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Showing 581–600 of 2058 publications.
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Strange, G. A.; Stewart, S.; Farthing, Melissa; Kasparian, Nadine Angele; Selbie, Lisa A.; O'Donnell, Clare P.; Ayer, Julian Ganesh J.; Cordina, Rachael Louise; Celermajer, David S.Background: There is a paucity of data describing the day-to-day experiences of adult Australians personally living with or caring for a child born with congenital heart disease (CHD). Such data would be of great practical importance to inform health care initiatives to improve outcomes. Methods: 588 men (38.3 11.9 years) and women (39.6 12.6 years, 78% of respondent patients) living with CHD and 1,091 adult carers (93% mothers) of children with CHD (median age 7.3 [IQR 3.513.3 years], 54% male), representing all Australian states and territories, responded to a comprehensive online survey designed and hosted by the Congenital Heart Alliance of Australia and New Zealand. Data on demographic factors, the nature of underlying CHD, interactions with health care services, psychological wellbeing and wider impacts of CHD were collected. Results: Most respondents were able to identify the type of CHD they (29% with a simple lesion such atrial septal defect, 17% tetralogy of Fallot) or their child had (21% with a simple lesion, 15% tetralogy of Fallot), whilst 90% cases of CHD had undergone cardiac surgery. Patients with CHD were mostly employed (70%) or studying (8.8%), whilst 9.1% were receiving disability benefits. In terms of transition care, 52% of adult patients had been referred by a paediatric to adult cardiologist with 84% still actively managed by a specialist. Overall, 31% of patients with CHD sought emergency care and required >10 days sick leave in the past 12 months. Moreover, 71% and 55% of patients, respectively, reported recent feelings of anxiety/worry or depressive thoughts related to their CHD (61% sought professional assistance). Consistent with high levels of disruption to daily living, 59% of carer respondents (24%>10 days) had taken carer's leave in the past 12 months. Conclusions: These contemporary, self-reported, Australian data reveal the burden of living and caring for CHD from an adult's perspective. Survey respondents highlighted the potential disconnect between paediatric and adult CHD services and suggest an important, unmet need for dedicated health services/community care to cost-effectively manage high levels of health care utilisation coupled with associated psychological distress. 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Chau, Katrina; Bobek, Gabriele; Xu, Bei; Stait-Gardner, Timothy; Price, William S.; Hennessy, Annemarie; Makris, AngelaPlacental growth factor (PlGF) is decreased in early gestation of pregnant women who subsequently develop pre-eclampsia. In this study, pre-emptive treatment with PlGF to prevent pre-eclampsia was evaluated in an in vivo rodent model of experimental pre-eclampsia (EPE) induced by TNF-? and in an in vitro model of human first-trimester trophoblast invasion. Pregnant C57/BL6 mice were treated with recombinant mouse placental growth factor-2 (rmPlGF-2) 100?g/kg/day IP from gestational day (gd) 10. Animals had EPE induced by continuous TNF-? infusion on gd 13 and were subject to either continuous blood pressure monitoring by radiotelemetry throughout pregnancy or live placenta T<inf>2</inf>-weighted magnetic resonance imaging (MRI) to demonstrate placental function on gd 17. There was no difference in BP (P>.99), proteinuria (P=.9) or T<inf>2</inf> values on MRI (P=.9) between control and rmPlGF-2-treated animals. On gd 13, animals treated with rmPlGF-2 demonstrated increased placenta PlGF (P=.01) and Toll-like receptor-3 (P=.03) mRNA expression as compared with controls. Fluorescent-labelled human uterine microvascular endothelial cells and HTR8/SVNeo cells were co-cultured on Matrigel and treated with recombinant human PlGF (rhPlGF) (10ng/mL) and/or TNF-? (0.5ng/mL). Trophoblast integration into endothelial networks was reduced by added TNF-? (P=.006), as was rhPlGF concentration in conditioned media (P<.0001). Cell integration was not ameliorated by addition of rhPlGF (P>.9). Although TNF-?-induced EPE was not reversed with pre-emptive rmPlGF-2, a further trial of pre-emptive rhPlGF in vivo is required to determine whether the absence of effect of rhPlGF demonstrated in vitro precludes PlGF as a preventative therapy for pre-eclampsia. 2019 John Wiley & Sons Australia, Ltd
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Yan, Bryan Ping Yen; Lai, William H.S.; Chan, Christy K.Y.; Au, Alex C.K.; Freedman, Ben Ben; Poh, Yukkee Cheung; Poh, Ming Zher[No abstract available]
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Billah, Muntasir; Ridiandries, Anisyah; Rayner, Benjamin Saul; Allahwala, Usaid K.; Dona, Anthony C.; Khachigian, Levon M.; Bhindi, RavinayDespite improved treatment options myocardial infarction (MI) is still a leading cause of mortality and morbidity worldwide. Remote ischemic preconditioning (RIPC) is a mechanistic process that reduces myocardial infarction size and protects against ischemia reperfusion (I/R) injury. The zinc finger transcription factor early growth response-1 (Egr-1) is integral to the biological response to I/R, as its upregulation mediates the increased expression of inflammatory and prothrombotic processes. We aimed to determine the association and/or role of Egr-1 expression with the molecular mechanisms controlling the cardioprotective effects of RIPC. This study used H9C2 cells in vitro and a rat model of cardiac ischemia reperfusion (I/R) injury. We silenced Egr-1 with DNAzyme (ED5) in vitro and in vivo, before three cycles of RIPC consisting of alternating 5min hypoxia and normoxia in cells or hind-limb ligation and release in the rat, followed by hypoxic challenge in vitro and I/R injury in vivo. Post-procedure, ED5 administration led to a significant increase in infarct size compared to controls (65.90 2.38% vs. 41.00 2.83%, p < 0.0001) following administration prior to RIPC in vivo, concurrent with decreased plasma IL-6 levels (118.30 4.30pg/ml vs. 130.50 1.29pg/ml, p < 0.05), downregulation of the cardioprotective JAKSTAT pathway, and elevated myocardial endothelial dysfunction. In vitro, ED5 administration abrogated IL-6 mRNA expression in H9C2 cells subjected to RIPC (0.95 0.20 vs. 6.08 1.40-fold relative to the control group, p < 0.05), resulting in increase in apoptosis (4.76 0.70% vs. 2.23 0.34%, p < 0.05) and loss of mitochondrial membrane potential (0.57 0.11% vs. 1.0 0.14%-fold relative to control, p < 0.05) in recipient cells receiving preconditioned media from the DNAzyme treated donor cells. This study suggests that Egr-1 functions as a master regulator of remote preconditioning inducing a protective effect against myocardial I/R injury through IL-6-dependent JAKSTAT signaling. 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
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Zhang, Yunjia; Cartland, Si; Henriquez, Rodney; Patel, Sanjay; Gammelgaard, Bente; Flouda, Konstantina; Hawkins, Clare L.; Rayner, Benjamin SaulAtherosclerosis is a chronic inflammatory disease of the vasculature characterised by the infiltration of activated neutrophils and macrophages at sites of damage within the vessel wall, which contributes to lesion formation and plaque progression. Selenomethionine (SeMet) is an organic form of selenium (Se), an essential trace element that functions in the regulation of the immune response by both bolstering the endogenous thioredoxin and glutathione antioxidant defence systems and by directly scavenging damaging oxidant species. This study evaluated the effect of dietary SeMet supplementation within a high fat diet fed apolipoprotein E deficient (ApoE?/-) mouse model of atherosclerosis. Dietary supplementation with SeMet (2 mg/kg) increased the tissue concentration of Se, and the expression and activity of glutathione peroxidase, compared to non-supplemented controls. Supplementation with SeMet significantly reduced atherosclerotic plaque formation in mouse aortae, resulted in a more stable lesion phenotype and improved vessel function. Concurrent with these results, SeMet supplementation decreased lesion accumulation of M1 inflammatory type macrophages, and decreased the extent of extracellular trap release from phorbol myristate acetate (PMA)-stimulated mouse bone marrow-derived cells. Importantly, these latter results were replicated within ex-vivo experiments on cultured neutrophils isolated from acute coronary syndrome patients, indicating the ability of SeMet to alter the acute inflammatory response within a clinically-relevant setting. Together, these data highlight the potential beneficial effect of SeMet supplementation as a therapeutic strategy for atherosclerosis. 2019
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Thavapalachandran, Sujitha; Grieve, Stuart M.; Hume, Robert D.; Le, Thi Yen Loan; Raguram, Kalyan; Hudson, James Edward; Pouliopoulos, Jim; Figtree, Gemma A.; Dye, Rafael P.; Barry, Anthony M.; Brown, Paula; Lu, Juntang; Coffey, Sean; Kesteven, Scott H.; Mills, Richard James; Rashid, Fairooj N.; Taran, Elena; Kovoor, Pramesh; Thomas, Liza; Denniss, Alan Robert; Kizana, Eddy; Seyedasli, Naisana; Xaymardan, Munira; Feneley, Michael P.; Graham, Robert M.; Harvey, Richard P.; Chong, James J.H.Therapies that target scar formation after myocardial infarction (MI) could prevent ensuing heart failure or death from ventricular arrhythmias. We have previously shown that recombinant human platelet-derived growth factor-AB (rhPDGF-AB) improves cardiac function in a rodent model of MI. To progress clinical translation, we evaluated rhPDGF-AB treatment in a clinically relevant porcine model of myocardial ischemia-reperfusion. Thirty-six pigs were randomized to sham procedure or balloon occlusion of the proximal left anterior descending coronary artery with 7-day intravenous infusion of rhPDGF-AB or vehicle. One month after MI, rhPDGF-AB improved survival by 40% compared with vehicle, and cardiac magnetic resonance imaging showed left ventricular (LV) ejection fraction improved by 11.5%, driven by reduced LV end-systolic volumes. Pressure volume loop analyses revealed improved myocardial contractility and energetics after rhPDGF-AB treatment with minimal effect on ventricular compliance. rhPDGF-AB enhanced angiogenesis and increased scar anisotropy (high fiber alignment) without affecting overall scar size or stiffness. rhPDGF-AB reduced inducible ventricular tachycardia by decreasing heterogeneity of the ventricular scar that provides a substrate for reentrant circuits. In summary, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias, and improved survival. Our findings suggest a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs. 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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Xu, Bei; Makris, Angela; Liu, Chiachi; Hennessy, AnnemarieObjectives: Integrins are cell adhesion receptors that participated in endovascular invasion by cytotrophoblasts in preeclampsia. This study aimed to investigate the effect of calcium on cellular pathways influencing the trophoblast integration into endothelial cellular networks in vitro. Study design: Red fluorescent-labelled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on Matrigel. Green fluorescent-labelled HTR-8/SVneo trophoblast cells were then co-cultured with endothelial cells in different concentrations of calcium for 24 h. Main outcome measures: The calcium effects on HTR-8/SVneo cell integration were quantified by Image J. Quantitative PCR was performed to measure mRNA expression of integrins ?1, ?5, ?6, ?1 and ?4. The concentrations of interleukin IL-6, matrix metalloproteinase-2 (MMP-2), MMP-9, PlGF and sFlt-1 in the conditioned medium were measured by ELISA while levels of cytokines IL-1?, IL-8, IL-10, TNF-? and INF-? were assessed by magnetic Luminex assays. Results: Both calcium depletion (0.4 mM) and low calcium (1.8 mM) groups demonstrated inhibited integration of trophoblast cells into endothelial cellular networks, compared with the normal calcium group (2.4 mM). The IL-6 production was reduced from conditioned media in both calcium depletion and low calcium groups. In calcium depletion group, mRNA expression of integrin ?5 and ?4 in trophoblasts was increased while integrin ?1 was decreased. Conclusions: The in vitro trophoblast cell integration into endothelial cellular networks could be modified by altering media calcium through integrin switch away from integrins ?5 and ?4 and towards integrin ?1 which may be required for healthy early trophoblast integration. 2020
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Shanmugalingam, Renuka; Mengesha, Zelalem Birhanu; Notaras, Stephanie; Liamputtong, Pranee; Fulcher, Ian; Lee, Gaksoo; Kumar, Roshika; Hennessy, Annemarie; Makris, AngelaBackground Non-adherence with medications in pregnancy is increasingly recognized and often results in a higher rate of preventable maternal and fetal morbidity and mortality. Non-adherence with prophylactic aspirin amongst high-risk pregnant women is associated with higher incidence of preeclampsia, preterm delivery and intrauterine growth restriction. Yet, the factors that influences adherence with aspirin in pregnancy, from the women's perspective, remains poorly understood. Objective The study is aimed at understanding the factors, from the women's perspective, that influenced adherence with prophylactic aspirin in their pregnancy. Study design A sequential-exploratory designed mixed methods quantitative (n = 122) and qualitative (n = 6) survey of women with recent high-risk pregnancy necessitating antenatal prophylactic aspirin was utilized. Women recruited underwent their antenatal care in one of three high-risk pregnancy clinics within the South Western Sydney Local Health District, Australia. The quantitative study was done through an electronic anonymous survey and the qualitative study was conducted through a face-to-face interview. Data obtained was analysed against women's adherence with aspirin utilizing phi correlation (?) with significance set at <0.05. Results Two key themes, from the women's perspective, that influenced their adherence with aspirin in pregnancy were identified; (1) pill burden and non-intention omission (2) communication and relationship with health care provider (HCP). Pill burden and its associated non-intentional omission, both strongly corelated with reduced adherence (? = 0.8, p = 0.02, ? = 0.8, p<0.01) whilst the use of reminder strategies minimized accidental omission and improved adherence (? = 0.9, p<0.01). Consistent communication between HCPs and a good patient-HCP relationship was strongly associated with improved adherence (? = 0.7, p = 0.04, ? = 0.9, p = <0.01) and more importantly was found to play an important role in alleviating factors that had potentials to negatively influence adherence with aspirin in pregnancy. Conclusion This study identified factors that both positively and negatively influenced adherence with aspirin amongst high-risk pregnant women. Is highlights the importance in recognizing the impact of pill burden in pregnancy and the need to counsel women on the utility of reminder strategies to minimize non-intentional omission. Importantly, it emphasizes on the importance of a positive patient-HCP relationship through effective and consistent communication to achieve the desired maternal and fetal outcomes. 2020 Shanmugalingam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Orchard, Jessica Joan; Li, Jialin; Freedman, Ben Ben; Webster, Ruth J.; Salkeld, Glenn P.; Hespe, Charlotte Mary; Gallagher, Robyn D.; Patel, Anushka A.; Kamel, Bishoy; Neubeck, Lis; Lowres, NicoleBACKGROUND: Internationally, most atrial fibrillation (AF) management guidelines recommend opportunistic screening for AF in people ?65 years of age and oral anticoagulant treatment for those at high stroke risk (CHA?DS?-VA?2). However, gaps remain in screening and treatment. METHODS AND RESULTS: General practitioners/nurses at practices in rural Australia (n=8) screened eligible patients (?65 years of age without AF) using a smartphone ECG during practice visits. eHealth tools included electronic prompts, guideline-based electronic decision support, and regular data reports. Clinical audit tools extracted de-identified data. Results were compared with an earlier study in metropolitan practices (n=8) and nonrandomized control practices (n=69). Cost-effectiveness analysis compared population-based screening with no screening and included screening, treatment, and hospitalization costs for stroke and serious bleeding events. Patients (n=3103, 34%) were screened (mean age, 75.16.8 years; 47% men) and 36 (1.2%) new AF cases were confirmed (mean age, 77.0 years; 64% men; mean CHA?DS?-VA, 3.2). Oral anticoagulant treatment rates for patients with CHA?DS?-VA?2 were 82% (screen detected) versus 74% (preexisting AF)(P=NS), similar to metropolitan and nonrandomized control practices. The incremental cost-effectiveness ratio for population-based screening was AU$16 578 per quality-adjusted life year gained and AU$84 383 per stroke prevented compared with no screening. National implementation would prevent 147 strokes per year. Increasing the proportion screened to 75% would prevent 177 additional strokes per year. CONCLUSIONS: An AF screening program in rural practices, supported by eHealth tools, screened 34% of eligible patients and was cost-effective. Oral anticoagulant treatment rates were relatively high at baseline, trending upward during the study. Increasing the proportion screened would prevent many more strokes with minimal incremental cost-effectiveness ratio change. eHealth tools, including data reports, may be a valuable addition to future programs. REGISTRATION: URL: https://www.anzctr.org.au. Unique identifier: ACTRN12618000004268. 2020 The Authors.
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Yan, Bernard; Tu, Hans T.H.; Lam, Christina; Swift, Corey; Ho, Ma Sze; Mok, Chung Tong Vincent; Sui, Yi; Sharpe, David M.; Ghia, Darshan K.; JANNES, J.; Davis, Stephen M.; Liu, Xinfeng; Freedman, Ben BenBackground and Purpose Paroxysmal atrial fibrillation (PAF) underlying acute stroke frequently evades detection by standard practice, considered to be a combination of routine electrocardiogram (ECG) monitoring, and 24-hour Holter recordings. We hypothesized that nurse-led in-hospital intermittent monitoring approach would increase PAF detection rate. Methods We recruited patients hospitalised for stroke/transient ischemic attack, without history of atrial fibrillation (AF), in a prospective multi-centre observational study. Patients were monitored using a smartphone-enabled handheld ECG (iECG) during routine nursing observations, and underwent 24-hour Holter monitoring according to local practice. The primary outcome was comparison of AF detection by nurse-led iECG versus Holter monitoring in patients who received both tests: secondary outcome was oral anticoagulant commencement at 3-month following PAF detection. Results One thousand and seventy-nine patients underwent iECG monitoring: 294 had iECG and Holter monitoring. AF was detected in 25/294 (8.5%) by iECG, and 8/294 (2.8%) by 24-hour Holter recordings (P<0.001). Median duration from stroke onset to AF detection for iECG was 3 days (interquartile range [IQR], 2 to 6) compared with 7 days (IQR, 6 to 10) for Holter recordings (P=0.02). Of 25 patients with AF detected by iECG, 11 were commenced on oral anticoagulant, compared to 5/8 for Holter. AF was detected in 8.8% (69/785 patients) who underwent iECG recordings only (P=0.8 vs. those who had both iECG and 24-hour Holter). Conclusions Nurse-led in-hospital iECG surveillance after stroke is feasible and effective and detects more PAF earlier and more frequently than routine 24-hour Holter recordings. Screening with iECG could be incorporated into routine post-stroke nursing observations to increase diagnosis of PAF, and facilitate institution of guideline-recommended anticoagulation. 2020 Korean Stroke Society.
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Zhao, Yunduo Charles; Vatankhah, Parham; Goh, Tiffany; Ju, Lining ArnoldVessel stenosis, atherosclerotic plaques and medical device intervention disturb blood flow which thereafter stimulate platelet adhesion and aggregation. In our Nature Materials 2019 paper[l], we designed microfluidic channels to elucidate the molecular insights of blood flow disturbance. Nevertheless, the mechanism associated with these microfluidics is poorly characterized. To this end, we developed a computational fluid dynamics (CFD) simulation approach to systematically analyze the hemodynamic influence of stenosis geometries and bulk flow mechanics. The flow trajectory analysis and non-Newtonian model benchmarks provide rheological evaluation of the stenosis microfluidics and a guideline for rigorous design and fabrication of microfluidic thrombosis models. 2020 CBMS-0001
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Martinez, Carlos; Wallenhorst, Christopher; Rietbrock, Stephan; Freedman, Ben BenBackground: In nonvalvular atrial fibrillation (AF), oral anticoagulants prevent ischemic strokes and transient ischemic attacks (TIAs), but nonpersistence with vitamin K antagonist (VKA) oral anticoagulant therapy (2050% at 1year) is problematic. The precise risk of stroke/TIA after VKA cessation and its time course during extended follow-up is unknown. Methods and Results: The study cohort of incident AF in patients receiving initial VKA between 2001 and 2013 was identified from the UK Clinical Practice Research Datalink (linked hospitalizations and causes of death). Using a nested case-control analysis, patients with incident stroke/TIA were matched to patients without stroke/TIA (controls). Relative risk with time since VKA cessation compared with current VKA use was approximated from conditional logistic regression. We studied 16696 patients with incident AF and initial VKA treatment. There were 489 stroke/TIA cases matched to 2137 controls (mean CHA<inf>2</inf>DS<inf>2</inf>-VASc score 4.3). Compared with current VKA use, the excess incidence rate of stroke/TIA following VKA cessation in the first year after AF diagnosis was 2.29 (95% CI, 0.983.90) per 100 person-years of VKA cessation or 1 additional stroke/TIA per 43 patients per year discontinuing VKA, compared with 1.43 (95% CI, 0.971.88) per 100 person-years corresponding to 1 additional stroke/TIA per 70 patients per year, when VKA was discontinued more than 1year after AF diagnosis. Conclusions: VKA cessation is associated with a continuous excess thromboembolic stroke/TIA risk. Increasing oral anticoagulant persistence, especially in the year after AF diagnosis, should be a therapeutic target to reduce stroke/TIA in AF. 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
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Mc Namara, Kevin Peter; Krass, Ines; Peterson, Gregory Mark; Alzubaidi, Hamzah Tareq; Grenfell, Robert D.; Freedman, Ben Ben; Dunbar, J. A.Background: Screening is a critical component of efforts to reduce the population burden of cardiovascular disease (CVD), by facilitating early use of cost-effective prevention and treatment strategies. While international evidence suggests that screening in community pharmacies improves screening access and identifies at-risk individuals, concerns from medical organisations about the absence of interdisciplinary coordination and related lack of continuity of care with general practice have significantly contributed to reluctance from some stakeholders to endorse, and engage with, pharmacy-based screening initiatives. The Cardiovascular Absolute Risk Screening (CARS) study was designed to address these challenges and promote an interprofessional approach to screening for cardiovascular disease risk by pharmacists. This study describes the impact of the CARS implementation model on interdisciplinary coordination and continuity of care. Methods: In addition to clinical training, pharmacists at eleven participating pharmacies were provided with implementation training, resources and support to promote interprofessional coordination. Completion of training and pharmacy implementation plans, both of which highlighted GP engagement strategies, were pre-requisites for screening commencement. Using mixed methods approaches, data were analyzed from screening records (n = 388), researcher interviews with patients at 610 weeks post-screening (n = 248, 64%), and pharmacist interviews (n = 10). Results: Screening records suggested that 94% of screened individuals were advised to seek formal GP assessment, and 98% consented to sharing of results. Among interviewed participants, 81% recalled direct pharmacist action to facilitate GP engagement. Among interviewees who had seen their GP already (n = 70), 79% reported that their GP was aware of the results (another 16% were uncertain). Pharmacists reported positive GP feedback stemming from efforts at early engagement, but an absence of ongoing collaboration. Conclusions: Use of implementation planning by pharmacists, alongside clinical training, can effectively promote an interdisciplinary coordination focus by pharmacists. 2019
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Orchard, Jessica Joan; Li, Jialin; Gallagher, Robyn D.; Freedman, Ben Ben; Lowres, Nicole; Neubeck, LisBackground: Screening for atrial fibrillation (AF) in people aged ?65 years is recommended by international guidelines. The Atrial Fibrillation Screen, Management And guideline-Recommended Therapy (AF-SMART) studies of opportunistic AF screening in 16 metropolitan and rural general practices were conducted from November 2016-June 2019. These studies trialled custom-designed eHealth tools to support all stages of AF screening in general practice. Methods: A realist evaluation of the AF-SMART studies, which aimed to explain the circumstances in which the program worked (or not) to increase the proportion of people screened for AF. The initial program theory was based on our previous research, policy documents and screening studies. To test this, we conducted 45 semi-structured interviews with general practitioners (GPs), nurses and practice managers across all participating practices, and collected observational and quantitative screening data. These data were analysed and interpreted to refine the program theory. Results: GPs/nurses liked the eHealth tools, although technical problems sometimes disrupted screening. Time was the main barrier to screening for GPs/nurses, so systems need to be very efficient. Practices with leadership from a senior GP 'screening champion' had broader uptake, especially from the nursing team. Providing regular feedback on screening data was beneficial for quality improvement and motivation. Clear protocols for follow-up of abnormal results were required for successful nurse-led screening in a hierarchical system. Participation in the program had broader benefits of improving AF knowledge and raising the profile of cardiovascular health in the practice. Screening for a shorter, more intense period (eg during influenza vaccination) worked well for practices where sufficient staff time was allocated. Conclusions: Introducing an AF screening program is likely to be successful in contexts where there is a senior GP 'screening champion', a clear protocol exists for abnormal results, and there is regular data reporting to staff. These contexts link to mechanisms around motivation, leadership, empowerment of nurses, and efficient screening systems. The contexts and mechanisms contribute to the longer-Term outcomes of increasing the proportion of people screened and treated for AF, which is recommended by guidelines as a key strategy for the prevention of AF-related stroke. Trial registrations: AF SMART (metropolitan): ACTRN12616000850471 (Australia New Zealand Clinical Trials Registry). AF SMART II (rural): ACTRN12618000004268 (Australia New Zealand Clinical Trials Registry). 2019 The Author(s).
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Barraclough, Jennifer Y.; Joan, Michelyn; Joglekar, Mugdha V.; Hardikar, Anandwardhan A.; Patel, SanjayBackground: The potential utility of microRNAs (miRNAs) in the diagnosis, prognosis, and treatment of multiple disease states has been an area of great interest since their discovery. In patients with cardiovascular disease, there is a large pool of literature amassed from the last decade assessing their diagnostic and prognostic potential. This systematic review sought to determine whether existing literature supports the use of miRNAs as prognostic markers after an Acute Coronary Syndrome (ACS) presentation. Methods: A systematic review of published articles from 20052019 using MEDLINE and EMBASE databases was undertaken independently by two reviewers. Studies addressing prognosis in an ACS population yielded 32 studies and 2 systematic reviews. Results/conclusion: 23 prospective studies reported significant differences in miRNA levels and 16 compared the predictive power of miRNAs. The most common miRNAs assessed included miR-133a,-208b,-21,-1,-34a,-150, and-423, shown to be involved in cell differentiation, apoptosis, and angiogenesis. Barriers to the use of miRNAs as prognostic markers include bias in miRNA selection, small sample size, variable normalization of data, and adjustment for confounders. Therefore, findings from this systematic review do not support the use of miRNAs for prognostication post-ACS beyond traditional cardiovascular risk factors, existing risk scores, and stratifications tools. 2019, MDPI AG. All rights reserved.
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Ravindran, Dhanya; Cartland, Si; Bursill, C. A.; Kavurma, Mary M.M3 is a broad-spectrum chemokine-binding protein that inactivates inflammatory chemokines, including CCL2, CCL5, and CX<inf>3</inf>CL1. The aim of this study was to compare whether M3 could inhibit angiogenesis driven by inflammation or ischemia. Here, apolipoprotein E/ mice were injected with adenoviral M3 (AdM3) or control adenoviral green fluorescent protein (AdGFP) 3 d prior to stimulating angiogenesis using 2 established models that distinctly represent inflammatory or ischemia-driven angiogenesis, namely the periarterial femoral cuff and hind limb ischemia. AdM3 reduced intimal thickening, adventitial capillary density, and macrophage accumulation in femoral arteries 21 d after periarterial femoral cuff placement compared with AdGFP-treated mice (P < 0.05). AdM3 also reduced mRNA expression of proangiogenic VEGF, inflammatory markers IL-6 and IL-1?, and vascular smooth muscle cell (VSMC)-activated synthetic markers Krpel-like family of transcription factor 4 (KLF4) and platelet-derived growth factor receptor ? (PDGFR?) in the inflammatory cuff model. In contrast, capillary density, VSMC content, blood flow perfusion, and VEGF gene expression were unaltered between groups in skeletal muscle following hind limb ischemia. In vitro, AdM3 significantly reduced human microvascular endothelial cell 1 proliferation, migration, and tubule formation by ~17, 71.3, and 8.7% (P < 0.05) in macrophage-conditioned medium associating with reduced VEGF and hypoxia-inducible factor 1? mRNA but not in hypoxia (1% O<inf>2</inf>). Compared with AdGFP, AdM3 also inhibited VSMC proliferation and migration and reduced mRNA expression of KLF4 and PDGFR? under inflammatory conditions. In contrast, AdM3 had no effect on VSMC processes in response to hypoxia in vitro. Our findings show that broad-spectrum inhibition of inflammatory chemokines by M3 inhibits inflammatory-driven but not ischemia-driven angiogenesis, presenting a novel strategy for the treatment of diseases associated with inflammatory-driven angiogenesis.Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. Broad-spectrum chemokine inhibition blocks inflammation-induced angiogenesis, but preserves ischemia-driven angiogenesis. FASEB J. 33, 1342313434 (2019). www.fasebj.org. FASEB.
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Chan, Alex H.P.; Filipe, Elysse C.; Tan, Richard P.; Santos, Miguel; Yang, Nianji; Hung, Juichien; Feng, Jieyao; Nazir, Sidra; Benn, Alexander J.; Ng, Martin K.C.; Rnjak-Kovacina, Jelena; Wise, Steven G.Current synthetic vascular grafts are not suitable for use in low-diameter applications. Silk fibroin is a promising natural graft material which may be an effective alternative. In this study, we compared two electrospun silk grafts with different manufacturing processes, using either water or hexafluoroisopropanol (HFIP) as solvent. This resulted in markedly different Youngs modulus, ultimate tensile strength and burst pressure, with HFIP spun grafts observed to have thicker fibres, and greater stiffness and strength relative to water spun. Assessment in a rat abdominal aorta grafting model showed significantly faster endothelialisation of the HFIP spun graft relative to water spun. Neointimal hyperplasia in the HFIP graft also stabilised significantly earlier, correlated with an earlier SMC phenotype switch from synthetic to contractile, increasing extracellular matrix protein density. An initial examination of the macrophage response showed that HFIP spun conduits promoted an anti-inflammatory M2 phenotype at early timepoints while reducing the pro-inflammatory M1 phenotype relative to water spun grafts. These observations demonstrate the important role of the manufacturing process and physical graft properties in determining the physiological response. Our study is the first to comprehensively study these differences for silk in a long-term rodent model. 2019, The Author(s).
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Li, Mengbo; Wang, Andy Yi Yang; Quek, Lake Ee; Vernon, Stephen Thomas; Figtree, Gemma A.; Yang, Jean Yee Hwa; OSullivan, John F.A small minority (< 3%) of protein-coding genetic variants are predicted to lead to loss of protein function. However, these predicted loss-of-function (pLOF) variants can provide insight into mode of transcriptional effect. To examine how these changes are propagated to phenotype, we determined associations with downstream metabolites. We performed association analyses of 37 pLOF variants previously reported to be significantly associated with disease in >400,000 subjects in UK Biobank with metabolites. We conducted these analyses in three community-based cohorts: the Framingham Heart Study (FHS) Offspring Cohort, FHS Generation 3, and the KORA F4 cohort. We identified 19 new low-frequency or rare (minor allele frequency (MAF) <5%) pLOF variant-metabolite associations, and 12 new common (MAF > 5%) pLOF variant-metabolite associations. Rare pLOF variants in the genes BTN3A2, ENPEP, and GEM that have been associated with blood pressure in UK Biobank, were associated with vasoactive metabolites indoxyl sulfate, asymmetric dimethylarginine (ADMA), and with niacinamide, respectively. A common pLOF variant in gene CCHCR1, associated with asthma in UK Biobank, was associated with histamine and niacinamide in FHS Generation 3, both reported to play a role in this disease. Common variants in olfactory receptor gene OX4C11 that associated with blood pressure in UK Biobank were associated with the nicotine metabolite cotinine, suggesting an interaction between altered olfaction, smoking behaviour, and blood pressure. These findings provide biological validity for pLOF variant-disease associations, and point to the effector roles of common metabolites. Such an approach may provide novel disease markers and therapeutic targets. 2019 Elsevier Inc.
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Zhu, Cheng; Chen, Yunfeng; Ju, Lining ArnoldMechanical forces are ubiquitous in a cell's internal structure and external environment. Mechanosensing is the process that the cell employs to sense its mechanical environment. In receptor-mediated mechanosensing, cell surface receptors interact with immobilized ligands to provide a specific way to receive extracellular force signals to targeted force-transmitting, force-transducing and force-supporting structures inside the cell. Conversely, forces generated endogenously by the cell can be transmitted via cytoplasmic proteinprotein interactions and regulate cell surface receptor activities in an insideout manner. Dynamic force spectroscopy analyzes these interactions on and inside cells to reveal various dynamic bonds. What is more, by integrating analysis of molecular interactions with that of cell signaling events involved in force-sensing and force-responding processes, one can investigate how dynamic bonds regulate the reception, transmission and transduction of mechanical signals. 2019 Elsevier Ltd
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Santos, Miguel; Reeves, Bryce; Michael, Praveesuda Lorwattanapongsa; Tan, Richard P.; Wise, Steven G.; Bilek, Marcela M.M.Plasma polymerized nanoparticles (PPN) formed in plasma reactors have been considered undesirable in technological applications. More recently however, PPN were proposed as a new class of multifunctional nanocarriers for drug delivery. Therefore, synthesis of PPN requires cost-effective collection strategies that maximize yield and improve reproducibility. This work shows that the collection of PPN in dusty plasmas is modulated by modifying the geometry of substrates from planar to well-shaped collectors. The electric field profile around the wells acts as an electrostatic lens, concentrating nanoparticles and significantly bolstering process yield. The aggregation of PPN is governed by a balance between plasma expansion throughout the wells, inter-particle repulsion, particle size and density. PPN are readily dispersed in aqueous solution yielding monodisperse populations. The use of a disposable well-shape collector provides a cost-effective nanoparticle collection approach that can be adopted in a wide range of plasma polymerization configurations without the need for reactor re-design. 2019, The Author(s).
