Echocardiographic and radiographic aortic remodeling in cats with confirmed systemic hypertension.

Systemic hypertension (SH) in cats may occur secondary to renal disease, hyperthyroidism, or idiopathic causes. Asymmetric dilation of the sinuses of Valsalva has been recognized in people with systemic hypertension as target organ damage (TOD). Aortic knob formation (lateral bowing of the aortic arch to proximal descending aorta on the posteroanterior/anteroposterior radiographic projection) is recognized as TOD in people due to SH. None of these changes have been reported in feline patients. The first objective of this retrospective case-controlled study was to compare echocardiographic changes in the aorta of 76 cats with systemic hypertension (SH) to those seen in 76 cats with normal blood pressure (NBP). Our second objective was to have blinded reviewers assess heart size and aortic shape and size from available thoracic radiographs of 49/76 cats with SH and 46/76 cats with NBP. A two-way unpaired t-test with significance set at alpha = 0.01 was used to evaluate aortic echocardiographic parameters. The mean of the aortic diameter and length of each aortic cusp was significantly larger in cats with SH than in cats with NBP. The aortic cusps were considered altered in size in 62 of 76 cats with SH, 12/62 ≥ with 0.5 mm, and 50/62 ≥ 1.0 mm. No significant difference in the vertebral heart score (VHS) was noted between groups. The aortic knob to lateral margin of the trachea in cats with SH had an area under the curve (AUC) of 0.74 (95% CI:0.61-0.87) with best cutoff of 1.12 cm with sensitivity of 81% and specificity of 69%.

AAVrh10 vector corrects pathology in animal models of GM1 gangliosidosis and achieves widespread distribution in the CNS of nonhuman primates.

GM1 gangliosidosis is a rare, inherited neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes the lysosomal hydrolase acid ß-galactosidase (ß-gal). ß-gal deficiency leads to toxic accumulation of GM1 ganglioside, predominantly in the central nervous system (CNS), resulting in progressive neurodegeneration. LYS-GM101 is an AAVrh.10-based gene therapy vector carrying the human GLB1 cDNA. The efficacy of intra-cerebrospinal fluid injection of LYS-GM101 analogs was demonstrated in GM1 mouse and cat models with widespread diffusion of ß-gal and correction of GM1 ganglioside accumulation in the CNS without observable adverse effects. Clinical dose selection was performed, based on a good-laboratory-practice study, in nonhuman primates (NHPs) using the clinical LYS-GM101 vector. A broadly distributed increase of ß-gal activity was observed in NHP brain 3 months after intra-cisterna magna injection of LYS-GM101 at 1.0 × 1012 vg/mL CSF and 4.0 × 1012 vg/mL CSF, with 20% and 60% increases compared with vehicle-treated animals, respectively. Histopathologic examination revealed asymptomatic adverse changes in the sensory pathways of the spinal cord and dorsal root ganglia in both sexes and at both doses. Taken as a whole, these pre-clinical data support the initiation of a clinical study with LYS-GM101 for the treatment of GM1 gangliosidosis.

Leading Diverse Workforces: Perspectives from Managers and Employers about Dyslexic Employees in Australian Workplaces.

BACKGROUND: Dyslexia is a specific learning disability affecting around 1 in 10 Australian adults. It presents unique challenges for employees in the workforce, yet community and workplace awareness of the challenges of dyslexia is limited. The aim of this preliminary research was to explore the experiences and perspectives of Australian employers and managers responsible for supervising employees with dyslexia in the workplace. MATERIALS AND METHODS: Using a qualitative research design, we conducted in-depth interviews with four managers who had current or previous experience managing employees with dyslexia. We used a deductive approach to analyse the data and categorise responses to the study questions. RESULTS: Participant responses indicated that there is a lack of awareness and understanding of dyslexia within Australian workplaces. Participants identified challenges facing employees with dyslexia in the workplace including, differing personal levels of confidence and comfort in disclosing disability; the possibility of discrimination, and a lack of inclusive organisational practices and processes. Suggestions for ways to improve workplaces for dyslexic employees included: additional support for leaders and managers to drive inclusive leadership, and additional training for leaders and managers on how to best support employees with dyslexia. CONCLUSIONS: While only a small sample size, this study indicates that further research is needed to better understand the working environment of Australian leaders and managers. It appears that leaders and mangers need skills and knowledge to better support employees with dyslexia and in doing so create more inclusive workplaces.

"You Don't Look Dyslexic": Using the Job Demands-Resource Model of Burnout to Explore Employment Experiences of Australian Adults with Dyslexia.

BACKGROUND: Employment and job security are key influences on health and wellbeing. In Australia, little is known about the employment lifecycle of adults with dyslexia. MATERIALS AND METHODS: Using a qualitative research design, this study sought to explore the experiences faced by adults with dyslexia seeking and retaining employment. In-depth interviews were conducted with a cohort either currently or previously in the labour market. We used the Job Demands Resource Model of Burnout (JD-R Model) to explore links between workplace characteristics and employee wellbeing. Deductive content analysis attained condensed and broad descriptions of participants' workplace experiences. RESULTS: Dyslexic adults (n = 14) participated; majority employed part/full-time and experienced challenges throughout their employment; exhaustion and burnout at work were reported, also fear and indecision about disclosure of dyslexia. A minority reported receiving positive, useful support from team members following disclosure. CONCLUSION: The JD-R Model provided a guiding framework. We found participants experienced a myriad of challenges that included risk of mental exhaustion, discrimination, limited access to support and fatigue, leaving them vulnerable to job burn-out. Dyslexia does not have to be a major barrier to success in any occupation. Yet, when in supportive, informed workplace environments, employees with dyslexia thrive.

An observational thoracic radiographic study of aortic remodeling in dogs with confirmed systemic hypertension.

Sustained systemic hypertension (SH) has been shown to cause target organ damage to various tissues in dogs and cats, including the aorta. Aortic dilatation occurs most commonly secondary to SH in people and develops prior to an aortic aneurysm. Our hypothesis was that blinded reviewers could be trained to recognize variable alterations of aortic shape and size on thoracic radiographs of canine patients with SH. A retrospective, observational, cross-sectional study was performed with three blinded reviewers evaluating thoracic radiographic images of 21 dogs with normal blood pressure compared to 145 dogs with system hypertension. Lateral radiographs showed variable aortic undulation and disproportionate enlargement of a portion of the aorta between the ascending and proximal descending aorta compared to the descending aorta just cranial to the diaphragm. On orthogonal projections, the aortic arch to proximal descending aorta bowed laterally similar to changes reported in people with the formation of an aortic "knob." After completing a training module, reviewers of the thoracic images had a 74% agreement with Fleiss' Kappa of 0.50 indicating moderate agreement recognizing SH changes to the thoracic aorta. The more experienced blinded reviewers had accuracies of 85% and 80% for identifying systemic hypertension, slightly better than the less experienced reviewer at 76%. The ratio of thoracic cavity width to aortic knob width was significantly different between the groups (median ratio 3.4 SH vs 4.1 normal). Evidence of target organ damage (TOD) to the thoracic aorta may prompt earlier recognition and treatment for systemic hypertension.

Limb girdle muscular dystrophy R12 (LGMD 2L, anoctaminopathy) mimicking idiopathic inflammatory myopathy: key points to prevent misdiagnosis.

OBJECTIVES: Diagnosing the idiopathic inflammatory myopathies (IIMs) can be challenging as several conditions, including genetic myopathies such as limb girdle muscular dystrophy type R12 (LGMD 2 l, anoctaminopathy) mimic the presentation. Here we describe learning points identified from review of four patients with LGMD 2 l who were initially incorrectly diagnosed with IIM. Our aim is to provide clinicians working in adult rheumatology services with a toolkit to help identify non-inflammatory presentations of myopathy. METHODS: We performed retrospective review of medical notes, laboratory results, muscle imaging and histological findings of four patients with LGMD 2 l who were previously misdiagnosed with IIM. We focussed on clinical presentation and progression, therapeutic agents used and events leading to revision of the diagnosis. RESULTS: Three male patients and one female patient with a mean age of 51 years at presentation were reviewed. In each case, treatment with immunosuppressants, in one case for >15 years, was observed without a clear therapeutic response. All patients were negative for anti-nuclear antibodies and available myositis-associated/specific autoantibodies and associated connective tissue disease features were absent. Prominent fatty infiltration and selective muscle involvement on thigh MRI was found in common. CONCLUSIONS: Adult-onset genetic myopathies, particularly LGMD R12, can mimic IIM. Accurate diagnosis is crucial to avoid the use of potentially harmful immunosuppressive therapies, to allow appropriate genetic counselling and to facilitate involvement in research studies.

Echocardiographic changes in the shape and size of the aortic cusps in dogs with confirmed systemic hypertension.

Systemic hypertension (SH) in dogs typically occurs secondary to renal disease, diabetes mellitus, hyperadrenocorticism, malignant adrenal tumors, or various medications. Echocardiography performed on people with SH has shown asymmetric dilation of the sinuses at the level of the aortic valves, previously undescribed in canine patients. The objective of this retrospective case-control study was to determine if there was a difference in size and shape of the aortic cusps at the level of the sinus of Valsalva in dogs with SH compared to dogs with normal blood pressure. We reviewed echocardiographic findings in 74 dogs with SH and 37 dogs with normal blood pressure (NBP), defined as less than 150 mmHg. Systemic hypertension was classified as mild (150-159 mm Hg), moderate (160-179 mm Hg), or severe (greater than 180 mm Hg). There was a significant difference (P < .001) in the mean size of the aorta cusps at the level of the sinuses in 67 of 74 dogs with SH and none of 37 dogs with NBP. Of the 74 dogs with SH, 70 had left ventricular hypertrophy (18 asymmetric, 15 concentric, and 37 eccentric). Additionally, there was aortic root dilatation in 15 dogs, aortic insufficiency in 21, mitral regurgitation in 50, and left atrial enlargement in 71. The standard deviation of the three cusp measurements between the dogs with SH and dogs with NBP had a sensitivity of 92% and specificity of 97% for diagnosis of SH. Asymmetric size of the aortic cusps on echocardiography is therefore a reliable indicator of SH in dogs.

The role of governance in Indigenous medical education research.

CONTEXT: This article considers the role of governance in Indigenous medical education research through the lens of an Australian Aboriginal research project titled Healing Conversations. The Healing Conversations project is developing and testing a targeted educational framework for improved clinical communication between healthcare practitioners and Australian Aboriginal peoples in regional and urban locations. It is proposed that an effective governance approach can support Indigenous and non-Indigenous stakeholders to work together in decision-making structures to enable outcomes that promote and prioritise Indigenous worldviews and values in medical education research. ISSUE: The case study explored here puts forth the notion of effective governance as one practical way to decolonise medical education research structures in both the urban and regional setting. The importance of relationships between Indigenous and non-Indigenous stakeholders is supported in tailored governance structures, as knowledge translation efforts are situated in mainstream tertiary education structures that hold collective responsibility and accountability for change in this space. LESSONS LEARNT: Reflections from the Healing Conversations research case study are outlined for future consideration regarding sustainable and effective Indigenous governance initiatives in medical education and research structures. This includes the importance of an Indigenous governance structure within the research team and a strong understanding of the roles and contributions of each research team member, along with the required humanistic qualities to action effective governance in Indigenous medical education research. Collaborative governance structures are fundamental as the inclusion and prioritisation of Indigenous worldviews and values is a key step in redressing Indigenous healthcare disparities and providing culturally safe healthcare institutions.

Abnormal epiphyseal development in a feline model of Sandhoff disease.

Sandhoff disease (SD) is caused by decreased function of the enzyme ß-N-acetylhexosaminidase, resulting in accumulation of GM2 ganglioside in tissues. Neural tissue is primarily affected and individuals with the infantile form of the disease generally do not survive beyond 4 years of age. Current treatments address neurometabolic deficits to improve lifespan, however, this extended lifespan allows clinical disease to become manifest in other tissues, including the musculoskeletal system. The impact of SD on bone and joint tissues has yet to be fully determined. In a feline model of infantile SD, animals were treated by intracranial injection of adeno-associated virus vectors to supply the central nervous system with corrective levels of hexosaminidase, resulting in a twofold to threefold increase in lifespan. As treated animals aged, signs of musculoskeletal disease were identified. The present study characterized bone and joint lesions from affected cats using micro-computed tomography and histology. All affected cats had similar lesions, whether or not they were treated. SD cats displayed a significant reduction in metaphyseal trabecular bone and markedly abnormal size and shape of epiphyses. Abnormalities increased in severity with age and appear to be due to alteration in the function of chondrocytes within epiphyseal cartilage, particularly the articular-epiphyseal complex. Older cats developed secondary osteoarthritic changes. The changes identified are similar to those seen in humans with mucopolysaccharidoses. Statement of clinical significance: the lesions identified will have significant implications on the quality of life of individuals whose lifespans are extended due to treatments for the primary neurological effects of SD.

Examining response process validity of script concordance testing: a think-aloud approach.

OBJECTIVES: This study investigated whether medical student responses to Script Concordance Testing (SCT) items represent valid clinical reasoning. Using a think-aloud approach students provided written explanations of the reasoning that underpinned their responses, and these were reviewed for concordance with an expert reference panel. METHODS: A set of 12, 11 and 15 SCT items were administered online to Year 3 (2018), Year 4 (2018) and Year 3 (2019) medical students respectively. Students' free-text descriptions of the reasoning supporting each item response were analysed, and compared with those of the expert panel. Response process validity was quantified as the rate of true positives (percentage of full and partial credit responses derived through correct clinical reasoning); and true negatives (percentage of responses with no credit derived through faulty clinical reasoning). RESULTS: Two hundred and nine students completed the online tests (response rate = 68.3%). The majority of students who had chosen the response which attracted full or partial credit also provided justifications which were concordant with the experts (true positive rate of 99.6% for full credit; 99.4% for partial credit responses). Most responses that attracted no credit were based on faulty clinical reasoning (true negative of 99.0%). CONCLUSIONS: The findings provide support for the response process validity of SCT scores in the setting of undergraduate medicine. The additional written think-aloud component, to assess clinical reasoning, provided useful information to inform student learning. However, SCT scores should be validated on each testing occasion, and in other contexts.

Two-eyed seeing: A useful gaze in Indigenous medical education research.

CONTEXT: Medical education has a role in preparing future health care practitioners to have the skills to meaningfully address health disparities while providing effective clinical care considerate of diversity in our societies. This calls for medical education researchers to approach their craft in ways that prioritise and value inputs from a broader range of perspectives and worldviews in an effort to redress the negative impacts of social, political and structural forces on health outcomes. METHODS: Given the entrenched health inequities experienced by Indigenous populations across the globe, this paper details an approach to medical education research put forward by Canadian Mi'kmaw Elders Murdena and Albert Marshall and named 'two-eyed seeing'. This approach provides the opportunity for medical education researchers to address the ongoing impacts of colonisation, racism and marginalisation on health outcomes by prioritising Indigenous worldviews in medical curricula. The need for researchers and medical academies to critically consider Indigenous governance and processes of respectful knowledge sharing within the wider institutional and societal contexts is addressed. CONCLUSIONS: The benefits of two-eyed seeing in the context of better preparing the future workforce to effectively meet the needs of those most vulnerable, and to action change against health inequities, situate it as a promising research approach in medical education.

Aortic to caudal vena cava ratio measurements using abdominal ultrasound are increased in dogs with confirmed systemic hypertension.

Chronically sustained systemic hypertension in dogs can damage the kidneys, eye, brain, heart, and vessels. In human medicine, systemic hypertension has been implicated as the most common risk factor for aorta dilation, which can progress to an aneurysm. Abdominal ultrasound has been commonly used to monitor the size of the abdominal aorta in people with systemic hypertension. In this retrospective cross-sectional abdominal ultrasound study, evaluation of the size of the abdominal aorta relative to the caudal vena cava was performed in 18 control dogs and 128 dogs with confirmed systemic hypertension. Preexisting conditions contributing to systemic hypertension in these dogs were renal disease, hyperadrenocorticism, diabetes mellitus, adrenal tumors, and previous administration of phenylpropanolamine or palladia. The abdominal aorta and caudal vena cava were assessed from longitudinal images cranial to the trifurcation with measurements made from outer border to outer border of the walls, being careful not to compress the caudal vena cava that would alter its size. Our hypothesis was the ratio of the diameter of the abdominal aorta to caudal vena cava would be higher in dogs with systemic hypertension compared to dogs with normal blood pressure. The mean abdominal aorta-caudal vena cava ratio was 1.028 in control dogs with a normal blood pressure and 1.515 in dogs with systemic hypertension. In dogs with confirmed systemic hypertension, the abdominal aorta was dilated compared to the caudal vena cava in the caudal abdomen. An increase in the abdominal aorta-caudal vena cava ratio in a dog should raise suspicion for the presence of systemic hypertension and prompt evaluation of blood pressure.

From temporal updating to temporal reasoning: Developments in young children's temporal representations.

Evidence from our research on young children's temporal understanding supports Hoerl & McCormack's view that young children rely on a temporal updating system to change representations over time. We propose that the shift from temporal updating to temporal reasoning is enabled by children's expanding representations of event sequences, along with developments in language, memory, and other cognitive competencies.

Construct validity of script concordance testing: progression of scores from novices to experienced clinicians.

OBJECTIVES: To investigate the construct validity of Script Concordance Testing (SCT) scores as a measure of the clinical reasoning ability of medical students and practising General Practitioners with different levels of clinical experience. METHODS: Part I involved a cross-sectional study, where 105 medical students, 19 junior registrars and 13 experienced General Practitioners completed the same set of SCT questions, and their mean scores were compared using one-way ANOVA. In Part II, pooled and matched SCT scores for 5 cohorts of students (2012 to 2017) in Year 3 (N=584) and Year 4 (N=598) were retrospectively analysed for evidence of significant progression. RESULTS: A significant main effect of clinical experience was observed [F(2, 136)=6.215, p=0.003]. The mean SCT score for General Practitioners (M=70.39, SD=4.41, N=13) was significantly higher (p=0.011) than that of students (M = 64.90, SD = 6.30, N=105). Year 4 students (M=68.90, SD= 7.79, N=584) scored a significantly higher mean score [t(552)=12.78, p<0.001] than Year 3 students (M = 64.03, SD=7.98, N=598). CONCLUSIONS: The findings that candidate scores increased with increasing level of clinical experience add to current evidence in the international literature in support of the construct validity of Script Concordance Testing. Prospective longitudinal studies with larger sample sizes are recommended to further test and build confidence in the construct validity of SCT scores.

Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation.

OBJECTIVE: Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin-deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD2B), distal myopathy with anterior tibial onset (DMAT)), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions. METHODS: We sequenced RNA from myogenic cells to identify a novel dysferlin pathogenic variant in two affected siblings that previously had only one disease-causing variant identified. We designed antisense oligonucleotides (AONs) to bypass the effects of this mutation on RNA splicing. RESULTS: We identified a new pathogenic point mutation deep within dysferlin intron 50i. This intronic variant causes aberrant mRNA splicing and inclusion of an additional pseudoexon (PE, we term PE50.1) within the mature dysferlin mRNA. PE50.1 inclusion alters the protein sequence, causing premature translation termination. We identified this mutation in 23 dysferlinopathy patients (seventeen families), revealing it to be one of the more prevalent dysferlin mutations. We used AON-mediated exon skipping to correct the aberrant PE50.1 splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression. INTERPRETATION: Deep intronic mutations can be a common underlying cause of dysferlinopathy, and importantly, could be treatable with AON-based exon-skipping strategies.

Medical student wellbeing - a consensus statement from Australia and New Zealand.

BACKGROUND: Medical student wellbeing - a consensus statement from Australia and New Zealand outlines recommendations for optimising medical student wellbeing within medical schools in our region. Worldwide, medical schools have responsibilities to respond to concerns about student psychological, social and physical wellbeing, but guidance for medical schools is limited. To address this gap, this statement clarifies key concepts and issues related to wellbeing and provides recommendations for educational program design to promote both learning and student wellbeing. The recommendations focus on student selection; learning, teaching and assessment; learning environment; and staff development. Examples of educational initiatives from the evidence-base are provided, emphasising proactive and preventive approaches to student wellbeing. MAIN RECOMMENDATIONS: The consensus statement provides specific recommendations for medical schools to consider at all stages of program design and implementation. These are: Design curricula that promote peer support and progressive levels of challenge to students. Employ strategies to promote positive outcomes from stress and to help others in need. Design assessment tasks to foster wellbeing as well as learning. Provide mental health promotion and suicide prevention initiatives. Provide physical health promotion initiatives. Ensure safe and health-promoting cultures for learning in on-campus and clinical settings. Train staff on student wellbeing and how to manage wellbeing concerns. CONCLUSION: A broad integrated approach to improving student wellbeing within medical school programs is recommended. Medical schools should work cooperatively with student and trainee groups, and partner with clinical services and other training bodies to foster safe practices and cultures. Initiatives should aim to assist students to develop adaptive responses to stressful situations so that graduates are prepared for the realities of the workplace. Multi-institutional, longitudinal collaborative research in Australia and New Zealand is needed to close critical gaps in the evidence needed by medical schools in our region.