Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

The 'Lazarus experience' : people with HIV making sense of their lives in the post-treatment era

The medico-scientific advances made in the treatment of HIV and AIDS, which emerged in the mid 1990s, were significant. The Highly Active Anti-Retroviral Treatments (HAART) or anti- HIV treatments have been positioned as resources that changed the way HIV is now medically and socially constructed. Although HIV remains incurable, it is now constructed as a chronic disease that is treatable, manageable and people are no longer positioned as living with a ‘death sentence’. The research on which this thesis is based explores the subjective lived experiences of people with HIV living in urban Australia in the context of this change. The effects that the treatments have had on corporeality have also changed the ways people are now living with HIV in the post-treatment era. It is an era in which treatments for HIV are taken-for-granted, but issues, doubts and concerns relating to treatment use are firmly embedded in the everyday life of people with HIV. The findings suggest that whilst AIDS-related mortality has decreased since the availability of effective treatments, the notion of ‘quality of life’, as subjectively constituted and defined, is an ongoing negotiation that is predicated on people locating meaningfulness in their everyday lives. Despite the decreased threat of failing health and death, the findings also suggest that people are continuing to be confronted by, and therefore positioned as, having to make sense of complex issues embedded in living with a disease for which there is no cure

Healthy Active Australia Community and Schools Grants Program - Panther Bytes: Final Evaluation Report

The Panther Bytes program was designed as a support program for promoting the importance of healthy diets and regular exercises in primary school children. The program focuses on diet, nutrition and physical activity as ways to redress poor eating habits and low exercise levels by utilising modern technology and interactions with elite athletes. The program is an initiative of the Panthers on the Prowl Community Development Foundation, which began as a concept in 2000 with support from the Panthers Board of Directors and the Panthers Rugby Leagues Club. This report provides the results of an independent evaluation of the Panther Bytes program conducted by the University of Western Sydney. The evaluation is based on findings from online questionnaires designed specifically for students who participated in the program, issues identified from focus groups with students, parents of students and teachers of students who participated in the program, and information obtained by the Panther Bytes program staff. In sum, evaluation outcomes are based on data from the following sources: 2 cohorts of students who participated in the program in 2009; 499 student online questionnaire responses (173 responses at the start of the program and 326 responses at the completion of the program); 3 focus groups in 2009 with a total of 13 students, 5 parents, 4 teachers and 1 school principal; Australian Fitness Education Award (AFEA) data collected by the Panther Bytes staff; a teacher evaluation questionnaire (‘Active Lifestyles – Panther Bytes Program’) designed and administered by Panther Bytes staff

Life with HIV and AIDS in the era of effective treatments : 'it's not just about living longer!'

This paper explores the lived experiences of people with Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS) in the era of effective treatments. Informed by post-structuralist epistemology, the aim of this paper is to interrogate the concept of quality of life within the context of living with HIV as a treatable, manageable and chronic disease, by critiquing the utility of the concept as a gauge by which the success of treatment intervention is assessed. In doing so, it draws on a theoretical analysis of the quality of life concept, and examines the complexities and difficulties embedded in treatment use, which in turn facilitates an exploration of the disparity between the ways that the healthy body is positioned within medical discourse and the subjectively constituted notion of well-being. A case study of a person with HIV will be presented to underscore the importance of quality of life as subjectively constituted rather than as a clinical outcome

Bereaved informal cancer carers making sense of the palliative care experiences at home

This qualitative study explored the positive meanings constructed and ascribed to the experience of providing palliative care at home by bereaved informal cancer carers, a group of individuals who are in a position to make sense of their caring experiences as a coherent whole. Twenty-two bereaved cancer carers, living in New South Wales (NSW), Australia, were interviewed as part of a larger mixed-method study examining the experience of informal cancer care. Participants were recruited through cancer support groups and cancer clinics, and through the Cancer Council NSW. Accounts of positive aspects of palliative caring were analysed using a thematic analytical approach from a constructionist perspective. The findings indicated that these bereaved carers gave accounts that accentuated the benefit and satisfaction derived from providing direct palliative care at home, which enabled them to construct positive meanings associated with their participation in the dying process, and as a result to ascribe subjectively meaningful interpretations to their loved ones' death and their sense of loss. This included a sense of reward for doing something good, meeting the expressed needs of the patient, continuing with normal life as much as possible, improving the conditions of the relationship and meeting cultural expectations of the right thing to do. Being present at the point of death was positioned as rewarding because it facilitated the process of saying goodbye, fostered inclusion of others, provided closure and was a spiritual experience. These findings suggest that there are positive and rewarding aspects associated with providing informal cancer care in a palliative context, and these aspects were pertinent and meaningful for carers in their endeavours to reconcile the difficulties and loss they experienced. This has implications for the prevention and amelioration of distress experienced by informal cancer carers, and suggests that future research should not ignore the positive aspects of providing palliative care

How do subjectively-constructed meanings ascribed to anti-HIV treatments affect treatment-adherent practice?

Anti-HIV treatment-adherent practice is a significant issue in HIV medical discourses on effective disease treatment and management. Findings from research studies into treatment (non)adherence have positioned the act as a medical issue that could be remedied by behavioral strategies. The present study, conducted in Sydney, Australia, aims to examine treatment-(non)adherent practice as a subjective expression of meanings ascribed to treatments by employing a narrative analytical approach informed by poststructuralist epistemology. The findings indicate that people with HIV negotiate and position treatments in particular ways that lead to multiple and varied understanding of treatments. The ways treatments are positioned in their everyday lives suggest that meanings ascribed to treatments impact on the way individuals negotiate demands embedded in the medically-constructed practice of adherence

Strength through adversity : bereaved cancer carers' accounts of rewards and personal growth from caring

Many studies have identified negative and distressing consequences experienced by informal cancer carers, but less attention has been given to positive and beneficial aspects of caring. This qualitative study examined the positive aspects of caring as subjectively constructed by bereaved informal cancer carers, a group of individuals who are in a position to make sense of their caring experiences as a coherent whole. Twenty-three bereaved informal cancer carers were interviewed, and their accounts were analyzed using a thematic analytical approach from a phenomenological perspective. The participants were able to identify positive and beneficial aspects of caring. These included the discovery of personal strength, through adversity, acceptance, and necessity; the deepening of their relationship with the person for whom they cared; and personal growth through altered relationships with others and altered perspectives on living. Many participants gave accounts of focusing on these positive benefits when they reflected on their caring experiences. We concluded that benefit finding in the face of adverse events serves an important function in allowing individuals to incorporate difficult experiences into their worldview in a meaningful way, thus maintaining positive beliefs about the world. This has implications for the development of interventions for informal cancer carers and for those who are bereaved following caring