Bridging the translational gap: what can synaptopathies tell us about autism?

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.

Efficacy of intravenous magnesium for the management of non-post operative atrial fibrillation with rapid ventricular response: A systematic review and meta-analysis.

BACKGROUND: Intravenous magnesium (IV Mg), a commonly utilized therapeutic agent in the management of atrial fibrillation (AF) with rapid ventricular response, is thought to exert its influence via its effect on cellular automaticity and prolongation of atrial and atrioventricular nodal refractoriness thus reducing ventricular rate. We sought to undertake a systematic review and meta-analysis of the effectiveness of IV Mg versus placebo in addition to standard pharmacotherapy in the rate and rhythm control of AF in the nonpostoperative patient cohort given that randomized control trials (RCTs) have shown conflicting results. METHODS: Randomized controlled trials comparing IV Mg versus placebo in addition to standard of care were identified via electronic database searches. Nine RCTs were returned with a total of 1048 patients. Primary efficacy endpoints were study-defined rate control and rhythm control/reversion to sinus rhythm. The secondary endpoint was patient experienced side effects. RESULTS: Our analysis found IV Mg in addition to standard care was successful in achieving rate control (odd ratio [OR] 1.87, 95% confidence interval [CI] 1.13-3.11, p = .02) and rhythm control (OR 1.45, 95% CI 1.04-2.03, p = .03). Although not well reported among studies, there was no significant difference between groups regarding the likelihood of experiencing side effects. CONCLUSIONS: IV Mg, in addition to standard-of-care pharmacotherapy, increases the rates of successful rate and rhythm control in nonpostoperative patients with AF with rapid ventricular response and is well tolerated.

Parental perspectives on Phelan-McDermid syndrome: Results of a worldwide survey.

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder characterised by hypotonia, speech problems, intellectual disability and mental health issues like regression, autism and mood disorders. In the development, implementation and dissemination of a new clinical guideline for a rare genetic disorder like PMS, the parental experienced perspective is essential. As information from literature is scarce and often conflicting the European Phelan-McDermid syndrome guideline consortium created a multi-lingual survey for parents of individuals with PMS to collect their lived experiences with care needs, genotypes, somatic issues, mental health issues and parental stress. In total, we analysed 587 completed surveys from 35 countries worldwide. Based on parental reporting, PMS appeared to be caused by a deletion of chromosome 22q13.3 in 78% (379/486) of individuals and by a variant in the SHANK3 gene in 22% (107/486) of the individuals. Parents reported a wide variety of developmental, neurological, and other clinical issues in individuals with PMS. The most frequently experienced issues were related to speech and communication, learning disabilities/intellectual disability, and behaviour. While most reported issues were present across all age groups and genotypes, the prevalence of epilepsy, lymphoedema, and mental health issues do appear to vary with age. Developmental regression also appeared to begin earlier in this cohort than described in literature. Individuals with PMS due to a 22q13.3 deletion had a higher rate of kidney issues and lymphoedema compared to individuals with SHANK3 variants. Parental stress was high, with specific contributing factors being child and context related in accordance with the PMS phenotype. The survey results led to various validated recommendations in the European PMS guideline including an age specific surveillance scheme, specific genetic counselling, structured healthcare evaluations on sleep and communication and a focus on family well-being.

Consensus recommendations on mental health issues in Phelan-McDermid syndrome.

Phelan-McDermid syndrome is a rare genetic condition caused by a deletion encompassing the 22q13.3 region or a pathogenic variant of the gene SHANK3. The clinical presentation is variable, but main characteristics include global developmental delay/intellectual disability (ID), marked speech impairment or delay, along with other features like hypotonia and somatic or psychiatric comorbidities. This publication delineates mental health, developmental and behavioural themes across the lifetime of individuals with PMS as informed by parents/caregivers, experts, and other key professionals involved in PMS care. We put forward several recommendations based on the available literature concerning mental health and behaviour in PMS. Additionally, this article aims to improve our awareness of the importance of considering developmental level of the individual with PMS when assessing mental health and behavioural issues. Understanding how the discrepancy between developmental level and chronological age may impact concerning behaviours offers insight into the meaning of those behaviours and informs care for individuals with PMS, enabling clinicians to address unmet (mental health) care needs and improve quality of life.

Facial expression recognition is linked to clinical and neurofunctional differences in autism.

BACKGROUND: Difficulties in social communication are a defining clinical feature of autism. However, the underlying neurobiological heterogeneity has impeded targeted therapies and requires new approaches to identifying clinically relevant bio-behavioural subgroups. In the largest autism cohort to date, we comprehensively examined difficulties in facial expression recognition, a key process in social communication, as a bio-behavioural stratification biomarker, and validated them against clinical features and neurofunctional responses. METHODS: Between 255 and 488 participants aged 6-30 years with autism, typical development and/or mild intellectual disability completed the Karolinska Directed Emotional Faces task, the Reading the Mind in the Eyes Task and/or the Films Expression Task. We first examined mean-group differences on each test. Then, we used a novel intersection approach that compares two centroid and connectivity-based clustering methods to derive subgroups based on the combined performance across the three tasks. Measures and subgroups were then related to clinical features and neurofunctional differences measured using fMRI during a fearful face-matching task. RESULTS: We found significant mean-group differences on each expression recognition test. However, cluster analyses showed that these were driven by a low-performing autistic subgroup (~ 30% of autistic individuals who performed below 2SDs of the neurotypical mean on at least one test), while a larger subgroup (~ 70%) performed within 1SD on at least 2 tests. The low-performing subgroup also had on average significantly more social communication difficulties and lower activation in the amygdala and fusiform gyrus than the high-performing subgroup. LIMITATIONS: Findings of autism expression recognition subgroups and their characteristics require independent replication. This is currently not possible, as there is no other existing dataset that includes all relevant measures. However, we demonstrated high internal robustness (91.6%) of findings between two clustering methods with fundamentally different assumptions, which is a critical pre-condition for independent replication. CONCLUSIONS: We identified a subgroup of autistic individuals with expression recognition difficulties and showed that this related to clinical and neurobiological characteristics. If replicated, expression recognition may serve as bio-behavioural stratification biomarker and aid in the development of targeted interventions for a subgroup of autistic individuals.

The Synaptic Gene Study: Design and Methodology to Identify Neurocognitive Markers in Phelan-McDermid Syndrome and NRXN1 Deletions.

Synaptic gene conditions, i.e., "synaptopathies," involve disruption to genes expressed at the synapse and account for between 0.5 and 2% of autism cases. They provide a unique entry point to understanding the molecular and biological mechanisms underpinning autism-related phenotypes. Phelan-McDermid Syndrome (PMS, also known as 22q13 deletion syndrome) and NRXN1 deletions (NRXN1ds) are two synaptopathies associated with autism and related neurodevelopmental disorders (NDDs). PMS often incorporates disruption to the SHANK3 gene, implicated in excitatory postsynaptic scaffolding, whereas the NRXN1 gene encodes neurexin-1, a presynaptic cell adhesion protein; both are implicated in trans-synaptic signaling in the brain. Around 70% of individuals with PMS and 43-70% of those with NRXN1ds receive a diagnosis of autism, suggesting that alterations in synaptic development may play a crucial role in explaining the aetiology of autism. However, a substantial amount of heterogeneity exists between conditions. Most individuals with PMS have moderate to profound intellectual disability (ID), while those with NRXN1ds have no ID to severe ID. Speech abnormalities are common to both, although appear more severe in PMS. Very little is currently known about the neurocognitive underpinnings of phenotypic presentations in PMS and NRXN1ds. The Synaptic Gene (SynaG) study adopts a gene-first approach and comprehensively assesses these two syndromic forms of autism. The study compliments preclinical efforts within AIMS-2-TRIALS focused on SHANK3 and NRXN1. The aims of the study are to (1) establish the frequency of autism diagnosis and features in individuals with PMS and NRXN1ds, (2) to compare the clinical profile of PMS, NRXN1ds, and individuals with 'idiopathic' autism (iASD), (3) to identify mechanistic biomarkers that may account for autistic features and/or heterogeneity in clinical profiles, and (4) investigate the impact of second or multiple genetic hits on heterogeneity in clinical profiles. In the current paper we describe our methodology for phenotyping the sample and our planned comparisons, with information on the necessary adaptations made during the global COVID-19 pandemic. We also describe the demographics of the data collected thus far, including 25 PMS, 36 NRXN1ds, 33 iASD, and 52 NTD participants, and present an interim analysis of autistic features and adaptive functioning.

What Contributes to Athlete Performance Health? A Concept Mapping Approach.

BACKGROUND: In high-performance sport, athlete performance health encompasses a state of optimal physical, mental, and social wellbeing related to an athlete's sporting success. The aim of this study was to identify the priority areas for achieving athlete performance health in Australia's high-performance sport system (HPSS). METHODS: Participants across five socioecological levels of Australia's HPSS were invited to contribute to this study. Concept mapping, a mixed-methods approach incorporating qualitative and quantitative data collection, was used. Participants brainstormed ideas for what athlete performance health requires, sorted the ideas into groups based on similar meaning and rated the importance, and ease of achieving each idea on a scale from 1 (not important/easiest to overcome) to 5 (extremely important/hardest to overcome). RESULTS: Forty-nine participants generated 97 unique statements that were grouped into 12 clusters following multidimensional scaling and hierarchical cluster analysis. The three clusters with highest mean importance rating were (mean importance rating (1-5), mean ease of overcoming (1-5)): 'Behavioral competency' (4.37, 2.30); 'Collaboration and teamwork' (4.19, 2.65); 'Valuing athlete wellbeing' (4.17, 2.77). The 12 clusters were grouped into five overarching domains: Domain one-Performance health culture; Domain two-Integrated strategy; Domain three-Operational effectiveness; Domain four-Skilled people; Domain five-Leadership. CONCLUSION: A diverse sample of key stakeholders from Australia's HPSS identified five overarching domains that contribute to athlete performance health. The themes that need to be addressed in a strategy to achieve athlete performance health in Australia's HPSS are 'Leadership', 'Skilled people', 'Performance health culture', 'Operational effectiveness', and 'Integrated strategy'.

An exploratory qualitative study exploring GPs' and psychiatrists' perceptions of post-traumatic stress disorder in postnatal women using a fictional case vignette.

Postnatal post-traumatic stress disorder (PTSD) affects 3%-4% of women who give birth. It is underdiagnosed and undertreated. Thus far, no studies have investigated doctors' perceptions of PTSD in postnatal women. We investigated whether GPs and psychiatrists perceive PTSD symptoms after birth to indicate pathology and what diagnosis and management they would offer. Semi-structured interviews were conducted with six GPs and seven psychiatrists using a fictional vignette featuring a woman experiencing PTSD following a traumatic birth. A framework analysis approach was used. Despite half the GPs recognizing trauma-related features in the vignette their most common diagnosis was postnatal depression whereas six of the seven psychiatrists identified PTSD. Management plans reflected this. Both GPs and psychiatrists lacked trust in timeliness of referrals to psychological services. Both suggested referral to specialist perinatal mental health teams. Results suggest women are unlikely to get a PTSD diagnosis during initial GP consultations, however the woman-centred care proposed by GPs means that a trauma-focussed diagnosis later in the care pathway was not ruled out. Further research is needed to confirm these findings, which suggest that an evidence base around best management for women with postnatal PTSD is sorely needed, especially to inform GP training.

The meaning of significant mean group differences for biomarker discovery.

Over the past decade, biomarker discovery has become a key goal in psychiatry to aid in the more reliable diagnosis and prognosis of heterogeneous psychiatric conditions and the development of tailored therapies. Nevertheless, the prevailing statistical approach is still the mean group comparison between "cases" and "controls," which tends to ignore within-group variability. In this educational article, we used empirical data simulations to investigate how effect size, sample size, and the shape of distributions impact the interpretation of mean group differences for biomarker discovery. We then applied these statistical criteria to evaluate biomarker discovery in one area of psychiatric research-autism research. Across the most influential areas of autism research, effect size estimates ranged from small (d = 0.21, anatomical structure) to medium (d = 0.36 electrophysiology, d = 0.5, eye-tracking) to large (d = 1.1 theory of mind). We show that in normal distributions, this translates to approximately 45% to 63% of cases performing within 1 standard deviation (SD) of the typical range, i.e., they do not have a deficit/atypicality in a statistical sense. For a measure to have diagnostic utility as defined by 80% sensitivity and 80% specificity, Cohen's d of 1.66 is required, with still 40% of cases falling within 1 SD. However, in both normal and nonnormal distributions, 1 (skewness) or 2 (platykurtic, bimodal) biologically plausible subgroups may exist despite small or even nonsignificant mean group differences. This conclusion drastically contrasts the way mean group differences are frequently reported. Over 95% of studies omitted the "on average" when summarising their findings in their abstracts ("autistic people have deficits in X"), which can be misleading as it implies that the group-level difference applies to all individuals in that group. We outline practical approaches and steps for researchers to explore mean group comparisons for the discovery of stratification biomarkers.

Angiotensin-Converting Enzyme 2 Activity Is Associated With Embolic Stroke of Undetermined Source.

[Figure: see text].

Sedation Modulates Frontotemporal Predictive Coding Circuits and the Double Surprise Acceleration Effect.

Two important theories in cognitive neuroscience are predictive coding (PC) and the global workspace (GW) theory. A key research task is to understand how these two theories relate to one another, and particularly, how the brain transitions from a predictive early state to the eventual engagement of a brain-scale state (the GW). To address this question, we present a source-localization of EEG responses evoked by the local-global task-an experimental paradigm that engages a predictive hierarchy, which encompasses the GW. The results of our source reconstruction suggest three phases of processing. The first phase involves the sensory (here auditory) regions of the superior temporal lobe and predicts sensory regularities over a short timeframe (as per the local effect). The third phase is brain-scale, involving inferior frontal, as well as inferior and superior parietal regions, consistent with a global neuronal workspace (GNW; as per the global effect). Crucially, our analysis suggests that there is an intermediate (second) phase, involving modulatory interactions between inferior frontal and superior temporal regions. Furthermore, sedation with propofol reduces modulatory interactions in the second phase. This selective effect is consistent with a PC explanation of sedation, with propofol acting on descending predictions of the precision of prediction errors; thereby constraining access to the GNW.

The Effect of Transitional Care on 30-Day Outcomes in Patients Hospitalised With Acute Heart Failure.

BACKGROUND: Patients admitted to hospital with acute heart failure (AHF) are at increased risk of readmission and mortality post-discharge. The aim of the study was to examine health service utilisation within 30 days post-discharge from an AHF hospitalisation. METHODS: This was a prospective, observational, non-randomised study of consecutive patients hospitalised with acute HF to one of 16 Victorian hospitals over a 30-day period each year and followed up for 30 days post-discharge. The project was conducted annually over three consecutive years from 2015 to 2017. RESULTS: Of the 1,197 patients, 56.3% were male with an average age of 77±13.23 years. Over half of the patients (711, 62.5%) were referred to an outpatient clinic and a third (391, 34.4%) to a HF disease management program. In-hospital mortality was 5.1% with 30 day-mortality of 9% and readmission rate of 24.4%. Patients who experienced a subsequent readmission less than 10 days post-discharge and between 11 and 20 days post-discharge had a five- to six-fold increase in risk of mortality (adjusted OR 5.02, 95% CI 2.11-11.97; OR 6.45, 95% CI 2.69-15.42; respectively) compared to patients who were not readmitted to hospital. An outpatient appointment within 30 days post-discharge significantly reduced the risk of 30-day mortality by 81% (95% CI 0.09-0.43). CONCLUSION: Patients admitted to hospital with AHF who experience a subsequent readmission within 20 days post-discharge are at increased risk of dying. However, early follow-up post-discharge may reduce this risk. Early post-discharge follow-up is vital to address this vulnerable period after a HF admission.

The Australian Institute of Sport framework for rebooting sport in a COVID-19 environment.

Sport makes an important contribution to the physical, psychological and emotional well-being of Australians. The economic contribution of sport is equivalent to 2-3% of Gross Domestic Product (GDP). The COVID-19 pandemic has had devastating effects on communities globally, leading to significant restrictions on all sectors of society, including sport. Resumption of sport can significantly contribute to the re-establishment of normality in Australian society. The Australian Institute of Sport (AIS), in consultation with sport partners (National Institute Network (NIN) Directors, NIN Chief Medical Officers (CMOs), National Sporting Organisation (NSO) Presidents, NSO Performance Directors and NSO CMOs), has developed a framework to inform the resumption of sport. National Principles for Resumption of Sport were used as a guide in the development of 'the AIS Framework for Rebooting Sport in a COVID-19 Environment' (the AIS Framework); and based on current best evidence, and guidelines from the Australian Federal Government, extrapolated into the sporting context by specialists in sport and exercise medicine, infectious diseases and public health. The principles outlined in this document apply to high performance/professional, community and individual passive (non-contact) sport. The AIS Framework is a timely tool of minimum baseline of standards, for 'how' reintroduction of sport activity will occur in a cautious and methodical manner, based on the best available evidence to optimise athlete and community safety. Decisions regarding the timing of resumption (the 'when') of sporting activity must be made in close consultation with Federal, State/Territory and/or Local Public Health Authorities. The priority at all times must be to preserve public health, minimising the risk of community transmission.

The Atrium and Embolic Stroke: Myopathy Not Atrial Fibrillation as the Requisite Determinant?

Atrial fibrillation (AF) is well-recognized in the pathophysiology of left atrial thrombogenesis and resultant cardioembolic stroke. Subclinical AF is believed to account for a significant proportion of embolic stroke. However, recent randomized control trials failed to demonstrate a significant benefit for oral anticoagulation, in an unselected population with embolic stroke of undetermined source. This has reinvigorated the focus on finding robust markers to identify patients at risk of cardioembolic stroke. Several nonfibrillatory atrial electrical markers, along with structural and biochemical abnormalities, have been associated with ischemic stroke, independently of AF. An increasingly complex relationship exists among vascular risk factors, atrial remodeling, and thrombogenesis. Identifying robust markers of an underlying atrial myopathy may allow for early identification of patients at risk for cardioembolic stroke. This review outlines the inconsistencies in the evidence for AF as the prerequisite for left atrial thrombogenesis and embolic stroke. It will highlight the current evidence and controversies for adverse atrial remodeling, independent from rhythm, as a plausible mechanism for left atrial thrombogenesis and ischemic stroke.

Racial Differences in Performance-Based Function and Potential Explanatory Factors Among Individuals With Knee Osteoarthritis.

OBJECTIVE: In individuals with knee osteoarthritis (OA), self-reported physical function is poorer in African Americans than in whites, but whether this difference holds true for objective assessments is unclear. The purpose of this study was to examine racial differences in performance-based physical function as well as potential underlying factors contributing to these racial differences. METHODS: Participants with knee OA from a randomized controlled trial completed the 2-minute step test (2MST), timed-up-and-go (TUG), and 30-second chair stand (30s-CST) at baseline. Race differences in performance-based function were assessed by logistic regression. Separate models were adjusted for sets of demographic, socioeconomic, psychological health, and physical health variables. RESULTS: In individuals with knee OA (n = 322; 72% women, 22% African American, mean ± SD age 66 ± 11 years, mean ± SD body mass index 31 ± 8 kg/m2 ), African Americans (versus whites) had greater unadjusted odds of poorer function (30s-CST odds ratio [OR] 2.79 [95% confidence interval (95% CI) 1.65-4.72], 2MST OR 2.37 [95% CI 1.40-4.03], and TUG OR 3.71 [95% CI 2.16-6.36]). Relationships were maintained when adjusted for demographic and psychological health covariates, but they were either partially attenuated or nonsignificant when adjusted for physical health and socioeconomic covariates. CONCLUSION: African American adults with knee OA had poorer unadjusted performance-based function than whites. Physical health and socioeconomic characteristics diminished these differences, emphasizing the fact that these factors may be important to consider in mitigating racial disparities in function.

Medium-Term Bioresorbable Scaffold Outcomes Utilising Data From an Australian Clinical Quality Registry.

BACKGROUND: Bioresorbable scaffolds (BRS) are a novel technology in coronary intervention. However, recent trials demonstrate higher rates of device failure compared to contemporary drug-eluting stents. This study sought to utilise a clinical quality registry to assess the medium-term safety of the Abbott Absorb BRS (Abbott Vascular, Santa Clara, CA, USA), in an Australian context. METHODS: A prospective, observational study of 192 BRS percutaneous coronary interventions (PCI) compared to 31,773 non-BRS PCIs entered in the Victorian Cardiac Outcomes Registry from 2013 to 2017. The main outcome measure was patient-oriented composite endpoint (POCE) events comprising all-cause mortality, any myocardial infarction (MI), and any revascularisation. RESULTS: Bioresorbable scaffolds patients (mean age 61.6±10.5 years, 79% male) were younger, had less comorbidity, less prior PCI, fewer ST elevation myocardial infarction (STEMI) presentations, lower rates of multi-lesion disease and more adjuvant devices compared to non-BRS PCI (all p<0.01). All-cause mortality was 2.1%, myocardial infarction (MI) 2.1%, scaffold thrombosis 3.1% and any revascularisation 14.1% (mean follow-up 27.4±8.9 months). POCE events occurred in 11.5% at 1 year and 16.9% at 2 years, comparable to pooled-trial data. Multivariate predictors of POCE were >1 scaffold used (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.9-11.4, p<0.01) and scaffold diameter ≤2.5 mm (OR 3.3, 95% CI 1.4-7.6, p=0.02). Over 95% guideline adherence was achieved in six of eight patient selection criteria and four of six device deployment criteria. CONCLUSION: In an Australian setting, BRS were used in non-complex patients. Most guidelines for use were adhered to and outcomes were comparable to pooled trial data. Clinical quality registries are effective in assessing novel treatments and technologies when potential safety concerns develop.

Association between excessive premature atrial complexes and cryptogenic stroke: results of a case-control study.

OBJECTIVE: Recent anticoagulation trials in all-comer cryptogenic stroke patients have yielded equivocal results, reinvigorating the focus on identifying reproducible markers of an atrial myopathy. We investigated the role of excessive premature atrial complexes (PACs) in ischaemic stroke, including cryptogenic stroke and its association with vascular risk factors. METHODS AND RESULTS: A case-control study was conducted utilising a multicentre institutional stroke database to compare 461 patients with an ischaemic stroke or transient ischaemic attack (TIA) with a control group consisting of age matched patients without prior history of ischaemic stroke/TIA. All patients underwent 24-hour Holter monitoring during the study period and atrial fibrillation was excluded. An excessive PAC burden, defined as ≥200 PACs/24 hours, was present in 25.6% and 14.7% (p<0.01), of stroke/TIA and control patients, respectively. On multivariate regression, excessive PACs (OR 1.97; 95% CI 1.29 to 3.02; p<0.01), smoking (OR 1.58; 95% CI 1.06 to 2.36; p<0.05) and hypertension (OR 1.53; 95% CI 1.07 to 2.17; p<0.05) were independently associated with ischaemic stroke/TIA. Excessive PACs remained the strongest independent risk factor for the cryptogenic stroke subtype (OR 1.95; 95% CI 1.16 to 3.28; p<0.05). Vascular risk factors that promote atrial remodelling, increasing age (≥75 years, OR 3.64; 95% CI 2.08 to 6.36; p<0.01) and hypertension (OR 1.54; 95% CI 1.01 to 2.34; p<0.05) were independently associated with excessive PACs. CONCLUSIONS: Excessive PACs are independently associated with cryptogenic stroke and may be a reproducible marker of atrial myopathy. Prospective studies assessing their utility in guiding stroke prevention strategies may be warranted.

Delayed conservative treatment of an acute lateral ankle sprain in a non-athlete female following walking boot immobilisation.

Lateral ankle sprains are a common injury with an estimated occurrence rate of 23 000 per day in the USA. Prolonged immobilisation and delayed referral to physical therapy are associated with poorer outcomes. The patient was a 49-year-old woman working as a surgical technologist. She sustained an inversion injury to her left ankle while descending from a stool. Her primary care physician examined her, issued a Controlled Ankle Movement (CAM) walking boot and immobilised her ankle for 6 weeks. Patients with grade I and II lateral ankle sprains who are treated with early mobilisation and referral to physical therapy have demonstrated earlier return to function compared with patients who are treated with prolonged immobilisation and delayed referral. Nevertheless, it remains common for individuals who have sustained a lateral ankle sprain to be immobilised. This case study highlights the importance of early mobilisation and early physical therapy referral for patients with lateral ankle sprains.

Poor reliability of P-wave terminal force V1 in ischemic stroke.

INTRODUCTION: Several ECG markers are postulated to represent underlying atrial remodelling and have been associated with ischemic stroke. P-wave terminal force in lead V1 (PTFV1) is one such marker. We examined the factors that contribute to the reliability of PTFV1 and its association with ischemic stroke. MATERIAL AND METHODS: Four hundred and thirty-five patients that presented with an ischemic stroke or transient ischemic attack (TIA) were identified through a prospectively maintained multi-site institutional stroke database. Control group consisted of age matched patients without prior history of an ischemic stroke or TIA. All patients underwent a 12-lead ECG and 24-hour Holter monitoring during the study period to exclude atrial fibrillation. RESULTS: Morphology consistent with PTFV1 occurred commonly in both the stroke/TIA and control groups. There was no significant difference in the median PTFV1 value between the stroke 3.96 mV ms [Interquartile range (IQR) 2.78-5.58] and control 4.23 mV ms [IQR 2.91-5.57] groups. Measurements of PTFV1 demonstrated excellent intra-observer reliability on assessment of the same P-wave (Intra class correlation (ICC) 0.91, p < 0.001) with narrow limits of agreement 2.21 to -2.95 mV ms. A change in the P wave assessed led to a significant reduction in reliability (ICC 0.79, p < 0.001). Inter-observer, inter P-wave assessment demonstrated further reduction in reliability (ICC 0.68, p < 0.002) with wide limits of agreement 6.17 to -5.78 mV ms, indicating significant under and overestimation of PTFV1. CONCLUSION: The utility of PTFV1 as a clinical marker for ischemic stroke is limited by the reduction in reliability associated with inter-observer and inter P-wave measurements.

Clinical Management of Glomerular Diseases.

Progressive glomerular damage can occur as a result of various etiologic factors including infections, medications, diseases, and autoimmune disorders. This article discusses the clinical management of the leading conditions associated with glomerular disease, including glomerulosclerosis, diabetic nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy. Glomerular damage and disease progression may lead to end stage renal disease. Clinical management is individualized, as based on causative factors and clinical manifestations, with the overall goal of limiting glomerular damage. Collaborative and comprehensive care is imperative to improving patient outcomes.