Search results for: clinical pathway

Authors: Blanche Aguida, Marootpong Pooam, Nathalie Jourdan, Margaret Ahmad

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COVID-19-related morbidity is associated with exaggerated inflammation and cytokine production in the lungs, leading to acute respiratory failure. The cellular mechanisms underlying these so-called ‘cytokine storms’ are regulated through the Toll-like receptor 4 (TLR4) signaling pathway and by reactive oxygen species (ROS). Both light (photobiomodulation) and magnetic fields (e.g., pulsed electromagnetic field) stimulation are non-invasive therapies known to confer anti-inflammatory effects and regulate ROS signaling pathways. Here we show that daily exposure to two 10-minute intervals of moderate-intensity infra-red light significantly lowered the inflammatory response induced via the TLR4 receptor signaling pathway in human cell cultures. Anti-inflammatory effects were likewise achieved by electromagnetic field exposure of cells to daily 10-minute intervals of either pulsed electromagnetic fields (PEMF) or to low-level static magnetic fields. Because current illumination and electromagnetic field therapies have no known side effects and are already approved for some medical uses, we have here developed protocols for verification in clinical trials of COVID 19 infection. These treatments are affordable, simple to implement, and may help to resolve the acute respiratory distress of COVID 19 patients both in the home and in the hospital.

Keywords: COVID 19, electromagnetic fields therapy, inflammation, photobiomodulation therapy

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Authors: Mohammadjavad Sotoudeheian

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COVID-19, which began in December 2019, uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter and spread through the cells. ACE2 mRNA is present in almost every organ, including nasopharynx, lung, as well as the brain. Ports of entry of SARS-CoV-2 into the central nervous system (CNS) may include arterial circulation, while viremia is remarkable. However, it is imperious to develop neurological symptoms evaluation CSF analysis in patients with COVID-19, but theoretically, ACE2 receptors are expressed in cerebellar cells and may be a target for SARS-CoV-2 infection in the brain. Recent evidence agrees that SARS-CoV-2 can impact the brain through direct and indirect injury. Two biomarkers for CNS injury, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL) detected in the plasma of patients with COVID-19. NFL, an axonal protein expressed in neurons, is related to axonal neurodegeneration, and GFAP is over-expressed in CNS inflammation. GFAP cytoplasmic accumulation causes Schwan cells to misfunction, so affects myelin generation, reduces neuroskeletal support over NfLs during CNS inflammation, and leads to axonal degeneration. Interleukin-6 (IL-6), which extensively over-express due to interleukin storm during COVID-19 inflammation, regulates gene expression, as well as GFAP through STAT molecular pathway. IL-6 also impresses the phosphoinositide 3-kinase (PI3K)/STAT/smads pathway. The PI3K/ protein kinase B (Akt) pathway is the main modulator upstream of the mammalian target of rapamycin (mTOR), and alterations in this pathway are common in neurodegenerative diseases. Most neurodegenerative diseases show a disruption of autophagic function and display an abnormal increase in protein aggregation that promotes cellular death. Therefore, induction of autophagy has been recommended as a rational approach to help neurons clear abnormal protein aggregates and survive. The mTOR is a major regulator of the autophagic process and is regulated by cellular stressors. The mTORC1 pathway and mTORC2, as complementary and important elements in mTORC1 signaling, have become relevant in the regulation of the autophagic process and cellular survival through the extracellular signal-regulated kinase (ERK) pathway.

Keywords: mTORC1, COVID-19, PI3K, autophagy, neurodegeneration

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Authors: Golyasamin Khanehzaei, Mohd. Bakri Ishak, Ahmad Makmom Hj Abdullah, Latifah Abd Manaf

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Abstract—Management of clinical waste is a critical problem worldwide. Immediate attention is required to manage the clinical waste in an appropriate way in newly developing economy country such as Malaysia. The increasing amount of clinical waste generated is resulted from rapid urbanization and growing number of private health care facilities in developing countries such as Malaysia. In order to develop a sensible clinical waste management system and improvement of the management, information on factors affecting clinical waste generation has the crucial role. This paper is the study of management characteristics of clinical waste and the level of efficiency of clinical waste management systems operating in private clinics located in Selangor, Malaysia. Are they following the proper international standards? By taking all of this in consideration the aim of this paper is to identify and discuss the current trend, current challenges and also the present opportunities among the challenges of clinical waste management in private clinics of Selangor, Malaysia. The SWOT analysis was characterized for the evaluation of strengths, weaknesses, opportunities and threats. The methodology for this study was constituted of direct observation, Informal interviews, Conducting SWOT analysis, conduction of one sustainability dimensions analysis and application. The results show that clinical waste management in private clinics is far from an ideal model.

Keywords: clinical waste, SWOT analysis, Selangor, Malaysia

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Authors: Tambe Daniel Atem

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Background: Clinical Research is an organized research on human beings intended to provide adequate information on the drug use as a therapeutic agent on its safety and efficacy. The significance of the study is to educate the global health and life science graduates in Clinical Research in depth to perform better as it involves testing drugs on human beings. Objectives: to provide an overall understanding of the scientific approach to the evaluation of new and existing medical interventions and to apply ethical and regulatory principles appropriate to any individual research. Methodology: It is based on – Primary data analysis and Secondary data analysis. Primary data analysis: means the collection of data from journals, the internet, and other online sources. Secondary data analysis: a survey was conducted with a questionnaire to interview the Clinical Research Professionals to understand the need of training to perform clinical trials globally. The questionnaire consisted details of the professionals working with the expertise. It also included the areas of clinical research which needed intense training before entering into hardcore clinical research domain. Results: The Clinical Trials market worldwide worth over USD 26 billion and the industry has employed an estimated 2,10,000 people in the US and over 70,000 in the U.K, and they form one-third of the total research and development staff. There are more than 2,50,000 vacant positions globally with salary variations in the regions for a Clinical Research Coordinator. R&D cost on new drug development is estimated at US$ 70-85 billion. The cost of doing clinical trials for a new drug is US$ 200-250 million. Due to an increase trained Clinical Research Professionals India has emerged as a global hub for clinical research. The Global Clinical Trial outsourcing opportunity in India in the pharmaceutical industry increased to more than $2 billion in 2014 due to increased outsourcing from U.S and Europe to India. Conclusion: Assessment of training need is recommended for newer Clinical Research Professionals and trial sites, especially prior the conduct of larger confirmatory clinical trials.

Keywords: clinical research, clinical trials, clinical research professionals

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Authors: Sedigheh Salemi, Mahnaz Sanjari, Maryam Aalaa, Mohammad Mirzabeigi

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Clinical governance is the framework within which the health service provider is required to ongoing accountability and improvement of the quality of their services. This cross-sectional study was conducted in 661 nurses who work in government hospitals from 35 hospitals of 9 provinces in Iran. The study was approved by the Nursing Council and was carried out with the authorization of the Research Ethics Committee. The questionnaire included 24 questions in which 4 questions focused on clinical governance defining from the nurses' perspective. The reliability was evaluated by Cronbach's alpha (α=0/83). Statistical analyzes were performed, using SPSS version 16. Approximately 40% of nurses correctly answered that clinical governance is not "system of punishment and rewards for the staff". The most nurses believed that "clinical efficacy" is one of the main components of clinical governance. A few of nurses correctly responded that "Evidence Based Practice" and "management" is not part of clinical governance. The small number of nurses correctly answered that the "maintenance of patient records" and "to recognize the adverse effects" is not the role of nurse in clinical governance. Most "do not know" answer was to the "maintenance of patient records". The most nurses unanimously believed that the implementation of clinical governance led to "promoting the quality of care". About a third of nurses correctly stated that the implementation of clinical governance will not lead to "an increase in salaries and benefits of the medical team". As a member of the health team, nurses are responsible in terms of participation in quality improvement and it is necessary to create an environment in which clinical care will flourish and serve to preserve the high standards.

Keywords: clinical governance, nurses, salary, health team

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Authors: T. Ferreira, A. Kulkarni, C. Bretscher, K. Richter, M. Ehrlich, A. Marchini

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H-1 protoparvovirus (H-1PV) is a virus with inherent oncolytic and oncosuppressive activities while remaining non-pathogenic in humans. H-1PV was the first oncolytic parvovirus to undergo clinical testing. Results from trials in patients with glioblastoma or pancreatic carcinoma showed an excellent safety profile and first signs of efficacy. H-1PV infection is vastly dependent on cellular factors, from cell attachment and entry to viral replication and egress. Hence, we believe that the characterisation of the parvovirus life cycle would ultimately help further improve H-1PV clinical outcome. In the present study, we explored the entry pathway of H-1PV in cervical HeLa and glioma NCH125 cancer cell lines. Electron and confocal microscopy showed viral particles associated with clathrin-coated pits and vesicles, providing the first evidence that H-1PV cell entry occurs through clathrin-mediated endocytosis. Accordingly, we observed that by blocking clathrin-mediated endocytosis with hypertonic sucrose, chlorpromazine, or pitstop 2, H-1PV transduction was markedly decreased. Accordingly, siRNA-mediated knockdown of AP2M1, which retains a crucial role in clathrin-mediated endocytosis, verified the reliance of H-1PV on this route to enter HeLa and NCH125 cancer cells. By contrast, we found no evidence of viral entry through caveolae-mediated endocytosis. Indeed, pre-treatment of cells with nystatin or methyl-β-cyclodextrin, both inhibitors of caveolae-mediated endocytosis, did not affect viral transduction levels. Unexpectedly, siRNA-mediated knockdown of caveolin-1, the main driver of caveolae-mediated endocytosis, increased H-1PV transduction, suggesting caveolin-1 is a negative modulator of H-1PV infection. We also show that H-1PV entry is dependent on dynamin, a protein responsible for mediating the scission of vesicle neck and promoting further internalisation. Furthermore, since dynamin inhibition almost completely abolished H-1PV infection, makes it unlikely that H-1PV uses macropinocytosis as an alternative pathway to enter cells. After viral internalisation, H-1PV passes through early to late endosomes as observed by confocal microscopy. Inside these endocytic compartments, the acidic environment proved to be crucial for a productive infection. Inhibition of acidification of pH dramatically reduced H-1PV transduction. Besides, a fraction of H-1PV particles was observed inside LAMP1-positive lysosomes, most likely following a non-infectious route. To the author's best knowledge, this is the first study to characterise the cell entry pathways of H-1PV. Along these lines, this work will further contribute to understand H-1PV oncolytic properties as well as to improve its clinical potential in cancer virotherapy.

Keywords: clathrin-mediated endocytosis, H-1 parvovirus, oncolytic virus, virus entry

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Authors: Hye-Kyung Kang

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Social justice is a central principle of the social work profession and education. However, scholars have long questioned the profession’s commitment to putting social justice values into practice. Clinical social work has been particularly criticized for its lack of attention to social justice and for failing to address the concerns of the oppressed. One prominent criticism of clinical social work is that it often relies on individual intervention and fails to take on system-level changes or advocacy. This concern evokes the historical macro-micro tension of the social work profession where micro (e.g., mental health counseling) and macro (e.g., policy advocacy) practices are conceptualized as separate domains, creating a false binary for social workers. One contributor to this false binary seems to be that most clinical practice models do not prepare social work students and practitioners to make a clear link between clinical practice and social justice. This paper presents a model of clinical social work practice that clearly recognizes the essential and necessary connection between social justice, advocacy, and clinical practice throughout the clinical process: engagement, assessment, intervention, and evaluation. Contemporary relational theories, critical social work frameworks, and anti-oppressive practice approaches are integrated to build a clinical social work practice model that addresses the urgent need for mental health practice that not only helps and heals the person but also challenges societal oppressions and aims to change them. The application of the model is presented through case vignettes.

Keywords: social justice, clinical social work, clinical social work model, integrative model

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Authors: Chengcao Sun, Shujun Li, Dejia Li

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Sulforaphane (SFN) possesses powerful chemo-preventive effects and plays a crucial role on oxidative stress and inflammatory. In our recent study, SFN treatment could relieve muscular dystrophy in mdx mice by activating Nrf2 (NF-E2 related factor 2). Moreover, our findings indicated that SFN-activated Nrf2 alleviated muscle inflammation in dystrophin-deficient mdx mice through suppressing NF-κB signaling pathway. Collectively, SFN-induced Nrf2 molecular pathway might be a promising approach for treatment of the patients with Duchenne muscular dystrophy.

Keywords: sulforaphane, Duchenne muscular dystrophy, Nrf2, inflammation, fibrosis, oxidative stress

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Authors: Jacqueline M. Dias, Amina A Khowaja

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Clinical education is one of the most important components of a nursing curriculum as it develops the students’ cognitive, psychomotor and affective skills. Clinical teaching ensures the integration of knowledge into practice. As the numbers of students increase in the field of nursing coupled with the faculty shortage, clinical preceptors are the best choice to ensure student learning in the clinical settings. The clinical preceptor role has been introduced in the undergraduate nursing programme. In Pakistan, this role emerged due to a faculty shortage. Initially, two clinical preceptors were hired. This study will explore clinical preceptors views and experiences of precepting Bachelor of Science in Nursing (BScN) students in an undergraduate program. A case study design was used. As case studies explore a single unit of study such as a person or very small number of subjects; the two clinical preceptors were fundamental to the study and served as a single case. Qualitative data were obtained through an iterative process using in depth interviews and written accounts from reflective journals that were kept by the clinical preceptors. The findings revealed that the clinical preceptors were dedicated to their roles and responsibilities. Another, key finding was that clinical preceptors’ prior knowledge and clinical experience were valuable assets to perform their role effectively. The clinical preceptors found their new role innovative and challenging; it was stressful at the same time. Findings also revealed that in the clinical agencies there were unclear expectations and role ambiguity. Furthermore, clinical preceptors had difficulty integrating theory into practice in the clinical area and they had difficulty in giving feedback to the students. Although this study is localized to one university, generalizations can be drawn from the results. The key findings indicate that the role of a clinical preceptor is demanding and stressful. Clinical preceptors need preparation prior to precepting students on clinicals. Also, institutional support is fundamental for their acceptance. This paper focuses on the views and experiences of clinical preceptors undertaking a newly established role and resonates with the literature. The following recommendations are drawn to strengthen the role of the clinical preceptors: A structured program for clinical preceptors is needed along with mentorship. Clinical preceptors should be provided with formal training in teaching and learning with emphasis on clinical teaching and giving feedback to students. Additionally, for improving integration of theory into practice, clinical modules should be provided ahead of the clinical. In spite of all the challenges, ten more clinical preceptors have been hired as the faculty shortage continues to persist.

Keywords: baccalaureate nursing education, clinical education, clinical preceptors, nursing curriculum

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Authors: Nanyombi Lubimbi, Josette Niyokindi

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Background: As in many other developing countries in Africa, Rwanda suffers from a chronic shortage of skilled Health Care professionals including Clinical Instructors. This shortage negatively affects the clinical instruction quality therefore impacting student-learning outcomes. Due to poor clinical supervision, it is often noted that students have no structure or consistent guidance in their learning process. The Clinical Educators and the Rwandan counterparts identified the need to create a favorable environment for learning. Description: During orientation the expectations of the student learning process, collaboration of the clinical instructors with the nurses and Clinical Educators is outlined. The ward managers facilitate structured learning by helping the students identify a maximum of two patients using the school’s objectives to guide the appropriate selection of patients. Throughout the day, Clinical Educators with collaboration of Clinical Instructors when present conduct an ongoing assessment of learning and provide feedback to the students. Post-conference is provided once or twice a week to practice critical thinking skills of patient cases that they have been taking care of during the day. Lessons Learned: The students are found to be more confident with knowledge and skills gained during rotations. Clinical facility evaluations completed by students at the end of their rotations highlight the student’s satisfaction and recommendation for continuation of structured learning. Conclusion: Based on the satisfaction of both students and Clinical Instructors, we have identified need for structured learning during clinical rotations. We acknowledge that more evidence-based practice is necessary to effectively address the needs of nursing and midwifery students throughout the country.

Keywords: Rwanda, clinical rotation, structured learning, critical thinking skills, post-conference

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Authors: Han-Qin Zheng, Yi-Fan Chiang-Hsieh, Chia-Hung Chien, Wen-Chi Chang

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As the most important non-vascular plants, algae have many research applications, including high species diversity, biofuel sources, adsorption of heavy metals and, following processing, health supplements. With the increasing availability of next-generation sequencing (NGS) data for algae genomes and transcriptomes, an integrated resource for retrieving gene expression data and metabolic pathway is essential for functional analysis and systems biology in algae. However, gene expression profiles and biological pathways are displayed separately in current resources, and making it impossible to search current databases directly to identify the cellular response mechanisms. Therefore, this work develops a novel AlgaePath database to retrieve gene expression profiles efficiently under various conditions in numerous metabolic pathways. AlgaePath, a web-based database, integrates gene information, biological pathways, and next-generation sequencing (NGS) datasets in Chlamydomonasreinhardtii and Neodesmus sp. UTEX 2219-4. Users can identify gene expression profiles and pathway information by using five query pages (i.e. Gene Search, Pathway Search, Differentially Expressed Genes (DEGs) Search, Gene Group Analysis, and Co-Expression Analysis). The gene expression data of 45 and 4 samples can be obtained directly on pathway maps in C. reinhardtii and Neodesmus sp. UTEX 2219-4, respectively. Genes that are differentially expressed between two conditions can be identified in Folds Search. Furthermore, the Gene Group Analysis of AlgaePath includes pathway enrichment analysis, and can easily compare the gene expression profiles of functionally related genes in a map. Finally, Co-Expression Analysis provides co-expressed transcripts of a target gene. The analysis results provide a valuable reference for designing further experiments and elucidating critical mechanisms from high-throughput data. More than an effective interface to clarify the transcript response mechanisms in different metabolic pathways under various conditions, AlgaePath is also a data mining system to identify critical mechanisms based on high-throughput sequencing.

Keywords: next-generation sequencing (NGS), algae, transcriptome, metabolic pathway, co-expression

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Authors: Ragy Raafat Gaber Attaalla

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Despite having the greatest rates of mortality and morbidity in the world, low- and middle-income (LMIC) nations trail high-income nations in terms of the number of clinical trials, the number of qualified researchers, and the amount of research information specific to their people. Health inequities and the use of precision medicine may be hampered by a lack of local genomic data, clinical pharmacology and pharmacometrics competence, and training opportunities. These issues can be solved by carrying out health care infrastructure development, which includes data gathering and well-designed clinical pharmacology training in LMICs. It will be advantageous if there is international cooperation focused at enhancing education and infrastructure and promoting locally motivated clinical trials and research. This paper outlines various instances where clinical pharmacology knowledge could be put to use, including pharmacogenomic opportunities that could lead to better clinical guideline recommendations. Examples of how clinical pharmacology training can be successfully implemented in LMICs are also provided, including clinical pharmacology and pharmacometrics training programmes in Africa and a Tanzanian researcher's personal experience while on a training sabbatical in the United States. These training initiatives will profit from advocacy for clinical pharmacologists' employment prospects and career development pathways, which are gradually becoming acknowledged and established in LMICs. The advancement of training and research infrastructure to increase clinical pharmacologists' knowledge in LMICs would be extremely beneficial because they have a significant role to play in global health.

Keywords: low- and middle-income, clinical pharmacology, pharmacometrics, career development pathways

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Authors: Irma Gabriela Lopez-Moreno, Elva Perez-Luque, Herlinda Aguilar-Zavala

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Introduction: Type 2 Diabetes Mellitus (T2DM) is characterized by combination of insulin resistance and deterioration of insulin secretion. Sfrp5 is a protein that antagonizes Wnt5a proteins by preventing it from reaching its receptor and activating the Wnt/β-catenin signaling pathway, this pathway is one of the most important regulators of adipogenesis. Although metformin decreases glucose levels its mechanisms of action are not fully known but it has been implicated in the inhibition of the Wnt/β-catenin signaling pathway. Objective: The objective was evaluating the effects of metformin on serum levels of Sfrp5 in patients with T2DM treated and not treated with metformin. Methods: Two groups of patients were selected: one group of T2DM patients treated with metformin (n = 35) and another group of subjects with recent diagnosis of T2DM untreated (n = 35) with a mean age of 48 ± 9 years. In these subjects anthropometric measures were taken as weight, height, waist and hip circumference, were calculated the percentage of body fat, visceral fat and muscle mass. In addition, were measured glucose levels, lipid profile, adiponectin and Sfrp5. Results: Sfrp5 were higher in metformin-treated patients compared to the untreated group (19.9 vs 13.6 ng/mL p < 0.001), a negative correlation was found between Sfrp5 levels and total cholesterol levels (r= -0.25, p = 0.03) and percentage of visceral fat (r = -0.26, p = 0.03) and a positive correlation with HDL cholesterol levels (r = 0.31, p = 0.01) and adiponectin (r=0.65, p = < 0.001). Conclusions: The findings show that metformin consumption increased levels of Sfrp5, which may lead to a decrease in the activation of the WNT/β-catenin pathway impacting on adipogenesis.

Keywords: adiponectin, diabetes, metformin, Sfrp5

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Authors: Jiahui Song, Ravindra Joshi

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High-intensity, nanosecond, pulsed electric fields have been shown to be useful non-thermal tools capable of producing a variety of specific cellular responses. While reversible and temporary changes are often desired based on electromanipulation, irreversible effects can also be important objectives. These include elimination of tumor cells and bacterial decontamination. A simple model-based rate-equation treatment of the various cellular biochemical processes was used to qualitatively predict the pulse number-dependent caspase activation and cell survival trends. The model incorporated the caspase-8 associated extrinsic pathway, the delay inherent in its activation, cytochrome c release, and the internal feedback mechanism between caspase-3 and Bid. Results were roughly in keeping with the experimental cell-survival data. A pulse-number threshold was predicted followed by a near-exponential fall-off. The intrinsic pathway was shown to be much weaker as compared to the extrinsic mechanism for electric pulse induced cell apoptosis. Also, delays of about an hour are predicted for detectable molecular concentration increases following electrical pulsing.

Keywords: apoptosis, cell survival, model, pathway

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Authors: Ozlem Oral, Emre Taskin, Aysel Yuce, Serap Dokmeci, Devrim Gozuacik

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Autophagy is an evolutionary conserved lysosome-dependent catabolic pathway, responsible for the degradation of long-lived proteins, abnormal aggregates and damaged organelles which cannot be degraded by the ubiquitin-proteasome system. Lysosomes degrade the substrates through the activity of lysosomal hydrolases and lysosomal membrane-bound proteins. Mutations in the coding region of these proteins cause malfunctional lysosomes, which contributes to the pathogenesis of lysosomal storage diseases. Gaucher disease is a lysosomal storage disease resulting from the mutation of a lysosomal membrane-associated glycoprotein called glucocerebrosidase and its cofactor saposin C. The disease leads to intracellular accumulation of glucosylceramide and other glycolipids. Because of the essential role of lysosomes in autophagic degradation, Gaucher disease may directly be linked to this pathway. In this study, we investigated the expression of autophagy and/or lysosome-related genes and proteins in fibroblast cells isolated from patients with different mutations. We carried out confocal microscopy analysis and examined autophagic flux by utilizing the differential pH sensitivities of RFP and GFP in mRFP-GFP-LC3 probe. We also evaluated lysosomal pH by active lysosome staining and lysosomal enzyme activity. Beside lysosomes, we also performed proteasomal activity and cell death analysis in patient samples. Our data showed significant attenuation in the expression of key autophagy-related genes and accumulation of their proteins in mutant cells. We found decreased the ability of autophagosomes to fuse with lysosomes, associated with elevated lysosomal pH and reduced lysosomal enzyme activity. Proteasomal degradation and cell death analysis showed reduced proteolytic activity of the proteasome, which consequently leads to increased susceptibility to cell death. Our data indicate that the major degradation pathways are affected by multifunctional lysosomes in mutant patient cells and may underlie in the mechanism of clinical severity of Gaucher patients. (This project is supported by TUBITAK-3501-National Young Researchers Career Development Program, Project No: 112T130).

Keywords: autophagy, Gaucher's disease, glucocerebrosidase, mutant fibroblasts

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Authors: Wenxing Chen, Guangying Chen, Yin Lu, Shile Huang

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Cryptotanshinone (CPT), a fat-soluble tanshinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit mTOR pathway, resulting in inhibition of cancer cell proliferation. However, the molecular mechanism how CPT acts on mTOR is unknown. Here, cancer cells expressing rapamycin-resistant mutant mTOR are also sensitive to CPT, while phosphorylation of AMPK and TSC2 was activated, suggesting that CPT inhibition of mTOR maybe due to activating upstream of mTOR, AMPK, but not directly binding to and inhibiting mTOR. Further results indicated that Compound C, inhibitor of AMPK, could partially reversed CPT inhibition effect on cancer cells, and dominant-negative AMPK in cancer cells conferred resistance to CPT inhibition of 4EBP1 and phosphorylation of S6K1, as well as sh-AMPK. Furthermore, compared with MEF cells with AMPK positive, MEF cells with AMPK knock out are less sensitive to CPT by the findings that 4E-BP1 and phosphorylation of S6K1 express comparatively much. Furthermore, downexpression of TSC2 slightly recovered expression of 4EBP1 and phosphorylation of S6K1, while co-immunoprecipitation of TSC2 did not affect expression of TSC1 by CPT. Collectively, the above-mentioned results suggest that CPT inhibited mTOR pathway mostly was due to activation of AMPK-TSC2 pathway rather than specific inhibition of mTOR and then induction of subsequent lethal cellular effect.

Keywords: cryptotanshinone, AMPK, TSC2, mTOR, cancer cells

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Authors: Vadim Makarov, Stewart T.Cole

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PBTZ169 is novel drug candidate with high efficacy in animals models, and its combination treatment of PBTZ169 with BDQ and pyrazinamide was shown to be more efficacious than the standard treatment for tuberculosis in a mouse model. The target of PBTZ169 is famous DprE1, an essential enzyme in cell wall biosynthesis. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Furthermore, this drug candidate demonstrated during preclinical research ‘drug like’ properties what made it an attractive drug candidate to treat tuberculosis in humans. During first clinical trials several cohorts of the healthy volunteers were treated by the single doses of PBTZ169 as well as two weeks repeated treatment was chosen for two maximal doses. As expected PBTZ169 was well tolerated, and no significant toxicity effects were observed during the trials. The study of the metabolism shown that human metabolism of PBTZ169 is very different from microbial or animals compound transformation. So main pathway of microbial, mice and less rats metabolism connected with reduction processes, but human metabolism mainly connected with oxidation processes. Due to this difference we observed several metabolites of PBTZ169 in humans with antitubercular activity, and now we can conclude that animal antituberculosis activity of PBTZ169 is a result not only activity of the drug itself, but it is a result of the sum activity of the drug and its metabolites. Direct antimicrobial plasma activity was studied, and such activity was observed for 24 hours after human treatment for some doses. This data gets high chance for good efficacy of PBTZ169 in human for treatment TB infection. Second phase of clinical trials was started summer of 2017 and continues to the present day. Available data will be presented.

Keywords: clinical trials, DprE1, PBTZ169, metabolism

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Authors: Shahad Nagoor, Lucy Hederman, Kevin Koidl, Annalina Caputo

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Doctors’ notes reflect their impressions, attitudes, clinical sense, and opinions about patients’ conditions and progress, and other information that is essential for doctors’ daily clinical decisions. Despite their value, clinical notes are insufficiently researched within the language processing community. Automatically extracting information from unstructured text data is known to be a difficult task as opposed to dealing with structured information such as vital physiological signs, images, and laboratory results. The aim of this research is to investigate how Natural Language Processing (NLP) techniques and machine learning techniques applied to clinician notes can assist in doctors’ decision-making in Intensive Care Unit (ICU) for coronavirus disease 2019 (COVID-19) patients. The hypothesis is that clinical outcomes like survival or mortality can be useful in influencing the judgement of clinical sentiment in ICU clinical notes. This paper introduces two contributions: first, we introduce COVID_ICU_BERT, a fine-tuned version of clinical transformer models that can reliably predict clinical sentiment for notes of COVID patients in the ICU. We train the model on clinical notes for COVID-19 patients, a type of notes that were not previously seen by clinicalBERT, and Bio_Discharge_Summary_BERT. The model, which was based on clinicalBERT achieves higher predictive accuracy (Acc 93.33%, AUC 0.98, and precision 0.96 ). Second, we perform data augmentation using clinical contextual word embedding that is based on a pre-trained clinical model to balance the samples in each class in the data (survived vs. deceased patients). Data augmentation improves the accuracy of prediction slightly (Acc 96.67%, AUC 0.98, and precision 0.92 ).

Keywords: BERT fine-tuning, clinical sentiment, COVID-19, data augmentation

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Authors: Hyeon Su Kim, Sungjin Park, Hae Ryung Chang, Hae Rim Jung, Young Zoo Ahn, Yon Hui Kim, Seungyoon Nam

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Ependymoma, one of the most common parenchymal spinal cord tumor, represents 3-6% of all CNS tumor. Especially intracranial ependymomas, which are more frequent in childhood, have a more poor prognosis and more malignant than spinal ependymomas. Although there are growing needs to understand pathogenesis, detailed molecular understanding of pathogenesis remains to be explored. A cancer cell is composed of complex signaling pathway networks, and identifying interaction between genes and/or proteins are crucial for understanding these pathways. Therefore, we explored each ependymoma in terms of differential expressed genes and signaling networks. We used Microsoft Excel™ to manipulate microarray data gathered from NCBI’s GEO Database. To analyze and visualize signaling network, we used web-based PATHOME algorithm and Cytoscape. We show HOX family and NEFL are down-regulated but SCL family is up-regulated in cerebrum and posterior fossa cancers over a spinal cancer, and JAK/STAT signaling pathway and Chemokine signaling pathway are significantly different in the both intracranial ependymoma comparing to spinal ependymoma. We are considering there may be an age-dependent mechanism under different histological pathogenesis. We annotated mutation data of each gene subsequently in order to find potential target genes.

Keywords: systems biology, ependymoma, deg, network analysis

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Authors: Jonah Kenei, Elisha Opiyo

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Electronic health records, as a repository of patient information, is nowadays the most commonly used technology to record, store and review patient clinical records and perform other clinical tasks. However, the accurate identification and retrieval of relevant information from clinical records is a difficult task due to the unstructured nature of clinical documents, characterized in particular by a lack of clear structure. Therefore, medical practice is facing a challenge thanks to the rapid growth of health information in electronic health records (EHRs), mostly in narrative text form. As a result, it's becoming important to effectively manage the growing amount of data for a single patient. As a result, there is currently a requirement to visualize electronic health records (EHRs) in a way that aids physicians in clinical tasks and medical decision-making. Leveraging text visualization techniques to unstructured clinical narrative texts is a new area of research that aims to provide better information extraction and retrieval to support clinical decision support in scenarios where data generated continues to grow. Clinical datasets in electronic health records (EHR) offer a lot of potential for training accurate statistical models to classify facets of information which can then be used to improve patient care and outcomes. However, in many clinical note datasets, the unstructured nature of clinical texts is a common problem. This paper examines the very issue of getting raw clinical texts and mapping them into meaningful structures that can support healthcare professionals utilizing narrative texts. Our work is the result of a collaborative design process that was aided by empirical data collected through formal usability testing.

Keywords: classification, electronic health records, narrative texts, visualization

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Authors: J. Magerman, P. Martin

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Nursing students' clinical abilities is highly dependent on the quality of the clinical experience obtained while placed in the clinical environment. The clinical environment has amongst other, key role players which include the clinical supervisor. The primary role of the clinical supervisor is to guide nursing students to become the best practice nursing professionals. However, globally literature alludes to the failure of educating institutions to deliver competent nursing professionals to meet the needs of patients and deliver quality patient care. At the participating university, this may be due to various factors such as large student numbers and social and environmental challenges experienced by clinical supervisors. The aim of this study was to explore and describe the lived experiences of clinical supervisors who supervise nursing students at a higher education institution. The study employed a qualitative research approach utilizing a descriptive phenomenological design. Purposive sampling was used to select participants, who supervised first and second year nursing studnets at the higher education institution under study. TH esample comprised of eight clinical supervisors who supervise first and secon year nursing studnets at teh institution under study. Data was collected by means of in-depht interviews. Data was analysed using Collaizzi's seven steps method of qualitative analysis. Five major themes identified , focussed on the experiences regarding time a sa constraint to job productivity, the impact of teh organisational culture on the fluidity of support, interpersonal relationships a sa dynamic communication process, impact on the self, and limited resources. Trustworthiness of the data was ensured by means of applying Guba's model of truth value, applicability, consistency and neutrality. Reflexivity was also used by the researcher to further enhance trustworthiness.

Keywords: clinical supervision, clinical supervisors, nursing students, clinical placements

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Authors: Michael Daly

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Background/Aims: The interplay of childhood self-control and early life social background in predicting adult health is currently unclear. We drew on rich data from two large nationally representative cohort studies to test whether individual differences in childhood self-control may: (i) buffer the health impact of social disadvantage, (ii) act as a mediating pathway underlying the emergence of health disparities, or (iii) compensate for the health consequences of socioeconomic disadvantage across the lifespan. Methods: We examined data from over 25,000 participants from the British Cohort Study (BCS) and the National Child Development Study (NCDS). Child self-control was teacher-rated at age 10 in the BCS and ages 7/11 in the NCDS. The Early life social disadvantage was indexed using measures of parental education, occupational prestige, and housing characteristics (i.e. housing tenure, home crowding). A range of health outcomes was examined: the presence of chronic conditions, whether illnesses were limiting, physiological dysregulation (gauged by clinical indicators), mortality, and perceptions of pain, psychological distress, and general health. Results: Childhood self-control and social disadvantage predicted each measure of adult health, with similar strength on average. An examination of mediating factors showed that adult smoking, obesity, and socioeconomic status explained the majority of these linkages. There was no systematic evidence that self-control moderated the health consequences of early social disadvantage and limited evidence that self-control acted as a key pathway from disadvantage to later health. Conclusions: Childhood self-control predicts adult health and may compensate for early life social disadvantage by shaping adult health behaviour and social status.

Keywords: personality and health, social disadvantage, health psychology, life-course development

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Authors: Seham Alsaif, Susan Wray

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Obesity is a worldwide disorder influencing women’s health and childbearing. There is a close relation between obesity and pregnancy related complications. Dyslipidemia and adipokine dysregulation are core environmental changes that may mechanistically link these complications with obesity in pregnant women. We have previously found that visfatin has a relaxant effect on mouse, rat and human myometrial contractility. We hypothesised that visfatin inhibits mouse myometrial contractility through the NAD+ pathway. This study was designed to examine the mechanism of action of visfatin on myometrial contractility. To examine the NAD+ pathway, FK866 which is a potent inhibitor of NAD+ biosynthesis was used. Methods: Myometrial strips from term pregnant mice were dissected, superfused with physiological saline and the effects of visfatin (10nM) on oxytocin-induced contractions (0.5nM) alone and after the infusion of FK866 (10uM) were studied. After regular contractions were established, contractility was examined for control (100%) and test response at 37 °C for 10 min each. Results: FK866 was found to inhibit the effect of visfatin on myometrial contractility (the AUC increased from 89±2% of control, P=0.0009 for visfatin alone to 97±4% of control, P>0.05 for visfatin combined with FK866, n=8). In conclusion, NAD+ pathway appears to be involved in the mechanism of action of visfatin on mouse myometrium. This could have a role in making new targets to prevent obesity-related complications.

Keywords: myometrium, obesity, oxytocin, pregnancy, visfatin

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Authors: Maryam Saeidi, Ehsan Motamedian, Seyed Abbas Shojaosadati

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Zymomonas mobilis is known as an example of the uncoupled growth phenomenon. This microorganism also has a unique metabolism that degrades glucose by the Entner–Doudoroff (ED) pathway. In this paper, a genome-scale metabolic model including 434 genes, 757 reactions and 691 metabolites was reconstructed to simulate uncoupled growth and study its effect on flux distribution in the central metabolism. The model properly predicted that ATPase was activated in experimental growth yields of Z. mobilis. Flux distribution obtained from model indicates that the major carbon flux passed through ED pathway that resulted in the production of ethanol. Small amounts of carbon source were entered into pentose phosphate pathway and TCA cycle to produce biomass precursors. Predicted flux distribution was in good agreement with experimental data. The model results also indicated that Z. mobilis metabolism is able to produce biomass with maximum growth yield of 123.7 g (mol glucose)-1 if ATP synthase is coupled with growth and produces 82 mmol ATP gDCW-1h-1. Coupling the growth and energy reduced ethanol secretion and changed the flux distribution to produce biomass precursors.

Keywords: genome-scale metabolic model, Zymomonas mobilis, uncoupled growth, flux distribution, ATP dissipation

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Authors: Joshua W. Edefo, Shafiul Azam, Murray D. Smith

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Introduction: In April 2022, the Welsh Government introduced the six goals for urgent and emergency care programs. One of these goals was to provide access to clinically safe alternatives, leading to the establishment of the Same Day Emergency Care (SDEC) program. The SDEC initiative aims to offer viable options that maintain patient safety while avoiding unnecessary hospital stays. The aim of the study is to determine the duration of patient stay in SDEC and compare it with that of Emergency department (ED) stay to ascertain if one of the objectives of SDEC is achieved. Methods: Patient stays and attendance datasets were constructed from Withybush SDEC and ED patient records. These records were provided by Hywel Dda University Health Board Informatics. Some hypothetical pathways were identified, notably SDEC visits involving a single attendance and ED visits then immediately transferred to SDEC. Descriptive statistics were used to summarise the data, and hypothesis tests for mean differences used the student t-test. Propensity scoring was employed to match a set of ED patient stays to SDEC patient stays which were then used to determine the average treatment effect (ATE) to compare durations of stay in SDEC with ED. Regression methods were used to model the natural logarithm of the duration of SDEC attendance, and the level of statistical significance was set to 0.05. Results: SDEC visits involving a single attendance (170 of 384; 44.3%) is the most frequently observed pathway with patient length of stay at 256 minutes (95%CI 237.4 - 275.1). The next most frequently observed pathway of patient stay was SDEC attendance after presenting to ED (80 of 384; 20.8%) and gave the length of stay of 440 minutes (95%CI 351.6 - 529.2). Time spent in this pathway significantly increased by 184 minutes (95%CI 118.0 - 250.2, support for no difference p<0.001) compared to the most seen pathway. When SDEC data were compared with ED, the estimate for the ATE from SDEC single attendance was -272 minutes (95%CI -334.1 - -210.5; p<0.001), while that of ED then SDEC pathway was -50.6 min (95%CI -182.7-81.5; p=0.453). Conclusion: When patients are admitted to SDEC and successfully discharged, their stays are significantly shorter, approximately 4.5 hours, compared to patients who spend their entire stay in the Emergency Department. That difference vanishes when the patient stay includes a period spent previously in ED before transfer to SDEC.

Keywords: attendance, emergency-department, patient-stay, same-day-emergency-care

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Authors: Gina Leisching, Ray-Dean Pietersen, Carel Van Heerden, Paul Van Helden, Ian Wiid, Bienyameen Baker

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The distinguishing factors that characterize the host response to infection with virulent Mycobacterium tuberculosis (M.tb) are largely confounding. We present an infection study with two genetically closely related M.tb strains that have vastly different pathogenic characteristics. The early host response to infection with these detergent-free cultured strains was analyzed through RNAseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenotype. Murine bone marrow-derived macrophages (BMDMs) were infected with either a hyper- (R5527) or hypovirulent (R1507) Beijing M. tuberculosis clinical isolate. RNAseq revealed 69 differentially expressed host genes in BMDMs during comparison of these two transcriptomes. Pathway analysis revealed activation of the stress-induced and growth inhibitory Gadd45 signaling pathway in hypervirulent infected BMDMs. Upstream regulators of interferon activation such as and IRF3 and IRF7 were predicted to be upregulated in hypovirulent-infected BMDMs. Additional analysis of the host immune response through ELISA and qPCR included the use of human THP-1 macrophages where a robust proinflammatory response was observed after infection with the hypervirulent strain. RNAseq revealed two early-response genes (IER3 and SAA3) and two host-defence genes (OASL1 and SLPI) that were significantly upregulated by the hypervirulent strain. The role of these genes under M.tb infection conditions are largely unknown but here we provide validation of their presence with use of qPCR and Western blot. Further analysis into their biological role under infection with virulent M.tb is required.

Keywords: host-response, Mycobacterium tuberculosis, RNAseq, virulence

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Authors: Kamran Jawed, Anu Jose Mattam, Zia Fatma, Saima Wajid, Malik Z. Abdin, Syed Shams Yazdani

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Worldwide demand of natural and sustainable fuels and chemicals have encouraged researchers to develop microbial platform for synthesis of short chain fatty acids as they are useful precursors to replace petroleum-based fuels and chemicals. In this study, we evaluated the role of fatty acid synthesis and β-oxidation cycle of Escherichia coli to produce butyric acid, a 4-carbon short chain fatty acid, with the help of three thioesterases, i.e., TesAT from Anaerococcus tetradius, TesBF from Bryantella formatexigens and TesBT from Bacteroides thetaiotaomicron. We found that E. coli strain transformed with gene for TesBT and grown in presence of 8 g/L glucose produced maximum butyric acid titer at 1.46 g/L, followed by that of TesBF at 0.85 g/L and TesAT at 0.12 g/L, indicating that these thioesterases were efficiently converting short chain fatty acyl-ACP intermediate of fatty acid synthesis pathway into the corresponding acid. The titer of butyric acid varied significantly depending upon the plasmid copy number and strain genotype. Deletion of genes for fatty acyl-CoA synthetase and acyl-CoA dehydrogenase, which are involved in initiating the fatty acid degradation cycle, and overexpression of FadR, which is a dual transcriptional regulator and exerts negative control over fatty acid degradation pathway, reduced up to 30% of butyric acid titer. This observation suggested that β-oxidation pathway is working synergistically with fatty acid synthesis pathway in production of butyric acid. Moreover, accelerating the fatty acid elongation cycle by overexpressing acetyl-CoA carboxyltransferase (Acc) and 3-hydroxy-acyl-ACP dehydratase (FabZ) or by deleting FabR, the transcription suppressor of elongation, did not improve the butyric acid titer, rather favored the long chain fatty acid production. Finally, a balance between cell growth and butyric acid production was achieved with the use of phosphorous limited growth medium and 14.3 g/L butyric acid, and 17.5 g/L total free fatty acids (FFAs) titer was achieved during fed-batch cultivation. We have engineered an E. coli strain which utilizes the intermediate of both fatty acid synthesis and degradation pathway, i.e. butyryl-ACP and -CoA, to produce butyric acid from glucose. The strategy used in this study resulted in highest reported titers of butyric acid and FFAs in engineered E. coli.

Keywords: butenoic acid, butyric acid, Escherichia coli, fed-batch fermentation, short chain fatty acids, thioesterase

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Authors: Shih-Ping Liu, Cheng-Hsuan Chang, Yu-Chuen Huang, Shih-Yin Chen, Woei-Cherng Shyu

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Embryonic stem cells (ES) and induced pluripotnet stem cells (iPS) are both pluripotent stem cells. For mouse stem cells culture technology, leukemia inhibitory factor (LIF) was used to maintain the pluripotency of stem cells in vitro. However, LIF is an expensive reagent. The goal of this study was to find out a pure compound extracted from Chinese herbal medicine that could maintain stem cells pluripotency to replace LIF and improve the iPS generation efficiency. From 20 candidates traditional Chinese medicine we found that Cordycepsmilitaris triggered the up-regulation of stem cells activating genes (Oct4 and Sox2) expression levels in MEF cells. Cordycepin, a major active component of Cordycepsmilitaris, also could up-regulate Oct4 and Sox2 gene expression. Furthermore, we used ES and iPS cells and treated them with different concentrations of Cordycepin (replaced LIF in the culture medium) to test whether it was useful to maintain the pluripotency. The results showed higher expression levels of several stem cells markers in 10 μM Cordycepin-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryonic body formation and differentiation confirmed that 10 μM Cordycepin-containing medium was capable to maintain stem cells pluripotency after four times passages. For mechanism analysis, microarray analysis indicated extracellular matrix and Jak/Stat signaling pathway as the top two deregulated pathways. In ECM pathway, we determined that the integrin αVβ5 expression levels and phosphorylated Src levels increased after Cordycepin treatment. In addition, the phosphorylated Jak2 and phosphorylated Sat3 protein levels were increased after Cordycepin treatment and suppressed with the Jak2 inhibitor, AG490. The expression of cytokines associated with Jak2/Stat3 signaling pathway were also up-regulated by Q-PCR and ELISA assay. Lastly, we used Oct4-GFP MEF cells to test iPS generation efficiency following Cordycepin treatment. We observed that 10 Μm Cordycepin significantly increased the iPS generation efficiency in day 21. In conclusion, we demonstrated Cordycepin could maintain the pluripotency of stem cells through both of ECM and Jak2/Stat3 signaling pathway and improved iPS generation efficiency.

Keywords: cordycepin, iPS cells, Jak2/Stat3 signaling pathway, molecular biology

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Authors: Maria Monica D. Espinosa

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This study aimed to identify and examine the characteristics of an effective leader in a Hospital institution from the perspectives of military nurse-managers. The researcher extracted the different facets of leadership from the stories of six nurse- managers from a military hospital. The stories which are in pre-reflective stage convey an unbiased perspective from which clinical leadership may be defined. Using Phenomenology as a method of Research, the lived experiences of the military nurse-managers served as empirical data which were reflected upon until the formulation of insights. The information from the co-researchers became gallows from which the characteristics of effective leadership in the clinical area were drawn. These insights were synthesized through layers of reflection that resulted to the knowledge about clinical leadership. The reflections are the following, (a) Clinical leaders develop their skills through experiences and hardwork; (b) Clinical leaders are devoted; (c) Clinical leaders are focused; (d) Clinical leaders are good in interpersonal relationship; (e) Clinical leaders are mentors; (f) Clinical leaders seek affirmation and recognition; and (g) Clinical leaders are responsible and dependable. The common themes that emerged from the nurse manager’s stories showed that clinical leadership maybe attained if leaders possessed the following traits, (a) The gift to establish a steadfast and firm management; (b) The proficiency to guide and encourage others towards the achievement of their goals and objectives; (c) The ability to instigate participative and collaborative work among his/her subordinates and (d) The aptitude and skill to address the institutional concerns in their unit. In the future, Clinical leaders should continually adapt an evaluation program on how they can relate socially with their subordinates, the result of which can be used as a basis in developing strategies on relationship enhancement. Moreover, they should empower the nurses by allowing them to voice out their opinions and concerns regarding assignments, role expectations, and workload issues to improve and strengthen the relationships among nurses. Lastly, they can incorporate a collaborative strategy to promote professional socialization attitudes of nurse managers who work with staff nurses to improve the quality of their proficiencies and enhance a positive clinical environment.

Keywords: clinical leadership, experiences, implications, military nurse - managers, phenomenology

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Authors: Naif Al-Jomah, Falah H Al-Mohanna, Abdelilah Aboussekhra

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Active breast cancer-associated fibroblasts (CAFs), the most influential cells in breast tumor microenvironment, express/secrete high levels of the proinvasive/metastatic interleukin-6 (IL-6). Therefore, we have tested here the effect of the IL-6 receptor (IL-6R) inhibitor tocilizumab (TCZ; Actemra) on different active breast CAFs. We have shown that TCZ potently and persistently suppresses the expression of various CAF biomarkers, namely α-SMA, SDF-1 as well as the STAT3 pathway and its downstream target AUF1. TCZ also inhibited the proliferation, migration and invasion abilities of active breast CAF cells. Additionally, TCZ repressed the ability of CAF cells in promoting epithelial-to-mesenchymal transition, and enhancing the migratory/invasive and proliferative capacities of breast cancer cells in vitro. Importantly, these findings were confirmed in orthotopic humanized breast tumors in mice. Furthermore, TCZ suppressed the expression of the pro-angiogenic factor VEGF-A and its transactivator HIF-1α in CAF cells, and consequently inhibited the angiogenic-promoting effect of active CAFs both in vitro and in orthotopic tumor xenografts. These results indicate that inhibition of the IL-6/STAT3/AUF1 pathway by TCZ can normalize active breast CAFs and suppress their paracrine pro-carcinogenic effects, which paves the way toward development of specific CAF-targeting therapy, badly needed for more efficient breast cancer treatments.

Keywords: angiogenesis, interleukin-6, paracrine, cancer-associated fibroblasts

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