Statistical analyses were carried out using MedCalc software 11.5.1.0 (MedCalc Software, Mariakerke, Belgium). The mean biological values for the last 2 months of each period were retained for analysis. The mean values during each period, for BP, convective volume, hypotension, cramps and dry body weight, were recorded.
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medcalc 11.5.1.0 product key
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated.
Statistical analysis was performed by using a commercially available statistical software package (SPSS for Windows, version 20.0; IBM-SPSS, Chicago, IL, USA) and the MedCalc program (version 11.5.1.0 for Windows; ; accessed: 2011-4-20). The study population was randomly assigned to a training group and a test group, in a ratio of 4:3. Only one randomly selected unaffected eye per patient was taken for statistical analysis. We determined the mean value (presented as mean standard deviation) of the main outcome parameters. The distribution of the values was assessed by using the Kolmogorov-Smirnov test. Differences in the demographic, ophthalmologic, and intracranial characteristics between the training group and the test group were then assessed by using two-tailed Student t test. Proportions were compared by using the χ2 test. All P values were two-sided.
To explore how the homophilic ATP1A1 interactions induce activin A production, we analyzed the amounts of, and signal transduction associated with, ATP1A1 in both fibroblasts and tumor cells. We used intracellular hydrogelation procedures29,30 to enrich plasma membrane fractions of BxPC-3 cells and PSCs (see Methods) and found that the amount of plasma membrane-localized ATP1A1 in fibroblasts, but not in tumor cells, was specifically increased upon direct tumor-fibroblast contact (Fig. 7a). Consistently, results of immunofluorescence staining without membrane permeabilization also showed enrichment of plasma membrane-localized ATP1A1 in fibroblasts upon direct contact (Fig. 7b, c). Interestingly, the increased membrane-localized ATP1A1 in fibroblasts during direct contact relied on high ATP1A1 expression in tumor cells, but not in ATP1A1-knockdown tumor cells (Fig. 7d, e). These results indicate that fibroblast ATP1A1 is trafficked to the adhesion junctions of fibroblasts upon contact with high levels of ATP1A1 from tumor cells, indicating a re-organization of the fibroblast membrane-localized ATP1A1. This re-organization may strengthen homophilic ATP1A1 interaction between tumor cells and fibroblasts.
Next, we investigated the ATP1A1-associated signaling responsible for driving activin A production. RNA sequencing data showed that the primary signaling pathways activated in fibroblasts upon direct contact with ATP1A1-overexpressing tumor cells (BxPC-3 and SU.86.86 cells, but not MIA PaCa-2 and PANC-1 cells) were calcium-dependent axonal guidance and CREB signaling (Fig. 7f). Consistently, intracellular Ca2+ concentration was specifically up-regulated in fibroblasts during direct co-culturing with ATP1A1-overexpressing tumor cells (Fig. 7g; Supplementary Fig. 7a), while inhibition of ATP1A1 interaction through silencing ATP1A1 in tumor cells diminished the intracellular Ca2+ concentration (Fig. 7h). In addition, treatment with a calcium channel inhibitor that abolished Ca2+ oscillations significantly suppressed activin A secretion (Fig. 7i). Therefore, ATP1A1-mediated calcium signaling regulates activin A production. It was noted that low-dose ouabain at picomolar to nanomolar concentrations binds to the extracellular domain of ATP1A1 resulting in ATP1A1-IP3R (inositol 1,4,5-triphosphate receptor) interactions for generating calcium oscillations and NF-κB activation31,32. We then used low-dose ouabain to treat fibroblasts and tumor cells and found that NF-κB signaling and activin A production were specifically induced in fibroblasts, but not in tumor cells (Supplementary Fig. 7b, c). These results suggest that ATP1A1 in the fibroblast membrane may re-organize upon direct contact with tumor cells expressing high levels of ATP1A1, thereby inducing calcium oscillations, NF-κB activation, and activin A secretion.
It was noted that activin A production is regulated by activation of the NF-κB pathway in normal and cancer cells25,33. Activation of the NF-κB transcriptional response is measured by phosphorylation of p65 at S536, which enhances the transcriptional activity of p6534. Consistently, phosphorylated p65 at S536 (p-p65) was significantly increased in fibroblasts after direct contact with BxPC-3 cells through ATP1A1 interaction (Fig. 7j, k; Supplementary Fig. 7d). In addition, the NF-κB inhibitor BAY117082 suppressed activin A production (Fig. 7l). These results suggest that activation of the NF-κB pathway occurs specifically in fibroblasts upon direct contact with ATP1A1-overexpressing tumor cells. Taken together, binding to high amounts of ATP1A1 of tumor cells enhances the amount of ATP1A1 at adhesion junctions of fibroblasts and triggers calcium oscillations, NF-κB activation, and activin A production.
Microsoft Excel 2010 and MedCalc version 11.5.1.0 were used for validation tests (sensitivity, specificity, and positive and negative predictive values) and analysis. Only those women who underwent all three procedures (TVS, HSGM, and hysteroscopy) were included in the validation test analysis.
As most accessible health care professionals, pharmacists are likely to encounter patients seeking advice about variety of CAM forms in their daily practice, and most community pharmacies are suppliers of these medicines. In Croatia, majority of pharmacy available forms of CAM are herbal products marketed as dietary supplements. A research conducted among Australian pharmacists identified safety concerns as primary barrier to pharmacists' recommendation of CAM, alongside with lack of knowledge, perceived lack of evidence and lack of time for patient consultation.4 In order to assure effective and safe use of CAM, and provide informed use to patients in pharmacies, an incorporation of CAM education in pharmacy curricula was proposed.4
The data were analyzed using MedCalc v. 11.5.1.0 (MedCalc Software, Ostend, Belgium) and SPSS for Windows v. 23.0 (IBM Corp., Armonk, NY, USA). Chi-square test was used to analyze pharmacists' use of dietary supplements and sources of information for their use. The Chi-square and Mann Whitney U tests were used to analyze pharmacists' perceptions and knowledge of dietary supplements. In order to evaluate factors that may affect pharmacists' decision to recommend dietary supplements to the patients, the binary logistic regression with forward-conditional algorithm has been performed. The following covariates were included: age, gender, year of work experience, family member in health care, chronic disease and personal use ever. Value of p
Previous research in the field of evidence based pharmacy have had divergent conclusions. Study by Al-Jazairi et al. found that senior pharmacists had more optimistic outlook on evidence based practice, and authors assumed that this is due to the fact that senior staff had more patient care experience which could have shaped the need of evidence based concept in practice.7 A simulated patient study conducted in Australian pharmacies showed numerous shortcomings in their practices regarding CAM recommendation and dispensing, including advising use of products with unproven efficacy and safety.13 Another study, by McKee et al., also revealed that pharmacists' decision on over-the-counter (OTC) drugs was not influenced by evidence.14 Moreover, the authors concluded that if community pharmacists aim to be considered as scientific health care professionals, they should discuss evidence with their patients.14 Therefore, pharmacists were expected to be a relevant source of objective information to the patients and serve as an advisor helping them reach an informed decision.15,16 That role of pharmacists was accepted positively by the both pharmacists and patients.12 However, this study showed a major obstacle in realizing that role as a significant factor influencing the decision to recommend dietary supplement was subjective, personal experience with the supplements. The need for stronger collaboration between all sides interested in ensuring the optimal use of dietary supplements was previously recognized.12,17 Inter-professional collaboration, especially between pharmacists and physicians, was perceived as important in improving patients' treatment outcomes and safety.18,19 To contribute to that collaboration, pharmacists would need further education about principles and application of evidence-based pharmacy, with special emphasis on senior pharmacists.
All included pharmacists scored highly on general knowledge test about dietary supplements. Despite the good knowledge scores, they did not use the high quality sources when recommending dietary supplements to their patients. Interestingly, a large proportion of less experienced pharmacists used labels on product containers as a source of information, although labels do not provide enough information to determine whether to use particular dietary supplement but just the information on how to use it. Pharmacists' decision to recommend the supplement was not based on objective evaluation of evidence about their efficacy and safety but instead on their own personal experience with the supplement. That was especially apparent with the senior pharmacists. Further education about the practice of evidence-based pharmacy is necessary, with special emphasis on senior pharmacists who might have missed that aspect during their formal education. 2ff7e9595c
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