Comparison of different dosing regimens (once weekly vs. twice weekly, and once weekly vs. once every two weeks) with epoetin delta in patients with chronic kidney disease: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Anaemia is a common complication of chronic kidney disease and prevalence increases with declining renal function. Renal anaemia has significant implications for the well-being and quality of life of patients and impacts on morbidity and mortality. Anaemia can be well managed by therapy with erythropoiesis-stimulating agents (ESAs). Previous clinical trials have shown that the only human cell-line-derived ESA, epoetin delta, is well tolerated and effective in maintaining haemoglobin levels in anaemic patients with chronic kidney disease. The half-life of epoetin delta suggests that administration of this agent is feasible once weekly and once every two weeks. We report on the design and rationale of a trial to compare once weekly <it>vs</it>. twice weekly, and once weekly <it>vs</it>. once every two weeks dosing of epoetin delta.</p> <p>Design and methods</p> <p>This is a randomized, open-label, multicentre trial. Patients aged 18 years or above with chronic kidney disease (Stages 3–5) are eligible to enter this trial. Two groups of patients form the trial population, those naïve to ESA therapy and those previously stable on ESA therapy. There are two primary objectives of this trial: 1) to demonstrate non-inferiority between twice weekly and once weekly dosing of epoetin delta in previously naïve patients (assessed by haemoglobin at Week 24); 2) to demonstrate non-inferiority between once weekly and once every two weeks dosing in previously stable patients (assessed by average haemoglobin over Weeks 16–24). Among the secondary analyses will be assessments of haematocrit, number(%) of patients meeting predefined targets for haemoglobin and haematocrit levels, and comparisons of average dose. All patients will receive study medication for 24 weeks and dose will be adjusted according to a predefined algorithm to achieve and maintain haemoglobin ≥ 11 g/dL. All patients completing this trial are eligible to enter a 2-year follow-up study to enable monitoring of emergent adverse events, anti-erythropoietin antibody responses, maintenance of efficacy and changes in diabetic retinopathy status.</p> <p>Discussion</p> <p>To our knowledge, this trial is the first to randomize ESA-naïve patients to different dosing regimens of the same ESA. Data generated will help in guiding the most appropriate dosing frequency for epoetin delta, particularly in those patients new to epoetin delta therapy.</p> <p>Trial registration</p> <p><b>ClinicalTrials.gov: </b>NCT00450333</p

Heterozygous Yeast Deletion Collection Screens Reveal Essential Targets of Hsp90

Hsp90 is an essential eukaryotic chaperone with a role in folding specific “client” proteins such as kinases and hormone receptors. Previously performed homozygous diploid yeast deletion collection screens uncovered broad requirements for Hsp90 in cellular transport and cell cycle progression. These screens also revealed that the requisite cellular functions of Hsp90 change with growth temperature. We present here for the first time the results of heterozygous deletion collection screens conducted at the hypothermic stress temperature of 15°C. Extensive bioinformatic analyses were performed on the resulting data in combination with data from homozygous and heterozygous screens previously conducted at normal (30°C) and hyperthermic stress (37°C) growth temperatures. Our resulting meta-analysis uncovered extensive connections between Hsp90 and (1) general transcription, (2) ribosome biogenesis and (3) GTP binding proteins. Predictions from bioinformatic analyses were tested experimentally, supporting a role for Hsp90 in ribosome stability. Importantly, the integrated analysis of the 15°C heterozygous deletion pool screen with previously conducted 30°C and 37°C screens allows for essential genetic targets of Hsp90 to emerge. Altogether, these novel contributions enable a more complete picture of essential Hsp90 functions

Determinants of preventable readmissions in the United States: a systematic review

<p>Abstract</p> <p>Background</p> <p>Hospital readmissions are a leading topic of healthcare policy and practice reform because they are common, costly, and potentially avoidable events. Hospitals face the prospect of reduced or eliminated reimbursement for an increasing number of preventable readmissions under nationwide cost savings and quality improvement efforts. To meet the current changes and future expectations, organizations are looking for potential strategies to reduce readmissions. We undertook a systematic review of the literature to determine what factors are associated with preventable readmissions.</p> <p>Methods</p> <p>We conducted a review of the English language medicine, health, and health services research literature (2000 to 2009) for research studies dealing with unplanned, avoidable, preventable, or early readmissions. Each of these modifying terms was included in keyword searches of readmissions or rehospitalizations in Medline, ISI, CINAHL, The Cochrane Library, ProQuest Health Management, and PAIS International. Results were limited to US adult populations.</p> <p>Results</p> <p>The review included 37 studies with significant variation in index conditions, readmitting conditions, timeframe, and terminology. Studies of cardiovascular-related readmissions were most common, followed by all cause readmissions, other surgical procedures, and other specific-conditions. Patient-level indicators of general ill health or complexity were the commonly identified risk factors. While more than one study demonstrated preventable readmissions vary by hospital, identification of many specific organizational level characteristics was lacking.</p> <p>Conclusions</p> <p>The current literature on preventable readmissions in the US contains evidence from a variety of patient populations, geographical locations, healthcare settings, study designs, clinical and theoretical perspectives, and conditions. However, definitional variations, clear gaps, and methodological challenges limit translation of this literature into guidance for the operation and management of healthcare organizations. We recommend that those organizations that propose to reward reductions in preventable readmissions invest in additional research across multiple hospitals in order to fill this serious gap in knowledge of great potential value to payers, providers, and patients.</p

Meta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia

Several polymorphisms in the Disrupted-in-Schizophrenia-1 (DISC1) gene are reported to be associated with schizophrenia. However, to date, there has been little effort to evaluate the evidence for association systematically. We carried out an imputation-driven meta-analysis, the most comprehensive to date, using data collected from 10 candidate gene studies and three genome-wide association studies containing a total of 11 626 cases and 15 237 controls. We tested 1241 single-nucleotide polymorphisms in total, and estimated that our power to detect an effect from a variant with minor allele frequency >5% was 99% for an odds ratio of 1.5 and 51% for an odds ratio of 1.1. We find no evidence that common variants at the DISC1 locus are associated with schizophrenia

Copper-Triggered Aggregation of Ubiquitin

Neurodegenerative disorders share common features comprising aggregation of misfolded proteins, failure of the ubiquitin-proteasome system, and increased levels of metal ions in the brain. Protein aggregates within affected cells often contain ubiquitin, however no report has focused on the aggregation propensity of this protein. Recently it was shown that copper, differently from zinc, nickel, aluminum, or cadmium, compromises ubiquitin stability and binds to the N-terminus with 0.1 micromolar affinity. This paper addresses the role of copper upon ubiquitin aggregation. In water, incubation with Cu(II) leads to formation of spherical particles that can progress from dimers to larger conglomerates. These spherical oligomers are SDS-resistant and are destroyed upon Cu(II) chelation or reduction to Cu(I). In water/trifluoroethanol (80∶20, v/v), a mimic of the local decrease in dielectric constant experienced in proximity to a membrane surface, ubiquitin incubation with Cu(II) causes time-dependent changes in circular dichroism and Fourier-transform infrared spectra, indicative of increasing β-sheet content. Analysis by atomic force and transmission electron microscopy reveals, in the given order, formation of spherical particles consistent with the size of early oligomers detected by gel electrophoresis, clustering of these particles in straight and curved chains, formation of ring structures, growth of trigonal branches from the rings, coalescence of the trigonal branched structures in a network. Notably, none of these ubiquitin aggregates was positive to tests for amyloid and Cu(II) chelation or reduction produced aggregate disassembly. The early formed Cu(II)-stabilized spherical oligomers, when reconstituted in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes and in POPC planar bilayers, form annular and pore-like structures, respectively, which are common to several neurodegenerative disorders including Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and prion diseases, and have been proposed to be the primary toxic species. Susceptibility to aggregation of ubiquitin, as it emerges from the present study, may represent a potential risk factor for disease onset or progression while cells attempt to tag and process toxic substrates

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Early chronic kidney disease: diagnosis, management and models of care

Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt