Parsing patterns: Emerging roles of tissue self-organization in health and disease.

Patterned morphologies, such as segments, spirals, stripes, and spots, frequently emerge during embryogenesis through self-organized coordination between cells. Yet, complex patterns also emerge in adults, suggesting that the capacity for spontaneous self-organization is a ubiquitous property of biological tissues. We review current knowledge on the principles and mechanisms of self-organized patterning in embryonic tissues and explore how these principles and mechanisms apply to adult tissues that exhibit features of patterning. We discuss how and why spontaneous pattern generation is integral to homeostasis and healing of tissues, illustrating it with examples from regenerative biology. We examine how aberrant self-organization underlies diverse pathological states, including inflammatory skin disorders and tumors. Lastly, we posit that based on such blueprints, targeted engineering of pattern-driving molecular circuits can be leveraged for synthetic biology and the generation of organoids with intricate patterns.

Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

A real-time signal processing software package for the electrophysiology laboratory.

BACKGROUND: Real-time signal processing has to date been difficult to implement in the clinical electrophysiology laboratory. To date, no open access software solutions are available in electrophysiology (EP) laboratories to facilitate real-time intraprocedural signal analysis. We aimed to develop an open access, scalable Python plug-in to allow real-time signal processing during human EP procedures. METHODS AND RESULTS: A Python-based plug in for the widely available EnsiteX mapping system was developed. This plug-in utilized the LiveSync feature of the system to allow real-time signal analysis. An open access library was developed to allow end-users to implement real-time signal analysis using this platform, implemented in the Python programming language https://github.com/anand9176/WaveWatch5000Public. CONCLUSION: We have developed and demonstrated the feasibility of a readily scalable and open-access Python-based plug in to an electroanatomic mapping system (EnSiteX) to allow real-time processing and display of electrogram (EGM) based information for the procedural electrophysiologist to view intraprocedurally in the electrophysiology laboratory. The availability, to the clinician, of traditional and novel EGM-based metrics at the time of intervention, such as atrial fibrillation ablation, allows for key mechanistic insights into critical unresolved questions regarding arrhythmia mechanism.

A comparative study of point-of-care protection from N95 filtering face-piece respirators in a Residential Aged Care Facility and a Tertiary Hospital-Respiratory protection challenges remain amidst long-term impacts of COVID-19.

This study compared the effectiveness of N95 FFRs in providing respiratory protection for healthcare staff in a residential aged care facility (RACF) and tertiary teaching hospital (TTH) who had previously passed their occupational respiratory protection program fit test. A total of 126 healthcare workers who were regularly using N95 FFRs and who had previously passed a fit test participated in this comparative study. In this study, participants were again fit tested with the PortaCount machine, and their self-assessed tolerability of wearing an N95 FFR was assessed using a standardized questionnaire. The main outcome measures included the pass rate of the fit test and the assessment of tolerability and comfort of the N95 FFR. Across all participants, the fit test pass rate was low (27%), indicating persistent gaps in respiratory protection programs for healthcare workers during the ongoing COVID-19 pandemic. Hospital workers were 3.7 times more likely to pass the test compared to their counterparts in RACFs (p < 0.001). It was also found that workers in RACFs reported higher levels of discomfort and overall dissatisfaction with N95 FFRs compared to hospital staff. These findings highlight the need for targeted interventions and improvements in respiratory protection practices beyond annual fit testing, particularly in RACFs, to ensure the safety of healthcare workers and the vulnerable population they serve.

Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial.

BACKGROUND: Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. OBJECTIVE: To evaluate the efficacy and safety of ritlecitinib, an oral JAK3 (Janus kinase)/TEC (tyrosine kinase expressed in hepatocelluar carcinoma) inhibitor, in patients with active nonsegmental vitiligo in a phase 2b trial (NCT03715829). METHODS: Patients were randomized to once-daily oral ritlecitinib ± 4-week loading dose (200/50 mg, 100/50 mg, 30 mg, or 10 mg) or placebo for 24 weeks (dose-ranging period). Patients subsequently received ritlecitinib 200/50 mg daily in a 24-week extension period. The primary efficacy endpoint was percent change from baseline in Facial-Vitiligo Area Scoring Index at week 24. RESULTS: A total of 364 patients were treated in the dose-ranging period. Significant differences from placebo in percent change from baseline in Facial-Vitiligo Area Scoring Index were observed for the ritlecitinib 50 mg groups with (-21.2 vs 2.1; P < .001) or without (-18.5 vs 2.1; P < .001) a loading dose and ritlecitinib 30 mg group (-14.6 vs 2.1; P = .01). Accelerated improvement was observed after treatment with ritlecitinib 200/50 mg in the extension period (n = 187). No dose-dependent trends in treatment-emergent or serious adverse events were observed across the 48-week treatment. LIMITATIONS: Patients with stable vitiligo only were excluded. CONCLUSIONS: Oral ritlecitinib was effective and well tolerated over 48 weeks in patients with active nonsegmental vitiligo.

Markov modeling of phase singularity interaction effects in human atrial and ventricular fibrillation.

Atrial and ventricular fibrillation (AF/VF) are characterized by the repetitive regeneration of topological defects known as phase singularities (PSs). The effect of PS interactions has not been previously studied in human AF and VF. We hypothesized that PS population size would influence the rate of PS formation and destruction in human AF and VF, due to increased inter-defect interaction. PS population statistics were studied in computational simulations (Aliev-Panfilov), human AF and human VF. The influence of inter-PS interactions was evaluated by comparison between directly modeled discrete-time Markov chain (DTMC) transition matrices of the PS population changes, and M/M/∞ birth-death transition matrices of PS dynamics, which assumes that PS formations and destructions are effectively statistically independent events. Across all systems examined, PS population changes differed from those expected with M/M/∞. In human AF and VF, the formation rates decreased slightly with PS population when modeled with the DTMC, compared with the static formation rate expected through M/M/∞, suggesting new formations were being inhibited. In human AF and VF, the destruction rates increased with PS population for both models, with the DTMC rate increase exceeding the M/M/∞ estimates, indicating that PS were being destroyed faster as the PS population grew. In human AF and VF, the change in PS formation and destruction rates as the population increased differed between the two models. This indicates that the presence of additional PS influenced the likelihood of new PS formation and destruction, consistent with the notion of self-inhibitory inter-PS interactions.

A Low-Cost Modular Imaging System for Rapid, Multiplexed Immunofluorescence Detection in Clinical Tissues.

To image 4-plex immunofluorescence-stained tissue samples at a low cost with cellular level resolution and sensitivity and dynamic range required to detect lowly and highly abundant targets, here we describe a robust, inexpensive (<$9000), 3D printable portable imaging device (Tissue Imager). The Tissue Imager can immediately be deployed on benchtops for in situ protein detection in tissue samples. Applications for this device are broad, ranging from answering basic biological questions to clinical pathology, where immunofluorescence can detect a larger number of markers than the standard H&E or chromogenic immunohistochemistry (CIH) staining, while the low cost also allows usage in classrooms. After characterizing our platform's specificity and sensitivity, we demonstrate imaging of a 4-plex immunology panel in human cutaneous T-cell lymphoma (CTCL) formalin-fixed paraffin-embedded (FFPE) tissue samples. From those images, positive cells were detected using CellProfiler, a popular open-source software package, for tumor marker profiling. We achieved a performance on par with commercial epifluorescence microscopes that are >10 times more expensive than our Tissue Imager. This device enables rapid immunofluorescence detection in tissue sections at a low cost for scientists and clinicians and can provide students with a hands-on experience to understand engineering and instrumentation. We note that for using the Tissue Imager as a medical device in clinical settings, a comprehensive review and approval processes would be required.

Personalized 3D-printed frames to reduce leak from N95 filtering facepiece respirators: A prospective crossover trial in health care workers.

Correctly fitting N95 filtering facepiece respirators (FFRs) have become increasingly important in health care throughout the COVID-19 pandemic. We evaluated the hypothesis that personalized 3D-printed frames could improve N95 FFRs quantitative fit test pass rates and test scores in health care workers (HCWs). HCWs were recruited at a tertiary hospital in Adelaide, Australia (ACTRN 12622000388718). A mobile iPhone camera + app was used to produce 3D scans of volunteers' faces, which were then imported into a software program to produce personalized virtual scaffolds suited to each user's face and their unique anatomical features. These virtual scaffolds were printed on a commercially available 3D printer, producing plastic (and then silicone-coated, biocompatible) frames that can be fitted inside existing hospital supply N95 FFR. The primary endpoint was improved pass rates on quantitative fit testing, comparing participants wearing an N95 FFR alone (control 1) with participants wearing the frame + N95 FFR (intervention 1). The secondary endpoint was the fit factor (FF) in these groups, and R-COMFI respirator comfort and tolerability survey scores. N = 66 HCWs were recruited. The use of intervention 1 increased overall fit test pass rates to 62/66 (93.8%), compared to 27/66 (40.9%) for controls. (OR for pFF pass 20.89 (95%CI: 6.77, 64.48, p < 0.001.) Average FF increased, with the use of intervention 1-179.0 (95%CI: 164.3,193.7), compared to 85.2 (95%CI: 70.4,100.0) with control 1. Pass rates and FF were improved with intervention 1 compared to control 1 for all stages of the fit-test: bending, talking, side-to-side, and up-down motion. (p < 0.001 all stages). Tolerability and comfort of the frame were evaluated with the validated R-COMFI respirator comfort score, showing improvement with the frame compared to N95 FFR alone (p = 0.006). Personalized 3D-printed face frames decrease leakage, improve fit testing pass rates and FF, and provide improved comfort compared to the N95 FFR alone. Personalized 3D-printed face frames represent a rapidly scalable new technology to decrease FFR leakage in HCW and potentially the wider population.

Alchemical Free Energy Calculations to Investigate Protein-Protein Interactions: the Case of the CDC42/PAK1 Complex.

Here, we show that alchemical free energy calculations can quantitatively compute the effect of mutations at the protein-protein interface. As a test case, we have used the protein complex formed by the small Rho-GTPase CDC42 and its downstream effector PAK1, a serine/threonine kinase. Notably, the CDC42/PAK1 complex offers a wealth of structural, mutagenesis, and binding affinity data because of its central role in cellular signaling and cancer progression. In this context, we have considered 16 mutations in the CDC42/PAK1 complex and obtained excellent agreement between computed and experimental data on binding affinity. Importantly, we also show that a careful analysis of the side-chain conformations in the mutated amino acids can considerably improve the computed estimates, solving issues related to sampling limitations. Overall, this study demonstrates that alchemical free energy calculations can conveniently be integrated into the design of experimental mutagenesis studies.

Understanding the origins of the basic equations of statistical fibrillatory dynamics.

The mechanisms governing cardiac fibrillation remain unclear; however, it most likely represents a form of spatiotemporal chaos with conservative system dynamics. Renewal theory has recently been suggested as a statistical formulation with governing equations to quantify the formation and destruction of wavelets and rotors in fibrillatory dynamics. In this perspective Review, we aim to explain the origin of the renewal theory paradigm in spatiotemporal chaos. The ergodic nature of pattern formation in spatiotemporal chaos is demonstrated through the use of three chaotic systems: two classical systems and a simulation of cardiac fibrillation. The logistic map and the baker's transformation are used to demonstrate how the apparently random appearance of patterns in classical chaotic systems has macroscopic parameters that are predictable in a statistical sense. We demonstrate that the renewal theory approach developed for cardiac fibrillation statistically predicts pattern formation in these classical chaotic systems. Renewal theory provides governing equations to describe the apparently random formation and destruction of wavelets and rotors in atrial fibrillation (AF) and ventricular fibrillation (VF). This statistical framework for fibrillatory dynamics provides a holistic understanding of observed rotor and wavelet dynamics and is of conceptual significance in informing the clinical and mechanistic research of the rotor and multiple-wavelet mechanisms of AF and VF.

Atrial fibrosis and substrate based characterization in atrial fibrillation: Time to move forwards.

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice. However, current therapeutic interventions for atrial fibrillation have limited clinical efficacy as a consequence of major knowledge gaps in the mechanisms sustaining atrial fibrillation. From a mechanistic perspective, there is increasing evidence that atrial fibrosis plays a central role in the maintenance and perpetuation of atrial fibrillation. Electrophysiologically, atrial fibrosis results in alterations in conduction velocity, cellular refractoriness, and produces conduction block promoting meandering, unstable wavelets and micro-reentrant circuits. Clinically, atrial fibrosis has also linked to poor clinical outcomes including AF-related thromboembolic complications and arrhythmia recurrences post catheter ablation. In this article, we review the pathophysiology behind the formation of fibrosis as AF progresses, the role of fibrosis in arrhythmogenesis, surrogate markers for detection of fibrosis using cardiac magnetic resonance imaging, echocardiography and electroanatomic mapping, along with their respective limitations. We then proceed to review the current evidence behind therapeutic interventions targeting atrial fibrosis, including drugs and substrate-based catheter ablation therapies followed by the potential future use of electro phenotyping for AF characterization to overcome the limitations of contemporary substrate-based methodologies.

Atrial fibrillation burden: an update-the need for a CHA2DS2-VASc-AFBurden score.

Atrial fibrillation (AF) is an established independent risk factor for stroke. Current guidelines regard AF as binary; either present or absent, with the decision for anti-coagulation driven by clinical variables alone. However, there are increasing data to support a biological gradient of AF burden and stroke risk, both in clinical and non-clinical AF phenotypes. As such, this raises the concept of combining AF burden assessment with a clinical risk score to refine and individualize the assessment of stroke risk in AF-the CHA2DS2VASc-AFBurden score. We review the published data supporting a biological gradient to try and construct a putative schema of risk attributable to AF burden.

Utilisation and safety of catheter ablation of atrial fibrillation in public and private sector hospitals.

BACKGROUND: Little is known about the utilisation and safety of catheter ablation of atrial fibrillation (AF) among public and private sector hospitals. AIMS: To examine the uptake of AF ablations and compare procedural safety between the sectors. METHOD: Hospitalisation data from all public and private hospitals in four large Australian states (NSW, QLD, VIC and WA) were used to identify patients undergoing AF ablation from 2012 to 17. The primary endpoint was any procedure-related complications up to 30-days post-discharge. Logistic regression was used to evaluate the association between treatment at a public hospital and risk of complications adjusting for covariates. RESULTS: Private hospitals performed most of the 21,654 AF ablations identified (n = 16,992, 78.5 %), on patients who were older (63.5 vs. 59.9y) but had lower rates of heart failure (7.9 % vs. 10.4 %), diabetes (10.2 % vs. 14.1 %), and chronic kidney diseases (2.4 % vs. 5.2 %) (all p < 0.001) than those treated in public hospitals. When compared with private hospitals, public hospitals had a higher crude rate of complications (7.25 % vs. 4.70 %, p < 0.001). This difference remained significant after adjustment (OR 1.74 [95 % CI 1.54-2.04]) and it occurred with both in-hospital (OR 1.83 [1.57-2.14]) and post-discharge (OR 1.39 [1.06-1.83]) complications, with certain complications including acute kidney injury (OR 5.31 [3.02-9.36]), cardiac surgery (OR 5.18 [2.19-12.27]), and pericardial effusion (OR 2.18 [1.50-3.16]). CONCLUSIONS: Private hospitals performed most of AF ablations in Australia with a lower rate of complications when compared with public hospitals. Further investigations are needed to identify the precise mechanisms of this observed difference.

PIKfyve regulates melanosome biogenesis.

PIKfyve, VAC14, and FIG4 form a complex that catalyzes the production of PI(3,5)P2, a signaling lipid implicated in process ranging from lysosome maturation to neurodegeneration. While previous studies have identified VAC14 and FIG4 mutations that lead to both neurodegeneration and coat color defects, how PIKfyve regulates melanogenesis is unknown. In this study, we sought to better understand the role of PIKfyve in melanosome biogenesis. Melanocyte-specific PIKfyve knockout mice exhibit greying of the mouse coat and the accumulation of single membrane vesicle structures in melanocytes resembling multivesicular endosomes. PIKfyve inhibition blocks melanosome maturation, the processing of the melanosome protein PMEL, and the trafficking of the melanosome protein TYRP1. Taken together, these studies identify a novel role for PIKfyve in controlling the delivery of proteins from the endosomal compartment to the melanosome, a role that is distinct from the role of PIKfyve in the reformation of lysosomes from endolysosomes.

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Complications of cardiac implantable electronic device placement in public and private hospitals.

BACKGROUND: Few safety data exist comparing clinical outcomes in Australian public and private hospitals. We hypothesised that differences could exist between public and private hospitals due to differences in acuity and patient-level co-morbidities. AIMS: To report comparative complications of cardiac implantable electronic device (CIED) placement in public and private hospitals. METHODS: We conducted an observational cohort study of outcomes of patients aged >18 years from 2010 to 2015 undergoing a new permanent pacemaker (PPM), implantable cardioverter defibrillator (ICD) or cardiac resynchronisation therapy pacemaker or defibrillator (CRT-D/P) implant in NSW and Queensland public and private hospitals. The primary endpoint was major CIED-related complications occurring in-hospital or within 90 days of discharge. The independent effect of hospital sector was determined using multiple logistic regression, adjusting for covariates, including age, sex, co-morbidities and procedural acuity. RESULTS: A total of 32 364 new CIED implants (PPM 23 845, ICD 5361 and CRT-D/P 3158) were included (49% in private hospitals). Overall, 8.0% of private hospital procedures and 9.6% public hospital procedures experienced at least one complication. After adjustment, the overall risk of CIED complications was similar in private and public hospitals (OR: 0.92, 95% CI: 0.84-1.00, P = 0.06). In analysis of individual complications, adjusted all-cause in-hospital mortality was higher in private hospitals, (OR: 1.49, 95% CI: 1.03-2.16, P = 0.036) primarily driven by an excess mortality in acute cases. The adjusted risk of in-hospital generator operation (OR: 0.53, 95% CI: 0.30-0.94, P = 0.03) and post-discharge infection (OR: 0.61, 95% CI: 0.46-0.81, P < 0.001) was lower in private hospitals. CONCLUSIONS: These data identify important similarities and differences in safety outcomes of CIED implantation between Australian public and private hospitals.

Institutional Variation in Quality of Cardiovascular Implantable Electronic Device Implantation: A Cohort Study.

Background: Cardiovascular implantable electronic devices (CIEDs) are associated with procedure-related complications, yet little is known about variation in complication rates among institutions that may suggest disparities in care quality. Objective: To assess institutional variation in risk-standardized complication rates (RSCRs) for CIED. Design: Cohort study. Setting: 174 hospitals in Australia and New Zealand, 98 of which implanted at least 25 CIEDs during the study period. Participants: 81 304 patients older than 18 years (mean, 74.7 years [SD, 12.4]; 37.9% female) who received a new CIED (65 711 permanent pacemakers [PPMs] and 15 593 implantable cardioverter-defibrillators [ICDs]) in 2010 to 2015. Measurements: RSCRs and frequencies of major device-related complications during hospitalization or within 90 days of discharge. Results: Of the cohort, 6664 patients (8.2%) had a major complication. Although complication rates were higher for ICDs than PPMs (10.04% vs. 7.76%), 76.5% of all complications were attributable to PPMs (5098 vs. 1566 for ICDs). Among hospitals that implanted at least 25 CIEDs, the median RSCR was 8.1%; however, rates varied from 5.3% to 14.3%, with 22 hospitals identified as having RSCRs that differed significantly from the national average. Similar variation was observed when RSCRs for PPM implantation (n = 96 hospitals) (median RSCR, 7.6% [range, 5.4% to 12.9%]) were considered separately from those for ICD placement (n = 68 hospitals) (median RSCR, 9.7% [range, 6.2% to 16.9%]) and persisted when only elective procedures were assessed (n = 88 hospitals) (median RSCR, 7.4% [range, 4.7% to 13.0%]). Limitation: Possible unmeasured confounding from the use of administrative data. Conclusion: CIED complications are common and vary among hospitals, suggesting institutional variation in CIED care quality. Concerted clinical and policy interventions are needed to address CIED-related complications. These efforts should preferentially target PPMs, because most CIED complications are attributable to these devices. Primary Funding Source: The Hospitals Contribution Fund Research Foundation.

The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas.

Genes and pathways that allow cells to cope with oncogene-induced stress represent selective cancer therapeutic targets that remain largely undiscovered. In this study, we identify a RhoJ signaling pathway that is a selective therapeutic target for BRAF mutant cells. RhoJ deletion in BRAF mutant melanocytes modulates the expression of the pro-apoptotic protein BAD as well as genes involved in cellular metabolism, impairing nevus formation, cellular transformation, and metastasis. Short-term treatment of nascent melanoma tumors with PAK inhibitors that block RhoJ signaling halts the growth of BRAF mutant melanoma tumors in vivo and induces apoptosis in melanoma cells in vitro via a BAD-dependent mechanism. As up to 50% of BRAF mutant human melanomas express high levels of RhoJ, these studies nominate the RhoJ-BAD signaling network as a therapeutic vulnerability for fledgling BRAF mutant human tumors.

Determining the Influence of Psychiatric Comorbidity on Hospital Admissions in Cardiac Patients Through Multilevel Modelling of a Large Hospital Activity Data Set.

BACKGROUND: Increasingly, big data derived from administrative hospital records can be subject to analytics to provide clinical insights. The aim of this study was to determine the impact of psychiatric comorbidity on length of hospital stay and number of hospital admissions in cardiac patients utilising routinely collected hospitalisation records. METHODS: We routinely collected clinical and socio-demographic variables extracted from 37,580 cardiac patients, between 18 and 65 years old, admitted to South Australian hospitals between 2001/02 to 2010/11 financial years with cardiac diagnoses used to derive patient level and separation level variables used in the modelling. Multi-level models were constructed to analyse the impact of psychiatric comorbidity on both length of stay and the total number of hospitalisations, allowing for interactions between socioeconomic status and the burden of disease. Possible confounders for these models were, sex, age, indigenous status, country of birth, and rural status. RESULTS: For cardiac patients a mental health diagnosis was associated with an increase of 12.5% in the length of stay, and an increase in the number of stays by 20.0%. CONCLUSIONS: This study demonstrates the potential utility of routinely collected hospitalisation records to demonstrate the impact of psychiatric comorbidity on health service utilisation.

Is Atrial Fibrillation a Stroke Risk Factor or Risk Marker? An Appraisal Using the Bradford Hill Framework for Causality.

Atrial fibrillation (AF) is strongly associated with stroke risk but association on its own does not necessarily imply causality. Is AF a cause (risk factor) of stroke? Would treatment that reduces AF burden also reduce the burden of stroke? Or, perhaps, AF is a risk marker associated with a vascular syndrome in which there is co-existing atrial structural and electrical remodelling that results in the clinical manifestation of AF and the risk of stroke in parallel. A number of recent studies appear to detach AF as a direct cause of stroke. Studies in which cardiac implantable devices have been used to collect AF data preceding stroke appear to show no immediate temporal relationship. The Global Anticoagulant Registry in the Field - Atrial Fibrillation (GARFIELD-AF) a large worldwide registry of non-valvular AF, has shown that the risk of death exceeds the risk of stroke and that mortality, together with stroke and bleeding risk, is predicted by other vascular risk factors, defined by the CHA2DS2VASc score. Sir Bradford Hill proposed criteria to assess whether two associated factors are causal, more than 50 years ago. This method of analysing cause and effect in a complex scenario could be applied to AF and stroke. This paper aims to clinically appraise the evidence for each criterion outlined by Bradford Hill to single out whether the collective data supports one or the other.