Austin Health

Approximately one-third of epilepsy patients will not achieve seizure freedom with current antiseizure medications, and the identification of novel treatment targets is needed. We characterized alterations in neuroinflammation-related mRNA levels to aid in the identification of possible molecular mediators of DRTLE and discuss the potential for immunomodulatory therapies in this condition. Temporal lobe samples from DRTLE and postmortem controls without neurological conditions were obtained. RT-qPCR of 60 genes of interest was performed on BioMark Fluidigm custom-made gene expression integrated fluidic circuits (IFC) and cycle threshold values were obtained and analyzed using the method. Correlation with various clinical parameters was assessed. Immunohistochemistry was performed on a subset of seven cases and four controls. Temporal lobe tissue from 17 DRTLE patients (age: 46.3 ± 12.8 years; female: 35.3%) and 12 controls (age: 56.1 ± 6.1 years; female: 33.3%) were analyzed. Compared to controls, TNF and CCL3 were upregulated 52.7 (p < .0002) and 68.9 (p < .0001)-fold, respectively. C3 was increased by 5.9-fold (p < .0001). IL1B and IL18 were increased 6.4 (p < .0001) and 5.2 (p < .0001) times, respectively. Microglial markers TMEM119 and P2RY12 had a 7.1 (p < .0001) and 5.9 (p < .0001)-fold increase, respectively, with overall lower but significant increases in general mononuclear cell-associated mRNA. There was only low-level or no upregulation of T cell and B cell associated mRNA. No correlation between mRNA alterations and clinical parameters was found. On immunohistochemistry, TMEM119 protein expression was noted in resected brain tissue from DRTLE but was largely absent from controls, consistent with the mRNA results. Given the cross-sectional study design, causality cannot be determined. However, this study suggests that proinflammatory mechanisms may play a role in the pathogenesis of the ongoing epileptic state in DRTLE. In particular, complement, inflammasome, and microglial/mononuclear cell-mediated inflammatory processes had the most significant elevations in mRNA, while B and T cell associated mRNA were less altered.

Malformations of cortical development (MCDs) are a frequent cause of drug-resistant epilepsy and a common indication for resective epilepsy surgery. As magnetic resonance imaging (MRI) lacks sensitivity for subtle MCDs, supplemental diagnostic tools are needed. This study aimed to characterize scalp electroencephalographic (EEG) patterns in MCDs and investigate their association with surgical outcomes. This was a retrospective case-control study including patients who underwent inpatient video-EEG monitoring at two Australian hospitals. Cases were individuals with MCDs confirmed on MRI or histopathology; controls included patients with other focal epilepsies. Two epileptologists independently reviewed interictal and seizure-onset EEG patterns using a standardized classification framework. Patterns were compared between cases and controls and assessed with respect to postoperative seizure outcomes, adjusting for antiseizure medication reduction. We included 38 cases with MCDs (52.6% females, median age = 34 years) and 114 controls (45.6% females, median age = 41 years). Among interictal patterns, repetitive epileptiform discharges type 1 and type 2 were more prevalent in patients with MCDs than controls (p = .002 and .005, respectively). Focal fast epileptiform discharges were also more frequent in MCD patients, after excluding nonlesional focal epilepsy controls (p = .038). Among seizure-onset patterns, paroxysmal fast activity was more prevalent in MCDs (p < .001). Among 38 patients who underwent surgery, 70.0% of MCDs and 75.0% of controls had favorable outcomes. No EEG pattern predicted postoperative seizure outcomes. Distinct scalp EEG patterns may support differentiation of MCDs from other focal epilepsies. Larger prospective studies are needed to clarify their role in detecting MRI-negative MCD or guiding targeted imaging.

Debilitating Symptom Complexes Attributed to Ticks (DSCATT) is a chronic, debilitating illness associated with tick bites in Australia. DSCATT is of unknown aetiology, can impact emotional well-being and has no recognised treatments. The development and piloting of a novel psychotherapeutic adjunctive intervention for DSCATT that aimed to increase daily functioning, improve quality of life and reduce the impact of symptoms in people with DSCATT. This is a single-site, intervention development and acceptability study. The intervention was developed iteratively according to a Human-Centred Design (HCD) approach and manualised across four phases, with input from end users at each phase: qualitative interviews, development of the intervention, piloting, and revising and refining the intervention. Acceptability of the prototype intervention was evaluated through thematic template analysis of exit interviews. Self-report measures were completed before and after intervention delivery. Following qualitative interviews with 13 participants (11 females and 2 males; aged 35-70 years), the intervention was informed by an Acceptance and Commitment Therapy (ACT) model interwoven with cognitive and behavioural strategies that targeted DSCATT-specific difficulties. The manualised intervention consisted of 12 1-h weekly individual sessions, delivered by psychologists via Telehealth (video call or telephone). Modules addressed the six core psychological processes of ACT, alongside DSCATT-specific modules addressing cognitive function, sleep and social relationships. Pilot testing and follow-up interviews were conducted in a separate sample of six individuals with DSCATT (all females; aged 46-71 years). All participants reported that the approach benefited their emotional well-being and overall health and would recommend it to others with DSCATT. This is a novel and theoretically driven psychotherapeutic intervention for DSCATT, co-produced with patient involvement across four phases. Pilot testing suggested the manualised intervention was feasible and acceptable, supporting future evaluation of feasibility and treatment outcomes with randomised controlled trials. This study involved the engagement and participation of individuals with DSCATT across four stages of the project, according to an HCD approach-the choice of the intervention; the development of the intervention; the piloting of the intervention, and the assessment of the intervention. The pilot study component of this project was prospectively registered on the Australian and New Zealand Clinical Trial Registry (ANZCTR); trial ID: ACTRN12621001032842.

People evaluate their singing ability to varying degrees of accuracy, but why these individual differences occur is largely unknown. Objectively evaluated, everyday singing ability is influenced by both genetic and environmental factors. Since singing self-evaluation (SSE) strongly correlates with everyday singing ability, it is possible that the same factors might influence both. Using a classical twin design, we estimated genetic and environmental influences on SSE and its phenotypic relationship with everyday singing ability in Australian twins (N = 996). Two validated measures of SSE were used: a single self-report item assessing overall singing ability (SSE-Single) and a four-item composite measure (SSE-Factor). Both measures showed significant genetic (SSE-Single A = 42%; SSE-Factor A = 53%) and unshared environmental influences (both E = 29%). Phenotypic correlations between the SSE measures and everyday singing ability ranged from rp = 0.67 - 0.68 and were significantly influenced by genetic, shared and unshared environmental factors (SSE-Single A = 41%, C = 51%, E = 8%; SSE-Factor A = 37%, C = 52%, E = 11%). Strong genetic correlations (rg = 0.63 - 0.64) were observed between SSE measures and everyday singing ability, as well as between both SSE measures (rg = 0.82), suggesting shared underlying genes. Taken together, our findings indicate that both genes and environments affect how individuals evaluate their own singing ability and how accurate these evaluations are compared to their actual ability.

The EILAT Conferences on New Antiepileptic Drugs (AEDs), which have taken place biennially since 1992, have traditionally offered a forum for stakeholders from industry and academia to present updates on potential antiseizure medications (ASMs) in development. We reviewed publicly accessible data on compounds that were presented at EILAT conferences over this period but failed to reach the ASM market. The overarching aim was to determine the most likely reason(s) for terminating development and to provide potentially useful clues to improve the efficiency of ASM development in the future. We restricted our analysis to investigational compounds in clinical development that targeted common epilepsies. Of 56 such compounds, 15 reached the ASM market, 11 are still in development, and 30 had their development for epilepsy indications terminated. Compounds whose development was terminated include atimepazole, beprodone, cannabidivarin, carabersat, conantokin-G, dezinamide, elpetrigine, flunarizine, fluorofelbamate, ICA-105665, isovaleramide, JNJ-40411813, losigamone, naluzotan, padsevonil, pitolisant, ralitoline, remacemide, safinamide, soretolide, talampanel, tonabersat, T2000, T2007, valnoctamide, valrocemide, VX-765, zandatrigine, zuranolone, and 534U87. For most of these compounds, termination of development occurred during phase 1 or phase 2. Unfavorable pharmacokinetic properties, such as short half-life or high drug-drug interaction potential, were a common likely cause of early termination. Overall, the most common reason for terminating clinical development was lack of efficacy, possibly related, at least in some cases, to use of suboptimal trial designs. Review of preclinical data suggested that, for many compounds, suboptimal clinical efficacy was unlikely to be primarily explained by their mechanism of action. In some instances, failure to pursue an epilepsy indication could be explained by prioritization of development for other neurological or psychiatric conditions. This may reflect the perception of the drug market for common epilepsies being relatively crowded, and only attractive for compounds with outstanding safety or efficacy advantages over existing medications.

Intra-operative hypotension is common during cardiopulmonary bypass and may contribute to tissue hypoxia. Tissue hypoxia has been linked to the development of postoperative kidney and brain injury. Vasopressors are used to treat hypotension during and after cardiopulmonary bypass. However, the effects of these drugs on renal and cerebral tissue oxygenation and perfusion are unknown. We tested the effects of four vasopressors on renal and cerebral tissue perfusion and oxygenation in a clinically-relevant ovine model of cardiopulmonary bypass. We studied 16 sheep before and after induction of anaesthesia and during 2.5 h of cardiopulmonary bypass. After commencing cardiopulmonary bypass at a target non-pulsatile flow of 2.4 l.min-1.m-2, we observed a baseline period with a target mean arterial pressure of 50-60 mmHg, after which we targeted a mean arterial pressure of 75-85 mmHg using a continuous infusion of metaraminol (n = 8); noradrenaline (n = 8); phenylephrine (n = 8); or vasopressin (n = 7). Sheep were allocated randomly to receive two of the four vasopressors. Compared with the pre-induction state, cardiopulmonary bypass significantly decreased renal medullary tissue perfusion (median (IQR [range]) decrease 55 (4-82 [1-99])%; p = 0.01) and medullary oxygen tension (mean (SD) difference 3.1 (2.5) kPa; p < 0.001). Cardiopulmonary bypass did not significantly alter cerebral tissue perfusion or oxygenation compared with the pre-induction state. Infusing noradrenaline significantly decreased medullary oxygen tension (mean (SD) difference 2.7 (1.6) kPa; p = 0.003). This decreasein medullary oxygen tension was significant compared with vasopressin (mean difference -3.4kPa, 95%CI -5.7 to -1.0; p = 0.008). No vasopressor infusion significantly altered renal medullary perfusion, cerebral tissue perfusion or oxygenation. Intra-operative noradrenaline during ovine cardiopulmonary bypass worsens renal medullary tissue oxygenation relative to vasopressin. These findings suggest that the choice of vasopressors may affect renal oxygenation.

The Australian Commission on Safety and Quality in Healthcare developed a list of sixteen potentially preventable Hospital-Acquired Complications (HACs) and an algorithm using International Classification of Disease (ICD) codes to detect them. We evaluated this algorithm's performance for diagnosing hospital-onset bloodstream infections (HO-BSI). Administrative records were extracted for episodes of admitted patient care from July 2016 to June 2017 at five Australian principal referral hospitals. We applied the BSI HAC algorithm to each episode, then randomly selected 50 patients deemed positive and negative for HO-BSI at each site. Reviewers blinded to HAC status applied the reference surveillance definition for HO-BSI. The positive predictive value (PPV) and negative predictive value (NPV) for the BSI HAC were calculated. We explored changes to the HAC algorithm to improve these metrics. Overall, 352 917 episodes were included; median (IQR) age was 54 (33-71) years, 49.6 % were female, and 43.8 % were elective admissions. Of these, 2229 (0.6 %) had a HO-BSI according to the HAC algorithm. Among manually reviewed episodes, the PPV for the HAC algorithm was 0.28 (95 % CI, 0.23-0.34) and the NPV was 1.00 (95 % CI, 0.98-1.00). The codes 'Sepsis, unspecified' and 'bacterial sepsis of newborn, unspecified' were both common triggers for HO-BSI HACs (accounting for 35.8 % and 18.4 % of HO-BSIs, respectively) and had poor PPV (0.06 and 0.03, respectively). Removal of these codes from the algorithm increased PPV to 0.53 (0.45-0.62). The HAC algorithm had sub-optimal PPV for HO-BSI. This performance was improved by removing the 'unspecified sepsis' ICD codes.