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Background: Proof-of-concept (PoC) development is a key step in implementation sciences. However, there is a dearth of studies in this area and the use of this term in health and social sciences is ambiguous., Objective: The objective was to remove the ambiguity surrounding the PoC and pilot study stage in the research development process using a standard system to rate the development of projects and applications provided by the Technology Readiness Levels (TRL) framework., Design: Mapping review and critical analysis using TRL as the standard measure., Search Strategy and Charting Method: PubMed and PsycInfo databases were searched for papers that reported PoC studies of mental health interventions up to August 2023. Data were extracted, described and tabulated., Eligibility Criteria: Included were PoC studies in mental health implementation research. Exclusion criteria were research relating to biomedical (drugs) development, neurocognitive tools, neuropsychology, medical devices, literature reviews or discussion papers or that did not include the term 'proof-of-concept' in the title, abstract or text., Results: From the 83 citations generated from the database search, 22 studies were included in this mapping review. Based on the study title, abstract and text, studies were categorised by research development stage according to the TRL framework. This review showed 95% of the studies used PoC incorrectly to describe the development stage of their research but which were not at this specific level of project development., Conclusions: The TRL was a useful reference framework to improve terminological clarity around the term 'proof-of-concept' in implementation research. To extend the use of TRL in implementation sciences, this framework has now been adapted and validated to a health and social science-related research context accompanied by a health-related glossary of research process terms and definitions to promote a common vocabulary and shared understanding in implementation sciences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB., Methods and Results: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up., Conclusion: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior. Effects of a HFD may also vary between sexes. The interaction between Age- and Sex- and Diet-related changes in neuroinflammation and cognitive function is an important and poorly understood area of research. This study was designed to examine the effects of HFD on neuroinflammation, behavior, and neurodegeneration in mice in the context of aging or sex differences. In a series of studies, young (2-3 months) or old (12-13 months) C57BL/6J male mice or young male and female C57Bl/6J mice were fed either a standard diet (SD) or a HFD for 5-6 months. Behavior was assessed in Activity Chamber, Y-maze, Novel Place Recognition, Novel Object Recognition, Elevated Plus Maze, Open Field, Morris Water Maze, and Fear Conditioning. Post-mortem analyses assessed a panel of inflammatory markers in the plasma and hippocampus. Additionally, proteomic analysis of the hypothalamus, neurodegeneration, neuroinflammation in the locus coeruleus, and neuroinflammation in the hippocampus were assessed in a subset of young and aged male mice. We show that HFD increased body weight and decreased locomotor activity across groups compared to control mice fed a SD. HFD altered anxiety-related exploratory behavior. HFD impaired spatial learning and recall in young male mice and impaired recall in cued fear conditioning in young and aged male mice, with no effects on spatial learning or fear conditioning in young female mice. Effects of Age and Sex were observed on neuroinflammatory cytokines, with only limited effects of HFD. HFD had a more significant impact on systemic inflammation in plasma across age and sex. Aged male mice had induction of microglial immunoreactivity in both the locus coeruleus (LC) and hippocampus an effect that HFD exacerbated in the hippocampal CA1 region. Proteomic analysis of the hypothalamus revealed changes in pathways related to metabolism and neurodegeneration with both aging and HFD in male mice. Our findings suggest that HFD induces widespread systemic inflammation and limited neuroinflammation. In addition, HFD alters exploratory behavior in male and female mice, and impairs learning and memory in male mice. These results provide valuable insight into the impact of diet on cognition and aging pathophysiology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators., Methods: The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA., Results: The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment., Conclusions: There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Pulmonary vein isolation (PVI) ablation is a standard therapy for paroxysmal atrial fibrillation (PAF). Lesion Index (LSI) is a metric to guide radiofrequency (RF) ablation using the TactiCath Ablation Catheter, Sensor Enabled with the EnSite Cardiac Mapping System (Abbott)., Objective: This study (NCT-03906461) was designed to capture best practices using LSI-guided catheter ablation to treat PAF subjects in a real-world setting., Methods: This prospective single-arm observational study enrolled 143 PAF subjects in the United States, Europe, and Japan undergoing de novo PVI with RF ablation. PVI lesions were assigned to 10 anatomically defined segments. Mean LSIs achieved for all lesions were analyzed. Follow-up was conducted between 3-6 months and 12 months after the procedure., Results: Pulmonary veins were isolated in all subjects. The mean achieved LSI was 4.9, with lower values in Europe (4.4) and Japan (4.5) than the United States (5.5). First-pass success, defined as no gaps requiring touch-up ablation after 20 minutes post isolation, was achieved in 76.2% of subjects. Use of high LSI (≥5) resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI (<5). At 12 months, 99.3% of subjects were free from procedure- or device-related serious adverse events and 95.7% (112/117) (35.0% on antiarrhythmic drugs) were free from recurrence and/or a repeat ablation procedure for atrial fibrillation / atrial flutter / atrial tachycardia., Conclusion: LSI-guided ablation strategies proved safe and effective despite differences in LSI workflows. Use of high LSI values resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Atypical left atrial flutter (AFL) may be macroreentrant or spatially localized. The relationship between the critical isthmus (CI) for localized reentry with sinus rhythm (SR) conduction slowing has not been systematically examined., Objective: To examine the correlation between CI sites for localized AFL (L-AFL) and deceleration zones (DZ) identified by isochronal late activation mapping (ILAM) during baseline rhythm., Methods: Patients with localized AFL who underwent high-density activation mapping of both SR and AFL were retrospectively analyzed. L-AFL was defined as reentry restricted to 2 wall segments of the left atrium. CI was defined by activation mapping and sites of successful termination during ablation. DZ, defined as >3 isochrones within 1 cm radius during baseline rhythm, were correlated to the locations of the CI., Results: Thirty-one consecutive patients that underwent detailed sinus rhythm and AFL high-density activation maps were analyzed at 3 centers. A mean 4060 ± 3275 and 6209 ± 8656 points were collected in ILAM and AFL activation maps, respectively. At least 1 DZ (1.7 ± 0.77) was identified in all patients. ILAM showed 3.27 ± 0.52 isochrones per DZ (168 ± 32 ms), and co-localized to CI sites at a distance of 6.7 ± 3 mm. A total of 34% ± 14% of the AFL cycle length was contained within 0.5 cm of the DZ., Conclusions: In patients with L-AFL, CI co-localized with DZ during baseline rhythm, suggesting that DZ mapping during SR may yield candidate targets for ablation as an adjunct to pulmonary vein isolation to prevent a subtype of AFL., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Introduction: Single-center observational studies have shown promising results with fragmented electrogram (FE)-guided ganglionated plexus (GP) ablation in patients with vagally mediated bradyarrhythmia (VMB). We aimed to compare the acute procedural characteristics during FE-guided GP ablation in patients with VMB performed by first-time operators and those of a single high-volume operator., Methods and Results: This international multicenter cohort study included data collected over 2 years from 16 cardiac hospitals. The primary operators were classified according to their prior GP ablation experience: a single high-volume operator who had performed > 50 GP ablation procedures (Group 1), and operators performing their first GP ablation cases (Group 2). Acute procedural characteristics and syncope recurrence were compared between groups. Forty-seven consecutive patients with VMB who underwent FE-guided GP ablation were enrolled, n = 31 in Group 1 and n = 16 in Group 2. The mean number of ablation points in each GP was comparable between groups. The ratio of positive vagal response during ablation on the left superior GP was higher in Group 1 (90.3% vs. 62.5%, p = .022). Ablation of the right superior GP increased heart rate acutely without any vagal response in 45 (95.7%) cases. The procedure time was longer in group 2 (83.4 ± 21 vs. 118.0 ± 21 min, respectively, p < .001). Over a mean follow-up duration of 8.0 ± 3 months (range 2-24 months), none of the patients suffered from syncope., Conclusion: This multi-center pilot study shows for the first time the feasibility of FE-guided GP ablation across a large group of procedure-naïve operators., (© 2021 Wiley Periodicals LLC.)

Background: Stereotactic ablative radiotherapy (SAbR) is an emerging therapy for refractory ventricular tachycardia (VT). However, the current workflow is complicated, and the precision and safety in patients with significant cardiorespiratory motion and VT targets near the stomach may be suboptimal., Objective: We hypothesized that automated 12-lead electrocardiogram (ECG) mapping and respiratory-gated therapy may improve the ease and precision of SAbR planning and facilitate safe radiation delivery in patients with refractory VT., Methods: Consecutive patients with refractory VT were studied at 2 hospitals. VT exit sites were localized using a 3-D computational ECG algorithm noninvasively and compared to available prior invasive mapping. Radiotherapy (25 Gy) was delivered at end-expiration when cardiac respiratory motion was ≥0.6 cm or targets were ≤2 cm from the stomach., Results: In 6 patients (ejection fraction 29% ± 13%), 4.2 ± 2.3 VT morphologies per patient were mapped. Overall, 7 out of 7 computational ECG mappings (100%) colocalized to the identical cardiac segment when prior invasive electrophysiology study was available. Respiratory gating was associated with smaller planning target volumes compared to nongated volumes (71 ± 7 vs 153 ± 35 cc, P < .01). In 2 patients with inferior wall VT targets close to the stomach (6 mm proximity) or significant respiratory motion (22 mm excursion), no GI complications were observed at 9- and 12-month follow-up. Implantable cardioverter-defibrillator shocks decreased from 23 ± 12 shocks/patient to 0.67 ± 1.0 ( P < .001) post-SAbR at 6.0 ± 4.9 months follow-up., Conclusions: A workflow including computational ECG mapping and protocol-guided respiratory gating is feasible, is safe, and may improve the ease of SAbR planning. Studies to validate this workflow in larger populations are required.

Purpose: Accessory pathway (AP) mapping is currently based on point-by-point mapping and identifying if a local electrogram's origin is atrial, pathway, or ventricular, which is time-consuming and prone to insufficient mapping. We sought to determine the feasibility of automated and high-density mapping to define AP location using open-window mapping (OWM), which does not rely on defining the electrogram's origin but simply detects the sharpest local signal at each point., Methods: We enrolled 23 consecutive patients undergoing catheter ablation for atrioventricular reentrant tachycardia. High-density mapping was performed using OWM and ablation was performed. The successful site of ablation was determined by the loss of pathway function., Results: OWM was 100% effective at identifying the successful site of ablation (average mapping time 7.3 ± 4.3 min.) Permanent AP elimination was achieved using a mean radiofrequency energy time of 18.5 ± 24.5 s/patient. Transiently successful ablations were 4.0 ± 1.8 mm from permanently successful sites and had lower contact force (5.1 ± 2.5 g vs. 11.7 ± 9.0 g; P = 0.041). Unsuccessful sites had similar contact force to permanently successful sites (12.2 ± 9.2 g vs. 11.7 ± 9.0 g; P = 0.856) but were 6.4 ± 2.0 mm away from successful sites., Conclusion: A novel technique of high-density, automated, and open-window mapping (OWM) effectively localizes APs without the need to differentiate the signal's site of origin. These findings suggest that OWM can be used to rapidly and successfully map and ablate APs. Both distances from the pathway and contact force were shown to be important for pathway ablation., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Clinically pertinent electrocardiogram (ECG) data from model systems, such as zebrafish, are crucial for illuminating factors contributing to human cardiac electrophysiological abnormalities and disease. Current zebrafish ECG collection strategies have not adequately addressed the consistent acquisition of high-quality traces or sources of phenotypic variation that could obscure data interpretation. Thus, we developed a novel platform to ensure high-quality recording of in vivo subdermal adult zebrafish ECGs and zebrafish ECG reading GUI (zERG), a program to acquire measurements from traces that commercial software cannot examine owing to erroneous peak calling. We evaluate normal ECG trait variation, revealing highly reproducible intervals and wave amplitude variation largely driven by recording artifacts, and identify sex and body size as potential confounders to PR, QRS and QT intervals. With this framework, we characterize the effect of the class I anti-arrhythmic drug flecainide acetate on adults, provide support for the impact of a Long QT syndrome model, and establish power calculations for this and other studies. These results highlight our pipeline as a robust approach to evaluate zebrafish models of human cardiac electrophysiological phenotypes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Aims and Objectives: To explore the quantitative and qualitative literature on the impact of nurse-led postdischarge telephone follow-up (TFU) call interventions on patient outcomes., Background: Adverse patient outcomes such as postdischarge problems, premature contact with health systems, inability to self-manage conditions and hospital readmissions all have an impact on the health and well-being, and satisfaction of patients as well as a financial impact on healthcare systems., Design: A mixed-study systematic review., Review Methods: A systematic search of CINAHL, Ebsco, PubMed, Quest and Cinch-Health databases was undertaken using the key terms "nurs*," "nurse-led," "nurse initiated," "discharge," "hospital," "telephone," "follow-up" and "telephone follow-up" to identify relevant original peer-reviewed studies published between 2010-2016. Ten articles were selected for inclusion. The selected papers were critically appraised. A sequential explanatory approach with a convergent synthesis was used to report findings following PRISMA guidelines., Results: The findings demonstrate that nurse-led TFU interventions have the potential to improve patient outcomes. The studies suggest patient satisfaction with TFU is one of the strongest positive outcomes from the interventions. However, the results do not support improvement in patient readmission or mortality., Conclusions: Of the 10 studies reviewed, only two were methodologically strong limiting the conclusions that can be drawn from the current research on this topic. Telephone follow-up interventions improve patient satisfaction and have the potential to meet patient information and communication needs, improve self-management and follow-up appointment attendance and reduce postdischarge problems. Further research is required to explore patients' perceptions of the most useful content of TFU calls, the efficacy of TFU calls and nurses' perceptions and experiences of conducting TFU interventions., Relevance to Clinical Practice: When conducted by a nurse, these interventions have the potential to enhance postdischarge care to patients and meet care needs. Patients perceive TFU as acceptable and are satisfied with this form of postdischarge care., (© 2019 John Wiley & Sons Ltd.)

Background: This study examined the postactivation potentiation effects of overloaded cycling on subsequent Wingate performance., Methods: Twenty anaerobic-trained men took part in this study. The participants were randomly allocated to complete three testing sessions separated by 7 days. Each week, participants either undertook a control session (CON) consisting of a sub-maximal cycling warm-up protocol followed by a Wingate Test, or separate sessions involving an overloaded 10-second cycling PAP protocol followed by a Wingate Test at 5 (T5) or 10 (T10) minutes, post-PAP protocol. Power outputs, cadence, total work, fatigue rate, heart rate and capillary lactate measures were recorded from each Wingate Test. Measures were compared between these sessions and between sessions that generated the greatest peak power output (Bestpeak-P) and mean power output (Bestmean-P) via repeated measures ANOVA with effect sizes (ES) also calculated., Results: A significantly greater mean power output, total work and lactate levels were exhibited during the T10 condition compared to the CON condition (P<0.05, ES=1.57). Whilst not significant (P=0.06), a greater peak power output was exhibited during the Bestpeak-P condition compared to the CON condition with a large effect (ES=0.95)., Conclusions: Results indicated that an overloaded cycling protocol increased power output and lactate measures in anaerobic-trained men during a 30-second, Wingate Test. Overloaded cycling enhances subsequent anaerobic performance and is therefore likely to provide greater training stimuli for anaerobically trained individuals.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%) 1-3 that frequently presents with ascending aortic aneurysm (AscAA) 4 . BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA 5-8 , impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

The apelin peptide is described as one of the most potent inotropic agents, produced endogenously in a wide range of cells, including cardiomyocytes. Despite positive effects on cardiac contractility in multicellular preparations, as well as indications of cardio-protective actions in several diseases, its effects and mechanisms of action at the cellular level are incompletely understood. Here, we report apelin effects on dynamic mechanical characteristics of single ventricular cardiomyocytes, isolated from mouse models (control, apelin-deficient [Apelin-KO], apelin-receptor KO mouse [APJ-KO]), and rat. Dynamic changes in maximal velocity of cell shortening and relaxation were monitored. In addition, more traditional indicators of inotropic effects, such as maximum shortening (in mechanically unloaded cells) or peak force development (in auxotonic contracting cells, preloaded using the carbon fibre technique) were studied. The key finding is that, using Apelin-KO cardiomyocytes exposed to different preloads with the 2-carbon fibre technique, we observe a lowering of the slope of the end-diastolic stress-length relation in response to 10 nM apelin, an effect that is preload-dependent. This suggests a positive lusitropic effect of apelin, which could explain earlier counter-intuitive findings on an apelin-induced increase in contractility occurring without matching rise in oxygen consumption., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Indigenous primary health-care (PHC) services participating in continuous quality improvement (CQI) cycles show varying patterns of performance over time. Understanding this variation is essential to scaling up and sustaining quality improvement initiatives. The aim of this study is to examine trends in quality of care for services participating in the ABCD National Research Partnership and describe patterns of change over time and examine health service characteristics associated with positive and negative trends in quality of care., Setting and Participants: PHC services providing care for Indigenous people in urban, rural, and remote northern Australia that had completed at least three annual audits of service delivery for at least one aspect of care (n = 73)., Methods/design: Longitudinal clinical audit data from use of four clinical audit tools (maternal health, child health, preventive health, Type 2 diabetes) between 2005 and 2013 were analyzed. Health center performance was classified into six patterns of change over time: consistent high improvement (positive), sustained high performance (positive), decline (negative), marked variability (negative), consistent low performance (negative), and no specific increase or decrease (neutral). Backwards stepwise multiple logistic regression analyses were used to examine the associations between health service characteristics and positive or negative trends in quality of care., Results: Trends in quality of care varied widely between health services across the four audit tools. Regression analyses of health service characteristics revealed no consistent statistically significant associations of population size, remoteness, governance model, or accreditation status with positive or negative trends in quality of care., Conclusion: The variable trends in quality of care as reflected by CQI audit tools do not appear to be related to easily measurable health service characteristics. This points to the need for a deeper or more nuanced understanding of factors that moderate the effect of CQI on health service performance for the purpose of strengthening enablers and overcoming barriers to improvement.

Study Objectives: To compare the use of sleep diagnostic tests, the risks, and cofactors, and outcomes of the care of Indigenous and non-indigenous Australian adults in regional and remote Australia in whom sleep related breathing disorders have been diagnosed., Methods: A retrospective cohort study of 200 adults; 100 Aboriginal and Torres Strait Islander and 100 non-indigenous adults with a confirmed sleep related breathing disorder diagnosed prior to September 2011 at Alice Springs Hospital and Cairns Hospital, Australia., Results: Results showed overall Indigenous Australians were 1.8 times more likely to have a positive diagnostic sleep study performed compared with non-indigenous patients, 1.6 times less likely in central Australia and 3.4 times more likely in far north Queensland. All regional and remote residents accessed diagnostic sleep studies at a rate less than Australia overall (31/100,000/y (95% confidence interval, 21-44) compared with 575/100,000/y)., Conclusion: The barriers to diagnosis and ongoing care are likely to relate to remote residence, lower health self-efficacy, the complex nature of the treatment tool, and environmental factors such as electricity and sleeping area. Indigeneity, remote residence, environmental factors, and low awareness of sleep health are likely to affect service accessibility and rate of use and capacity to enhance patient and family education and support following a diagnosis. A greater understanding of enablers and barriers to care and evaluation of interventions to address these are required., Commentary: A commentary on this article appears in this issue on page 1255., (© 2015 American Academy of Sleep Medicine.)

Background: Obstructive sleep apnoea is recognised as a common but under-diagnosed health issue. Currently, there is very little published data relating to the burden and impact of obstructive sleep apnoea among indigenous populations. The purpose of this review was to investigate the prevalence, impact, risk factors and treatment of obstructive sleep apnoea in indigenous populations in high-income countries., Methods: An integrative review was conducted on 25 English language studies and reports that investigated obstructive sleep apnoea among indigenous populations in high-income countries. Studies that did not focus on indigenous populations in the results or discussion were excluded. Eligible studies were identified by searching PubMed, Web of Science and Google Scholar databases and reference lists of eligible studies. Publication dates range from 1998 to 2012., Results: Synthesis of studies indicates the prevalence of obstructive sleep apnoea is higher and severity is greater in indigenous populations compared with non-indigenous populations. Comparable risk factors for obstructive sleep apnoea were identified in indigenous and non-indigenous populations, with only three studies identifying ethnicity as an independent risk factor., Conclusions: Indigenous populations in high-income countries are subject to an overall greater prevalence of obstructive sleep apnoea that is also more severe. A higher prevalence of obesity, alcohol and tobacco use and comorbid medical conditions associated with low socioeconomic status rather than indigenous status per se appears to explain this disparity.

Study Objectives: To describe the growth of publicly funded polysomnography (PSG) in Australia since 2004 and to compare this with earlier growth., Methods: Longitudinal census-level data stratified by jurisdiction were retrieved from the Medicare Australia online database., Results: There has been a near doubling in provision of PSG since the introduction of publicly funded in-home PSG under the Australian national Medicare program available to all Australian citizens in 2008. Overall annual PSG rates have risen from 339 in 2005 to 608 in 2012 per 100,000. This growth has exceeded that of comparable diagnostic procedures and all Medicare services overall. Queensland remains the leading jurisdiction per 100,000 Medicare enrollees for accessing Medicare-funded PSG., Conclusion: The continued growth in publicly funded PSG provision in Australia is unlikely to abate. The disparity in Australia between the estimated prevalence of sleep disorders, particularly obstructive sleep apnea, and the number of people having PSGs would suggest there remain a large number of undiagnosed cases. Support for the development of appropriate diagnostic and screening algorithms will be key in ensuring sustainable, effective, efficient, and accessible PSG services.

Antibody solutions are typically much more viscous than solutions of globular proteins at equivalent volume fraction. Here we propose that this is due to molecular entanglements that are caused by the elongated shape and intrinsic flexibility of antibody molecules. We present a simple theory in which the antibodies are modeled as linear polymers that can grow via reversible bonds between the antigen binding domains. This mechanism explains the observation that relatively subtle changes to the interparticle interaction can lead to large changes in the viscosity. The theory explains the presence of distinct power law regimes in the concentration dependence of the viscosity as well as the correlation between the viscosity and the charge on the variable domain in our antistreptavidin IgG1 model system.

Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches.

The underlying reasons for why some mAb (monoclonal antibody) clones are much more inclined to induce a Russell body (RB) phenotype during immunoglobulin biosynthesis remain elusive. Although RBs are morphologically understood as enlarged globular aggregates of immunoglobulins deposited in the endoplasmic reticulum (ER), little is known about the properties of the RB-inducing mAb clones as secretory cargo and their physical behaviors in the extracellular space. To elucidate how RB-inducing propensities, secretion outputs, and the intrinsic physicochemical properties of individual mAb clones are interrelated, we used HEK293 cells to study the biosynthesis of 5 human IgG mAbs for which prominent solution behavior problems were known a priori. All 5 model mAbs with inherently high condensation propensities induced RB phenotypes both at steady state and under ER-to-Golgi transport block, and resulted in low secretion titer. By contrast, one reference mAb that readily crystallized at neutral pH in vitro produced rod-shaped crystalline bodies in the ER without inducing RBs. Another reference mAb without notable solution behavior issues did not induce RBs and was secreted abundantly. Intrinsic physicochemical properties of individual IgG clones thus directly affected the biosynthetic steps in the ER, and thereby produced distinctive cellular phenotypes and influenced IgG secretion output. The findings implicated that RB formation represents a phase separation event or a loss of colloidal stability in the secretory pathway organelles. The process of RB induction allows the cell to preemptively reduce the extracellular concentration of potentially pathogenic, highly aggregation-prone IgG clones by selectively storing them in the ER.

Aim: The aim of this study was to assess the impact of a pilot screening program for rheumatic heart disease (RHD) on patient quality of life (QOL) and health services., Methods: A QOL questionnaire (CHQ-PF28) was used to assess the impact of RHD screening on children with a potentially abnormal screening echocardiogram and matched normal controls. The health service response to a potentially abnormal screening echocardiogram and the impact of the screening program on health services was evaluated using medical record review, carer interviews and surveys of health-care providers., Results: QOL was assessed in 68 children. Potentially abnormal screening echocardiograms were associated with poorer QOL in the General Health Perception (P < 0.05) and Parental Impact - Emotional (P < 0.05) domains. Health services contacted 82% of children with potentially abnormal echocardiograms, and clinical review occurred in 56%. A potentially abnormal echocardiogram was associated with a change in management in 6% (2/34) of children. When surveyed, 49% of health providers were aware of the RHD screening program, 29% had seen children referred with screening abnormalities and 85% of these providers stated this had an impact on local health-care delivery., Conclusions: This pilot RHD screening program was associated with poorer child and carer QOL for those with potentially abnormal results, greater health provider workload and suboptimal clinical follow-up. The adoption of screening for RHD in high-risk populations should be approached cautiously. Further research is required to facilitate and validate improved echocardiographic diagnostic criteria for RHD and the systematic assessment of the benefits and adverse effects of such screening., (© 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Multi-parametric electrophysiological measurements using optical methods have become a highly valued standard in cardiac research. Most published optical mapping systems are expensive and complex. Although some applications demand high-cost components and complex designs, many can be tackled with simpler solutions. Here, we describe (1) a camera-based voltage and calcium imaging system using a single 'economy' electron-multiplying charge-coupled device camera and demonstrate the possibility of using a consumer camera for imaging calcium transients of the heart, and (2) a photodiode-based voltage and calcium high temporal resolution measurement system using single-element photodiodes and an optical fibre. High-throughput drug testing represents an application where system scalability is particularly attractive. Therefore, we tested our systems on tissue exposed to a well-characterized and clinically relevant calcium channel blocker, nifedipine, which has been used to treat angina and hypertension. As experimental models, we used the Langendorff-perfused whole-heart and thin ventricular tissue slices, a preparation gaining renewed interest by the cardiac research community. Using our simplified systems, we were able to monitor simultaneously the marked changes in the voltage and calcium transients that are responsible for the negative inotropic effect of the compound.

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.

Electroanatomic mapping the interrelation of intracardiac electrical activation with anatomic locations has become an important tool for clinical assessment of complex arrhythmias. Optical mapping of cardiac electrophysiology combines high spatiotemporal resolution of anatomy and physiological function with fast and simultaneous data acquisition. If applied to the clinical setting, this could improve both diagnostic potential and therapeutic efficacy of clinical arrhythmia interventions. The aim of this study was to explore this utility in vivo using a rat model. To this aim, we present a single-camera imaging and multiple light-emitting-diode illumination system that reduces economic and technical implementation hurdles to cardiac optical mapping. Combined with a red-shifted calcium dye and a new near-infrared voltage-sensitive dye, both suitable for use in blood-perfused tissue, we demonstrate the feasibility of in vivo multi-parametric imaging of the mammalian heart. Our approach combines recording of electrophysiologically-relevant parameters with observation of structural substrates and is adaptable, in principle, to trans-catheter percutaneous approaches.

Design of experiment and statistical analyses were applied to evaluate the effects of several formulation components on the thermal and colloidal stability for a series of monoclonal antibody (mAb) formulations. The high-throughput assessment of the protein stability was performed by measuring the temperature of hydrophobic exposure (T(h) , thermal stability) and the diffusion interaction parameter (k(D) , colloidal stability). To correlate the measured parameters with protein stability, the propensity to aggregate was tested by exposing the mAb samples to two types of stress: mechanical stress caused by shaking agitation and thermal stress. Mechanical stress led to increased formation of large particles, whereas temperature stress resulted in an increase in oligomers. The data obtained from the stress studies were used to determine the critical values for the stability parameters. The optimal formulation compositions were determined based on the statistical models and the predication tests. This approach of high-throughput thermal and colloidal stability screening can be applied to the characterization and prediction of protein formulation properties., (Copyright © 2011 Wiley-Liss, Inc.)

Purpose: To assess the effect of sugar molecules on solution viscosity at high protein concentrations., Methods: A high throughput dynamic light scattering method was used to measure the viscosity of monoclonal antibody solutions. The effects of protein concentration, type of sugar molecule (trehalose, sucrose, sorbitol, glucose, fructose, xylose and galactose), temperature and ionic strength were evaluated. Differential scanning fluorimetry was used to reveal the effect of the same sugars on protein stability and to provide insight into the mechanism by which sugars increase viscosity., Results: The addition of all seven types of sugar molecules studied result in a significant increase in viscosity of high concentration monoclonal antibody solutions. Similar effects of sugars were observed in the two mAbs examined; viscosity could be reduced by increasing the ionic strength or temperature. The effect by sugars was enhanced at higher protein concentrations., Conclusions: Disaccharides have a greater effect on the solution viscosity at high protein concentrations compared to monosaccharides. The effect may be explained by commonly accepted mechanisms of interactions between sugar and protein molecules in solution.

The purpose of this study was to demonstrate the utility of combining a design of experiment (DOE) approach with high-throughput formulation screening to identify the main factors affecting protein thermostability and solution viscosity. The optimization of buffer compositions was guided by statistical analysis of the data to obtain the targeted combination of low viscosity and high thermostability. Different monoclonal antibody (mAb) formulation variables were evaluated in the study to achieve optimization of two parameters: (i) thermostability characterized by temperature of hydrophobic exposure and (ii) viscosity. High-throughput measurements were employed to characterize both parameters. The significance of each factor and the two-way interactions between them was studied by multivariable regression analysis. An experimental design was used to estimate the significance of all factors, including interaction effects. The range of optimal buffer compositions that maximized thermostability and minimized viscosity of a mAb formulation was determined. The described high-throughput methods are well suited for characterization of multiple protein formulation compositions with minimized resources such as time and material. The DOE approach can be successfully applied to the screening of mAb formulations early in the development lifecycle., (Copyright © 2010 Wiley-Liss, Inc.)

The spatiotemporal properties of the Ca(2+)-release process in skeletal muscle fibers from normal and mdx fibers were determined using the confocal-spot detection technique. The Ca(2+) indicator OGB-5N was used to record action potential-evoked fluorescence signals at consecutive locations separated by 200 nm along multiple sarcomeres of FDB fibers loaded with 10- and 30-mM EGTA. Three-dimensional reconstructions of fluorescence transients demonstrated the existence of microdomains of increased fluorescence around the Ca(2+)-release sites in both mouse strains. The Ca(2+) microdomains in mdx fibers were regularly spaced along the fiber axis, displaying a distribution similar to that seen in normal fibers. Nevertheless, both preparations differed in that in 10-mM EGTA Ca(2+) microdomains had smaller amplitudes and were wider in mdx fibers than in controls. In addition, Ca(2+)-dependent fluorescence transients recorded at selected locations within the sarcomere of mdx muscle fibers were not only smaller, but also slower than their counterparts in normal fibers. Notably, differences in the spatial features of the Ca(2+) microdomains recorded in mdx and normal fibers, but not in the amplitude and kinetics of the Ca(2+) transients, were eliminated in 30-mM EGTA. Our results consistently demonstrate that Ca(2+)-release flux calculated from release sites in mdx fibers is uniformly impaired with respect to those normal fibers. The Ca(2+)-release reduction is consistent with that previously measured using global detection techniques.

Studies of age-related changes in motor function in nonhuman primates have been based exclusively on unimanual motor tasks. In this study, we examined whether aging affects bimanual motor coordination in the monkey model. In addition, we compared performance of ovariectomized and intact females on the task, to examine whether estrogen deficiency impairs motor function. The task required 29 rhesus monkeys (6-26 years old) to extract a maximum of 15 raisins from a testing hole-board. While the task could most efficiently be performed with two hands, other motor strategies were possible. The number of raisins extracted per minute was measured in each of eight sessions, the first and last of which were videotaped for analysis of motor patterns. The number of raisins retrieved per minute declined significantly with age. All monkeys improved with practice, but aged monkeys improved more slowly than young ones. The proportion of bimanual actions tended to increase between the first and the last sessions but was not significantly different between young and aged monkeys. Hormonal status did not affect performance. Finally, performance on the bimanual task was significantly correlated with performance on a previously administered unimanual motor test emphasizing speed, suggesting that age-related motor slowing may explain deficits in both tasks.

Using a two-microelectrode voltage clamp technique, we investigated possible mechanisms underlying the impaired excitation-contraction coupling in skeletal muscle fibres of the mdx mouse, a model of the human disease Duchenne muscular dystrophy. We evaluated the role of the transverse tubular system (T-system) by using the potentiometric indicator di-8 ANEPPS, and that of the sarcoplasmic reticulum (SR) Ca2+ release by measuring Ca2+ transients with a low affinity indicator in the presence of high EGTA concentrations under voltage clamp conditions. We observed minimal differences in the T-system structure and the T-system electrical propagation was not different between normal and mdx mice. Whereas the maximum Ca2+ release elicited by voltage pulses was reduced by approximately 67% in mdx fibres, in agreement with previous results obtained using AP stimulation, the voltage dependence of SR Ca2+ release was identical to that seen in normal fibres. Taken together, our data suggest that the intrinsic ability of the sarcoplasmic reticulum to release Ca2+ may be altered in the mdx mouse.

The mdx mouse, a model of the human disease Duchenne muscular dystrophy, has skeletal muscle fibres which display incompletely understood impaired contractile function. We explored the possibility that action potential-evoked Ca(2+) release is altered in mdx fibres. Action potential-evoked Ca(2+)-dependent fluorescence transients were recorded, using both low and high affinity Ca(2+) indicators, from enzymatically isolated fibres obtained from extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of normal and mdx mice. Fibres were immobilized using either intracellular EGTA or N-benzyl-p-toluene sulphonamide, an inhibitor of the myosin II ATPase. We found that the amplitude of the action potential-evoked Ca(2+) transients was significantly decreased in mdx mice with no measured difference in that of the surface action potential. In addition, Ca(2+) transients recorded from mdx fibres in the absence of EGTA also displayed a marked prolongation of the slow decay phase. Model simulations of the action potential-evoked transients in the presence of high EGTA concentrations suggest that the reduction in the evoked sarcoplasmic reticulum Ca(2+) release flux is responsible for the decrease in the peak of the Ca(2+) transient in mdx fibres. Since the myoplasmic Ca(2+) concentration is a critical regulator of muscle contraction, these results may help to explain the weakness observed in skeletal muscle fibres from mdx mice and, possibly, Duchenne muscular dystrophy patients.