Psychometric properties of the Norwegian version of the Safety Attitudes Questionnaire (SAQ), Generic version (Short Form 2006)

<p>Abstract</p> <p>Background</p> <p>How to protect patients from harm is a question of universal interest. Measuring and improving safety culture in care giving units is an important strategy for promoting a safe environment for patients. The Safety Attitudes Questionnaire (SAQ) is the only instrument that measures safety culture in a way which correlates with patient outcome. We have translated the SAQ to Norwegian and validated the translated version. The psychometric properties of the translated questionnaire are presented in this article.</p> <p>Methods</p> <p>The questionnaire was translated with the back translation technique and tested in 47 clinical units in a Norwegian university hospital. SAQ's (the Generic version (Short Form 2006) the version with the two sets of questions on perceptions of management: on unit management and on hospital management) were distributed to 1911 frontline staff. 762 were distributed during unit meetings and 1149 through the postal system. Cronbach alphas, item-to-own correlations, and test-retest correlations were calculated, and response distribution analysis and confirmatory factor analysis were performed, as well as early validity tests.</p> <p>Results</p> <p>1306 staff members completed and returned the questionnaire: a response rate of 68%. Questionnaire acceptability was good. The reliability measures were acceptable. The factor structure of the responses was tested by confirmatory factor analysis. 36 items were ascribed to seven underlying factors: Teamwork Climate, Safety Climate, Stress Recognition, Perceptions of Hospital Management, Perceptions of Unit Management, Working conditions, and Job satisfaction. Goodness-of-Fit Indices showed reasonable, but not indisputable, model fit. External validity indicators – recognizability of results, correlations with "trigger tool"-identified adverse events, with patient satisfaction with hospitalization, patient reports of possible maltreatment, and patient evaluation of organization of hospital work – provided preliminary validation.</p> <p>Conclusion</p> <p>Based on the data from Akershus University Hospital, we conclude that the Norwegian translation of the SAQ showed satisfactory internal psychometric properties. With data from one hospital only, we cannot draw strong conclusions on its external validity. Further validation studies linking the SAQ-scores to patient outcome data should be performed.</p

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were funded through a Medical Research Council programme leader grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and HES were funded by the Eli Lilly Company. JMB received funding through a Lilly Research Award Program (LRAP) grant (Eli Lilly). RP received funding from the Marie Curie grant “Extrabrain” (European Commission). AC is a senior principal research fellow and PMS a principal research fellow of the National Health and Medical Research Council of Australia. Tissue samples were from Randy Woltjer at the Oregon Alzheimer’s Disease Center. The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017

High effectiveness of self-help programs after drug addiction therapy

BACKGROUND: The self-help groups Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) are very well established. AA and NA employ a 12-step program and are found in most large cities around the world. Although many have argued that these organizations are valuable, substantial scepticism remains as to whether they are actually effective. Few treatment facilities give clear recommendations to facilitate participation, and the use of these groups has been disputed. The purpose of this study was to examine whether the use of self-help groups after addiction treatment is associated with higher rates of abstinence. METHODS: One hundred and fourteen patients, 59 with alcohol dependency and 55 with multiple drug dependency, who started in self-help groups after addiction treatment, were examined two years later using a questionnaire. Return rate was 66%. Six (5%) of the patients were dead. RESULTS: Intention-to-treat-analysis showed that 38% still participated in self-help programs two years after treatment. Among the regular participants, 81% had been abstinent over the previous 6 months, compared with only 26% of the non-participants. Logistic regression analysis showed OR = 12.6, 95% CI (4.1–38.3), p < 0.001, for participation and abstinence. CONCLUSION: The study has several methodological problems; in particular, correlation does not necessarily indicate causality. These problems are discussed and we conclude that the probability of a positive effect is sufficient to recommend participation in self-help groups as a supplement to drug addiction treatment. PREVIOUS PUBLICATION: This article is based on a study originally published in Norwegian: Kristensen O, Vederhus JK: Self-help programs in drug addiction therapy. Tidsskr Nor Laegeforen 2005, 125:2798–2801

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class

The effects of socioeconomic status, accessibility to services and patient type on hospital use in Western Australia: a retrospective cohort study of patients with homogenous health status

BACKGROUND: This study aimed to investigate groups of patients with a relatively homogenous health status to evaluate the degree to which use of the Australian hospital system is affected by socio-economic status, locational accessibility to services and patient payment classification. METHOD: Records of all deaths occurring in Western Australia from 1997 to 2000 inclusive were extracted from the WA mortality register and linked to records from the hospital morbidity data system (HMDS) via the WA Data Linkage System. Adjusted incidence rate ratios of hospitalisation in the last, second and third years prior to death were modelled separately for five underlying causes of death. RESULTS: The independent effects of socioeconomic status on hospital utilisation differed markedly across cause of death. Locational accessibility was generally not an independent predictor of utilisation except in those dying from ischaemic heart disease and lung cancer. Private patient status did not globally affect utilisation across all causes of death, but was associated with significantly decreased utilisation three years prior to death for those who died of colorectal, lung or breast cancer, and increased utilisation in the last year of life in those who died of colorectal cancer or cerebrovascular disease. CONCLUSION: It appears that the Australian hospital system may not be equitable since equal need did not equate to equal utilisation. Further it would appear that horizontal equity, as measured by equal utilisation for equal need, varies by disease. This implies that a 'one-size-fits-all' approach to further improvements in equity may be over simplistic. Thus initiatives beyond Medicare should be devised and evaluated in relation to specific areas of service provision

Genome-wide profiling of G protein-coupled receptors in cerebellar granule neurons using high-throughput, real-time PCR

<p>Abstract</p> <p>Background</p> <p>G protein-coupled receptors (GPCRs) are major players in cell communication, regulate a whole range of physiological functions during development and throughout adult life, are affected in numerous pathological situations, and constitute so far the largest class of drugable targets for human diseases. The corresponding genes are usually expressed at low levels, making accurate, genome-wide quantification of their expression levels a challenging task using microarrays.</p> <p>Results</p> <p>We first draw an inventory of all endo-GPCRs encoded in the murine genome. To profile GPCRs genome-wide accurately, sensitively, comprehensively, and cost-effectively, we designed and validated a collection of primers that we used in quantitative RT-PCR experiments. We experimentally validated a statistical approach to analyze genome-wide, real-time PCR data. To illustrate the usefulness of this approach, we determined the repertoire of GPCRs expressed in cerebellar granule neurons and neuroblasts during postnatal development.</p> <p>Conclusions</p> <p>We identified tens of GPCRs that were not detected previously in this cell type; these GPCRs represent novel candidate players in the development and survival of cerebellar granule neurons. The sequences of primers used in this study are freely available to those interested in quantifying GPCR expression comprehensively.</p

Evaluation of Wuchereria bancrofti GST as a Vaccine Candidate for Lymphatic Filariasis

Lymphatic parasites survive for years in a complex immune environment by adopting various strategies of immune modulation, which includes counteracting the oxidative free radical damage caused by the host. We now know that the filarial parasites secrete antioxidant enzymes. Among these, the glutathione-S-transferases (GSTs) have the potent ability to effectively neutralize cytotoxic products arising from reactive oxygen species (ROS) that attack cell membranes. Thus, GSTs have the potential to protect the parasite against host oxidative stress. GSTs of several helminthes, including schistosomes, fasciola and the filarial parasite Seteria cervi, are also involved in inducing protective immunity in the host. The schistosome 28 kDa GST has been successfully developed into a vaccine and is currently in Phase II clinical trials. Thus, GST appears to be a potential target for vaccine development. Therefore, in the present study, we cloned W. bancrofti GST, and expressed and purified the recombinant protein. Immunization and challenge experiments showed that 61% of protection could be achieved against B. malayi infections in a jird model. In vitro studies confirm that the anti-WbGST antibodies participate in the killing of B. malayi L3 through an ADCC mechanism and enzymatic activity of WbGST appears to be critical for this larvicidal function

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

<p>Abstract</p> <p>Background</p> <p>Calcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central to regions in the brainstem with Aδ- and C-fibers; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that processes nociceptive information from the trigeminovascular system, such as the spinal trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level, using a set of newly well characterized antibodies. In addition, double-stainings with CGRP and myelin basic protein (MBP, myelin), synaptophysin (synaptic vesicles) or IB4 (C-fibers in general) were performed.</p> <p>Results</p> <p>In the STN, the highest density of CGRP immunoreactive fibers were found in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP was expressed in fibers of laminae I and II. The CGRP staining was similar in rat, except for CGRP positive neurons that were found close to the central canal. In C1, the receptor components were detected in laminae I and II, however these fibers were distinct from fibers expressing CGRP as verified by confocal microscopy.</p> <p>Conclusions</p> <p>This study demonstrates the detailed expression of CGRP and its receptor components within STN in the brainstem and in the spinal cord at C1-level, and shows the possibility of CGRP acting postjunctionally in these areas putatively involved in primary headaches.</p