Designing and Psychometric Assessment of the Questionnaire for Artificial Airway Patients’ Satisfaction with Nurse's Non-verbal Communication during Nursing Cares

Background & Aim: Verbal communication disorder is one of the most important problems of mechanically ventilated patients which can lead to anxiety and decrease satisfaction. The purpose of this study is designing and psychometric assessment of the questionnaire for artificial airway patients’ satisfaction with nurses nonverbal communication during nursing cares. Materials & Methods: This is a methodological study which was performed using Waltz 2010 method in 4 steps, namely conceptual model definition, determination of goals and tools design, compiling initial plan, and determining reliability and validity in 2016. The study population includes all patients with artificial airway in 3 hospitals under the supervision of Shiraz University of Medical Sciences. Totally, 240 patients were selected for the study, using convenience sampling. The questionnaire validity was evaluated using face, construct, and content validities. Pearson correlation coefficient and Cronbach's alpha were used to evaluate the external and internal reliabilities. SPSS Software V.19 was used for data analysis. Results: The initial version of questionnaire was designed with 27 items. After face and content validation process, the second version was designed in 24 items. The maximum score for all items was 1.5. The values of CVI and CVR were obtained at 0.89 and 0.88, respectively. For construct validity, the items were reduced to 12, based on explanatory factor analysis. The final questionnaire was obtained in 3 satisfaction dimensions namely providing physiologic, social, and emotional-psychological needs with predictive power of 47.706. The Cronbach's alpha value was calculated at 0.67. Pearson correlation coefficient was calculated at 0.67, which suggests the validity and reliability of the questionnaire. Conclusion: Considering the limitation of data availability for evaluating the satisfaction of artificial airway patients with nursing communication, the questionnaire can be an efficient tool for detecting the patient-nurse communicational challenges and patients’ needs in different areas as well as improving care services quality

Effects of edge-stiffened web openings on the behaviour of cold-formed steel channel sections under compression

The use of cold-formed steel (CFS) channel sections are becoming popular as the load-carrying members in building structures, and such channel sections often include web openings for the ease of installation of services. Traditional web openings are normally punched, and are unstiffened which can restrict the size and spacing of web openings. Recently, a new generation of CFS channel sections with edge-stiffened web openings has been developed, and is widely used in New Zealand. However, no experimental investigation has been reported in the literature for such channel sections under compression. In this paper, a total of 75 results comprising 26 axial compression tests and 49 finite element analysis results are reported on the compression resistance of CFS channel sections with both edge-stiffened and unstiffened web openings. For comparison, channel sections without web openings were also tested. For all specimens, initial imperfections were measured using a laser scanner. A nonlinear elasto-plastic finite element model was also developed, and the results showed good agreement with the test results. A parametric study was conducted using the validated finite element model to investigate the effect of opening spacing and column length on compression resistance of channel sections. It is shown that for the case of a channel section having seven edge-stiffened web openings, the compression resistance increased by as much as 22%, compared to a plain channel section. For comparison, the same section having unstiffened web openings had a 20% reduction in compression resistance, compared to a plain channel section

Finite-Element Analysis of the Eaves Joint of Cold-Formed Steel Portal Frames having Single Channel-Sections

A finite element model is described for the eaves joint of a cold-formed steel portal frame that comprises a single channel section for the column and rafters eaves connections. The members are connected to the brackets through both screws and bolts. Such a joint detail is commonly used in practice in New Zealand and Australia, where the function of the screws is to prevent slip of the joint during frame erection since the bolt holes are detailed for nominal clearance. The results of the finite element model are compared against two experimental test results. In both, the critical mode of failure is a combination of torsion of the eaves joint and shear failure of screws. It is found that at ultimate load, the bolts have not engaged i.e. they have slipped. It is shown that the stiffness of the joints can be accurately predicted from the equations of bolt and screw stiffness of Zaharia and Dubina (2000). It is also shown that the finite element model can be used to determine both an upper and lower bound to the failure load

Interactome network analysis identifies multiple caspase-6 interactors involved in the pathogenesis of HD

Caspase-6 (CASP6) has emerged as an important player in Huntington disease (HD), Alzheimer disease (AD) and cerebral ischemia, where it is activated early in the disease process. CASP6 also plays a key role in axonal degeneration, further underscoring the importance of this protease in neurodegenerative pathways. As a protein's function is modulated by its protein-protein interactions we performed a high throughput yeast-2-hybrid (Y2H) screen against ∼17,000 human proteins to gain further insight into the function of CASP6. We identified a high confidence list of 87 potential CASP6 interactors. From this list, 61% are predicted to contain a CASP6 recognition site. Of nine candidate substrates assessed, six are cleaved by CASP6. Proteins that did not contain a predicted CASP6 recognition site were assessed using a LUMIER assay approach and 51% were further validated as interactors by this method. Of note, 54% of the high-confidence interactors identified show alterations in human HD brain at the mRNA level, and there is a significant enrichment for previously validated huntingtin (HTT) interactors. One protein of interest, STK3, a proapoptotic kinase, was validated biochemically to be a CASP6 substrate. Furthermore, our results demonstrate that in striatal cells expressing mutant huntingtin (mHTT) an increase in full length and fragment levels of STK3 are observed. We further show that caspase-3 is not essential for the endogenous cleavage of STK3. Characterization of the interaction network provides important new information regarding key pathways of interactors of CASP6 and highlights potential novel therapeutic targets for HD, AD and cerebral ischemia

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Astrocyte function intertwines with the extracellular matrix, whose glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities are found in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We generated human induced pluripotent stem cell-derived FXS and control astrocytes and we found that several pathways associated with urokinase plasminogen activator (uPA) that modulates degradation of extracellular matrix were activated in FXS astrocytes compared with controls. Expression of uPA was increased in FXS astrocytes and levels of uPA were also increased in conditioned medium collected from FXS astrocyte cultures. Levels of uPA correlated inversely with intracellular Ca2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB, indicating effects of uPA on neuronal plasticity. FXS-specific changes of gene expression during neuronal differentiation preceding astrogenesis likely contributed to altered properties of FXS astrocytes. Our results identified uPA as an important regulator of astrocyte function and demonstrated that increased uPA in human FXS astrocytes modulated astrocytic responses and neuronal plasticity.Peer reviewe

Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

SummaryN-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative disease. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2Q150/Q150, 18-month HdhQ92/Q92 and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trial

AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease.

Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. To date, there is no treatment to halt or reverse the course of HD. Lowering of either total or only the mutant HTT expression is expected to have therapeutic benefit. This can be achieved by engineered micro (mi)RNAs targeting HTT transcripts and delivered by an adeno-associated viral (AAV) vector. We have previously showed a miHTT construct to induce total HTT knock-down in Hu128/21 HD mice, while miSNP50T and miSNP67T constructs induced allele-selective HTT knock-down in vitro. In the current preclinical study, the mechanistic efficacy and gene specificity of these selected constructs delivered by an AAV serotype 5 (AAV5) vector was addressed using an acute HD rat model. Our data demonstrated suppression of mutant HTT messenger RNA, which almost completely prevented mutant HTT aggregate formation, and ultimately resulted in suppression of DARPP-32-associated neuronal dysfunction. The AAV5-miHTT construct was found to be the most efficient, although AAV5-miSNP50T demonstrated the anticipated mutant HTT allele selectivity and no passenger strand expression. Ultimately, AAV5-delivered-miRNA-mediated HTT lowering did not cause activation of microglia or astrocytes suggesting no immune response to the AAV5 vector or therapeutic precursor sequences. These preclinical results suggest that using gene therapy to knock-down HTT may provide important therapeutic benefit for HD patients and raised no safety concerns, which supports our ongoing efforts for the development of an RNA interference-based gene therapy product for HD