Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2AR- and βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion: Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits

The health and economic benefits of reducing intimate partner violence: an Australian example.

BACKGROUND: Intimate partner violence (IPV) has important impacts on the health of women in society. Our aim was to estimate the health and economic benefits of reducing the prevalence of IPV in the 2008 Australian female adult population. METHODS: Simulation models were developed to show the effect of a 5 percentage point absolute feasible reduction target in the prevalence of IPV from current Australian levels (27%). IPV is not measured in national surveys. Levels of psychological distress were used as a proxy for exposure to IPV since psychological conditions represent three-quarters of the disease burden from IPV. Lifetime cohort health benefits for females were estimated as fewer incident cases of violence-related disease and injury; deaths; and Disability Adjusted Life Years (DALYs). Opportunity cost savings were estimated for the health sector, paid and unpaid production and leisure from reduced incidence of IPV-related disease and deaths. Workforce production gains were estimated by comparing surveyed participation and absenteeism rates of females with moderate psychological distress (lifetime IPV exposure) against high or very high distress (current IPV exposure), and valued using the friction cost approach (FCA). The impact of improved health status on unpaid household production and leisure time were modelled from time use survey data. Potential costs associated with interventions to reduce IPV were not considered. Multivariable uncertainty analyses and univariable sensitivity analyses were undertaken. RESULTS: A 5 percentage point absolute reduction in the lifetime prevalence of IPV in the 2008 Australian female population was estimated to produce 6000 fewer incident cases of disease/injury, 74 fewer deaths, 5000 fewer DALYs lost and provide gains of 926,000 working days, 371,000 days of home-based production and 428,000 leisure days. Overall, AUD371 million in opportunity cost savings could be achievable. The greatest economic savings would be home-based production (AUD147 million), followed by leisure time (AUD98 million), workforce production (AUD94 million) and reduced health sector costs (AUD38 million). CONCLUSIONS: This study contributes new knowledge about the economic impact of IPV in females. The findings provide evidence of large potential opportunity cost savings from reducing the prevalence of IPV and reinforce the need to reduce IPV in Australia, and elsewhere

Evidence synthesis indicates contentless experiences in meditation are neither truly contentless nor identical

Contentless experience involves an absence of mental content such as thought, perception, and mental imagery. In academic work it has been classically treated as including states like those aimed for in Shamatha, Transcendental, and Stillness Meditation. We have used evidence synthesis to select and review 135 expert texts from within the three traditions. In this paper we identify the features of contentless experience referred to in the expert texts and determine whether the experiences are the same or different across the practices with respect to each feature. We identify 65 features reported or implied in one or more practices, with most being reported or implied in all three. While there are broad similarities in the experiences across the traditions, we find that there are differences with respect to four features and possibly many others. The main difference identified is that Shamatha involves substantially greater attentional stability and vividness. Another key finding is that numerous forms of content are present in the experiences, including wakefulness, naturalness, calm, bliss/joy, and freedom. The findings indicate that meditation experiences described as contentless in the academic literature can in fact involve considerable variation, and that in many and perhaps most cases these experiences are not truly contentless. This challenges classical understandings in academic research that in these so-called contentless experiences all content is absent, and that the experiences are therefore an identical state of pure consciousness or consciousness itself. Our assessment is that it remains an open question whether the experiences aimed for in the three practices should be classed as pure consciousness. Implications of our analysis for neuroscientific and clinical studies and for basic understandings of the practices are discussed.</p

The economic benefits of reducing physical inactivity: an Australian example

Background: Physical inactivity has major impacts on health and productivity. Our aim was to estimate the health and economic benefits of reducing the prevalence of physical inactivity in the 2008 Australian adult population. The economic benefits were estimated as &lsquo;opportunity cost savings&rsquo;, which represent resources utilized in the treatment of preventable disease that are potentially available for re-direction to another purpose from fewer incident cases of disease occurring in communities.Methods: Simulation models were developed to show the effect of a 10% feasible, reduction target for physical inactivity from current Australian levels (70%). Lifetime cohort health benefits were estimated as fewer incident cases of inactivity-related diseases; deaths; and Disability Adjusted Life Years (DALYs) by age and sex. Opportunity costs were estimated as health sector cost impacts, as well as paid and unpaid production gains and leisure impacts from fewer disease events associated with reduced physical inactivity. Workforce production gains were estimated by comparing surveyed participation and absenteeism rates of physically active and inactive adults, and valued using the friction cost approach. The impact of an improvement in health status on unpaid household production and leisure time were modeled from time use survey data, as applied to the exposed and non-exposed population subgroups and valued by suitable proxy. Potential costs associated with interventions to increase physical activity were not included. Multivariable uncertainty analyses and univariate sensitivity analyses were undertaken to provide information on the strength of the conclusions.Results: A 10% reduction in physical inactivity would result in 6,000 fewer incident cases of disease, 2,000 fewer deaths, 25,000 fewer DALYs and provide gains in working days (114,000), days of home-based production (180,000) while conferring a AUD96 million reduction in health sector costs. Lifetime potential opportunity cost savings in workforce production (AUD12 million), home-based production (AUD71 million) and leisure-based production (AUD79 million) was estimated (total AUD162 million 95% uncertainty interval AUD136 million, AUD196 million).Conclusions: Opportunity cost savings and health benefits conservatively estimated from a reduction in population-level physical inactivity may be substantial. The largest savings will benefit individuals in the form of unpaid production and leisure gains, followed by the health sector, business and government.<br /

A Modelling Study of Indoor Air Chemistry: The Surface Interactions of Ozone and Hydrogen Peroxide

Indoor surfaces play a key role in indoor chemistry, including modification of indoor oxidant concentrations. This study utilises the INdoor CHEmical Model in Python (INCHEM-Py) to investigate the impact of surface transformations and their impact on indoor gas-phase chemistry. INCHEM-Py has been developed to simulate the surface deposition of ozone and hydrogen peroxide onto nine and six individual surfaces respectively in a typical bedroom, kitchen and office for normal indoor concentrations in the absence of household activities. The results show that 91 to 96% of these oxidants are deposited onto indoor surfaces under our simulated conditions. In the bedroom, 38 to 44% of indoor ozone and hydrogen peroxide is deposited onto soft fabric surfaces, with 41 to 54% of ozone deposition occurring on plastic surfaces in the kitchen and office. Total indoor concentrations of straight-chained aldehydes (C1-C10) ranged from 4 to 5 ppb, with nonanal having the highest individual concentration (1.7, 1.6 and 1.5 ppb in the bedroom, kitchen and office respectively), primarily as a result of emissions from plastics following ozone deposition. Aldehyde concentrations following hydrogen peroxide deposition were often less than 0.01 ppb. Understanding how reactions and deposition on different indoor surfaces impact indoor air chemistry will enable internal surface selection with a view to improving overall indoor air quality

Indoor Cooking and Cleaning as a Source of Outdoor Air Pollution in Urban Environments

&lt;jats:p&gt;Common household activities including cooking and cleaning contribute to indoor air pollution. Here, a modelling study has been conducted to identify how these indoor sources of air pollution affect outdoor environments.&lt;/jats:p&gt

Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

2017 GJMPP Monograph Series: Grace Jordan McFadden Professors Program

The Grace Jordan McFadden Professors Program (GJMPP), formerly the African American Professors Program (AAPP)/Carolina Diversity Professors Program (CDPP) at the University of South Carolina, is honored to publish its sixteenth edition of this annual monograph series. AAPP recognizes the significance of offering its scholars a venue through which to engage actively in research and to publish their refereed papers that continually contribute to their respective fields of study. Parallel with the publication of their manuscripts is the opportunity to gain visibility among colleagues throughout postsecondary institutions at national and international levels. Scholars who have contributed papers for this monograph are acknowledged for embracing the value of including this responsibility within their academic milieu. Writing across disciplines adds broadly to the intellectual diversity of these manuscripts. From neophytes to quite experienced individuals, the chapters have been researched and written in depth. Founded in 1997 through the Department of Educational Leadership and Policies in the College of Education, AAPP was designed originally to address the under-representation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored historically by the University of South Carolina, the W. K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits doctoral students for disciplines in which African Americans currently are underrepresented among faculty in higher education. The continuation of this monograph series is seen as responding to a window of opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, at the same time, to allow for the dissemination of products of scholarship to a broader community. The importance of this series has been voiced by one of our 2002 AAPP graduates, Dr. Shundelle LaTjuan Dogan, formerly an Administrative Fellow at Harvard University, a Program Officer for the Southern Education Foundation, and a Program Officer for the Arthur M. Blank Foundation in Atlanta, Georgia. She is currently a Corporate Citizenship and Corporate Affairs Manager for IBM-International Business Machines in Atlanta, Georgia and has written an impressive Foreword for the 2014 monograph. Dr. Dogan wrote: “One thing in particular that I want to thank you for is having the African American Professors Program scholars publish articles for the monograph. I have to admit that writing the articles seemed like extra work at the time. However, in my recent interview process, organizations have asked me for samples of my writing. Including an article from a published monograph helped to make my portfolio much more impressive. You were ‘right on target’ in having us do the monograph series” (AAPP 2003 Monograph, p. xi). The Grace Jordan McFadden Professors Program purports to advance the tradition of spearheading international scholarship in higher education as evidenced through inspiration from this group of interdisciplinary manuscripts. I hope that you will envision these published papers for serving as an invaluable contribution to your own professional and career enhancement. John McFadden, PhD The Benjamin Elijah Mays Distinguished Professor Emeritus Director, Grace Jordan McFadden Professors Program University of South Carolina Columbia, South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1004/thumbnail.jp

Diamond Line - Fall 2020

In following up the premier issue of The Diamond Line, the fall 2020 editorial staff had big shoes to fill. We took on the challenge of creating something that would uphold the framework of Issue 1 while simultaneously branching out from its margins. Like the editors before us, we had a vision, but ours took a new form — bright, warm colors. Sunset colors. Moons. Playful lines. Isolation and introspection. A stroll through an art gallery. A coming-of-age story bound between two groovy orange bookends. While Issue 2 does not have an overarching theme, we chose the cover art, “Pandemic Prom” by Autumn Blaylock, because it beautifully encompassed the pages within and the vision we were working toward

Diamond Line - Fall 2020

In following up the premier issue of The Diamond Line, the fall 2020 editorial staff had big shoes to fill. We took on the challenge of creating something that would uphold the framework of Issue 1 while simultaneously branching out from its margins. Like the editors before us, we had a vision, but ours took a new form — bright, warm colors. Sunset colors. Moons. Playful lines. Isolation and introspection. A stroll through an art gallery. A coming-of-age story bound between two groovy orange bookends. While Issue 2 does not have an overarching theme, we chose the cover art, “Pandemic Prom” by Autumn Blaylock, because it beautifully encompassed the pages within and the vision we were working toward