An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings

Objectives: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. Methods: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. Results: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. Conclusions: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF

Technologies to Support Assessment of Movement During Video Consultations: Exploratory Study

Background Understanding and assessing patients’ body movements is essential for physical rehabilitation but is challenging in video consultations, as clinicians are frequently unable to see the whole patient or observe the patient as they perform specific movements. Objective The objective of this exploratory study was to assess the use of readily available technologies that would enable remote assessment of patient movement as part of a video consultation. Methods We reviewed the literature and available technologies and chose four technologies (Kubi and Pivo desktop robots, Facebook Portal TV, wide-angle webcam), in addition to help from a friend or a simple mobile phone holder, to assist video consultations. We used 5 standard assessments (sit-to-stand, timed “Up &amp; Go,” Berg Balance Test, ankle range of motion, shoulder range of motion) as the “challenge” for the technology. We developed an evaluation framework of 6 items: efficacy, cost, delivery, patient setup, clinician training and guidance, and safety. The coauthors, including 10 physiotherapists, then took the roles of clinician and patient to explore 7 combinations of 5 technologies. Subsequently, we applied our findings to hypothetical patients based on the researchers’ family members and clinical experience. Results Kubi, which allowed the clinician to remotely control the patient’s device, was useful for repositioning the tablet camera to gain a better view of the patient’s body parts but not for tracking movement. Facebook Portal TV was useful, but only for upper body movement, as it functions based on face tracking. Both Pivo, with automated full body tracking using a mobile phone, and the wide-angle webcam for a laptop or desktop computer show promise. Simple solutions such as having a friend operate a mobile phone and use of a mobile phone holder also have potential. The setup of these technologies will require better instructions than are currently available from suppliers, and successful use will depend on the technology readiness of patients and, to some degree, of clinicians. Conclusions Technologies that may enable clinicians to assess movement remotely as part of video consultations depend on the interplay of technology readiness, the patient’s clinical conditions, and social support. The most promising off-the-shelf approaches seem to be use of wide-angle webcams, Pivo, help from a friend, or a simple mobile phone holder. Collaborative work between patients and clinicians is needed to develop and trial technological solutions to support video consultations assessing movement. </jats:sec

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design

Background Heart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively. Methods The REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others. Conclusions This trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF

Receptor-Mediated Enhancement of Beta Adrenergic Drug Activity by Ascorbate In Vitro and In Vivo

RATIONALE: Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors. OBJECTIVES: Extending this work to beta 2 adrenergic systems in vitro and in vivo. METHODS: Ultraviolet spectroscopy was used to study ascorbate binding to adrenergic receptor preparations and peptides. Force transduction studies on acetylcholine-contracted trachealis preparations from pigs and guinea pigs measured the effect of ascorbate on relaxation due to submaximal doses of beta adrenergic agonists. The effect of inhaled albuterol with and without ascorbate was tested on horses with heaves and sheep with carbachol-induced bronchoconstriction. MEASUREMENTS: Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentration-dependent spectral shifts. Dose- dependence curves were obtained for the relaxation of pre-contracted trachealis preparations due to beta agonists in the presence and absence of varied ascorbate. Tachyphylaxis and fade were also measured. Dose response curves were determined for the effect of albuterol plus-and-minus ascorbate on airway resistance in horses and sheep. MAIN RESULTS: Ascorbate binds to the beta 2 adrenergic receptor at physiological concentrations. The receptor recycles dehydroascorbate. Physiological and supra-physiological concentrations of ascorbate enhance submaximal epinephrine and isoproterenol relaxation of trachealis, producing a 3-10-fold increase in sensitivity, preventing tachyphylaxis, and reversing fade. In vivo, ascorbate improves albuterol's effect on heaves and produces a 10-fold enhancement of albuterol activity in "asthmatic" sheep. CONCLUSIONS: Ascorbate enhances beta-adrenergic activity via a novel receptor-mediated mechanism; increases potency and duration of beta adrenergic agonists effective in asthma and COPD; prevents tachyphylaxis; and reverses fade. These novel effects are probably caused by a novel mechanism involving phosphorylation of aminergic receptors and have clinical and drug-development applications

Antihypertensive Drug Guanabenz Is Active In Vivo against both Yeast and Mammalian Prions

Background: Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans. [br/] Methodology/Principal Findings: Here we report the discovery of the in vivo antiprion activity of Guanabenz (GA), an agonist of a2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast prions using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrPSc clearance in a cell-based assay. These effects are very specific as evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on a2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prolonging slightly but significantly the survival of treated animals. [br/] Conclusion/Significance: GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based diseases. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases

Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function

The mitogen-activated protein kinase-activated protein kinase-5 (MK5) resides predominantly in the nucleus of resting cells, but p38MAPK, extracellular signal-regulated kinases-3 and -4 (ERK3 and ERK4), and protein kinase A (PKA) induce nucleocytoplasmic redistribution of MK5. The mechanism by which PKA causes nuclear export remains unsolved. In the study reported here we demonstrated that Ser-115 is an in vitro PKA phosphoacceptor site, and that PKA, but not p38MAPK, ERK3 or ERK4, is unable to redistribute MK5 S115A to the cytoplasm. However, the phosphomimicking MK5 S115D mutant resides in the cytoplasm in untreated cells. While p38MAPK, ERK3 and ERK4 fail to trigger nuclear export of the kinase dead T182A and K51E MK5 mutants, S115D/T182A and K51E/S115D mutants were able to enter the cytoplasm of resting cells. Finally, we demonstrated that mutations in Ser-115 affect the biological properties of MK5. Taken together, our results suggest that Ser-115 plays an essential role in PKA-regulated nuclear export of MK5, and that it also may regulate the biological functions of MK5

Cost-Effectiveness of “Golden Mustard” for Treating Vitamin A Deficiency in India

BACKGROUND: Vitamin A deficiency (VAD) is an important nutritional problem in India, resulting in an increased risk of severe morbidity and mortality. Periodic, high-dose vitamin A supplementation is the WHO-recommended method to prevent VAD, since a single dose can compensate for reduced dietary intake or increased need over a period of several months. However, in India only 34 percent of targeted children currently receive the two doses per year, and new strategies are urgently needed. METHODOLOGY: Recent advancements in biotechnology permit alternative strategies for increasing the vitamin A content of common foods. Mustard (Brassica juncea), which is consumed widely in the form of oil by VAD populations, can be genetically modified to express high levels of beta-carotene, a precursor to vitamin A. Using estimates for consumption, we compare predicted costs and benefits of genetically modified (GM) fortification of mustard seed with high-dose vitamin A supplementation and industrial fortification of mustard oil during processing to alleviate VAD by calculating the avertable health burden in terms of disability-adjusted life years (DALY). PRINCIPAL FINDINGS: We found that all three interventions potentially avert significant numbers of DALYs and deaths. Expanding vitamin A supplementation to all areas was the least costly intervention, at $23-$50 per DALY averted and $1,000-$6,100 per death averted, though cost-effectiveness varied with prevailing health subcenter coverage. GM fortification could avert 5 million-6 million more DALYs and 8,000-46,000 more deaths, mainly because it would benefit the entire population and not just children. However, the costs associated with GM fortification were nearly five times those of supplementation. Industrial fortification was dominated by both GM fortification and supplementation. The cost-effectiveness ratio of each intervention decreased with the prevalence of VAD and was sensitive to the efficacy rate of averted mortality. CONCLUSIONS: Although supplementation is the least costly intervention, our findings also indicate that GM fortification could reduce the VAD disease burden to a substantially greater degree because of its wider reach. Given the difficulties in expanding supplementation to areas without health subcenters, GM fortification of mustard seed is an attractive alternative, and further exploration of this technology is warranted

Carrion Availability in Space and Time

Introduction Availability of carrion to scavengers is a central issue in carrion ecology and management, and is crucial for understanding the evolution of scavenging behaviour. Compared to live animals, their carcasses are relatively unpredictable in space and time in natural conditions, with a few exceptions (see below, especially Sect. “Carrion Exchange at the Terrestrial-Aquatic Interface”). Carrion is also an ephemeral food resource due to the action of a plethora of consumers, from microorganisms to large vertebrates, as well as to desiccation (i.e., loss of water content; DeVault et al. 2003; Beasley et al. 2012; Barton et al. 2013; Moleón et al. 2014). With a focus on vertebrate carcasses, here we give an overview of (a) the causes that produce carrion, (b) the rate of carrion production, (c) the factors affecting carrion quality, and (d) the distribution of carrion in space and time, both in terrestrial and aquatic environments (including their interface). In this chapter, we will focus on naturally produced carrion, whereas non-natural causes of animal mortality are described in chapter “Human-Mediated Carrion: Effects on Ecological Processes”. However, throughout this chapter we also refer to extensive livestock carrion, because in the absence of strong restrictions such as those imposed in the European Community after the bovine spongiform encephalopathy crisis (Donázar et al. 2009; Margalida et al. 2010), the spatiotemporal availability of carrion of extensive livestock and wild ungulates is similar

The use of 3D surface scanning for the measurement and assessment of the human foot

<p>Abstract</p> <p>Background</p> <p>A number of surface scanning systems with the ability to quickly and easily obtain 3D digital representations of the foot are now commercially available. This review aims to present a summary of the reported use of these technologies in footwear development, the design of customised orthotics, and investigations for other ergonomic purposes related to the foot.</p> <p>Methods</p> <p>The PubMed and ScienceDirect databases were searched. Reference lists and experts in the field were also consulted to identify additional articles. Studies in English which had 3D surface scanning of the foot as an integral element of their protocol were included in the review.</p> <p>Results</p> <p>Thirty-eight articles meeting the search criteria were included. Advantages and disadvantages of using 3D surface scanning systems are highlighted. A meta-analysis of studies using scanners to investigate the changes in foot dimensions during varying levels of weight bearing was carried out.</p> <p>Conclusions</p> <p>Modern 3D surface scanning systems can obtain accurate and repeatable digital representations of the foot shape and have been successfully used in medical, ergonomic and footwear development applications. The increasing affordability of these systems presents opportunities for researchers investigating the foot and for manufacturers of foot related apparel and devices, particularly those interested in producing items that are customised to the individual. Suggestions are made for future areas of research and for the standardization of the protocols used to produce foot scans.</p