John Hunter Hospital

The impact of clinical trials extends beyond knowledge gained. However, broader impacts, including social, health and economic benefits to patients and communities are rarely assessed. In rural and remote regions where inclusion of local populations in clinical trials is limited, these assessments are even more rare. The Healthy Rural Hearts (HealthyRHearts) study aimed to reduce cardiovascular disease (CVD) risk in rural Australians through a medical nutrition therapy (MNT) intervention delivered via telehealth following a primary care heart health assessment. This provided an opportunity to evaluate its impacts more broadly and to guide future investment in rural clinical trials. Data on the impacts of the HealthyRHearts study were obtained from administrative records, document analysis, relevant websites/databases and in-depth interviews using three methods within the Framework to Assess Impact from Translational Health Research (FAIT). These include (1) a modification of the Payback Framework reported as quantified metrics, (2) a cost-consequence analysis (CCA) to determine return on investment and (3) a narrative account of impact generated from the study using qualitative data. The modified Payback Framework identified significant knowledge advancement through publications, training materials and economic benefits from employment opportunities and leveraged funding. However, the greatest impacts were improvements in rural healthcare and research capacity through training and support offered to dietitians, project staff, general (primary care) practice staff and patients. The majority of patients had improved CVD risk scores, activation in healthcare participation, health literacy and quality of life at trial completion. The CCA demonstrated a modest return of $1.31 ($0.69-1.89) for each Australian dollar invested. Dietitians and general practice staff interviewed identified personal satisfaction as a benefit of participation, with dietitians reporting economic benefits as a result of their new skills. Patients reported that their nutrition knowledge and dietary behaviours improved, leading to perceived improvements in their health and wellbeing. The HealthyRHearts trial delivered significant impact in knowledge gain, while building healthcare and research capacity and capability in rural communities. Patient and community benefits were also delivered, with a potentially small but positive return on investment, suggesting that investment in rural clinical trials has broad-ranging benefits beyond research outcomes alone.

This propensity score-matched study utilized data from the MSBase registry to compare outcomes between patients discontinuing OCR due to safety concerns ("Switchers") and those continuing treatment ("Continuers"). Matching was performed using inverse probability of treatment weighting (IPTW) to balance treatment duration and baseline characteristics. Primary outcomes included annualized relapse rate (ARR), time to first relapse, 24-48 weeks confirmed disability worsening (CDW), and progression independent of relapse activity (PIRA). From an initial cohort of 310 Switchers and 1,315 Continuers, 66 patients who experienced at least one safety event and switched from OCR were matched with 66 Continuers. PS-IPTW analyses revealed higher ARR in Switchers (0.08, 95% CI: 0.05-0.14) versus Continuers (0.038, 95% CI: 0.02-0.07; p=0.040). Time to first relapse showed no significant difference (HR=2.23, 95% CI: 0.68-7.28; p=0.183). Trends toward increased CDW24 weeks risk (PS-IPTW HR=2.11, 95% CI: 0.93-4.75; p=0.073), while no significant difference was found at 48 weeks (HR=1.81, 95% CI: 0.83-3.30; p=0.201). PIRA risk showed a trend toward an increase in Switchers (HR=2.45, 95% CI: 0.95-6.29; p=0.063). In this propensity-score-matched analysis, OCR discontinuation due to safety concerns was associated with increased relapse activity and trends toward greater disability progression. These findings highlight the importance of maintaining therapeutic intensity and systematic monitoring during treatment transitions to mitigate safety risks Conclusion: Further research is needed to develop strategies for effectively managing adverse events to optimize patient outcomes.

• ACPA-positive RA arises from the interaction between primed immune systems and the articular connective tissue substrate. • ACPA-positive RA develops as thresholds of articular stiffness are crossed producing normal age incidence distributions. • Increases in articular stiffness at menopause account for the earlier age incidence peak in women. • Greater articular stiffness causes more severe RA in late-life may explain “difficult-to-treat” RA. • Arterial and articular stiffness correlate. This partly accounts for the excess cardiovascular disease in ACPA-positive RA. The dramatic scientific and therapeutic advances of the last century have transformed outcomes in the management of anti-CCP positive rheumatoid arthritis (ACPA + RA). However, therapeutic challenges remain. While ACPA + RA is fundamentally an immunological disease the Immuno-Biomechanical Model (IBM) adopts a novel perspective proposing that ACPA + RA is the outcome of the interaction between primed immune systems and the connective tissue substrate. The model starts with the simple premise that ACPA + RA develops as immunologically primed individuals cross biomechanical thresholds of articular stiffness and that subsequent RA severity is similarly influenced by articular stiffness. This biologically plausible model is based upon established RA epidemiology and observational studies informed by studies of connective tissue biomechanics. The hypothetical implications of the model are explored graphically revealing how changes in articular stiffness could explain the unimodal age incidence distributions, the earlier age peak in women, the paradox of increasing RA severity in the face of declining RA incidence in late-life and suggesting new potential mechanisms for delayed treatment failure and refractory RA. The model suggests that a component of the excess cardiovascular disease in ACPA + RA may have a biomechanical basis not influenced by standard immunotherapies that contributes to the persistence of excess CVD regardless of the therapeutic advances in RA therapeutics. The IBM presents a plausible hypothesis describing a landscape for further research with broad implications for the treatment of ACPA + RA.

Introduction Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease involving injury and a dysregulated repair response of an ageing epithelium. Here we investigate the contribution of senescence and telomere shortening to bleomycin-induced injury in alveolar epithelial cells (EpCs) derived from lung parenchymal tissue of patients with pulmonary fibrosis (PF), predominantly IPF, in vitro . Methods Injury responses of EpCs in air liquid interface (ALI) culture were assessed by ELISA, qPCR and/or immunofluorescence at 48 and 96 h post-bleomycin (30 μg·mL −1 ) treatment. Telomere length was evaluated by qPCR and corroborated by fluorescence in situ hybridisation (FISH). Results Bleomycin treatment increased markers of inflammation ( i.e. interleukin-6 and −36γ) and senescence ( i.e. p16 and p21) in EpCs from PF patients (PF-EpCs) ( p <0.05); responses markedly higher than control EpCs (Ctrl-EpCs). Conversely, the effects of bleomycin on the expression of type I and type II alveolar EpC markers were supressed or down-regulated in cultures of PF-EpCs (when compared to Ctrl-EpCs), whereas the percentage of keratin 17 positive type I and II intermediate EpCs were increased ( p <0.05). Telomere length was also significantly shorter in PF- than Ctrl-EpCs at baseline and further reduced post-bleomycin treatment ( p <0.05). Induction of telomere shortening by cell passaging augmented bleomycin-induced PF-EpC injury, whereas pharmacological telomerase activation and selected senotherapeutics were protective. Conclusion This study provides evidence that senescence-associated telomere shortening increases the susceptibility of IPF-lung EpCs to injury. Our cell-based lung epithelial injury model has utility as a pre-clinical tool for drug discovery and the evaluation of potential senotherapeutics for IPF treatment.

Vocal cord dysfunction (VCD), or inducible laryngeal obstruction (ILO), is an episodic upper airway disorder that can mimic anaphylaxis. To determine the prevalence of VCD/ILO among adults referred to allergy clinic for suspected anaphylaxis and to identify clinical markers that distinguish VCD/ILO from anaphylaxis. We conducted a retrospective study of adults referred for suspected anaphylaxis to a tertiary allergy clinic in Newcastle, Australia, in 2023. Patients were classified as confirmed VCD/ILO (laryngoscopy-proven), suspected VCD/ILO (spirometry findings or high clinical suspicion after exclusion of alternate diagnoses), anaphylaxis, or other. Demographics, triggers, comorbidities, clinical features, investigations, and health care utilization were compared between laryngoscopy-confirmed VCD/ILO and anaphylaxis. Among 133 adults, 11 (8.3%) had laryngoscopy-confirmed VCD/ILO. Inclusion of suspected cases (n = 21 [15.8%]) increased prevalence of VCD/ILO to 24.1% (n = 32). Compared with anaphylaxis, VCD/ILO was characterized by predominant upper airway symptoms, including throat tightness (100% vs 53.8%, P = .004), stridor (36.4% vs 1.9%, P = .003), dysphonia (72.7% vs 17.3%, P < .001), and cough (54.5% vs 1.9%, P < .001) with fewer systemic symptoms (urticaria 18.2% vs 84.6%, P < .001; gastrointestinal 9.1% vs 44.2%, P = .04; cardiovascular 0% vs 55.8%, P < .01). Multiple triggers were more common in VCD/ILO (72.7% vs 1.9%, P < .001), particularly aerosolized chemicals (36.4% vs 0%, P < .001). IgE sensitization to the proposed trigger was uncommon (9.1% vs 63.5%, P < .008) in VCD/ILO. VCD/ILO is a frequent differential diagnosis in adults referred for anaphylaxis. Recognition of its characteristic clinical features and trigger profiles may prevent misdiagnosis, reduce health care utilization, and improve patient outcomes.

Background: Cardiac CT acquired during the acute stroke imaging protocol is an emerging diagnostic modality to detect cardiac thrombi. We aimed to determine its diagnostic yield in a large, international, multicenter study. Methods: We performed an individual patient data meta-analysis by pooling prospective and retrospective observational data of patients with acute ischemic stroke (AIS) who underwent cardiac CT (ECG-gated or non-ECG-gated) as part of the acute imaging protocol between May 2018 and June 2024. We excluded patients with a TIA or stroke mimic. The primary outcome was the proportion of patients with a cardiac thrombus detected on cardiac CT. Secondary outcomes were additional scan time and radiation dose, comparison of yield with echocardiography, and 90-day mortality and recurrent ischemic stroke rates. Results: We included 3940 patients from 4 hospitals (median age 74 [IQR 63-82], 58.0% male, median NIHSS 6 [IQR 3-12], median time onset to hospital arrival 100 minutes [IQR 62-185]). Atrial fibrillation at baseline was present in 23.1% patients, and 29.6% had a large vessel occlusion. Cardiac CT was non-diagnostic in 17 (0.4%) patients. In total, cardiac CT detected 254 cardiac thrombi in 243/3923 (6.2%) patients. Thrombi were located in the left atrial appendage (n=193), left atrium (n=19), and left ventricle (n=42). Of 95/243 (39.1%) patients with a cardiac thrombus that underwent echocardiography (median interval cardiac CT-echocardiography: 2 days), transthoracic echocardiography detected a thrombus in 18/92 (19.6%) patients and transesophageal echocardiography in 2/5 (40.0%) patients. The diagnostic yield in patients that underwent both modalities was higher for cardiac CT (OR 7.5 [CI 4.0-15.3], p&lt;0.001). Median additional scan time was 6 minutes (IQR 5-7) for ECG-gated and 17 seconds (IQR 15-63) for non-ECG-gated cardiac CT. Median additional radiation dose was 5.4mSv (IQR 3.0-7.6). Patients with a cardiac thrombus on cardiac CT had higher 90-day mortality than those without a thrombus (33.3% vs 14.6%, p&lt;0.001). We found no difference in 90-day recurrent stroke rate (5.4% vs 4.4%, p=0.50). Conclusion: Routine cardiac CT performed during the acute stroke imaging protocol detects a cardiac thrombus in 1 out of 16 patients with AIS, with a 7-times higher yield than routine echocardiography. Mortality rate was doubled in patients with a cardiac thrombus, but 90-day stroke recurrence risk did not differ.