Restructuring and hospital care: Sub-national trends, differentials, and their impacts; New Zealand from 1981

An analysis of the "nation's health" is the central concern of this study. Its genesis was a detailed, technical, time-series research on regional and ethnic differentials in health in New Zealand. But as this work progressed it became increasingly evident that the results of this more narrow analysis could make a wider contribution to the development of a knowledge-base on health trends and on the impacts of policy on these. In a sense, the analysis provides a demographic audit of health trends over the last two decades. The focus here is different from that in most other studies on restructuring of the New Zealand health system as their concern was either to review in detail the rewriting of policy per se, and attendant structural and institutional changes (Fougere 2001), or to identify how these changes relate to changes in mortality (Blakely et al. 2008). The research question reported here was, instead, to analyse the most crucial of health outcomes, „how long we live and how often we end up in hospital‟, identified in the earlier quotation, to report patterns and trends in hospital use nationally and sub-nationally over the period under review, and to determine the degrees to which various sub-populations benefited, or did not benefit, from these changes. The analysis focuses on the hospital sector in the system, but it will also show relations between this and other sectors, formal (e.g. primary health) and less formal (notably the healthcare afforded sickness and invalid beneficiaries). Thus two questions are addressed: 1. whether or not the nation‟s population health improved over the period and; 2. whether or not there was a convergence in patterns of health gain across its constituent sub-populations defined geographically and ethnically. This monograph deals with sub-national differences in health in New Zealand over a period of substantial socio-economic restructuring and associated radical changes in health policy, health systems and their related information systems (see also, Text Appendix A). It complements the recently published analysis of national ethnic trends in mortality (Blakely et al. 2004), but differs in several critical respects. That study reviewed health status by emphasising aetiologies and causes of death. In contrast, the present analysis focuses on actuarial dimensions of both mortality and morbidity and on health as measured by functional capacity rather than the disease orientated „burden of disease‟. It goes beyond health status issues to look at the system itself, to assess whether health policy outcomes were generated more through efficiency-gain (economic or service delivery, such as those resulting in a convergence sub-nationally of supply and demand effects), or through health gains, or ideally, by both. To do this, and as a by-product to analyse changes in health status and the system in an era of restructuring, innovative methodologies and composite time-series indices combining the two dimensions of a „nation‟s health‟, needing hospital care and longevity, have had to be custom-designed. To achieve this objective, the ensuing analysis is often technical, and may introduce concepts that are unfamiliar to some readers. In order to look at possible inequalities of outcome, comparisons were made between regions and ethnic groups, as well as age-groups and genders, and as a result, in places the analysis becomes rather complex

17β-Estradiol dysregulates innate immune responses to Pseudomonas aeruginosa respiratory infection and is modulated by estrogen receptor antagonism

ABSTRACT Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to P. aeruginosa . We used wild-type and CF mice, which we hormone manipulated, inoculated with P. aeruginosa , and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosa . We found that female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males ( P &lt; 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice ( P = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with P. aeruginosa and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa . ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy. </jats:p

Living with rheumatic heart disease at the intersection of biomedical and Aboriginal worldviews

Rheumatic heart disease (RHD) significantly impacts the lives of First Nations Australians. Failure to eliminate RHD is in part attributed to healthcare strategies that fail to understand the lived experience of RHD. To rectify this, a PhD study was undertaken in the Northern Territory (NT) of Australia, combining Aboriginal ways of knowing, being and doing with interviews (24 participants from clinical and community settings) and participant observation to privilege Aboriginal voices, including the interpretations and experiences of Aboriginal co-researchers (described in the adjunct article). During analysis, Aboriginal co-researchers identified three interwoven themes: maintaining good feelings; creating clear understanding (from good information); and choosing a good djalkiri (path). These affirm a worldview that prioritises relationships, positive emotions and the wellbeing of family/community. The findings demonstrate the inter-connectedness of knowledge, choice and behaviour that become increasingly complex in stressful and traumatic health, socioeconomic, political, historical and cultural contexts. Not previously heard in the RHD domain, the findings reveal fundamental differences between Aboriginal and biomedical worldviews contributing to the failure of current approaches to communicating health messages. Mitigating this, Aboriginal co-researchers provided targeted recommendations for culturally responsive health encounters, including: communicating to create positive emotions; building trust; and providing family and community data and health messages (rather than individualistic)

Salicylaldoximes and anthranylaldoximes as alternatives to phenol-based estrogen receptor ligands

Estrogens play a crucial role in the development and function of female reproductive tissues. They have positive effects on the maintenance of bone mineral density, on the liver, and on the cardiovascular and central nervous systems. Selective Estrogen Receptor Modulators (SERMs) are particularly attractive as therapeutic agents because they are able to block estrogen action at those sites where stimulation would be undesirable, such as the breast and uterus, but at the same time stimulate estrogen actions in other tissues where they are desired, such as the bone and liver. Most synthetic estrogen receptor ligands possess a phenolic ring, mimicking the phenolic "Aring" of the natural ligand estradiol. In an attempt to increase the structural diversity of estrogen receptor (ER) ligands, we designed and synthesized molecules containing unprecedented replacements of the prototypical phenolic "A-ring" of estrogens with an oxime and a hydroxy- (salicylaldoximes) or aminomoieties (anthranylaldoximes), forming intramolecularly H-bonded pseudocycles. These new classes of compounds showed interesting ER binding properties on both receptor subtypes (ERα and ERβ). These results proved that the six-membered ring formed by an intramolecular hydrogen bond, and containing an exocyclic oxime OH, is an effective stereoelectronic replacement of the phenolic ring of typical ER ligands

Delineation of a unique protein-protein interaction site on the surface of the estrogen receptor

Recent studies have identified a series of estrogen receptor (ER)interacting peptides that recognize sites that are distinct from the classic coregulator recruitment (AF2) region. Here, we report the structural and functional characterization of an ER alpha-specific peptide that binds to the liganded receptor in an AF2-independent manner. The 2-angstrom crystal structure of the ER/peptide complex reveals a binding site that is centered on a shallow depression on the beta-hairpin face of the ligand-binding domain. The peptide binds in an unusual extended conformation and makes multiple contacts with the ligand-binding domain. The location and architecture of the binding site provides an insight into the peptide's ER subtype specificity and ligand interaction preferences. In vivo, an engineered coactivator containing the peptide motif is able to strongly enhance the transcriptional activity of liganded ER alpha, particularly in the presence of 4-hydroxytamoxifen. Furthermore, disruption of this binding surface alters ER's response to the coregulator TIF2. Together, these results indicate that this previously unknown interaction site represents a bona fide control surface involved in regulating receptor activity

Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

BACKGROUND: Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. METHODS AND RESULTS: Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II-induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. CONCLUSIONS: Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women

Radiosynthesis and evaluation of talazoparib and its derivatives as PARP-1-targeting agents

Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of

Statistical analysis plan for the stepped wedge clinical trial Healing Right Way—enhancing rehabilitation services for Aboriginal Australians after brain injury

Background Aboriginal Australians are known to suffer high levels of acquired brain injury (stroke and traumatic brain injury) yet experience significant barriers in accessing rehabilitation services. The aim of the Healing Right Way trial is to evaluate a culturally secure intervention for Aboriginal people with newly acquired brain injury to improve their rehabilitation experience and quality of life. Following publication of the trial protocol, this paper outlines the statistical analysis plan prior to locking the database. Methods The trial involves a stepped wedge design with four steps over 3 years. Participants were 108 adult Aboriginal Australians admitted to one of eight hospitals (four rural, four urban) in Western Australia within 6 weeks of onset of a new stroke or traumatic brain injury who consented to follow-up for 26 weeks. All hospital sites started in a control phase, with the intervention assigned to pairs of sites (one metropolitan, one rural) every 26 weeks until all sites received the intervention. The two-component intervention involves training in culturally safe care for hospital sites and enhanced support provided to participants by Aboriginal Brain Injury Coordinators during their hospital stay and after discharge. The primary outcome is quality of life as measured by the Euro QOL–5D-3L VAS. A mixed effects linear regression model will be used to assess the between-group difference at 26 weeks post-injury. The model will control for injury type and severity, age at recruitment and time since commencement of the trial, as fixed effects. Recruitment site and participant will be included as random effects. Secondary outcomes include measurements of function, independence, anxiety and depression, carer strain, allied health occasions of service received and hospital compliance with minimum processes of care based on clinical guidelines and best practice models of care. Discussion The trial will provide the first data surrounding the effectiveness of an intervention package for Aboriginal people with brain injury and inform future planning of rehabilitation services for this population. The statistical analysis plan outlines the analyses to be undertaken. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12618000139279. Registered 30 January, 2018

Considerations for Child Cancer Survivors and Immunocompromised Children to Prevent Secondary HPV-associated Cancers

Survivors of childhood cancer and other immunocompromised children are at high risk for the development of secondary Human Papillomavirus (HPV)-associated cancers. In this overview, the authors examine the epidemiology of vaccine efficacy, the natural history of HPV infections, and accelerated HPV-associated cancer development in these populations. The authors highlight the opportunities for preventive care and future research directives