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Healthcare workers are under increasing pressure to use limited resources more efficiently and improve patient outcomes. Healthcare redesign, a quality improvement methodology derived from the automotive industry, is a proven means of achieving these goals. Continuing Professional Development (CPD) opportunities for nurses seeking to build their capacity for healthcare redesign often come in the form of university courses, which can be costly and prohibitively time-consuming. We developed a Massive Open Online Course (MOOC) with a view to increasing the number of healthcare workers undertaking CPD in healthcare redesign and subsequently using these principles in their workplaces. The aim of the current study is to describe the development of our MOOC and its initial feedback from users. Materials and Methods: The theoretical and practical components of an existing postgraduate award course unit were made fit for purpose by being arranged into six weekly modules, before being transposed to an established learning management platform for MOOCs. Related quizzes, videos and interactive activities were then developed and included in each of these modules. Peer review of this content was completed by subject matter and teaching and learning experts prior to the MOOC being launched. Results: After running for nine months, 578 participants had enrolled in the MOOC, of whom 118 (20%) had followed through to completion. Participants were overwhelmingly from Australia (89%) and identified as female (78%). Preliminary feedback obtained from participants was positive, with 81% of respondents agreeing that they were satisfied with their experience, and 82% intending to apply their knowledge in practice. Conclusions: The MOOC has addressed a learning need by providing a brief and free form of education; learning from its development will help others seeking similar educational solutions. Initial feedback suggests the MOOC has been well-received and is likely to be translated into practice.

The Australian state of Tasmania has seen a spike in Emergency Department presentations in recent years, particularly among the elderly. A novel extended scope occupational therapy (ESOT) service was implemented by the Tasmanian Health Service, aimed at supporting hospital avoidance. Clients were referred to the ESOT service by other services after being assessed as having a high risk of imminent hospital presentation. Occupational Therapists provided short-term interventions related to falls, mobility, nutrition, and initiated onward referrals to other services. A convergent parallel mixed methods design was used to evaluate the ESOT service. Quantitative data from routinely collected administrative records and a purpose-built survey of referring clinicians were used alongside qualitative data from semi-structured interviews with clients/carers, to enable the triangulation of data. Quantitative data were analysed using descriptive statistics, while qualitative data collected in interviews were thematically analysed. A total of 104 extended scope interventions were provided to 100 clients. Most clients were able to stay at home. Qualitative data revealed that mobility, support, and facilitating access to support services were factors which added value to the client and carer experience. In conclusion, the ESOT program contributed to potentially avoiding hospital admissions and to improving the quality of life of participating clients.

Objective To compare the processes and outcomes of care in patients who had a stroke treated in urban versus rural hospitals in Australia.Design Observational study using data from a multicentre national registry.Setting Data from 50 acute care hospitals in Australia (25 urban, 25 rural) which participated in the Australian Stroke Clinical Registry during the period 2010–2015.Participants Patients were divided into two groups (urban, rural) according to the Australian Standard Geographical Classification Remoteness Area classification. Data pertaining to 28 115 patients who had a stroke were analysed, of whom 8159 (29%) were admitted to hospitals located within rural areas.Primary and secondary outcome measures Regional differences in processes of care (admission to a stroke unit, thrombolysis for ischaemic stroke, discharge on antihypertensive medication and provision of a care plan), and survival analyses up to 180 days and health-related quality of life at 90–180 days.Results Compared with those admitted to urban hospitals, patients in rural hospitals less often received thrombolysis (urban 12.7% vs rural 7.5%, p

Objectives: Individuals living in rural areas have comparatively less access to acute stroke care than their urban counterparts. Understanding the local barriers and facilitators to the use of current best practice for acute stroke may inform efforts to reduce this disparity. Methods: A qualitative study featuring semi-structured interviews and focus groups was conducted in the Australian state of Tasmania. Clinical staff from a range of disciplines involved in acute stroke care were recruited from three of the state’s four major public hospitals (one urban and two rural). A semi-structured interview guide based on the findings of an earlier quantitative study was used to elicit discussion about the barriers and facilitators associated with providing acute stroke care. An inductive process of thematic analysis was then used to identify themes and subthemes across the data set. Results: Two focus groups and five individual interviews were conducted. Four major themes were identified from analysis of the data: systemic issues, clinician factors, additional support and patient-related factors. Acute stroke care within the study’s urban hospital was structured and comprehensive, aided by the hospital’s acute stroke unit and specialist nursing support. In contrast, care provided in the study’s rural hospitals was somewhat less comprehensive, and often constrained by an absence of infrastructure or poor access to existing resources. Conclusion: The identified factors help to characterise acute stroke care within urban and rural hospitals and will assist quality improvement efforts in Tasmania’s hospitals.

Abstract Background With the increasing burden of mental illness globally, it is becoming common for hospitalised patients with chronic medical conditions to have a comorbidity of mental illness. This combination could prolong length of stay (LOS) of this patient cohort. We conducted an investigation in Tasmania, Australian hospitals to characterise this cohort and assess if co-morbidity of mental illness is a distinguishing factor that generates LOS variation across different chronic medical conditions. Methods The retrospective study analysed 16,898 admissions of patients with a primary diagnosis of one of five chronic medical conditions: lung or colorectal cancer, chronic obstructive pulmonary disease (COPD), type II diabetes, ischaemic heart disease (IHD) and stroke. Data were from July 2010 to June 2015, across four hospitals that collectively cover 95% of public hospital admissions in Tasmania, Australia. Descriptive statistics were used to compare characteristics of patients between the scenarios of with and without co-morbidity of mental illness. We used negative binomial regression models to assess whether co-morbidity of mental illness, along with its sub-types, after adjustment for potential confounding variables, associated with LOS variation in patients of each medical condition. Based on the adjusted LOS variation, we estimated differences in bed days’ use between patients with and without comorbidity of mental illness. Results Patients with co-morbidity of mental illness were significantly younger in comparison to patients without mental illness. With each medical condition, patients with comorbidity of mental illness had incurred higher bed days’ use than for those without mental illness. In cancer and stroke cohorts, co-morbidity of mental illness unfavourably affected the LOS variation by as high as 97% (CI: 49.9%–159%) and 109% (78%–146%), respectively. Though mental and behavioural disorders due to psychoactive substances was a dominant sub-type of mental illness across the medical conditions, it contributed significant unfavourable LOS variation only in the stroke patients i.e. 36.3% (CI: 16.2%–59.9%). Conclusions Mental illness consistently produced unfavourable LOS variation. Upskilling of healthcare teams and greater reporting and analysis of LOS variation for this patient cohort, and the sub-cohorts within it, are necessary to provide improved medical care and achieve system efficiencies.

Background: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88])., Conclusions: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often owing to lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here, we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes., Methods: We quantified cell-surface trafficking of 18,796 variants in KCNH2 using a Multiplexed Assay of Variant Effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping (APC). We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1,458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian LQTS penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events., Results: Variant MAVE trafficking scores and APC peak tail currents were highly correlated (Spearman Rank-order ρ = 0.69). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian LQTS penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became non-significant when peak-tail current and penetrance estimates were also available. The area under the ROC for 20-year event outcomes based on patient-specific sex and QTc (AUC 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (AUC 0.86 [0.83-0.89]) or attainable APC peak tail current data (AUC 0.84 [0.81-0.88])., Conclusion: High throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale while LQTS penetrance estimates and APC peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

Background: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype., Objective: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G., Methods: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers. We used in silico predictors and functional studies with peripheral blood and patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Isolated RNA was studied by reverse transcription polymerase chain reaction. iPSC-CMs were further characterized at baseline and after nonsense-mediated decay (NMD) inhibition, using quantitative polymerase chain reaction (qPCR), RNA-sequencing, and cellular electrophysiology. American College of Medical Genetics and Genomics (ACMG) criteria were used to adjudicate variant pathogenicity., Results: Variant heterozygotes displayed a spectrum of disease phenotypes, spanning from mild ventricular dysfunction with palpitations to severe ventricular arrhythmias requiring device shocks or progressive cardiomyopathy requiring heart transplantation. Consistent with in silico predictors, the c.970-4A>G FLNC variant activated a cryptic splice acceptor site, introducing a 3-bp insertion containing a premature termination codon. NMD inhibition upregulated aberrantly spliced transcripts by qPCR and RNA-sequencing. Patch clamp studies revealed irregular spontaneous action potentials, increased action potential duration, and increased sodium late current in proband-derived iPSC-CMs. These findings fulfilled multiple ACMG criteria for pathogenicity., Conclusion: Clinical, in silico, and functional evidence support the prediction that the intronic c.970-4A>G VUS disrupts splicing and drives ACM, enabling reclassification from VUS to pathogenic., (Copyright © 2023. Published by Elsevier Inc.)

Background: Rare protein-altering variants in SCN5A , KCNQ1 , and KCNH2 are major causes of Brugada syndrome and the congenital long QT syndrome. While splice-altering variants lying outside 2-bp canonical splice sites can cause these diseases, their role remains poorly described. We implemented 2 functional assays to assess 12 recently reported putative splice-altering variants of uncertain significance and 1 likely pathogenic variant without functional data observed in Brugada syndrome and long QT syndrome probands., Methods: We deployed minigene assays to assess the splicing consequences of 10 variants. Three variants incompatible with the minigene approach were introduced into control induced pluripotent stem cells by CRISPR genome editing. We differentiated cells into induced pluripotent stem cell-derived cardiomyocytes and studied splicing outcomes by reverse transcription-polymerase chain reaction. We used the American College of Medical Genetics and Genomics functional assay criteria (PS3/BS3) to reclassify variants., Results: We identified aberrant splicing, with presumed disruption of protein sequence, in 8/10 variants studied using the minigene assay and 1/3 studied in induced pluripotent stem cell-derived cardiomyocytes. We reclassified 8 variants of uncertain significance to likely pathogenic, 1 variant of uncertain significance to likely benign, and 1 likely pathogenic variant to pathogenic., Conclusions: Functional assays reclassified splice-altering variants outside canonical splice sites in Brugada Syndrome- and long QT syndrome-associated genes.

Many genes, including KCNH2, contain "hotspot" domains associated with a high density of variants associated with disease. This has led to the suggestion that variant location can be used as evidence supporting classification of clinical variants. However, it is not known what proportion of all potential variants in hotspot domains cause loss of function. Here, we have used a massively parallel trafficking assay to characterize all single-nucleotide variants in exon 2 of KCNH2, a known hotspot for variants that cause long QT syndrome type 2 and an increased risk of sudden cardiac death. Forty-two percent of KCNH2 exon 2 variants caused at least 50% reduction in protein trafficking, and 65% of these trafficking-defective variants exerted a dominant-negative effect when co-expressed with a WT KCNH2 allele as assessed using a calibrated patch-clamp electrophysiology assay. The massively parallel trafficking assay was more accurate (AUC of 0.94) than bioinformatic prediction tools (REVEL and CardioBoost, AUC of 0.81) in discriminating between functionally normal and abnormal variants. Interestingly, over half of variants in exon 2 were found to be functionally normal, suggesting a nuanced interpretation of variants in this "hotspot" domain is necessary. Our massively parallel trafficking assay can provide this information prospectively., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability., Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record-derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells., Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP., Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier; NCT03394859.