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Introduction: Myosin IXB (MYO9B) is an unconventional myosin with RhoGAP activity and thus is a regulator of actin cytoskeletal organization. MYO9B was previously shown to be necessary for skeletal growth and health and to play a role in actin-based functions of both osteoblasts and osteoclasts. However, its role in responses to mechanical stimulation of bone cells has not yet been described. Therefore, experiments were undertaken to determine the role of MYO9B in bone cell responses to mechanical stress both in vitro and in vivo. Methods: MYO9B expression was knocked down in osteoblast and osteocyte cell lines using RNA interference and the resulting cells were subjected to mechanical stresses including cyclic tensile strain, fluid shear stress, and plating on different substrates (no substrate vs. monomeric or polymerized collagen type I). Osteocytic cells were also subjected to MYO9B regulation through Slit-Robo signaling. Further, wild-type or Myo9b -/- mice were subjected to a regimen of whole-body vibration (WBV) and changes in bone quality were assessed by micro-CT. Results: Unlike control cells, MYO9B-deficient osteoblastic cells subjected to uniaxial cyclic tensile strain were unable to orient their actin stress fibers perpendicular to the strain. Osteocytic cells in which MYO9B was knocked down exhibited elongated dendrites but were unable to respond normally to treatments that increase dendrite length such as fluid shear stress and Slit-Robo signaling. Osteocytic responses to mechanical stimuli were also found to be dependent on the polymerization state of collagen type I substrates. Wild-type mice responded to WBV with increased bone tissue mineral density values while Myo9b -/- mice responded with bone loss. Discussion: These results demonstrate that MYO9B plays a key role in mechanical stress-induced responses of bone cells in vitro and in vivo.

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The objective of this study was to determine the extent that nebulized glycosylated caffeic acid phenylether ester-4-O-alpha-D-glucopyranoside (G-CAPE) attenuates particulate-induced airway inflammation in healthy horses. Our hypothesis was that nebulization with G-CAPE would result in improved respiratory scores, higher arterial oxygen partial pressure, and less inflammatory airway infiltrates in horses with induced airway inflammation, compared with untreated controls. Five healthy adult horses were housed inside a climate controlled, closed barn on straw bedding and fed ad lib moldy grass hay for 16 days to induce airway inflammation. An experimental crossover study was performed in which animals were treated with 200 mg G-CAPE dissolved in 45 mL of 10% triethanolamine (G-CAPE group) or 45 mL of 10% triethanolamine (CONTROL group), and clinical respiratory scoring, arterial blood gases, and bronchoalveolar lavages (BALs) were collected at predetermined time points up to 24 h post nebulization. While the mean neutrophil percentage decreased in treated horses compared to controls (9.3 ± 2.0 and 16.9 ± 2.4, respectively) at 6 hours post treatment (t = 6 h), the difference did not achieve statistical significance (p = 0.1154). Blood gas analysis did not differ significantly between groups. There was a significant difference in the mean respiratory scores of G-CAPE-treated horses between baseline and at 1-h post treatment (from 3.2 ± 0.7 to 1.6 ± 0.7, p = 0.0013). This study demonstrates that a single nebulized dose of G-CAPE decreased clinical respiratory scores 1 h post administration and decreased BAL percentage of neutrophils 6 h post administration in horses with particulate induced airway inflammation. This compound shows promise as an anti-inflammatory and warrants further investigation.

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Photoimmunotherapy has attracted much attention recently for the treatment of metastatic tumors. The development of smart nanocomposites for imaging-guided therapies is needed to improve the efficacy of cancer treatment. Herein, a PEGylated nanocomposite was developed for photothermal-immunotherapy. In particular, this nanocomposite was formulated by hybridizing Fe3O4 nanoparticles (FNPs) with reduced-graphene oxide (rGO) through electrostatic interaction, modified by PEG-NH2 on the surface of FNPs/rGO. The FNPs/rGO-PEG nanocomposites are excellent agents for photothermal therapy (PTT) under irradiation by an 805 nm laser. This nanocomposite could promote the activity of the host antitumor immune response efficiently because of the reduction of tumor-associated macrophages by the incorporation of FNPs. In our experiments, we observed FNPs/rGO-PEG based PTT induced immunogenic cell death accompanied by the release of danger-associated molecular patterns. We also found that FNPs/rGO-PEG + laser irradiation of animal tumors could activate dendritic cells (DCs) in tumor draining lymph nodes. In vivo antitumor studies revealed that FNPs/rGO-PEG nanocomposites, when combined with laser irradiation, could result in desirable photothermal effects and destroy primary tumors. Moreover, intratumoral injection of FNPs/rGO-PEG nanocomposites into 4T1 orthotopic mouse breast tumors, in combination with near-infrared laser irradiation, significantly increased the median survival time of tumor-bearing animals. FNPs/rGO-PEG nanocomposites could also be used for magnetic resonance imaging, which may lead to a MRI-guided photothermal-immunotherapy for metastatic cancers. This study could lead to a cancer treatment strategy that combines PTT with immunotherapies using FNPs/rGO-PEG nanocomposites.

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Fibrotic diseases, such as Dupuytren's contracture (DC), involve excess scar tissue formation. The differentiation of fibroblasts into myofibroblasts is a significant mechanism in DC, as it generates tissue contraction in areas without wound openings, leading to the deposition of scar tissue, and eventually flexing one or more fingers in a restrictive fashion. Additionally, DC has a high recurrence rate. Previously, we showed that N-dihydrogalactochitosan (GC), an immunostimulant, inhibited myofibroblast differentiation in a DC fibroblast culture. Our goal of this study was to expand our previous study to include other DC and normal cell lines and other chitosan derivatives (GC and single-walled carbon nanotube-conjugated GC) to determine the specific mechanism of inhibition. Derivative-incorporated and vehicle control (water) anchored fibroblast-populated collagen matrices (aFPCM) were used to monitor compaction (anchored matrix height reduction) using microscopy and optical coherence tomography (OCT) for six days. Fibroblasts were unable to compact chitosan derivative aFPCM to the same extent as vehicle control aFPCM in repeated experiments. Similarly, chitosan derivative aFPCM contracted less than control aFPCM when released from anchorage. Proliferative myofibroblasts were identified by the presence of alpha smooth muscle actin via myofibroblast proliferative assay. In all tested conditions, a small percentage of myofibroblasts and proliferative cells were present. However, when aFPCM were treated with transforming growth factor-beta 1 (TGF-ß1), all tested samples demonstrated increased myofibroblasts, proliferation, compaction, and contraction. Although compaction and contraction were reduced, there was sufficient tension present in the chitosan derivative aFPCM to allow exogenous stimulation of the myofibroblast phenotype.

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Combined phototherapy and immunotherapy demonstrates strong potential in the treatment of metastatic cancers. An upconversion nanoparticle (UCNP) based antigen-capturing nanoplatform is designed to synergize phototherapies and immunotherapy. In particular, this nanoplatform is constructed via self-assembly of DSPE-PEG-maleimide and indocyanine green (ICG) onto UCNPs, followed by loading of the photosensitizer rose bengal (RB). ICG significantly enhances the RB-based photodynamic therapy efficiency of UCNP/ICG/RB-mal upon activation by a near-infrared (NIR) laser, simultaneously achieving selective photothermal therapy. Most importantly, tumor-derived protein antigens, arising from phototherapy-treated tumor cells, can be captured and retained in situ, due to the functionality of maleimide, which further enhance the tumor antigen uptake and presentation by antigen-presenting cells. The synergized photothermal, photodynamic, and immunological effects using light-activated UCNP/ICG/RB-mal induces a tumor-specific immune response. In the experiments, intratumoral administration of UCNP/ICG/RB-mal, followed by noninvasive irradiation with an NIR laser, destroys primary tumors and inhibits untreated distant tumors, using a poorly immunogenic, highly metastatic 4T1 mammary tumor model. With the simultaneous use of anti-CTLA-4, about 84% of the treated tumor-bearing mice achieve long-term survival and 34% of mice develop tumor-specific immunity. Overall, this antigen-capturing nanoplatform provides a promising approach for the treatment of metastatic cancers.

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As a result of their unique compositions and properties, nanomaterials have recently seen a tremendous increase in use for novel cancer therapies. By taking advantage of the optical absorption of near-infrared light, researchers have utilized nanostructures such as carbon nanotubes, gold nanorods, and graphene oxide sheets to enhance photothermal therapies and target the effect on the tumor tissue. However, new uses for nanomaterials in targeted cancer therapy are coming to light, and the efficacy of photothermal therapy has increased dramatically. In this work, we review some of the current applications of nanomaterials to enhance photothermal therapy, specifically as photothermal absorbers, drug delivery vehicles, photoimmunological agents, and theranostic tools.

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OBJECTIVES: The Addenbrooke's Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE-III cutoff scores for the detection of dementia, and explored its relationship with functional ability. METHODS: Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability. RESULTS: Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia. CONCLUSIONS: This study represents one of the largest and most clinically diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018, 24, 854-863).

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REVIEW QUESTION: What are parents' and guardians' experiences of barriers and facilitators in accessing autism spectrum disorder diagnostic services for their children?

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Background Little attention has been given to in-depth examination of what high-fidelity simulation is like for nursing students within the context of a pediatric emergency, such as a cardiopulmonary arrest. It is possible that such high-fidelity simulation could provoke in nursing students intense psychological reactions. Purpose The purpose of this study was to learn about baccalaureate nursing students' lived experience of high-fidelity simulation of pediatric cardiopulmonary arrest. Method Phenomenological methods were used. Twenty-four interviews were conducted with 12 students and were analyzed for themes. Results The essence of the experience is that it was eye-opening. The students found the simulation to be a surprisingly realistic nursing experience as reflected in their perceiving the manikin as a real patient, thinking that they were saving their patient's life, feeling like a real nurse, and feeling relief after mounting stress. It was a surprisingly valuable learning experience in that the students had an increased awareness of the art and science of nursing and increased understanding of the importance of teamwork and were feeling more prepared for clinical practice and wanting more simulation experiences. Conclusion Educators should capitalize on the benefits of high-fidelity simulation as a pedagogy, while endeavoring to provide psychologically safe learning.

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OBJECTIVES: The aim of this review was to identify and synthesize the best available evidence to address two questions: i) what is the experience of smoking during pregnancy for Indigenous women? and ii) what are the smoking cessation needs of Indigenous women who smoke during pregnancy? INTRODUCTION: Smoking during pregnancy not only affects pregnant women's general health but also causes such serious problems as pre-term delivery, low birth weight, and sudden infant death. Rates of smoking during pregnancy are particularly high among Indigenous women. Learning about Indigenous women's experiences of smoking during pregnancy and associated smoking cessation needs is important to providing informed health care to them. INCLUSION CRITERIA: The participants of interest were Indigenous women who smoked during a current or past pregnancy. The phenomena of interest were the experiences of smoking during pregnancy for Indigenous women and the smoking cessation needs of Indigenous women during pregnancy. The context was any community worldwide where pregnant Indigenous women live. Studies considered for this review were those in which qualitative data were gathered and analysed on the phenomena of interest, including mixed methods research. METHODS: A comprehensive search was conducted for published studies in academic databases (i.e. PubMed, CINAHL, PsycINFO, Embase, Sociological Abstracts, SocINDEX, and Web of Science), unpublished studies in sources of gray literature (i.e. ProQuest Dissertations and Theses, OAIster, LILACS, MedNar, Google, Google Scholar, OpenGrey and relevant websites), and any additional studies in reference lists. Language and date limiters were not applied. The searches included all studies globally and were carried out on October 31, 2016. Studies that met the inclusion criteria were assessed for methodological quality by two reviewers independently, using the criteria of the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. Descriptive details of each study accepted for this review were extracted in accordance with the elements of the JBI Data Extraction Form for Qualitative Research. The research findings that were relevant to the phenomena of interest and had participant voice were extracted from each included study and synthesized using the JBI meta-aggregative approach. The synthesized findings were assigned confidence scores in accordance with the JBI ConQual approach. RESULTS: Thirteen studies were included in this review following careful consideration of the methodological quality of each study. The studies yielded a total of 116 research findings, which were grouped into 19 categories and then aggregated to form five synthesized findings. Confidence in the findings was determined to be low to very low (see ConQual Summary of Findings). CONCLUSION: There is a small body of research evidence on Indigenous women's experiences of smoking during pregnancy and their smoking cessation needs. Confidence in the synthesized findings is constrained due to methodological limitations in many of the primary studies included in this review, along with mixed credibility of the research findings from across primary studies.

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The information inherent in cigarette ash in the form of trace-metal concentrations may be of use in a forensic context as it can indicate the brand from which the ash originated. This knowledge might help place suspects at crime scenes or determine how many people may have been present. To develop and test statistical models capable of classifying ash samples according to brand, commercial cigarettes procured in the U.S. and overseas were "smoked" using a peristaltic pump, mimicking the range of human smoking habits. Ash samples were digested in a mixture of nitric and hydrochloric acid applying microwave digestion and analyzed using inductively coupled plasma-mass spectrometry. Principal component analysis of the elemental data showed intrinsic differences between brands. Partial least squares-discriminant analysis demonstrated that brand classification yields good sensitivity and specificity for a number of models tested. Varying smoking parameters did not impact the classification of ash samples.

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Early timing of adrenarche, associated with relatively high levels of dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S) in children, has been linked with mental health problems, particularly anxiety. However, little is known about possible neurobiological mechanisms underlying this association. The pituitary gland is a key component of the hypothalamic-pituitary-adrenal (HPA) axis, the activation of which triggers the onset of adrenarche. The purpose of this study was to examine the extent to which pituitary gland volume mediated the relationship between levels of DHEA/DHEA-S relative to age (i.e., adrenarcheal timing) and symptoms of anxiety in 95 children (50 female, M age 9.50 years, SD 0.34 years). Relatively high DHEA and DHEA-S (DHEA/S) levels were found to be associated with larger pituitary gland volumes. There was no significant direct effect of relative DHEA/S levels on overall symptoms of anxiety. However, results supported an indirect link between relatively high DHEA/S levels and symptoms of social anxiety, mediated by pituitary gland volume. No sex differences were observed for any relationship. Our findings suggest that neurobiological mechanisms may be partly responsible for the link between relatively early adrenarche and anxiety symptoms in children. One possible mechanism for this finding is that an enlarged pituitary gland in children experiencing relatively advanced adrenarche might be associated with hyper-activity/reactivity of the HPA axis. Further research is needed to understand the role of stress in the link between adrenarcheal timing and HPA-axis function, especially in relation to the development of anxiety symptoms in children and adolescents.

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BACKGROUND: The debate within the multiple sclerosis (MS) community initiated by the chronic cerebrospinal venous insufficiency (CCSVI) hypothesis and the subsequent liberation procedure placed some people with MS at odds with health care professionals and researchers. OBJECTIVE: This study explored decision making regarding the controversial liberation procedure among people with MS. SUBJECTS AND METHODS: Fifteen people with MS (procedure, n=7; no procedure, n=8) participated in audiotaped semistructured interviews exploring their thoughts and experiences related to the liberation procedure. Data were transcribed and analyzed using an iterative, consensus-based, thematic content-analysis approach. RESULTS: Participants described an imbalance of motivating factors affirming the procedure compared to hesitating factors that provoked the participant to pause or reconsider when deciding to undergo the procedure. Collegial conversational relationships with trusted sources (eg, MS nurse, neurologist) and ability to critically analyze the CCSVI hypothesis were key hesitating factors. Fundraising, family enthusiasm, and the ease of navigation provided by medical tourism companies helped eliminate barriers to the procedure. CONCLUSION: Knowledge of factors that helped to popularize the liberation procedure in Canada may inform shared decision making concerning this and future controversies in MS.

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Despite the absence of scientific evidence demonstrating the efficacy of the "liberation procedure" in treating multiple sclerosis (MS), thousands of MS patients worldwide have undergone the procedure. The study objective was to explore the experience of liberation procedure decision making for individuals with MS. Fifteen adults in Newfoundland and Labrador, Canada, each participated in an in-depth interview. The data analysis revealed three groups of people: "waiters," "early embracers," and "late embracers." Using van Manen's hermeneutic phenomenological approach, we identified three themes each in the stories of the early and late embracers and four themes in the waiters' stories. A characteristic of the late embracers and waiters was skepticism, whereas desperation set the embracers apart from the waiters. With a deeper understanding of the experience, nurses can be more attuned to the perspectives of MS patients while helping them make informed decisions about undergoing the liberation procedure.

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It has long been suspected that the illicit distribution of cocaine in the United States has led to a large-scale contamination of the currency supply. To investigate the extent of contamination, 418 currency samples (4174 bills) were collected from 90 locations around the United States from 1993 to 2009. The extent of their cocaine contamination was quantitated via gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. The level of cocaine contamination was determined to average 2.34 ng/bill across all denominations ($1, $5, $10, $20, $50, and $100). Levels of cocaine contamination on currency submitted to the Federal Bureau of Investigation Laboratory in criminal cases over the 1993-2001 timeframe had significantly higher contamination than currency in general circulation. A mathematical model was developed based on the background survey that indicates the likelihood of drawing a bill in specific concentration ranges. For example, there is a 0.8349 likelihood that random bill will have contamination less than 20 ng.

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Photovoice is a method in which participants use photography to identify, express, and disseminate their experiences. We conducted photovoice projects with women living with HIV/AIDS (N=21) to explore opportunities and challenges associated with the method. Photovoice provided a means to achieve two key principles of ethical public health practice: It gives participants opportunities to define their health priorities, and facilitates participant empowerment. Ethical challenges that were encountered related to exposing, through photographs, one's identity as living with HIV/AIDS, illicit activities, and other people. We discuss lessons learned for future practice to maximize the ethical opportunities and manage the challenges associated with using photovoice as an HIV-related CBPR strategy.

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OBJECTIVES: To determine whether obesity correction equations for the Canadian general population, which are dependent on the prevalence of obesity, are appropriate for use in Atlantic Canada, which has the highest obesity rates in the country. Also, to compare the accuracy of the national equations to equations developed specifically for the Atlantic Canadian population. METHODS: The dataset consisted of Canadian Community Health Survey (CCHS) 2007-2008 data collected on 17,126 Atlantic Canadians and a subsample of adults, who provided measured height and weight (MHW) data. Atlantic correction equations were developed in the MHW subsample. Using separate multiple regression models for men and women, self-reported body mass index (BMI) was corrected by multiplying the self-reported estimate by its corresponding model coefficient and adding the model intercept. Paired t-tests were used to determine whether corrected mean BMI values were significantly more accurate (i.e., closer to measured data) than the equivalent means based on self-reported data. The analyses were repeated using the national equations. RESULTS: Both the Atlantic and the national equations yielded corrected obesity estimates that were significantly more accurate than those based on self-report. CONCLUSION: The results provide some evidence of the generalizability of the national equations to atypical regions of Canada.

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Metastatic melanoma is a skin cancer with poor prognosis. In situ photoimmunotherapy (ISPI) is a promising modality for the treatment of metastatic melanoma that combines local, selective photothermal therapy with immunological stimulation. A preliminary clinical study was conducted to evaluate the safety and therapeutic effects of ISPI for late-stage melanoma patients using imiquimod as the immune modifier. Eleven patients received ISPI in one or multiple 6-week treatment cycles applied to a 200-cm2 treatment site, which usually contained multiple cutaneous metastases. ISPI consisted of three main components applied directly to the cutaneous metastases: 1) local application of topical imiquimod; 2) injection of indocyanine green (ICG); and 3) an 805 nm laser for local irradiation. All patients completed at least one cycle of treatment. The most common adverse effects were rash and pruritus at the treatment sites. No grade 4 toxicity was observed. Complete response was observed in six patients. All lesions in the treatment area of the patients responded to ISPI, eight of which achieved complete local response (CLR). CLR was observed in the non-treatment site (regional) lesions in four patients. Five patients were still alive at the time of last follow-up. The probability of 12-month overall survival was 70%. This study demonstrates that ISPI with imiquimod is safe and well tolerated. The patient response rate is promising. ISPI can be easily applied on an outpatient basis and can be combined with other modalities to improve the therapeutic response of metastatic melanoma.

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