Although the value of patient and public involvement and engagement (PPIE) activities in the development of new interventions and tools is well known, little guidance exists on how to perform these ...activities in a meaningful way. This is particularly true within large research consortia that target multiple objectives, include multiple patient groups, and work across many countries. Without clear guidance, there is a risk that PPIE may not capture patient opinions and needs correctly, thereby reducing the usefulness and effectiveness of new tools. Mobilise-D is an example of a large research consortium that aims to develop new digital outcome measures for real-world walking in 4 patient cohorts. Mobility is an important indicator of physical health. As such, there is potential clinical value in being able to accurately measure a person's mobility in their daily life environment to help researchers and clinicians better track changes and patterns in a person's daily life and activities. To achieve this, there is a need to create new ways of measuring walking. Recent advancements in digital technology help researchers meet this need. However, before any new measure can be used, researchers, health care professionals, and regulators need to know that the digital method is accurate and both accepted by and produces meaningful outcomes for patients and clinicians. Therefore, this paper outlines how PPIE structures were developed in the Mobilise-D consortium, providing details about the steps taken to implement PPIE, the experiences PPIE contributors had within this process, the lessons learned from the experiences, and recommendations for others who may want to do similar work in the future. The work outlined in this paper provided the Mobilise-D consortium with a foundation from which future PPIE tasks can be created and managed with clearly defined collaboration between researchers and patient representatives across Europe. This paper provides guidance on the work required to set up PPIE structures within a large consortium to promote and support the creation of meaningful and efficient PPIE related to the development of digital mobility outcomes.
The nociceptin/orphanin FQ peptide receptor (NOP), activated by its endogenous peptide ligand nociceptin/orphanin FQ (N/OFQ), exerts several effects including modulation of pain signalling. We have ...examined, for the first time, the tissue distribution of the NOP receptor in clinical visceral and somatic pain disorders by immunohistochemistry and assessed functional effects of NOP and μ-opioid receptor activation in cultured human and rat dorsal root ganglion (DRG) neurons. Quantification of NOP-positive nerve fibres within the bladder suburothelium revealed a remarkable several-fold increase in detrusor overactivity (P < 0.0001) and painful bladder syndrome patient specimens (P = 0.0014) compared with controls. In postmortem control human DRG, 75% to 80% of small/medium neurons (≤50 μm diameter) in the lumbar (somatic) and sacral (visceral) DRG were positive for NOP, and fewer large neurons; avulsion-injured cervical human DRG neurons showed similar numbers. NOP immunoreactivity was significantly decreased in injured peripheral nerves (P = 0.0004), and also in painful neuromas (P = 0.025). Calcium-imaging studies in cultured rat DRG neurons demonstrated dose-dependent inhibition of capsaicin responses in the presence of N/OFQ, with an IC50 of 8.6 pM. In cultured human DRG neurons, 32% inhibition of capsaicin responses was observed in the presence of 1 pM N/OFQ (P < 0.001). The maximum inhibition of capsaicin responses was greater with N/OFQ than μ-opioid receptor agonist DAMGO. Our findings highlight the potential of NOP agonists, particularly in urinary bladder overactivity and pain syndromes. The regulation of NOP expression in visceral and somatic sensory neurons by target-derived neurotrophic factors deserves further study, and the efficacy of NOP selective agonists in clinical trials.
Objectives
To examine the severity of coronary artery disease (CAD) in people from rural or remote Western Australia referred for invasive coronary angiography (ICA) in Perth and their subsequent ...management; to estimate the cost savings were computed tomography coronary angiography (CTCA) offered in rural centres as a first line investigation for people with suspected CAD.
Design
Retrospective cohort study.
Setting, participants
Adults with stable symptoms in rural and remote WA referred to Perth public tertiary hospitals for ICA evaluation during the 2019 calendar year.
Main outcome measures
Severity and management of CAD (medical management or revascularisation); health care costs by care model (standard care or a proposed alternative model with local CTCA assessment).
Results
The mean age of the 1017 people from rural and remote WA who underwent ICA in Perth was 62 years (standard deviation, 13 years); 680 were men (66.9%), 245 were Indigenous people (24.1%). Indications for referral were non‐ST elevation myocardial infarction (438, 43.1%), chest pain with normal troponin level (394, 38.7%), and other (185, 18.2%). After ICA assessment, 619 people were medically managed (60.9%) and 398 underwent revascularisation (39.1%). None of the 365 patients (35.9%) without obstructed coronaries (< 50% stenosis) underwent revascularisation; nine patients with moderate CAD (50–69% stenosis; 7%) and 389 with severe CAD (≥ 70% stenosis or occluded vessel; 75.5%) underwent revascularisation. Were CTCA used locally to determine the need for referral, 527 referrals could have been averted (53%), the ICA:revascularisation ratio would have improved from 2.6 to 1.6, and 1757 metropolitan hospital bed‐days (43% reduction) and $7.3 million in health care costs (36% reduction) would have been saved.
Conclusion
Many rural and remote Western Australians transferred for ICA in Perth have non‐obstructive CAD and are medically managed. Providing CTCA as a first line investigation in rural centres could avert half of these transfers and be a cost‐effective strategy for risk stratification of people with suspected CAD.
Atrial fibrillation (AF) is the most common chronic arrhythmia in adults and its prevalence is increasing. Due to its serious cardiovascular complications there is a strong need to understand ...predisposing risk factors to develop effective prevention strategies. There are a few established risk factors but a number of further risk factors have been suggested including obesity, metabolic syndrome, sleep-disordered breathing, and inflammation. The aim of this study was to investigate established and emerging risk factors for AF in a cohort study of 4,267 adults in Busselton, Western Australia, without a history of AF at baseline in 1994/95 who were followed for 15 years for incident AF events. Baseline measurement included questionnaire, clinical assessment and blood sample. A total of 343 (8 %) experienced AF during follow-up. Cox regression analysis confirmed advancing age, male sex, taller height, being on hypertension treatment and higher body mass index (BMI) as the major common risk factors (all p < 0.001). However, further modelling showed the effect of being on hypertension treatment may be stronger in women (p = 0.001) and the effect of BMI stronger in men (p = 0.004). After adjustment for these factors, no other factors were strongly related (p < 0.001) although short PR interval, history of valvular heart disease, stroke, chronic obstructive pulmonary disease, lung function and adiponectin level were marginally related (p < 0.05). This cohort study of predictors for incident AF has confirmed the major established risk factors. However, recently suggested potential novel risk factors for AF (inflammation, sleep-disordered breathing, glucose/metabolic disorders) were not confirmed in this study.
To describe temporal trends in appropriate antithrombotic therapy use in hospitalised atrial fibrillation (AF) patients and identify evidence-treatment gaps in clinical practice.
Retrospective cohort ...study from January 2009–March 2016.
Tertiary and secondary teaching hospitals in Perth, Western Australia.
Hospitalised adults with non-valvular AF.
We identified 11,294 index AF admissions, with a mean age of 76.9 years, 45.8% women and 86.3% at high risk of stroke (CHA2DS2-VASc score ≥2 in men and ≥3 in women). In high risk subjects use of appropriate antithrombotic therapy improved over time with increasing oral anticoagulant (OAC) use and declining sole antiplatelet use (both trend p<0.001). However, by study end only 45.3% of high-risk patients were receiving OAC therapy. In low risk patients, receipt of OAC therapy was steady throughout the study at 40.5% (trend p=0.10). The gender gap in OAC use narrowed over time, with no significant difference between high risk men and women by study end. Use of OAC therapy in elderly patients (age ≥75 years) remained lower than younger patients (age <65 years) over the entire period, with only 31% of elderly patients receiving OAC therapy at study end. From 2012 onwards use of non-vitamin K oral anticoagulants (NOACs) doubled each year with declining warfarin use (both trend p<0.001).
Despite substantial uptake of NOACs, OAC therapy in AF patients at high risk of stroke remains under-utilised in Western Australia and over-utilised in low risk patients. Further work is required to reduce treatment-risk mismatch for stroke prevention in AF patients.
Decorin and biglycan are closely related abundant extracellular matrix proteoglycans that have been shown to bind to C1q. Given the overall structural similarities between C1q and mannose-binding ...lectin (MBL), the two key recognition molecules of the classical and the lectin complement pathways, respectively, we have examined functional consequences of the interaction of C1q and MBL with decorin and biglycan. Recombinant forms of human decorin and biglycan bound C1q via both collagen and globular domains and inhibited the classical pathway. Decorin also bound C1 without activating complement. Furthermore, decorin and biglycan bound efficiently to MBL, but only biglycan could inhibit activation of the lectin pathway. Other members of the collectin family, including human surfactant protein D, bovine collectin-43, and conglutinin also showed binding to decorin and biglycan. Decorin and biglycan strongly inhibited C1q binding to human endothelial cells and U937 cells, and biglycan suppressed C1q-induced MCP-1 and IL-8 production by human endothelial cells. In conclusion, decorin and biglycan act as inhibitors of activation of the complement cascade, cellular interactions, and proinflammatory cytokine production mediated by C1q. These two proteoglycans are likely to down-regulate proinflammatory effects mediated by C1q, and possibly also the collectins, at the tissue level.
To determine if increasing hospitalisations for non-valvular atrial fibrillation (NVAF) in Western Australia (WA) was due to incident (first-ever) or repeat hospitalisations, an ageing population ...structure, changing procedural practice or a combination of these factors.
We conducted a longitudinal retrospective population study on all WA residents aged 25–94 years between 2000 and 2013, with a principal hospital discharge diagnosis of NVAF. Person-linked hospital morbidity and mortality records were used to measure annual rate ratios (RRs) and 95% confidence intervals (CIs) in the total and incident NVAF (25–94 years) hospitalisations, further stratified by sex and by age-specific standardised groups (25–44, 45–64, 65–75, 75–84, 85–94 years).
There were 55,532 total hospitalisations for NVAF between 2000 and 2013, patient mean age 68.3 years, and 58% male. Annual age- and sex- standardised rates for total NVAF hospitalisation increased by 3.0%/year (RR 1.030; 95%CI; 1.028, 1.038), and in both men and women. The largest absolute increase in hospitalisation rate occurred in those aged 85–94 years (∆613/100,000 men and women combined). Incident NVAF hospitalisations showed a borderline decline of 0.5%/year (RR 0.99; 95%CI; 0.99, 1.0) with a statistically significant trend in women but not men. The rate of AF admissions associated with a catheter ablation increased by 13%/year (95%CI; 13.1%, 15.3%).
The increasing rates of total hospitalisation for NVAF is driven more by repeat than incident admissions, escalating hospitalisations in the very elderly, and more frequent interventional procedures. These drivers have major economic and healthcare planning implications.
•Atrial fibrillation hospitalisation rates (standardised) rose from 2000 to 2013.•These hospitalisations were driven by repeat admissions, not incident cases.•Catheter ablations in atrial fibrillation related hospitalisations rose 13%/year.
Appropriate anticoagulant therapy for patients with atrial fibrillation (AF) requires assessment of stroke and bleeding risks. However, risk stratification schemas such as CHA2DS2-VASc and HAS-BLED ...have modest predictive capacity for patients with AF. Multilabel machine learning (ML) techniques may improve predictive performance and support decision-making for anticoagulant therapy. We compared the performance of multilabel ML models with the currently used risk scores for predicting outcomes in AF patients.
This was a retrospective cohort study of 9670 patients, mean age 76.9 years, 46% women, who were hospitalized with non-valvular AF, and had 1-year follow-up. The outcomes were ischemic stroke (167), major bleeding (430) admissions, all-cause death (1912) and event-free survival (7387). Discrimination and calibration of ML models were compared with clinical risk scores by area under the curve (AUC). Risk stratification was assessed using net reclassification index (NRI).
Multilabel gradient boosting classifier chain provided the best AUCs for stroke (0.685 95% CI 0.676, 0.694), major bleeding (0.709 95% CI 0.703, 0.716) and death (0.765 95% CI 0.763, 0.768) compared to multi-layer neural networks and classifier chain using support vector machine. It provided modest performance improvement for stroke compared to AUC of CHA2DS2-VASc (0.652, NRI = 3.2%, p-value = 0.1), but significantly improved major bleeding prediction compared to AUC of HAS-BLED (0.522, NRI = 22.8%, p-value < 0.05). It also achieved greater discriminant power for death compared with AUC of CHA2DS2-VASc (0.606, p-value < 0.05). ML models identified additional risk features such as hemoglobin level, renal function.
Multilabel ML models can outperform clinical risk stratification scores for predicting the risk of major bleeding and death in non-valvular AF patients.
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