Home care clients: a research protocol for studying their pathways.

BACKGROUND: Enhancing non-clinical home care supports and services for older adults to live well is a strategic priority in developed countries, including Canada. Underpinning these supports and services are structures of care that are reflected in home care policies, programs and practices within jurisdictions. These approaches to care exist at multiple levels and inform interactions, perceptions, and care assessment, planning and provision, ultimately shaping the supports that are delivered. Jurisdictional differences in approaches to care mean that pathways through home care systems may differ, depending on where one lives. The goal of this study is to understand how approaches to care shape the pathways of older adult home care clients with chronic and long term conditions in two Canadian health jurisdictions. METHODS: This longitudinal mixed-methods study has three interrelated research streams informed by aspects of the socio-ecological framework. We will examine client pathways using a retrospective analysis of home care assessment data (Resident Assessment Instrument- Home Care) in two health authorities (Client/Service Data Stream). We will analyze interview data from older adult home care clients and a cluster of each client's family or friend caregiver(s), home support worker(s), care/case coordinator(s) and potentially other professionals at up to three points over 18 months using a prospective qualitative comparative case study design (Constellation Data Stream). We will review home care policies relevant to both health authorities and interview key informants regarding the creation and implementation of policies (Policy Stream). Our study will apply an integrated knowledge translation (iKT) approach that engages knowledge users in research design, analysis and interpretation to facilitate relevancy of results. DISCUSSION: Applying a mixed-method research design to understand approaches to care within and between two jurisdictions will contribute to the evidence base on older adult home care client pathways. Study results will identify how potential differences are experienced by clients and their families. An understanding of the policies will help to contextualize these findings. The iKT model will ensure that findings are useful for strategic planning and decision-making, and supporting changes in care practice.

Domestic violence and mental health in older adults.

Domestic violence affects every age group and is present throughout the life span, but, while the mental health impact of domestic violence is clearly established in working age adults, less is known about the nature and impact of domestic violence among older adults. This review, therefore, aimed to synthesize findings on the prevalence, nature, and impact of domestic violence among older adults, and its identification and management. Electronic searches were conducted of Medline, PsycINFO, Cinahl, and Embase to identify studies reporting on the mental health and domestic violence in older adults. Findings suggested that, although prevalence figures are variable, the likely lifetime prevalence for women over the age of 65 is between 20-30%. Physical abuse is suggested to decrease with age, but rates of emotional abuse appear to be stable over the lifespan. Among older adults, domestic violence is strongly associated with physical and mental health problems, and the scarce research comparing the impact of domestic violence across the age cohorts suggests that the physical health of older victims may be more severely affected than younger victims. In contrast, there is evidence that older victims may experience less psychological distress in response to domestic violence than younger victims. Internationally, evidence on the management of domestic violence in older adults is sparse. Findings suggest, however, that identification of domestic violence is poor among older adults, and there are very limited options for onwards referral and support.

A systematic review of the prevalence and odds of domestic abuse victimization among people with dementia.

Little is known about the prevalence of domestic abuse in later life or after the onset of dementia. Given the expanding population of dementia sufferers, it is imperative to identify the degree to which domestic abuse occurs within this population. The aim of this study was to establish the prevalence (lifetime and past year), odds, and trajectory of domestic abuse victimization among people with dementia. Systematic searches of 20 electronic databases were performed from inception to June 2016, using a pre-defined search strategy for English language articles containing data on the prevalence and/or odds of adult lifetime or past year domestic abuse among people with dementia. Six studies met the inclusion criteria. Among patients with dementia, the past year median prevalence of physical and psychological domestic abuse victimization is 11% and 19%, respectively. Findings from cross-sectional studies show an increased odds of domestic abuse among people with dementia vs those without. Trajectory information indicated that domestic abuse was more prevalent in relationships with a pre-morbid history of abuse. The lack of research into this area is highlighted by the small number of includable studies. There is a need for further research into the impact of dementia on domestic abuse.

A service evaluation of measuring fluid responsiveness in acutely unwell hypotensive patients outside of critical care.

INTRODUCTION: Early recognition and prompt, appropriate management may reduce mortality in patients with sepsis. The Surviving Sepsis Campaign's guidelines suggest the use of dynamic measurements to guide fluid resuscitation in sepsis; although these methods are rarely employed to monitor cardiac output in response to fluid administration outside intensive care units. This service evaluation investigated the introduction of a nurse led protocolised goal-directed fluid management using a non-invasive cardiac output monitor to the standard assessment of hypotensive ward patients. METHODS: We introduced the use of a goal-directed fluid management protocol into our critical care outreach teams' standard clinical assessment. Forty-nine sequential patients before and thirty-nine after its introduction were included in the assessment. RESULTS: Patients in the post-intervention cohort received less fluid in the 6 h following outreach assessment (750mls vs 1200mls). There were no differences in clinical background or rates of renal replacement therapy, but rates of invasive and non-invasive ventilation were reduced (0% vs 31%). Although the groups were similar, the post-intervention patients had lower recorded blood pressures. CONCLUSION: IV fluid therapy in the patient with hypotension complicating sepsis can be challenging. Excessive IV fluid administration is commonplace and associated with harm, and the use of advanced non-invasive haemodynamic monitoring by trained nurses can provide objective evaluation of individualised response to treatment. Avoiding excessive IV fluid and earlier institution of appropriate vasopressor therapy may improve patient outcomes. IMPLICATIONS FOR CLINICAL PRACTICE: Adoption of dynamic measures of cardiac output outside of critical care by trained critical care nurses is feasible and may translate into improved patient outcomes. In hospitals with a nurse-led critical care outreach service, consideration should be given to such an approach.

Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer's subjects?

BACKGROUND: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects. METHODS: In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function. RESULTS: In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs. CONCLUSIONS: In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

AGO2 Mediates MYC mRNA Stability in Hepatocellular Carcinoma.

Deregulated RNA-binding proteins (RBP), such as Argonaute 2 (AGO2), mediate tumor-promoting transcriptomic changes during carcinogenesis, including hepatocellular carcinoma (HCC). While AGO2 is well characterized as a member of the RNA-induced silencing complex (RISC), which represses gene expression through miRNAs, its role as a bona fide RBP remains unclear. In this study, we investigated AGO2's role as an RBP that regulates the MYC transcript to promote HCC. Using mRNA and miRNA arrays from patients with HCC, we demonstrate that HCCs with elevated AGO2 levels are more likely to have the mRNA transcriptome deregulated and are associated with poor survival. Moreover, AGO2 overexpression stabilizes the MYC transcript independent of miRNAs. These observations provide a novel mechanism of gene regulation by AGO2 and provide further insights into the potential functions of AGO2 as an RBP in addition to RISC. IMPLICATIONS: Authors demonstrate that the RBP Argonaute 2 stabilizes the MYC transcript to promote HCC.

Correction to: Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

An amendment to this paper has been published and can be accessed via the original article.

Epigenetic silencing of the endothelin-B receptor gene in non-small cell lung cancer.

Endothelin-1 is overexpressed in several tumor types. Activation of the endothelin-A (ETA) receptor may promote cell growth, angiogenesis and invasion, and inhibits the apoptotic process, while activation of the endothelin-B (ETB) receptor may induce cell death by apoptosis and inhibit tumor progression. Hypermethylation and subsequent silencing of the ETB receptor gene promoter has been reported in some cancer types. As the endothelin pathway is subject to research for pharmacological cancer treatment, we investigated the extent of epigenetic deregulation of the ETB receptor gene in non-small cell lung cancer (NSCLC). We scanned 64 NSCLC paired tumor/normal surgical specimens for the ETB receptor promoter for methylation by developing four pyrosequencing assays that covered 24 CpGs. The ETB receptor promoter was significantly hypermethylated in 31 (48%) of tumor samples, presenting considerably higher methylation in 22/24 CpG sites compared with the normal counterpart tissues. ETB receptor mRNA levels were reduced in all lung tumors compared with normal adjacent lung tissue, indicating the potentially important involvement of this gene in lung cancer development. Furthermore, tumor samples with ETB receptor gene methylation tended to have lower receptor mRNA levels compared with unmethylated tumor specimens, suggesting a primary epigenetic role in ETB receptor silencing. Our results point to a significant involvement of ETB receptor epigenetic deregulation in the pathogenesis of lung cancer making the gene a promising candidate biomarker for response to regimens modulating the endothelin axis.

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study).

BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. DISCUSSION: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01843075 . Registration 30 April 2013.

Comparison of long-term numerical and experimental total knee replacement wear during simulated gait loading.

Pre-clinical experimental wear testing of total knee replacement (TKR) components is an invaluable tool for evaluating new implant designs and materials. However, wear testing can be a lengthy and expensive process, and hence parametric studies evaluating the effects of geometric, loading, or alignment perturbations may at times be cost-prohibitive. The objectives of this study were to develop an adaptive FE method capable of simulating wear of a polyethylene tibial insert and to compare predicted kinematics, weight loss due to wear, and wear depth contours to results from a force-controlled experimental knee simulator. Finite element-based computational wear predictions were performed to 5 million gait cycles using both force- and displacement-controlled inputs. The displacement-controlled inputs, by accurately matching the experimental tibiofemoral motion, provided an evaluation of the simple wear theory. The force-controlled inputs provided an evaluation of the overall numerical method by simultaneously predicting both kinematics and wear. Analysis of the predicted wear convergence behavior indicated that 10 iterations, each representing 500,000 gait cycles, were required to achieve numerical accuracy. Using a wear factor estimated from the literature, the predicted kinematics, polyethylene wear contours, and weight loss were in reasonable agreement with the experimental data, particularly for the stance phase of gait. Although further development of the simplified wear theory is important, the initial predictions are encouraging for future use in design phase implant evaluation. In contrast to the experimental testing which occurred over approximately 2 months, computational wear predictions required only 2h.

Key issues in human resource planning for home support workers in Canada.

OBJECTIVE: This paper is a synthesis of research on recruitment and retention challenges for home support workers (HSWs) in Canada. PARTICIPANTS: Home support workers (HSWs) provide needed support with personal care and daily activities to older persons living in the community. METHODS: Literature (peer reviewed, government, and non-government documents) published in the past decade was collected from systematic data base searches between January and September 2009, and yielded over 100 references relevant to home care human resources for older Canadians. RESULTS: Four key human resource issues affecting HSWs were identified: compensation, education and training, quality assurance, and working conditions. To increase the workforce and retain skilled employees, employers can tailor their marketing strategies to specific groups, make improvements in work environment, and learn about what workers value and what attracts them to home support work. CONCLUSIONS: Understanding these HR issues for HSWs will improve recruitment and retention strategies for this workforce by helping agencies to target their limited resources. Given the projected increase in demand for these workers, preparations need to begin now and consider long-term strategies involving multiple policy areas, such as health and social care, employment, education, and immigration.

A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples.

BACKGROUND: We have compared mutation analysis by DNA sequencing and Amplification Refractory Mutation System™ (ARMS™) for their ability to detect mutations in clinical biopsy specimens. METHODS: We have evaluated five real-time ARMS assays: BRAF 1799T>A, [this includes V600E and V600K] and NRAS 182A>G [Q61R] and 181C>A [Q61K] in melanoma, EGFR 2573T>G [L858R], 2235-2249del15 [E746-A750del] in non-small-cell lung cancer, and compared the results to DNA sequencing of the mutation 'hot-spots' in these genes in formalin-fixed paraffin-embedded tumour (FF-PET) DNA. RESULTS: The ARMS assays maximised the number of samples that could be analysed when both the quality and quantity of DNA was low, and improved both the sensitivity and speed of analysis compared with sequencing. ARMS was more robust with fewer reaction failures compared with sequencing and was more sensitive as it was able to detect functional mutations that were not detected by DNA sequencing. DNA sequencing was able to detect a small number of lower frequency recurrent mutations across the exons screened that were not interrogated using the specific ARMS assays in these studies. CONCLUSIONS: ARMS was more sensitive and robust at detecting defined somatic mutations than DNA sequencing on clinical samples where the predominant sample type was FF-PET.

DNA methylation in circulating tumour DNA as a biomarker for cancer.

Free circulating DNA, which is thought to be derived from the primary tumour, can be detected in the blood of patients with cancer. Detection of genetic and epigenetic alteration in this tumour DNA offers a potential source of development of prognostic and predictive biomarkers for cancer. One such change is DNA methylation of the promotor region of tumour suppressor genes. This causes down regulation of tumour suppressor gene expression, a frequent event in carcinogenesis. Hypermethylation of the promotor region of a number of genes has been detected in many tumour types and more recently these changes have been detected in circulating tumour DNA. This review will summarise the literature detailing DNA methylation in circulating tumour DNA and discuss some of the current controversies and technical challenges facing its use as a potential biomarker for cancer.

Isolation and extraction of circulating tumor DNA from patients with small cell lung cancer.

There is no consensus on the optimal protocol for isolation of circulating tumor DNA. We report our comparison of several extraction methods and variables that may affect yield, quality, and contamination of tumor DNA. DNA was extracted from the plasma and serum of five healthy volunteers by means of four different commercially available kits and DNA yield was quantified by real-time PCR. DNA was extracted using the optimum kit from the plasma and serum of an additional 10 healthy volunteers and 10 patients with small cell lung cancer (SCLC) to compare yield and DNA fragment size in plasma versus serum and in those with SCLC versus controls. Time to sample processing was also examined. We found that DNA yield was greatest using the QIAamp Viral Spin Kit. Delayed time to processing led to increased DNA concentrations in serum, but not plasma. The plasma DNA concentration in SCLC patients was significantly higher than in healthy volunteers (24.5 ng/mL versus 5.1 ng/mL, P= 0.002). In contrast, there was no significant difference in serum DNA concentrations between controls and patients that may be explained by the wide variability and range of DNA concentrations in serum. A significantly higher proportion of longer fragments (272 bp/60 bp) was observed in the plasma DNA extracted from patients with SCLC than in healthy controls (13% versus 8%, P= 0.04). There was absence of DNA fragments of 512 bp in healthy control plasma, but faint bands were observed in serum, which is thought to be due to cellular contamination. We conclude that plasma is a more reliable source of tumor DNA then serum and have optimized a robust procedure for plasma tumor DNA isolation that can be applied to translational research studies.

Wear in the prosthetic shoulder: association with design parameters.

Total replacement of the glenohumeral joint provides an effective means for treating a variety of pathologies of the shoulder. However, several studies indicate that the procedure has not yet been entirely optimized. Loosening of the glenoid component remains the most likely cause of implant failure, and generally this is believed to stem from either mechanical failure of the fixation in response to high tensile stresses, or through osteolysis of the surrounding bone stock in response to particulate wear debris. Many computational studies have considered the potential for the former, although only few have attempted to tackle the latter. Using finite-element analysis an investigation, taking into account contact pressures as well as glenohumeral kinematics, has thus been conducted, to assess the potential for polyethylene wear within the artificial shoulder. The relationships between three different aspects of glenohumeral design and the potential for wear have been considered, these being conformity, polyethylene thickness, and fixation type. The results of the current study indicate that the use of conforming designs are likely to produce slightly elevated amounts of wear debris particles when compared with less conforming joints, but that the latter would be more likely to cause material failure of the polyethylene. The volume of wear debris predicted was highly influenced by the rate of loading, however qualitatively it was found that wear predictions were not influenced by the use of different polyethylene thicknesses nor fixation type while the depth of wearing was. With the thinnest polyethylene designs (2 mm) the maximum depth of the wear scar was seen to be upwards of 20% higher with a metal-backed fixation as opposed to a cemented design. In all-polyethylene designs peak polymethyl methacrylate tensile stresses were seen to reduce with increasing polyethylene thickness. Irrespective of the rate of loading of the shoulder joint, the current study indicates that it is possible to optimize glenoid component design against abrasive wear through the use of high conformity designs, possessing a polyethylene thickness of at least 6 mm.

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

PURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.