young, P.; Thabane, L.; Billot, L.; et al.Introduction: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. Methods and analysis: REVISE is an international, randomised, concealed, stratified, blinded parallelgroup individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial.Item Metadata only Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.(American College of Physicians, 2023) Venetis, C.; Choi, S.K.Y.; Jorm, L.; Zhang, X.; Ledger, W.; Lui, K.; Havard, A.; Chapman, M.; Norman, R.J.; Chambers, G.M.Background: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ARTconceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. Objective: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. Design: Propensity score–weighted population-based cohort study. Setting: New South Wales, Australia. Participants: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. Measurements: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups—those with and without a parental history of infertility (NC-infertile and NC-fertile). Results: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n ¼ 747 018), ARTconceived singleton infants (n ¼ 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n ¼ 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n ¼ 13 574). Limitations: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. Conclusion: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility.Item Open Access A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth(eLife Sciences Publications, 2021) Gillis, J.L.; Hinneh, J.A.; Ryan, N.K.; Irani, S.; Moldovan, M.; Quek, L.-E.; Shrestha, R.; Hanson, A.R.; Xie, J.; Hoy, A.J.; Holst, J.; Centenera, M.M.; Mills, I.G.; Lynn, D.J.; Selth, L.A.; Butler, L.M.Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.