Objectives Cardiac ischemia–reperfusion (I-R) injury remains a significant problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. ...We have shown that high-molecular-weight polyethylene glycol (PEG) (15-20 kD) can protect cardiac myocytes in vitro from hypoxia–reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo. Methods Adult rats underwent left anterior descending artery occlusion for 60 minutes followed by 48 hours or 4 weeks of reperfusion. One milliliter of 10% PEG solution or phosphate-buffered saline (PBS) control (n = 10 per group) was administered intravenously (IV) immediately before reperfusion. Results Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hour after IV delivery. The PEG group had significant recovery of left ventricular ejection fraction at 4 weeks versus a 25% decline in the PBS group ( P < .01). There was 50% less LV fibrosis in the PEG group versus PBS with smaller peri-infarct and remote territory fibrosis ( P < .01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, P < .01) and ERK (4-fold, P < .05) phosphorylation compared to PBS controls at 48 hours. PEG also inhibited apoptosis as measured by TUNEL-positive nuclei (56% decrease, P < .02) and caspase 3 activity (55% decrease, P < .05). Conclusions High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately before reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current international consensus is that 'early' referral to palliative care services improves cancer patient and family carer outcomes. In practice, however, these referrals are not routine. An ...approach which directly addresses identified barriers to early integration of palliative care is required. This protocol details a trial of a standardized model of early palliative care (Care Plus) introduced at key defined, disease-specific times or transition points in the illness for people with cancer. Introduced as a 'whole of system' practice change for identified advanced cancers, the key outcomes of interest are population health service use change. The aims of the study are to examine the effect of Care Plus implementation on (1) acute hospitalisation days in the last 3 months of life; (2) timeliness of access to palliative care; (3) quality and (4) costs of end of life care; and (5) the acceptability of services for people with advanced cancer.
Multi-site stepped wedge implementation trial testing usual care (control) versus Care Plus (practice change). The design stipulates 'control' periods when usual care is observed, and the process of implementing Care Plus which includes phases of planning, engagement, practice change and evaluation. During the practice change phase, all patients with targeted advanced cancers reaching the transition point will, by default, receive Care Plus. Health service utilization and unit costs before and after implementation will be collated from hospital records, and state and national health service administrative datasets. Qualitative data from patients, consumers and clinicians before and after practice change will be gathered through interviews and focus groups.
The study outcomes will detail the impact and acceptability of the standardized integration of palliative care as a practice change, including recommendations for ongoing sustainability and broader implementation.
Australian New Zealand Clinical Trials Registry ACTRN 12619001703190 . Registered 04 December 2019.
Full text
Available for:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular ...level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy.
A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α
-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH.
Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload.
Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure.
Accurate pre-operative imaging plays a vital role in patient selection for surgery and in allocating stage-appropriate therapies to patients diagnosed with pancreatic cancer (PC). This study aims to: ...(1) understand the current diagnosis and staging practices for PC; and (2) explore the factors (barriers and enablers) that influence the use of a pancreatic protocol computed tomography (PPCT) or magnetic resonance imaging (MRI) to confirm diagnosis and/or accurately stage PC.
Semi-structured interviews were conducted with radiologists, surgeons, gastroenterologists, medical and radiation oncologists from the states of New South Wales (NSW) and Victoria, Australia. Interviews were conducted either in person or via video conferencing. All interviews were recorded, transcribed verbatim, de-identified and data were thematically coded according to the 12 domains explored within the Theoretical Domains Framework (TDF). Common belief statements were generated to compare the variation between participant responses.
In total, 21 clinicians (5 radiologists, 10 surgeons, 2 gastroenterologists, 4 medical and radiation oncologists) were interviewed over a four-month-period. Belief statements relevant to the TDF domains were generated. Across the 11 relevant domains, 20 themes and 30 specific beliefs were identified. All TDF domains, with the exception of social influences were identified by participants as relevant to protocol-based imaging using either a PPCT or MRI, with the domains of knowledge, skills and environmental context and resources being offered by most participants as being relevant in influencing their decisions.
To maximise outcomes and personalise therapy it is imperative that diagnosis and staging investigations using the most appropriate imaging modalities are conducted in a timely, efficient and effective manner. The results provide an understanding of specialists' opinion and behaviour in relation to a PPCT or MRI and should be used to inform the design of future interventions to improve compliance with this practice.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AbstractContextEvidence-based resource allocation is receiving increasing attention as we strive for equity, transparency, and cost-effectiveness across health care. In the context of finite ...resources, which of our patients with terminal illness should be prioritized for urgent palliative care? ObjectivesTo develop the scoring system for the novel Responding to Urgency of Need in Palliative Care triage tool. MethodsOnline international discrete choice experiment involving palliative care clinicians to establish the relative importance of seven key attributes of palliative care triage identified during an earlier qualitative study. ResultsParticipants ( n = 772) were mainly female (79.9%) with a decade of clinical experience. All attributes contributed significantly (all P-values < 0.001) and independently to clinician assessment of urgency. This study found physical suffering (coefficient 3.45; 95% confidence interval: 3.24 to 3.66) was the most important determinant of urgency, followed by imminent dying (coefficient 1.56; 1.43 to 1.69), psychological suffering (coefficient 1.49; 1.37 to 1.60), caregiver distress (coefficient 1.47; 1.35 to 1.59), discrepancy between care needs and care arrangements (coefficient 1.14; 1.02 to 1.26), mismatch between current and desired site of care (coefficient 0.94; 0.85 to 1.03), and unmet communication needs (coefficient 0.84; 0.76 to 0.92). ConclusionPalliative care triage, which is complex and contextual, has been made more transparent through this discrete choice experiment. The Responding to Urgency of Need in Palliative Care triage tool provides an important step toward evidence-based assessment of priority for palliative care. Further research is underway to determine the validity of the tool in clinical practice and its impact on patient and caregiver outcomes.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Treatment of elderly patients with lung cancer is significantly hindered by concerns about treatment tolerability, toxicity and limited clinical trial data in the elderly; potentially giving rise to ...treatment nihilism amongst clinicians. This study aims to describe survival in elderly patients with lung cancer and explore potential causes for excess mortality.
Patients diagnosed with lung cancer in the Victorian Lung Cancer Registry between 2011–2018 were analysed (n=3481). Patients were age-categorised and compared using Cox-regression modelling to determine mortality risk, after adjusting for confounding. Probability of being offered cancer treatments was also determined, further stratified by disease stage.
The eldest patients (≥80 years old) had significantly shorter median survival compared with younger age groups (<60 years: 2.0 years; 60–69 years: 1.5 years; 70–79 years: 1.6 years; ≥80 years: 1.0 years; p<0.001). Amongst those diagnosed with stage 1 or 2 lung cancer, there was no significant difference in adjusted-mortality between age groups. However, in those diagnosed with stage 3 or 4 disease, the eldest patients had an increased adjusted-mortality risk of 28% compared with patients younger than 60 years old (p=0.005), associated with markedly reduced probability of cancer treatment, after controlling for sex, performance status, comorbidities and histology type (OR 0.24, compared with <60 years old strata; p<0.001).
Compared to younger patients, older patients with advanced-stage lung cancer have a disproportionately higher risk of mortality and lower likelihood of receiving cancer treatments, even when performance status and comorbidity are equivalent. These healthcare inequities could be indicative of widespread treatment nihilism towards elderly patients.
Right ventricular (RV) failure, which occurs in the setting of pressure overload, is characterized by abnormalities in mechanical and energetic function. The effects of these cell- and tissue-level ...changes on organ-level RV function are unknown. The primary aim of this study was to investigate the effects of myofiber mechanics and mitochondrial energetics on organ-level RV function in the context of pressure overload using a multiscale model of the cardiovascular system. The model integrates the mitochondria-generated metabolite concentrations that drive intracellular actin-myosin cross-bridging and extracellular myocardial tissue mechanics in a biventricular heart model coupled with simple lumped parameter circulations. Three types of pressure overload were simulated and compared to experimental results. The computational model was able to capture a wide range of cardiovascular physiology and pathophysiology from mild RV dysfunction to RV failure. Our results confirm that, in response to pressure overload alone, the RV is able to maintain cardiac output (CO) and predict that alterations in either RV active myofiber mechanics or RV metabolite concentrations are necessary to decrease CO.
Background Correction of significant tricuspid regurgitation (TR) at the time of continuous-flow (CF) left ventricular assist device (LVAD) implantation has been shown to be beneficial in several ...recently published studies. The most common technique is ring annuloplasty followed by valve replacement. Our center has primarily used the De Vega annuloplasty, and the durability of this repair is the focus of this study. Methods This was a retrospective review of 35 consecutive patients who underwent CF LVAD implantation and De Vega tricuspid valve annuloplasty (TVA) for severe TR and were alive at 1 year. Echocardiograms were obtained preoperatively, intraoperatively, at discharge, and at 1 year after operation. Results The TR in 32 of 35 patients (91.4%, group A) improved from severe preoperatively to insignificant at the time of discharge after De Vega TVA, and 3 patients (8.6%, group B) had moderate residual TR. At 1-year follow-up, 29 of 32 (90.6%) patients in group A had insignificant TR, 2 (6.3%) had moderate TR, and 1 (3.1%) had severe TR. In group B, 2 of 3 patients had no progression of their moderate TR at 1 year and 1 had severe TR. Overall, 2 of 35 (5.7%) patients had severe TR at 1 year after De Vega TVA and LVAD implantation. Conclusions We conclude from this consecutive cohort of patients undergoing CF LVAD implantation and De Vega TVA that this technique is very durable at 1 year and has the advantages of a shorter operative time relative to ring annuloplasty and decreased cost because a prosthetic implant is not used.
This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease.
We examined 200 patients with descending thoracic aortic disease including ...acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study.
Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years.
Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta ≥4.1 cm because of its larger initial size and more rapid growth.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
