In search of an efficient strategy to monitor disease status of chronic heart failure outpatients

_Introduction_ Blood biomarkers have the potential to monitor the severity of chronic heart failure (CHF). Studies correlating repeated measurements of blood biomarkers with repeatedly assessed New York Heart Association (NYHA) class over a prolonged follow-up period, and concomitantly investigating their associations with clinical endpoints, have not yet been performed. _Methods_ Between 2011–2013, 263 CHF patients were included. At inclusion and subsequently every 3 months, we measured N-terminal pro-B-type natriuretic (NT-proBNP), high-sensitivity troponin T (Hs-TnT) and C-reactive protein (CRP), and assessed NYHA class. The primary endpoint comprised heart failure hospitalisation, cardiovascular mortality, cardiac transplantation or left ventricular assist device implantation. Time-dependent Cox models were used. _Results_ Mean age was 67 ± 13 years, 72% were men and 27% were in NYHA class III–IV. We obtained 886 repeated measures (median 3 [IQR 2–5] per patient). The primary endpoint was reached in 41 patients during a median follow-up of 1.0 [0.6–1.4] year. Repeatedly measured NT-proBNP and Hs-TnT were significantly associated with repeatedly assessed NYHA class, whereas CRP was not (NT-proBNP: β [95% CI]: 1.56 [1.17–2.06]ln(ng/l) increase per point increase in NYHA class, p = 0.002; HsTNT: β [95% CI]: 1.58 [1.21–2.07]). Serially measured NT-proBNP (HR [95% CI]:2.86 [1.73–4.73]), CRP (1.69 [1.21–2.34]) and NYHA class (2.33 [1.51–3.62]) were positively and independently associated with the primary endpoint, whereas Hs-TnT lost statistical significance after multivariable adjustment. A model containing serially measured NYHA class and NT-proBNP displayed a C-index of 0.84, while serially measured NYHA class and CRP showed a C-index of 0.82. _Conclusion_ Temporal NT-proBNP, CRP and NYHA class patterns are independently associated with adverse clinical outcome. Serially measured NT-proBNP and NYHA class are best suited for monitoring CHF outpatients

From CoNFLict to Confidence: Solving a Diagnostic Dilemma Using Neurofilament Light – A Case Report

Distinguishing neurodegenerative from primary psychiatric conditions is often challenging for clinicians, particularly when assessing older people presenting with neuropsychiatric symptoms. Measurement of fluid biomarkers of neurodegeneration is an emerging approach offering improved diagnostic accuracy. This report explores the use of emerging fluid biomarkers to address diagnostic challenges, framed around a case where the diagnosis of delirium with dementia was revised based on biomarker analysis, enabling treatment of a primary mood disorder with disabling psychiatric symptoms

Evaluation of a Workplace Disability Prevention Intervention in Canada: Examining Differing Perceptions of Stakeholders

Introduction Workplace disability prevention is important, but stakeholders can differ in their appreciation of such interventions. We present a responsive evaluation of a workplace disability prevention intervention in a Canadian healthcare organization. Three groups of stakeholders were included: designers of the intervention, deliverers, and workers. The aim was to examine the appreciation of this intervention by analyzing the discrepancies with respect to what these various stakeholders see as the causes of work disability, what the intervention should aim at to address this problem, and to what extent the intervention works in practice. Methods A qualitative research method was used, including data-triangulation: (a) documentary materials; (b) semi-structured interviews with the deliverers and workers (n = 14); (c) participatory observations of group meetings (n = 6); (d) member-checking meetings (n = 3); (e) focus-group meetings (n = 2). A grounded theory approach, including some ethnographic methodology, was used for the data-analysis. Results Stakeholders’ perceptions of causes for work disability differ, as do preferred strategies for prevention. Designers proposed work-directed measures to change the workplace and work organizations, and individual-directed measures to change workers’ behaviour. Deliverers targeted individual-directed measures, however, workers were mostly seeking work-directed measures. To assess how the intervention was working, designers sought a wide range of outcome measures. Deliverers focused on measurable outcomes targeted at reducing work time-loss. Workers perceived that this intervention offered short-term benefits yet fell short in ensuring sustainable return-to-work. Conclusion This study provides understanding of where discrepancies between stakeholders’ perceptions about interventions come from. Our findings have implications for workplace disability prevention intervention development, implementation and evaluation criteria

NK1-r antagonist treatment comparable to decompressive craniectomy in reducing intracranial pressure following stroke

Background and Purpose: The morbidity and early mortality associated with stroke is largely attributable to cerebral edema and elevated intracranial pressure (ICP). Existing pharmacotherapies do not target the underlying pathophysiology and are often ineffective in sustainably lowering ICP, whilst decompressive craniectomy (DC) surgery is life-saving yet with surgical/peri-operative risk and increased morbidity in the elderly. Accordingly, there is an urgent need for therapies that directly target the mechanisms of edema genesis. Neurogenic inflammation, mediated by substance P (SP) binding to the tachykinin NK1 receptor (NK1-r), is associated with blood-brain barrier (BBB) disruption, cerebral edema and poor outcome post-stroke. NK1-r antagonist treatment ameliorates BBB dysfunction and cerebral edema in rodent stroke models. However, treatment has not been investigated in a large animal model, an important step toward clinical translation. Consequently, the current study compared the efficacy of NK1-r antagonist treatment to DC surgery in reducing ICP post-stroke in a clinically relevant ovine model. Methods: Anesthetized female Merino sheep (65 ± 6 kg, 18-24 months) underwent sham surgery (n = 4) or permanent middle cerebral artery occlusion (n = 22). Stroke animals were randomized into one of 5 treatments: 1×NK1 bolus (4 h), 2×NK1 bolus (4 h;9 h), 3×NK1 bolus (4 h;9 h;14 h), DC surgery (performed at 4 h) or saline vehicle. ICP, blood pressure and blood gasses were monitored for 24 h post-stroke. At 24 h post-stroke anesthetized animals underwent MRI followed by perfusion and brains removed and processed for histological assessment. Results: 2×NK1, 3×NK1 administration or DC surgery significantly (p < 0.05) reduced ICP compared to vehicle. 1×NK1 was ineffective in sustainably lowering ICP. On MRI, midline shift and cerebral edema were more marked in vehicles compared to NK1-r treatment groups. Conclusion: Two or three boluses of NK1-r antagonist treatment reduced ICP comparable to DC surgery, suggesting it may provide a novel alternative to invasive surgery for the management of elevated ICP.Annabel J. Sorby-Adams, Anna V. Leonard, Jan W. Hoving, Nawaf Yassi, Robert Vink, Adam J. Wells and Renée J. Turne

Age, sex, and setting in the etiology of stroke study (ASSESS): Study design and protocol

RATIONALE: Stroke etiology and risk factors vary by age, sex, setting (hospital or community-based) and by region. Identifying these differences would improve our understanding of stroke etiology, diagnosis, and treatment. AIM: The Age, Sex and Setting in the Etiology of Stroke Study (ASSESS) is a multicenter cohort study to assess differences in stroke etiology. METHODS AND DESIGN: Data from all centers will be categorized according to age, sex, setting, stroke subtypes. Centers with extensive hospital- or community-based data regarding stroke from Argentina, Australia, Canada, India, Iran, Italy, Ghana, Nigeria, Thailand, the United Kingdom and the United States have agreed to participate so far. STUDY OUTCOMES: The primary outcome includes differences in stroke etiology in study centers. The secondary outcomes include stroke incidence, risk factors, preventive strategies, and short- and long-term outcomes. CONCLUSION: ASSESS will enable comparisons of data from different regions to determine the age and sex distribution of the most common causes of stroke in each setting. This will help clinicians to tailor the assessment and treatment of stroke patients on the basis of their specific local characteristics. It will also empower stroke epidemiologists to design preventive measures by targeting the specific characteristics of each population

Determining the temporal profile of intracranial pressure changes following transient stroke in an ovine model

Cerebral edema and elevated intracranial pressure (ICP) are the leading cause of death in the first week following stroke. Despite this, current treatments are limited and fail to address the underlying mechanisms of swelling, highlighting the need for targeted treatments. When screening promising novel agents, it is essential to use clinically relevant large animal models to increase the likelihood of successful clinical translation. As such, we sought to develop a survival model of transient middle cerebral artery occlusion (tMCAO) in the sheep and subsequently characterize the temporal profile of cerebral edema and elevated ICP following stroke in this novel, clinically relevant model. Merino-sheep (27M;31F) were anesthetized and subject to 2 h tMCAO with reperfusion or sham surgery. Following surgery, animals were allowed to recover and returned to their home pens. At preselected times points ranging from 1 to 7 days post-stroke, animals were re-anesthetized, ICP measured for 4 h, followed by imaging with MRI to determine cerebral edema, midline shift and infarct volume (FLAIR, T2 and DWI). Animals were subsequently euthanized and their brain removed for immunohistochemical analysis. Serum and cerebrospinal fluid samples were also collected and analyzed for substance P (SP) using ELISA. Intracranial pressure and MRI scans were normal in sham animals. Following stroke, ICP rose gradually over time and by 5 days was significantly (p < 0.0001) elevated above sham levels. Profound cerebral edema was observed as early as 2 days post-stroke and continued to evolve out to 6 days, resulting in significant midline shift which was most prominent at 5 days post-stroke (p < 0.01), in keeping with increasing ICP. Serum SP levels were significantly elevated (p < 0.01) by 7 days post-tMCAO. We have successfully developed a survival model of ovine tMCAO and characterized the temporal profile of ICP. Peak ICP elevation, cerebral edema and midline shift occurred at days 5-6 following stroke, accompanied by an elevation in serum SP. Our findings suggest that novel therapeutic agents screened in this model targeting cerebral edema and elevated ICP would most likely be effective when administered prior to 5 days, or as early as possible following stroke onset.Annabel J. Sorby-Adams, Anna V. Leonard, Levi E. Elms, Oana C. Marian, Jan W. Hoving, Nawaf Yassi, Robert Vink, Emma Thornton and Renée J. Turne

Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (Mobile Stroke Unit - TASTE-A): Protocol for a prospective randomised, open-label, blinded endpoint, phase II superiority trial of tenecteplase versus alteplase for ischaemic stroke patients presenting within 4.5 hours of symptom onset to the mobile stroke unit

Introduction Mobile stroke units (MSUs) equipped with a CT scanner are increasingly being used to assess and treat stroke patients' prehospital with thrombolysis and transfer them to the most appropriate hospital for ongoing stroke care and thrombectomy when indicated. The effect of MSUs in both reducing the time to reperfusion treatment and improving patient outcomes is now established. There is now an opportunity to improve the efficacy of treatment provided by the MSU. Tenecteplase is a potent plasminogen activator, which may have benefits over the standard of care stroke lytic alteplase. Specifically, in the MSU environment tenecteplase presents practical benefits since it is given as a single bolus and does not require an infusion over an hour like alteplase. Objective In this trial, we seek to investigate if tenecteplase, given to patients with acute ischaemic stroke as diagnosed on the MSU, improves the rate of early reperfusion. Methods and analysis TASTE-A is a prospective, randomised, open-label, blinded endpoint (PROBE) phase II trial of patients who had an ischaemic stroke assessed in an MSU within 4.5 hours of symptom onset. The primary endpoint is early reperfusion measured by the post-lysis volume of the CT perfusion lesion performed immediately after hospital arrival. Ethics and dissemination The study was approved by the Royal Melbourne Hospital Human Ethics committee. The findings will be published in peer-reviewed journals, presented at academic conferences and disseminated among consumer and healthcare professional audiences. Trial registration number NCT04071613