OCE-205 in rats and non-human primates: Pharmacokinetic and pharmacodynamic analysis.

Treatment for complications associated with the hemodynamic consequences of decompensated cirrhosis remains suboptimal. Terlipressin, the latest pharmacological management of hepatorenal syndrome-acute kidney injury (HRS-AKI), targets the vasopressin system but has serious side effects. OCE-205 is a novel peptide designed to target the vasopressin receptor system as a mixed V1a agonist/antagonist, resulting in effective partial agonism without V2 agonism. We examined the in vivo pharmacokinetic/pharmacodynamic properties of OCE-205 in healthy rats and cynomolgus monkeys. OCE-205 was administered by IV or SC bolus injection; arginine vasopressin (AVP) or terlipressin were comparators. After IV OCE-205 administration in rats, mean plasma concentration decreased in a mostly linear manner to 2 mg/mL after 120 min, and for SC administration, slowly decreased to ∼50 ng/mL after 300 min. Compared with pre-test values, arterial blood pressure values significantly increased after all OCE-205 doses tested. For monkeys, the concentration after IV OCE-205 administration was mostly linear to 5 ng/mL after 180 min, and for SC administration, ∼3 ng/mL after 480 min. Subcutaneous OCE-205 administration increased mean arterial pressure (MAP) versus baseline, with ΔMAP in OCE-205-treated animals marked and long-lasting while terlipressin induced an increase from baseline in MAP, with negligible ΔMAP, on average, by 150 min after administration in all groups. AVP, but not OCE-205, significantly increased blood lactate concentrations. OCE-205 was well tolerated in adult male rats and cynomolgus monkeys following single-dose bolus administration. The preclinical results of OCE-205, with its demonstrated V1a selective partial agonist activity and potentially tolerable safety profile, suggest its potential utility for treatment of the cardiovascular complications of cirrhosis. Institutional protocol number: Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee (IACUC) on November 27, 2006 under protocol FRI 06-011, and by the Sinclair Research Center IACUC under protocol S11177.

OCE-205, A Novel, Selective Vasopressin Receptor Mixed Agonist-Antagonist: Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics from a Phase 1 Study in Healthy Volunteers.

BACKGROUND: OCE-205, a novel, selective vasopressin V1a receptor mixed agonist/antagonist with no V2 receptor activity, may treat the portal hypertension-related complications of end-stage liver disease with an improved therapeutic profile over currently utilized nonselective full-agonist vasopressin analogs. OBJECTIVES: This Phase 1, double-blind, placebo-controlled, within-dose-group randomized trial investigated the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of OCE-205 in healthy adults. METHODS: Subjects received a single intravenous dose of OCE-205 0.1, 0.3, 0.45, 0.6, or 0.9 mg, or placebo infused over 6 h. Safety and tolerability were assessed, and blood samples were obtained for pharmacokinetic analyses. Sixty-four subjects were randomized and treated. RESULTS: Area under the concentration-time curve (AUC) and maximum plasma concentrations (Cmax) were approximately dose-proportional across doses from 0.1 to 0.9 mg. OCE-205 terminal half-life was ~ 1.5 h. Diastolic, and to a lesser extent systolic, blood pressure increased in all OCE-205 dose groups; pulse rate decreased. Overall changes in mean arterial pressure were similar to changes in diastolic blood pressure. Absolute changes in cardiac output, by echocardiogram, were somewhat dose-dependent, with mean reductions of 3-12% after the 0.9 mg dose, and individual reductions ≤ 20 to 25% across all doses. The most frequent adverse events were abdominal pain, abnormal gastrointestinal sounds, and diarrhea, with no reported cases of mesenteric ischemia. Adverse events were generally mild or moderate in severity. CONCLUSION: OCE-205 was safe and well tolerated, with a pharmacodynamic profile achieving submaximal partial agonism consistent with mixed agonism-antagonism of the V1a receptor. OCE-205 shows promise as a treatment for some complications of end-stage liver disease.

Partial vasopressin 1a receptor agonism reduces portal hypertension and hyperaldosteronism and induces a powerful diuretic and natriuretic effect in rats with cirrhosis and ascites.

The vasopressin system has emerged as a therapeutic focus for lowering portal hypertension and reducing splanchnic vasodilation in patients with refractory ascites. Clinically available vasopressin agonists are limited by preferential selectivity for V1 receptors that also have steep concentration-response curves with potential risks of excess vasoconstriction and/or complete antidiuretic effects. OCE-205 is a novel, selective, partial V1a receptor agonist with mixed agonist/antagonist activity and no V2 receptor activation at therapeutic doses. We carried out two studies assessing the in vivo effects of OCE-205 in different rat models of cirrhosis and ascites. In a carbon tetrachloride rat cirrhosis model, OCE-205 administration produced a marked reduction in portal hypertension and hyperaldosteronism, along with robust diuretic and natriuretic effects. These effects were accompanied by marked decreases in ascites volume, with three of five animals experiencing total mobilization of ascites. There was no evidence of fluid overload or sodium or water retention, confirming OCE-205's lack of V2 receptor activity. In a second, corroborative study using a bile duct ligation rat model of ascites, OCE-205 produced significant decreases in ascites volume and body weight and a significant increase in urine volume versus vehicle. Urine sodium excretion increased significantly after the first administration of OCE-205 relative to vehicle; however, repeat administration over 5 days did not lead to hyponatremia. Thus, in separate in vivo models, the mixed agonist/antagonist OCE-205 demonstrated relevant and expected endpoint findings consistent with its known mechanism of action and in vitro pharmacology without apparent unwanted effects or nonspecific toxicities.

Empirical validation of ELM trained neural networks for financial modelling.

The purpose of this work is to compare predictive performance of neural networks trained using the relatively novel technique of training single hidden layer feedforward neural networks (SFNN), called Extreme Learning Machine (ELM), with commonly used backpropagation-trained recurrent neural networks (RNN) as applied to the task of financial market prediction. Evaluated on a set of large capitalisation stocks on the Australian market, specifically the components of the ASX20, ELM-trained SFNNs showed superior performance over RNNs for individual stock price prediction. While this conclusion of efficacy holds generally, long short-term memory (LSTM) RNNs were found to outperform for a small subset of stocks. Subsequent analysis identified several areas of performance deviations which we highlight as potentially fruitful areas for further research and performance improvement.

Development of a New Hydrogel Anion Exchange Membrane for Swine Wastewater Treatment.

We developed a proprietary anion exchange membrane (AEM) for wastewater treatment as an alternative to commercial products. Following the successful development of a hydrogel cation exchange membrane on a porous ceramic support, we used the same approach to fabricate an AEM. Different positively charged monomers and conditions were tested, and all AEMs were tested for nitrate and phosphate anion removal from buffers by electrodialysis. The best AEM was tested further with real swine wastewater for phosphate removal by electrodialysis and nitrate removal in a bioelectrochemical denitrification system (BEDS). Our new AEM showed better phosphate removal compared with a commercial membrane; however, due to its low permselectivity, the migration of cations was detected while operating a two-chambered biocathode BEDS in which the membrane was utilized as a separator. After improving the permselectivity of the membrane, the performance of our proprietary AEM was comparable to that of a commercial membrane. Because of the usage of a porous ceramic support, our AEM is self-supporting, sturdy, and easy to attach to various frames, which makes the membrane better suited for harsh and corrosive environments, such as swine and other animal farms and domestic wastewater.

A model of lived experience leadership for transformative systems change: Activating Lived Experience Leadership (ALEL) project.

PURPOSE: This discursive paper presents a lived experience leadership model as developed as part of the Activating Lived Experience Leadership (ALEL) project project to increase the recognition and understanding of lived experience leadership in mental health and social sectors. The model of lived experience leadership was formulated through a collaboration between the South Australian Lived Experience Leadership & Advocacy Network and the Mental Health and Suicide Prevention Research and Education Group. DESIGN/METHODOLOGY/APPROACH: As one of the outcomes of the ALEL research project, this model incorporates findings from a two-year research project in South Australia using participatory action research methodology and cocreation methodology. Focus groups with lived experience leaders, interviews with sector leaders and a national survey of lived experience leaders provided the basis of qualitative data, which was interpreted via an iterative and shared analysis. This work identified intersecting lived experience values, actions, qualities and skills as characteristics of effective lived experience leadership and was visioned and led by lived experience leaders. FINDINGS: The resulting model frames lived experience leadership as a social movement for recognition, inclusion and justice and is composed of six leadership actions: centres lived experience; stands up and speaks out; champions justice; nurtures connected and collective spaces; mobilises strategically; and leads change. Leadership is also guided by the values of integrity, authenticity, mutuality and intersectionality, and the key positionings of staying peer and sharing power. ORIGINALITY/VALUE: This model is based on innovative primary research, which has been developed to encourage understanding across mental health and social sectors on the work of lived experience leaders in seeking change and the value that they offer for systems transformation. It also offers unique insights to guide reflective learning for the lived experience and consumer movement, workers, clinicians, policymakers and communities.

Forced sex, rape and sexual exploitation: attitudes and experiences of high school students in South Kivu, Democratic Republic of Congo.

This paper reports on fieldwork carried out in 2011 with the aim of investigating the attitudes and reported behaviour of Congolese high school students concerning sexual relationships. A total of 56 boys and girls aged 16-20 from two urban and two rural high schools in South Kivu Province took part in focus groups, and 40 of these were subsequently interviewed individually. The majority of boys felt that they were entitled to sex from their girlfriends and that if persuasion was unsuccessful, the use of force was legitimate; this, in their minds, did not constitute rape. Girls, on the other hand, were clear that such forced sex was rape. However it may be understood, rape was perceived as having increased in recent years and was explained by weak legal systems, pornography and provocative dressing by girls. Boys were angry at the competition from older, often married, men who were able to provide monetary and other incentives to the girls.

Barriers to use of refractive services in Mozambique.

PURPOSE: Uncorrected refractive error remains a leading cause of visual impairment (VI) across the globe with Mozambique being no exception. The establishment of an optometry profession in Mozambique that is integrated into the public health system denotes significant progress with refractive services becoming available to the population. As the foundations of a comprehensive refractive service have now been established, this article seeks to understand what barriers may limit their uptake by the general population and inform decision making on improved service delivery. METHODS: A community-based cross-sectional study using two-stage cluster sampling was conducted. Participants with VI were asked to identify barriers that were reflective of their experiences and perceptions of accessing refractive services. A total of 4601 participants were enumerated from 76 clusters in Nampula, Mozambique. RESULTS: A total of 1087 visually impaired participants were identified (884 with near and 203 with distance impairment). Cost was the most frequently cited barrier, identified by more than one in every two participants (53%). Other barriers identified included lack of felt need (20%), distance to travel (15%), and lack of awareness (13%). In general, no significant influence of sex or type of VI on barrier selection was found. Location had a significant impact on the selection of several barriers. Pearson χ analysis indicated that participants from rural areas were found to feel disadvantaged regarding the distance to services (p ≤ 0.001) and adequacy of hospital services (p = 0.001). CONCLUSIONS: For a comprehensive public sector refractive service to be successful in Mozambique, those planning its implementation must consider cost and affordability. A clear strategy for overcoming lack of felt need will also be needed, possibly in the form of improved advocacy and health promotion. The delivery of refractive services in more remote rural areas merits careful and comprehensive consideration.

The development of a public optometry system in Mozambique: a Cost Benefit Analysis.

BACKGROUND: The economic burden of uncorrected refractive error (URE) is thought to be high in Mozambique, largely as a consequence of the lack of resources and systems to tackle this largely avoidable problem. The Mozambique Eyecare Project (MEP) has established the first optometry training and human resource deployment initiative to address the burden of URE in Lusophone Africa. The nature of the MEP programme provides the opportunity to determine, using Cost Benefit Analysis (CBA), whether investing in the establishment and delivery of a comprehensive system for optometry human resource development and public sector deployment is economically justifiable for Lusophone Africa. METHODS: A CBA methodology was applied across the period 2009-2049. Costs associated with establishing and operating a school of optometry, and a programme to address uncorrected refractive error, were included. Benefits were calculated using a human capital approach to valuing sight. Disability weightings from the Global Burden of Disease study were applied. Costs were subtracted from benefits to provide the net societal benefit, which was discounted to provide the net present value using a 3% discount rate. RESULTS: Using the most recently published disability weightings, the potential exists, through the correction of URE in 24.3 million potentially economically productive persons, to achieve a net present value societal benefit of up to $1.1 billion by 2049, at a Benefit-Cost ratio of 14:1. When CBA assumptions are varied as part of the sensitivity analysis, the results suggest the societal benefit could lie in the range of $649 million to $9.6 billion by 2049. CONCLUSION: This study demonstrates that a programme designed to address the burden of refractive error in Mozambique is economically justifiable in terms of the increased productivity that would result due to its implementation.

Field data: distributions and costs of road-traffic fatalities in South Africa.

BACKGROUND: Road-traffic crashes and fatalities constitute major social and economic issues in South Africa. They are a major cause of morbidity and mortality comparable to HIV/AIDS, homicides, and some chronic diseases. METHODS: Road-traffic accident data for the year 2003 obtained from the Department of Transport, Pretoria, South Africa were used for this study. The valuation of the costs of road-traffic crashes and fatalities in South Africa is based on the gross output or human capital approach. RESULTS: 10,197 fatal road crashes and 12,353 fatalities were reported during the study period. More than 50% of the fatal road crashes and fatalities occurred in only three out of 11 provinces. The Northern Cape, which is the least populated province, had the highest fatal road crashes per 100,000 population and fatalities per 100,000 population. The number of road-traffic fatalities in the rural areas was 2.7 times that in the urban areas. The total costs of the road-traffic fatalities which was about R 8 billion (>US$ 1 billion) is about 0.6% of the country's nominal GDP for 2003. 60% of the cases and costs of road-traffic fatalities involved persons aged 20-39 years, although this age group is only 27% of the country's population. The rural areas accounted for 73% and the urban areas 27% of the total costs of fatal road-traffic crashes. CONCLUSION: Those living in the rural areas of the South African society and those aged 20-49 years constitute high-risk groups of road-traffic crashes and fatalities. They are also responsible for most of the attendant costs of fatal crashes and fatalities in the country.

The economics of landmine clearance in Afghanistan.

This paper presents an economic evaluation of landmine clearance in Afghanistan. The main benefits comprise increased agricultural output, saved transport time and running costs, saved human casualties and the saved costs of supporting refugees and displaced persons. An investment of US$100 million between 1988 and 1998 is estimated to provide annual benefits of $50.3 million per annum between 1999 and 2008. This translates into net present values of between $935 and $1,744 million, depending on the rate of discount used. This contrasts with the negative NPVs estimated for several other countries.