Search results for: therapeutic efficacy

Authors: Gerhard Gritsch, Ana Skupch, Manfred Hartmann, Wolfgang Frühwirt, Hannes Perko, Dieter Grossegger, Tilmann Kluge

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Rehabilitation of stroke patients is dominated by classical physiotherapy. Nowadays, a field of research is the application of neurofeedback techniques in order to help stroke patients to get rid of their motor impairments. Especially, if a certain limb is completely paralyzed, neurofeedback is often the last option to cure the patient. Certain exercises, like the imagination of the impaired motor function, have to be performed to stimulate the neuroplasticity of the brain, such that in the neighboring parts of the injured cortex the corresponding activity takes place. During the exercises, it is very important to keep the motivation of the patient at a high level. For this reason, the missing natural feedback due to a movement of the effected limb may be replaced by a synthetic feedback based on the motor-related brain function. To generate such a synthetic feedback a system is needed which measures, detects, localizes and visualizes the motor related µ-rhythm. Fast therapeutic success can only be achieved if the feedback features high specificity, comes in real-time and without large delay. We describe such an approach that offers a 3D visualization of µ-rhythms in real time with a delay of 500ms. This is accomplished by combining smart EEG preprocessing in the frequency domain with source localization techniques. The algorithm first selects the EEG channel featuring the most prominent rhythm in the alpha frequency band from a so-called motor channel set (C4, CZ, C3; CP6, CP4, CP2, CP1, CP3, CP5). If the amplitude in the alpha frequency band of this certain electrode exceeds a threshold, a µ-rhythm is detected. To prevent detection of a mixture of posterior alpha activity and µ-activity, the amplitudes in the alpha band outside the motor channel set are not allowed to be in the same range as the main channel. The EEG signal of the main channel is used as template for calculating the spatial distribution of the µ - rhythm over all electrodes. This spatial distribution is the input for a inverse method which provides the 3D distribution of the µ - activity within the brain which is visualized in 3D as color coded activity map. This approach mitigates the influence of lid artifacts on the localization performance. The first results of several healthy subjects show that the system is capable of detecting and localizing the rarely appearing µ-rhythm. In most cases the results match with findings from visual EEG analysis. Frequent eye-lid artifacts have no influence on the system performance. Furthermore, the system will be able to run in real-time. Due to the design of the frequency transformation the processing delay is 500ms. First results are promising and we plan to extend the test data set to further evaluate the performance of the system. The relevance of the system with respect to the therapy of stroke patients has to be shown in studies with real patients after CE certification of the system. This work was performed within the project ‘LiveSolo’ funded by the Austrian Research Promotion Agency (FFG) (project number: 853263).

Keywords: real-time EEG neuroimaging, neurofeedback, stroke, EEG–signal processing, rehabilitation

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Authors: Raj Chandran, Saul Datwyler, Jaime Marino, Daniel West, Karla Grasso, Adam Buss, Hina Syed, Zina Al Sahouri, Jennifer Yen, Krista Caudle, Beth McQuiston

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The Alinity i TBI test is Therapeutic Goods Administration (TGA) registered and is a panel of in vitro diagnostic chemiluminescent microparticle immunoassays for the measurement of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) in plasma and serum. The Alinity i TBI performance was evaluated in a multi-center pivotal study to demonstrate the capability to assist in determining the need for a CT scan of the head in adult subjects (age 18+) presenting with suspected mild TBI (traumatic brain injury) with a Glasgow Coma Scale score of 13 to 15. TBI has been recognized as an important cause of death and disability and is a growing public health problem. An estimated 69 million people globally experience a TBI annually1. Blood-based biomarkers such as glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have shown utility to predict acute traumatic intracranial injury on head CT scans after TBI. A pivotal study using prospectively collected archived (frozen) plasma specimens was conducted to establish the clinical performance of the TBI test on the Alinity i system. The specimens were originally collected in a prospective, multi-center clinical study. Testing of the specimens was performed at three clinical sites in the United States. Performance characteristics such as detection limits, imprecision, linearity, measuring interval, expected values, and interferences were established following Clinical and Laboratory Standards Institute (CLSI) guidance. Of the 1899 mild TBI subjects, 120 had positive head CT scan results; 116 of the 120 specimens had a positive TBI interpretation (Sensitivity 96.7%; 95% CI: 91.7%, 98.7%). Of the 1779 subjects with negative CT scan results, 713 had a negative TBI interpretation (Specificity 40.1%; 95% CI: 37.8, 42.4). The negative predictive value (NPV) of the test was 99.4% (713/717, 95% CI: 98.6%, 99.8%). The analytical measuring interval (AMI) extends from the limit of quantitation (LoQ) to the upper LoQ and is determined by the range that demonstrates acceptable performance for linearity, imprecision, and bias. The AMI is 6.1 to 42,000 pg/mL for GFAP and 26.3 to 25,000 pg/mL for UCH-L1. Overall, within-laboratory imprecision (20 day) ranged from 3.7 to 5.9% CV for GFAP and 3.0 to 6.0% CV for UCH-L1, when including lot and instrument variances. The Alinity i TBI clinical performance results demonstrated high sensitivity and high NPV, supporting the utility to assist in determining the need for a head CT scan in subjects presenting to the emergency department with suspected mild TBI. The GFAP and UCH-L1 assays show robust analytical performance across a broad concentration range of GFAP and UCH-L1 and may serve as a valuable tool to help evaluate TBI patients across the spectrum of mild to severe injury.

Keywords: biomarker, diagnostic, neurology, TBI

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Authors: Yogita Patil-Sen

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Superparamagnetic Iron Oxide Nanoparticles (SPIONs) have become increasingly important materials for separation of specific bio-molecules, drug delivery vehicle, contrast agent for MRI and magnetic hyperthermia for cancer therapy. Hyperthermia is emerging as an alternative cancer treatment to the conventional radio- and chemo-therapy, which have harmful side effects. When subjected to an alternating magnetic field, the magnetic energy of SPIONs is converted into thermal energy due to movement of particles. The ability of SPIONs to generate heat and potentially kill cancerous cells, which are more susceptible than the normal cells to temperatures higher than 41 °C forms the basis of hyerpthermia treatement. The amount of heat generated depends upon the magnetic properties of SPIONs which in turn is affected by their properties such as size and shape. One of the main problems associated with SPIONs is particle aggregation which limits their employability in in vivo drug delivery applications and hyperthermia cancer treatments. Coating the iron oxide core with thermally responsive lipid based nanostructures tend to overcome the issue of aggregation as well as improve biocompatibility and can enhance drug loading efficiency. Herein we report suitability of SPIONs and silica coated core-shell SPIONs, which are further, coated with various lipids for drug delivery and magnetic hyperthermia applications. The synthesis of nanoparticles is carried out using the established methods reported in the literature with some modifications. The nanoparticles are characterised using Infrared spectroscopy (IR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and Vibrating Sample Magnetometer (VSM). The heating ability of nanoparticles is tested under alternating magnetic field. The efficacy of the nanoparticles as drug carrier is also investigated. The loading of an anticancer drug, Doxorubicin at 18 °C is measured up to 48 hours using UV-visible spectrophotometer. The drug release profile is obtained under thermal incubation condition at 37 °C and compared with that under the influence of alternating magnetic field. The results suggest that the nanoparticles exhibit superparamagnetic behaviour, although coating reduces the magnetic properties of the particles. Both the uncoated and coated particles show good heating ability, again it is observed that coating decreases the heating behaviour of the particles. However, coated particles show higher drug loading efficiency than the uncoated particles and the drug release is much more controlled under the alternating magnetic field. Thus, the results demonstrate that lipid coated SPIONs exhibit potential as drug delivery vehicles for magnetic hyperthermia based cancer therapy.

Keywords: drug delivery, hyperthermia, lipids, superparamagnetic iron oxide nanoparticles (SPIONS)

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Authors: Shashi Bala, Neha A. Chugh, Subhash C. Bansal, Mohal L. Garg, Ashwani Koul

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Purpose: The present study was designed to evaluate the radioprotective efficacy of Aloe vera from whole body X-ray exposure in rodents. Materials and Methods: For this purpose, after on week’s acclimatization, male balb/c mice procured from Central Animal House, Panjab University, Chandigarh (India), were divided into four groups: Group I mice served as control. Group II mice were orally administrated Aloe vera pulp extract (50 mg/ kg body weight) on alternate days for 30 days. Group III mice were subjected to whole body X-ray irradiation to cumulative dose of 2Gy (0.258Gy twice a day for four days in the last week). Group IV animals were pretreated with Aloe vera pulp extract on alternate days as in Group II and in the last week of the study, they were exposed to X-ray as in Group III. Results: Spleen of X-ray irradiated mice showed histopathological alterations accompanied with enhanced activity of lactate dehydrogenase (LDH) in serum. Elevated levels of reactive oxygen species (ROS), lipid peroxidation (LPO), enhanced activities in Glutathione based enzymes such as Glutathione peroxidase (GSH-Px), Glutathione reductase (GR), Catalase (CAT), Superoxide dismutase (SOD) associated with depletion in reduced Glutathione (GSH) concentration were observed after X-ray exposure in blood plasma and spleen.. Pro-inflammatory cytokines like tumor necrosis factors (TNF-α) and Inteleukin-6 (IL-6) levels were also found to be enhanced in serum of irradiated mice. Irradiation-induced significant elevation in Total leucocyte counts (TLC), neutrophil counts and decline in platelet counts, associated with unaltered levels of red blood cell counts (RBC’s) and haemoglobin (Hb) in various treatment groups. Clastogenic damage and apoptosis was also found to be increase in splenic tissue of X-ray exposed mice as assessed by micronucleus and TUNEL assay. However, X-ray irradiated animals administered with Aloe vera revealed significant improvement in levels of ROS/ LPO, LDH activity, and antioxidant mechanism. Aloe vera pretreated animals exhibited less severe damage, and early recovery in micronucleated cells, hematological parameters, apoptotic cells and inflammatory markers as compared to X-ray exposed mice. Conclusion: These results indicate that the radioprotective potential of Aloe vera against X-ray induced damage. This may be due to its free radical scavenging, antioxidant, anti-apoptotic and anti-inflammatory properties.

Keywords: aloe vera, antioxidant defense system, lactate dehydrogenase (LDH), micronucleus assay, x-ray

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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: Naiara Ozamiz Etcebarria, Sonia Ruiz De Azua Garcia, Agurtzane Ortiz Jauregi, Virginia Guillen Cañas

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Introduction: The most relevant competencies of a health professional are an adequate communication capacity, which will influence the satisfaction of professionals and patients, therapeutic compliance, conflict prevention, clinical outcomes´ improvement and efficiency of health services. The ability of Active listening , empathy, assertiveness and social skills, are important abilities to develop in all professions in which there is a relationship with other people. In the field of health, it is even more important to have adequate qualities so that the treatment with the patient will be adequate and satisfactory. We conducted a research with students of third year in the Degree of Medicine with the objectives: - to know how the active listening, empathy, assertiveness and social skills of students are. - to know if there are differences according to different demographic variables, such as sex, language, age, number of siblings and interest in the subject. Material and Methods: The students of the Third year in the Degree of Medicine (N = 212) participated voluntarily. Sociodemographic data were collected. Descriptive and comparative analysis of the averages of the students with respect to active listening, empathy, assertiveness and social skills were performed. Once the questionnaires were collected, they were entered into the SPSS 21 database. Four communicational aspects were evaluated: The active listening questionnaire, the TECA empathy questionnaire, the ACDA questionnaire and the EHS questionnaire Social Skills Scale. The active listening questionnaire assesses these factors: Listening without interruption and less contradiction, Listening with 100% attention, Listening beyond words, Listening encouraging the other to go deeper. The TECA questionnaire of cognitive and affective empathy evaluates: Adoption of perspectives, Emotional Comprehension, Emphasizing stress, Empathic joy. The EHS questionnaire Social Skills Scale: Self-expression in social situations, Defending one's own rights as a consumer, Expressing anger or dissatisfaction, Refusing to do and cutting interactions off, Making requests, Initiating positive interactions with the other sex. The ACDA questionnaire Assertiveness Assessment Scale evaluates self-assertiveness and heteroaservitivity. Applicability: To train these skills is so important for clinical practice of medical students and these capabilities that can be measured in a longitudinal way time. Ethical-legal aspects: The data were anonymous. The study was approved by the Ethics Committee. Results: The students of the Third year in the Degree of Medicine (34.4% Basque speakers and 65.6% Spanish speakers) with average age 20.93, (27.8% men and 72.2% women). There are no differences in social skills between men and women. The Basque speaker students of are more heteroactive (ACDA) than Spanish students. Active listening has a high correlation with social skills, especially with self-expression in social situations. Listening without interruption has a high correlation with self-expression in social situations and initiating positive interactions with the opposite sex. Adoption of perspectives presents a high correlation with auto- assertiveness. Emotional understanding presents a high correlation with positive interactions with the opposite sex. Empathic joy correlates with self-assertiveness, self-expression in social situations, and initiating positive interactions with the opposite sex.

Keywords: active listening, assertiveness, communicational skills, empathy, students of medicine

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Authors: Clara Voyvodic

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Transitions from conflict to peace are by no means smooth nor linear, particularly from the perspective of those living through them. Over the last few decades, the changing focus in peacebuilding studies has come to appreciate the everyday experience of communities and how that provides a lens through which the relative success or efficacy of these transitions can be understood. In particular, the demobilization of a significant conflict actor is not without consequences, not just for the macro-view of state stabilization and peace, but for the communities who find themselves without a clear authority of territorial control. In Colombia, the demobilization and disarmament of the FARC guerilla group provided a brief respite to the conflict and a major political win for President Manuel Santos. However, this victory has proven short-lived. Drawing from extensive field research in Colombia within the last year, including interviews with local communities and actors operating in these regions, field observations, and other primary resources, this paper examines the post-accord transitions in Colombia and the everyday security experiences of local communities in regions formerly controlled by the FARC. In order to do so, the research focused on a semi-ethnographic approach in the northern region of the department of Antioquia and the coastal area of the border department of Nariño that documented how individuals within these marginalized communities have come to understand and negotiate their security in the years following the accord and the demobilization of the FARC. This presentation will argue that the removal of the FARC as an informal governance actor opened a space for multiple actors to attempt to control the same territory, including the state. This shift has had a clear impact on the everyday security experiences of the local communities. With an exploration of the dynamics of local governance and its impact on lived security experiences, this research seeks to demonstrate how distinct patterns of armed group behavior are emerging not only from a vacuum of control left by the FARC but from an increase in state presence that nonetheless remains inconsistent and unpersuasive as a monopoly of force in the region. The increased multiplicity of actors, particularly the state, has meant that the normal (informal) rules for communities to navigate these territories are no longer in play as the identities, actions, and intentions of different competing groups have become frustratingly opaque. This research provides a prescient analysis on how the shifting dynamics of territorial control in a post-peace accord landscape produce uncertain realities that affect the daily lives of the local communities and endanger the long-term prospect of human-centered security.

Keywords: armed actors, conflict transitions, informal governance, post-accord, security experiences

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Authors: Md. M. Hossain, Regan Roat, Jenica Christopherson, Colette Free, Zhiguang Guo

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Long noncoding RNA (lncRNA) mediated post-transcriptional gene regulation, and their epigenetic landscapes have been shown to be involved in many human diseases. However, their regulation in diabetes through governing islet’s β-cell function and survival needs to be elucidated. Due to the technical and ethical constraints, it is difficult to study their role in β-cell function and survival in human under in vivo condition. In this study, humanized mice have been developed through transplanting human pancreatic islet under the kidney capsule of NOD.SCID mice and induced β-cell death leading to diabetes condition to study lncRNA mediated regulation. For this, human islets from 3 donors (3000 IEQ, purity > 80%) were transplanted under the kidney capsule of STZ induced diabetic NOD.scid mice. After at least 2 weeks of normoglycecemia, lymphocytes from diabetic NOD mice were adoptively transferred and islet grafts were collected once blood glucose reached > 200 mg/dl. RNA from human donor islets, islet grafts from humanized mice with either adoptive lymphocyte transfer (ALT) or PBS control (CTL) were ribodepleted; barcoded fragment libraries were constructed and sequenced on the Ion Proton sequencer. lncRNA expression in isolated human islets, islet grafts from humanized mice with and without induced β-cell death and their regulation in human islets function in vitro under glucose challenge, cytokine mediated inflammation and induced apoptotic condition were investigated. Out of 3155 detected lncRNAs, 299 that highly expressed in islets were found to be significantly downregulated and 224 upregulated in ALT compared to CTL. Most of these are found to be collocated within 5 kb upstream and 1 kb downstream of 788 up- and 624 down-regulated mRNAs. Genomic Regions Enrichment of Annotations Analysis revealed deregulated and collocated genes are related to pancreas endocrine development; insulin synthesis, processing, and secretion; pancreatitis and diabetes. Many of them, that found to be located within enhancer domains for islet specific gene activity, are associated to the deregulation of known islet/βcell specific transcription factors and genes that are important for β-cell differentiation, identity, and function. RNA sequencing analysis revealed aberrant lncRNA expression which is associated to the deregulated mRNAs in β-cell function as well as in molecular pathways related to diabetes. A distinct set of candidate lncRNA isoforms were identified as highly enriched and specific to human islets, which are deregulated in human islets from donors with different BMIs and with type 2 diabetes. These RNAs show an interesting regulation in cultured human islets under glucose stimulation and with induced β-cell death by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the media of islets cultured with cytokines. Results of this study suggest that the islet specific lncRNAs are deregulated in human islet with β-cell death, hence important in diabetes. These lncRNAs might be important for human β-cell function and survival thus could be used as biomarkers and novel therapeutic targets for diabetes.

Keywords: β-cell, humanized mouse, pancreatic islet, LncRNAs

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Authors: Beth Jacobs

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The landmark movement of Western clinical psychology in the 20th century was the development of psychotherapy. The landmark movement of clinical psychology in the 21st century will be the absorption of meditation practices from Buddhist psychology. While millions of people explore meditation and related philosophy, very few people are exposed to the materials of original Buddhism on this topic, especially to the Theravadan Abhidharma. The Abhidharma is an intricate system of lists and matrixes that were used to understand and remember Buddha’s teaching. The Abhidharma delineates the first psychological system of Buddhism, how the mind works in the universe of reality and why meditation training strengthens and purifies the experience of life. Its lists outline the psychology of mental constructions, perception, emotion and cosmological causation. While the Abhidharma is technical, elaborate and complex, its essential purpose relates to the central purpose of clinical psychology: to relieve human suffering. Like Western depth psychology, the methodology rests on understanding underlying processes of consciousness and perception. What clinical psychologists might describe as therapeutic improvement, the Abhidharma delineates as a specific pathway of purified actions of consciousness. This paper discusses the concept of 'path' as presented in aspects of the Theravadan Abhidharma and relates this to current clinical psychological views of therapy outcomes and gains. The core path in Buddhism is the Eight-Fold Path, which is the fourth noble truth and the launching of activity toward liberation. The path is not composed of eight ordinal steps; it’s eight-fold and is described as opening the way, not funneling choices. The specific path in the Abhidharma is described in many steps of development of consciousness activities. The path is not something a human moves on, but something that moments of consciousness develop within. 'Cittas' are extensively described in the Abhidharma as the atomic-level unit of a raw action of consciousness touching upon an object in a field, and there are 121 types of cittas categorized. The cittas are embedded in the mental factors, which could be described as the psychological packaging elements of our experiences of consciousness. Based on these constellations of infinitesimal, linked occurrences of consciousness, citta are categorized by dimensions of purification. A path is a chain of citta developing through causes and conditions. There are no selves, no pronouns in the Abhidharma. Instead of me walking a path, this is about a person working with conditions to cultivate a stream of consciousness that is pure, immediate, direct and generous. The same effort, in very different terms, informs the work of most psychotherapies. Depth psychology seeks to release the bound, unconscious elements of mental process into the clarity of realization. Cognitive and behavioral psychologies work on breaking down automatic thought valuations and actions, changing schemas and interpersonal dynamics. Understanding how the original Buddhist concept of positive human development relates to the clinical psychological concept of therapy weaves together two brilliant systems of thought on the development of human well being.

Keywords: Abhidharma, Buddhist path, clinical psychology, psychotherapeutic outcome

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Authors: F. A. Thomas, M. Schrafl-Altermatt, R. Treier, S. Kaufmann

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Stroke is the main cause of adult disability. Especially upper limb function is affected in most patients. Recently, cooperative hand movements have been shown to be a promising type of upper limb training in stroke rehabilitation. In these movements, which are frequently found in activities of daily living (e.g. opening a bottle, winding up a blind), the force of one upper limb has to be equally counteracted by the other limb to successfully accomplish a task. The use of standardized and reliable clinical assessments is essential to evaluate the efficacy of therapy and the functional outcome of a patient. Many assessments for upper limb function or impairment are available. However, the evaluation of cooperative hand movement tasks are rarely included in those. Thus, the aim of this study was (i) to develop a novel clinical assessment (CASA - Cooperative Activity Stroke Assessment) for the evaluation of patients’ capacity to perform cooperative hand movements and (ii) to test its inter- and interrater reliability. Furthermore, CASA scores were compared to current gold standard assessments for upper extremity in stroke patients (i.e. Fugl-Meyer Assessment, Box & Blocks Test). The CASA consists of five cooperative activities of daily living including (1) opening a jar, (2) opening a bottle, (3) open and closing of a zip, (4) unscrew a nut and (5) opening a clipbox. Here, the goal is to accomplish the tasks as fast as possible. In addition to the quantitative rating (i.e. time) which is converted to a 7-point scale, also the quality of the movement is rated in a 4-point scale. To test the reliability of CASA, fifteen stroke subjects were tested within a week twice by the same two raters. Intra-and interrater reliability was calculated using the intraclass correlation coefficient (ICC) for total CASA score and single items. Furthermore, Pearson-correlation was used to compare the CASA scores to the scores of Fugl-Meyer upper limb assessment and the box and blocks test, which were assessed in every patient additionally to the CASA. ICC scores of the total CASA score indicated an excellent- and single items established a good to excellent inter- and interrater reliability. Furthermore, the CASA score was significantly correlated to the Fugl-Meyer and Box & Blocks score. The CASA provides a reliable assessment for cooperative hand movements which are crucial for many activities of daily living. Due to its non-costly setup, easy and fast implementation, we suggest it to be well suitable for clinical application. In conclusion, the CASA is a useful tool in assessing the functional status and therapy related recovery in cooperative hand movement capacity in stroke patients.

Keywords: activitites of daily living, clinical assessment, cooperative hand movements, reliability, stroke

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Authors: Santhani M. Selveindran

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Background: Natural disasters are traumatic global events that are becoming increasing more common, with significant psychosocial impact on survivors. This impact results not only in psychosocial distress but, for many, can lead to psychosocial disorders and chronic psychopathology. While there are currently available interventions that seek to prevent and treat these psychosocial sequelae, their effectiveness is uncertain. The evidence-base is emerging with more primary studies evaluating the effectiveness of various psychosocial interventions for survivors of natural disasters, which remains to be synthesized. Aim of Review: To identify, critically appraise and synthesize the current evidence-base on the effectiveness of psychosocial interventions in preventing or treating Post-Traumatic Stress Disorder (PTSD), Major Depressive Disorder (MDD) and/or Generalized Anxiety Disorder (GAD) in adults and children who are survivors of natural disasters. Methods: A protocol was developed as a guide to carry out this review. A systematic search was conducted in eight international electronic databases, three grey literature databases, one dissertation and thesis repository, websites of six humanitarian and non-governmental organizations renowned for their work on natural disasters, as well as bibliographic and citation searching for eligible articles. Papers meeting the specific inclusion criteria underwent quality assessment using the Downs and Black checklist. Data were extracted from the included papers and analysed by way of narrative synthesis. Results: Database and website searching returned 3777 papers where 31 met the criteria for inclusion. Additional 2 papers were obtained through bibliographic and citation searching. Methodological quality of most papers was fair. Twenty-five studies evaluated psychological interventions, five, social interventions whereas three studies evaluated ‘mixed’ psychological and social interventions. All studies, irrespective of methodological quality, reported post-intervention reductions in symptom scores for PTSD, depression and/or anxiety and where assessed, reduced diagnosis of PTSD and MDD, and produced improvements in self-efficacy and quality of life. Statistically significant results were seen in 27 studies. However, three studies demonstrated that the evaluated interventions may not have been very beneficial. Conclusions: The overall positive results suggest that any psychosocial interventions are favourable and should be delivered to all natural disaster survivors, irrespective of age, country, and phase of disaster. Yet, heterogeneity and methodological shortcomings of the current evidence-base makes it difficult to draw definite conclusions needed to formulate categorical guidance or frameworks. Further, rigorously conducted research is needed in this area, although the feasibility of such, given the context and nature of the problem, is also recognized.

Keywords: psychosocial interventions, natural disasters, survivors, effectiveness

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Authors: Aarti Sharma, Sarita Kumar, Pushplata Tripathi

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Aedes aegypti L. is one of the most important insect vectors in the world transmitting several diseases of concern; dengue fever, dengue haemorrhagic fever and yellow fever. Though since ages the control of dengue vector is primarily relied upon the use of synthetic chemical insecticides, the continued and indiscriminate use of insecticides for their control has received wide public apprehension because of multifarious problems including insecticide resistance, resurgence of pest species, environmental pollution, toxic hazards to humans and non-target organisms. These problems have necessitated the need to explore and develop alternative strategies using eco-friendly and bio-degradable plant products. Bio-insecticides, despite being the focus of research nowadays, have not been investigated much regarding their physiological effects on the mosquitoes. Thus, the present studies were carried out to investigate the anti-mosquito potential of the leaf and stem hexane extracts of Achyranthes aspera against early fourth instars of Aedes aegypti L and their effects on the histological architecture of their midgut. The larvicidal bioassays conducted with the A. aspera leaf hexane extracts revealed the respective LC30, LC50 and LC90 values of 66.545 ppm, 82.555 ppm, 139.817 ppm while the assays with stem hexane extracts resulted in respective values of 54.982 ppm, 68.133 ppm, 115.075 ppm. The studies clearly indicate the efficacy of extracts as larvicidal agents against Ae. aegypti, the stem extracts being found more effective than the leaf extracts. When the larvae assayed with extracts were investigated for the modifications in the histo-architecture of the midgut, the studies showed significant damage, shrinkage, distortion and vacuolization of gut tissues and peritrophic membrane causing disintegration of epithelial cells and cytoplasmic organelles; extent of toxicity and damage varied depending upon the concentration and exposure time period. These changes revealed appreciable stomach poison potential of A. aspera extracts against Ae. aegypti larvae, which may have also caused adverse impact on the growth and development of larvae. These effects were also found to be more pronounced with the stem extract than the leaf extract. Our findings may prove significant suggesting the use of A. aspera extract as a bio-insecticide against early fourth instar larvae of Ae. aegypti. Further studies are needed to identify the bioactive component in the extracts and to ascertain the use of component in the fields as anti-mosquito control agent.

Keywords: Achyranthes aspera, Aedes aegypti, histological architecture, larvicidal, midgut, stomach poison

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Authors: Louise Reyntjens

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The last quarter of the twentieth century was characterized by the emergence of a new kind of terrorism: religiously-inspired terrorism. Islam finds itself at the heart of this new wave, considering the number of international attacks committed by Islamic-inspired perpetrators. With religiously inspired terrorism as an operating framework, governments increasingly rely on immigration law to counter such terrorism. Immigration law seems particularly useful because its core task consists of keeping ‘unwanted’ people out. Islamic terrorists more often than not have an immigrant background and will be subject to immigration law. As a result, immigration law becomes more and more ‘securitized’. The European migration crisis has reinforced this trend. The research explores the human rights consequences of immigration law’s securitization in Europe. For this, the author selected four European countries for a comparative study: Belgium, France, the United Kingdom and Sweden. All these countries face similar social and security issues but respond very differently to them. The United Kingdom positions itself on the repressive side of the spectrum. Sweden on the other hand also introduced restrictions to its immigration policy but remains on the tolerant side of the spectrum. Belgium and France are situated in between. This contribution evaluates the situation in Belgium. Through a series of legislative changes, the Belgian parliament (i) greatly expanded the possibilities of expelling foreign nationals for (vaguely defined) reasons of ‘national security’; (ii) abolished almost all procedural protection associated with this decision (iii) broadened, as an extra security measure, the possibility of depriving individuals condemned of terrorism of their Belgian nationality. Measures such as these are obviously problematic from a human rights perspective; they jeopardize the principle of legality, the presumption of innocence, the right to protection of private and family life and the prohibition on torture. Moreover, this contribution also raises questions about the efficacy of immigration law’s suitability as a counterterrorism instrument. Is it a legitimate step, considering the type of terrorism we face today? Or, is it merely a strategic move, considering the broader maneuvering space immigration law offers and the lack of political resistance governments receive when infringing the rights of foreigners? Even more so, figures demonstrate that today’s terrorist threat does not necessarily stem from outside our borders. Does immigration law then still absorb - if it has ever done so (completely) - the threat? The study’s goal is to critically assess, from a human rights perspective, the counterterrorism strategies European governments have adopted. As most governments adopt a variation of the same core concepts, the study’s findings will hold true even beyond the four countries addressed.

Keywords: Belgium, counterterrorism strategies, human rights, immigration law

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Authors: Vanessa G. P. Severino, Eliangela Cristina Candida Costa, Nubia Alves Mariano Teixeira Pires Gomides, Lucilia Kato, Afif Felix Monteiro, Maria Anita Lemos Vasconcelos Ambrosio, Carlos Henrique Gomes Martins

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One of the biomes present in Brazil is known as Cerrado, which is a vast tropical savanna ecoregion, particularly in the states of Goiás, Mato Grosso do Sul, Mato Grosso, Tocantins and Minas Gerais. Many species of plants are characterized as endemic and they have therapeutic value for a large part of the population, especially to the rural communities. Given that, the southeastern region of the state of Goiás contains about 21 rural communities, which present a form of organization based on the use of natural resources available. One of these rural communities is named of Coqueiros, where the knowledge about the medicinal plants was very important to this research. Thus, this study focuses on the ethnobotanical survey of this community on the use of Kielmeyera coriacea to treat diseases. From the 37 members interviewed, 76% indicated this species for the treatment of intestinal infection, leukemia, anemia, gastritis, gum pain, toothache, cavity, arthritis, arthrosis, healing, vermifuge, rheumatism, antibiotic, skin problems, mycoses and all kinds of infections. The medicinal properties attributed during the interviews were framed in the body system (disease categories), adapted from ICD 10; thus, 20 indications of use were obtained, among five body systems. Therefore, the root of this species was select to chemical and biological (antioxidant and antimicrobial) studies. From the liquid-liquid extraction of ethanolic extract of root (EER), the hexane (FH), ethyl acetate (FAE), and hydro alcoholic (FHA) fractions were obtained. The chemical profile study of these fractions was performed by LC-MS, identifying major compounds such as δ-tocotrienol, prenylated acylphoroglucinol, 2-hydroxy-1-methoxyxanthone and quercitrin. EER, FH, FAE and FHA were submitted to biological tests. FHA presented the best antioxidant action (EC50 201.53 μg mL-1). EER inhibited the bacterial growth of Streptococcus pyogenes and Pseudomonas aeruginosa, microorganisms associated with rheumatism, at Minimum Inhibitory Concentration (MIC) of 6.25 μg mL-1. In addition, the FH-10 subfraction, obtained from FH fractionation, presented MIC of 1.56 μg mL-1 against S. pneumoniae; EER also inhibited the fungus Candida glabrata (MIC 7.81 μg mL- 1). The FAE-4.7.3 fraction, from the fractionation of FAE, presented MIC of 200 μg mL-1 against Lactobacillus casei, which is one of the causes of caries and oral infections. By the correlation of the chemical and biological data, it is possible to note that the FAE-4.7.3 and FH-10 are constituted 4-hydroxy-2,3-methylenedioxy xanthone, 3-hydroxy-1,2-dimethoxy xanthone, lupeol, prenylated acylphoroglucinol and quercitrin, which could be associated with the biological potential found. Therefore, this study provides an important basis for further investigations regarding the compounds present in the active fractions of K. coriacea, which will permit the establishment of a correlation between ethnobotanical survey and bioactivity.

Keywords: biological activity, ethnobotanical survey, Kielmeyera coriacea Mart., LC-MS profile

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Authors: Cameron Wilson, Megan Hanrahan, Katie Brittain, Riona McArdle, Alison Keogh, Lynn Rochester

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Background: The loss of mobility and functional dependence is a significant marker in the progression of neurodegenerative diseases such as Parkinson’s Disease (PD). Pharmacological, surgical, and therapeutic treatments are available that can help in the management and amelioration of PD symptoms; however, these only prolong more severe symptoms. Accordingly, ensuring people with PD can maintain independence and a healthy wellbeing are essential in establishing an effective treatment option for those afflicted. Existing literature reviews have examined experiences in engaging with PD treatment options and the impact of PD on independence and wellbeing. Although, the literature fails to explore the influence of treatment options on independence and wellbeing and therefore misses what people value in their treatment. This review is the first that synthesises the impact of mobility-related treatments on independence and wellbeing in people with PD and their carers, offering recommendations to clinical practice and provides a conceptual framework (in development) for future research and practice. Objectives: To explore the impact of mobility-related treatment (both pharmacological and non-pharmacological) on the independence and wellbeing of people with PD and their carers. To propose a conceptual framework to patients, carers and clinicians which captures the qualities people with PD value as part of their treatment. Methods: We performed a critical interpretive synthesis of qualitative evidence, searching six databases for reports that explored the impact of mobility-related treatments (both drug and non-pharmacological) on independence and wellbeing in Parkinson’s Disease. The types of treatments included medication (Levodopa and Amantadine), dance classes, Deep-Brain Stimulation, aquatic therapies, physical rehabilitation, balance training and foetal transplantation. Data was extracted, and quality was assessed using an adapted version of the NICE Quality Appraisal Tool Appendix H before being synthesised according to the critical interpretive synthesis framework and meta-ethnography process. Results: From 2301 records, 28 were eligible. Experiences and impact of treatment pathway on independence and wellbeing was similar across all types of treatments and are described by five inter-related themes: (i) desire to maintain independence, (ii) treatment as a social experience during and after, (iii) medication to strengthen emotional health, (iv) recognising physical capacity and (v) emphasising the personal journey of Parkinson’s treatments. Conclusion: There is a complex and inter-related experience and effect of PD treatments common across all types of treatment. The proposed conceptual framework (in development) provides patients, carers, and clinicians recommendations to personalise the delivery of PD treatment, thereby potentially improving adherence and effectiveness. This work is vital to disseminate as PD treatment transitions from subjective and clinically captured assessments to a more personalised process supplemented using wearable technology.

Keywords: parkinson's disease, medication, treatment, dance, review, healthcare, delivery, levodopa, social, emotional, psychological, personalised healthcare

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Authors: Fouad Mrad, Viviane Zaccour

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The accelerated developments in the political, economic, environmental, security, health, and social folders are exhausting planners across the world, especially in Arab countries. The impact of the tension is multifaceted and has resulted in conflicts, wars, migration, and human insecurity. The potential cross-cutting role that science, innovation and technology can play in supporting Arab societies to address these pressing challenges is a serious, unique chance for the people of the region. This opportunity is based on the existing capacity of educated youth and inaccessible talents in the local universities and research centers. It has been accepted that Arab countries have achieved major advancements in the economy, education and social wellbeing since the 70s of the 20th Century. Mainly direct outcome of the oil and other natural resources. The UN Secretary-General, during the Education Summit in Sep 2022, stressed that “Learning continues to underplay skills, including problem-solving, critical thinking and empathy.” Stars of Science by Qatar Foundation was launched in 2009 and has been sustained through 2023. Consistent mission from the start: To mobilize a new generation of Pan-Arab innovators and problem solvers by encouraging youth participation and interest in Science, Technology and Entrepreneurship throughout the Arab world via the program and its social media activities. To make science accessible and attractive to mass audiences by de-mystifying the process of innovation. Harnessing best practices within reality TV to show that science, engineering, and innovation are important in everyday life and can be fun.” Thousands of Participants learned unforgettable lessons; winners changed their lives forever as they learned and earned seed capital; they became drivers of change in their countries and families; millions of viewers were exposed to an innovative experimental process, and culturally, several relevant national institutions adopted the SOS track in their national initiatives. The program exhibited experientially youth self-efficacy as the most distinct core property of human agency, which is an individual's belief in his or her capacity to execute behaviors necessary to produce specific performance attainments. In addition, the program proved that innovations are performed by networks of people with different sets of technological, useful knowledge, skills and competencies introduced by socially shared technological knowledge as a main determinant of economic activities in any economy.

Keywords: science, invention, innovation, Qatar foundation, QSTP, prototyping

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Authors: Katarzyna Drela, Miroslaw Wielgos, Mikolaj Wrobel, Barbara Lukomska

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Mesenchymal stem cells (MSCs) have a great potential in regenerative medicine. Since the initial number of isolated MSCs is limited, in vitro propagation is often required to reach sufficient numbers of cells for therapeutic applications. During long-term culture MSCs may undergo genetic or epigenetic alterations that subsequently increase the probability of spontaneous malignant transformation. Thus, factors that influence genomic stability of MSCs following long-term expansions need to be clarified before cultured MSCs are employed for clinical application. The aim of our study was to investigate the potential for spontaneous transformation of human neonatal cord blood (HUCB-MSCs) and adult bone marrow (BM-MSCs) derived MSCs. Materials and Methods: HUCB-MSCs and BM-MSCs were isolated by standard Ficoll gradient centrifugations method. Isolated cells were initially plated in high density 106 cells per cm2. After 48 h medium were changed and non-adherent cells were removed. The malignant transformation of MSCs in vitro was evaluated by morphological changes, proliferation rate, ability to enter cell senescence, the telomerase expression and chromosomal abnormality. Proliferation of MSCs was analyzed with WST-1 reduction method and population doubling time (PDT) was calculated at different culture stages. Then the expression pattern of genes characteristic for mesenchymal or epithelial cells, as well as transcriptions factors were examined by RT-PCR. Concomitantly, immunocytochemical analysis of gene-related proteins was employed. Results: Our studies showed that MSCs from all bone marrow isolations ultimately entered senescence and did not undergo spontaneous malignant transformation. However, HUCB-MSCs from one of the 15 donors displayed an increased proliferation rate, failed to enter senescence, and exhibited an altered cell morphology. In this sample we observed two different cell phenotypes: one mesenchymal-like exhibited spindle shaped morphology and express specific mesenchymal surface markers (CD73, CD90, CD105, CD166) with low proliferation rate, and the second one with round, densely package epithelial-like cells with significantly increased proliferation rate. The PDT of epithelial-like populations was around 1day and 100% of cells were positive for proliferation marker Ki-67. Moreover, HUCB-MSCs showed a positive expression of human telomerase reverse transcriptase (hTERT), cMYC and exhibit increased number of CFU during the long-term culture in vitro. Furthermore, karyotype analysis revealed chromosomal abnormalities including duplications. Conclusions: Our studies demonstrate that HUCB-MSCs are susceptible to spontaneous malignant transformation during long-term culture. Spontaneous malignant transformation process following in vitro culture has enormous effect on the biosafety issues of future cell-based therapies and regenerative medicine regimens.

Keywords: mesenchymal stem cells, spontaneous, transformation, long-term culture

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Authors: Vivek Bhat, Rohini Kelkar, Sanjay Biswas

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Introduction: Cancer patients are at increased risk of bacterial infections. This may due to the disease process itself, the effect of chemotherapeutic drugs or invasive procedures such as catheterization. A wide variety of bacteria including some emerging pathogens are increasingly being reported from these patients. The incidence of multidrug-resistant organisms particularly in the Gram negative group is also increasing, with higher resistance rates seen to cephalosporins, β-lactam/β-lactam inhibitor combinations, and the carbapenems. This study documents the bacteriological spectrum of infections and their resistance patterns in cancer patients. Methods: This study includes all bacterial isolates recovered from infections cancer patients over a period of 18 months. Samples included Blood cultures, Pus/wound swabs, urine, tissue biopsies, body fluids, catheter tips and respiratory specimens such as sputum and bronchoalveolar lavage (BAL). All samples were processed in the microbiology laboratory as per standard laboratory protocols. Organisms were identified to species level and antimicrobial susceptibility testing was performed manually by the disc diffusion technique or in the Vitek-2 (Biomereux, France) instrument. Interpretations were as per Clinical laboratory Standards Institute (CLSI) guidelines. Results: A total of 1150 bacterial isolates were cultured from 884 test samples during the study period. Of these 227 were Gram-positive and 923 were Gram-negative organisms. Staphylococcus aureus (99 isolates) was the commonest Gram-positive isolate followed by Enterococcus (79) and Gr A Streptococcus (30). Among the Gram negatives, E. coli (304), Pseudomonas aeruginosa (201) and Klebsiella pneumoniae (190) were the most common. Of the Staphylococcus aureus isolates 27.2% were methicillin resistant. Only 5.06% enterococci were vancomycin resistant. High rates of resistance to cefotaxime and ciprofloxacin were seen amongst E. coli (84.8% & 83.55%) and Klebsiella pneumoniae (71 & 62.1%) respectively. Resistance to carbapenems (meropenem) was high at 70% in Acinetobacter spp.; however all isolates were sensitive to colistin. Among the aminoglycosides, amikacin retained good efficacy against Escherichia coli (82.9%) and Pseudomonas aeruginosa (78.1%). Occasional isolates of emerging pathogens such as Chryseobacterium indologens, Roseomonas, and Achromobacter xyloxidans were also recovered. Conclusion: The common infections in cancer patients include respiratory, wound, tract infections and sepsis. The commonest isolates include Staphylococcus aureus, Enterococci, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. There is a high level of resistance to the commonly used antibiotics among Gram-negative organisms.

Keywords: bacteria, resistance, infection, cancer

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Authors: Ahlam Ali, Katrina Lappin, Jaine Blayney, Ken Mills

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Leukaemia is the most frequently (30%) occurring type of paediatric cancer. Of these, approximately 80% are acute lymphoblastic leukaemia (ALL) with acute myeloid leukaemia (AML) cases making up the remaining 20% alongside other leukaemias. Unfortunately, children with AML do not have promising prognosis with only 60% surviving 5 years or longer. It has been highlighted recently the need for age-specific therapies for AML patients, with paediatric AML cases having a different mutational landscape compared with AML diagnosed in adult patients. Drug Repurposing is a recognized strategy in drug discovery and development where an already approved drug is used for diseases other than originally indicated. We aim to identify novel combination therapies with the promise of providing alternative more effective and less toxic induction therapy options. Our in-silico analysis highlighted ‘cell death and survival’ as an aberrant, potentially targetable pathway in paediatric AML patients. On this basis, 83 apoptotic inducing compounds were screened. A preliminary single agent screen was also performed to eliminate potentially toxic chemicals, then drugs were constructed into a pooled library with 10 drugs per well over 160 wells, with 45 possible pairs and 120 triples in each well. Seven cell lines were used during this study to represent the clonality of AML in paediatric patients (Kasumi-1, CMK, CMS, MV11-14, PL21, THP1, MOLM-13). Cytotoxicity was assessed up to 72 hours using CellTox™ Green reagent. Fluorescence readings were normalized to a DMSO control. Z-Score was assigned to each well based on the mean and standard deviation of all the data. Combinations with a Z-Score <2 were eliminated and the remaining wells were taken forward for further analysis. A well was considered ‘successful’ if each drug individually demonstrated a Z-Score <2, while the combination exhibited a Z-Score >2. Each of the ten compounds in one well (155) had minimal or no effect as single agents on cell viability however, a combination of two or more of the compounds resulted in a substantial increase in cell death, therefore the ten compounds were de-convoluted to identify a possible synergistic pair/triple combinations. The screen identified two possible ‘novel’ drug pairing, with BCL2 inhibitor ABT-737, combined with either a CDK inhibitor Purvalanol A, or AKT/ PI3K inhibitor LY294002. (ABT-737- 100 nM+ Purvalanol A- 1 µM) (ABT-737- 100 nM+ LY294002- 2 µM). Three possible triple combinations were identified (LY2409881+Akti-1/2+Purvalanol A, SU9516+Akti-1/2+Purvalanol A, and ABT-737+LY2409881+Purvalanol A), which will be taken forward for examining their efficacy at varying concentrations and dosing schedules, across multiple paediatric AML cell lines for optimisation of maximum synergy. We believe that our combination screening approach has potential for future use with a larger cohort of drugs including FDA approved compounds and patient material.

Keywords: AML, drug repurposing, ABT-737, apoptosis

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Authors: Birgit Rasmussen, Thomas Maribo, Bente S. Toft

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BACKGROUND: Cardiac rehabilitation is the standard treatment for ischemic heart disease. Cardiac rehabilitation improves quality of life, reduces mortality and the risk of readmission, and provides patients with valuable knowledge and encouragement from peers and staff. Still, less than half of eligible patients enroll. Face-to-face interventions have the potential to support patients' decision-making and increase enrolment in cardiac rehabilitation. However, we lack knowledge of the content and characteristics of interventions. AIM: The aim was to outline and evaluate the content and characteristics of studies that have reported on face-to-face interventions to encourage enrolment in cardiac rehabilitation in patients with ischemic heart disease. METHOD: This scoping review followed the Joanne Briggs Institute methodology. Based on an a-priori protocol that defined the systematic search criteria, six databases were searched for studies published between 2001 and 2023. Two reviewers independently screened and selected studies. All authors discussed the summarized data prior to the narrative presentation. RESULTS: After screening and full text review of 5583 records, 20 studies of heterogeneous design and content were included. Four studies described the key contents in face-to-face interventions to be education, support of autonomy, addressing reasons for change, and emotional and cognitive support while showing understanding. Two studies used motivational interviewing to target patients' experiences and address worries and anticipated difficulties. Four quantitative studies found associations between enrolment and intention to attend, cardiac rehabilitation barriers, exercise self-efficacy, and perceived control. When patients asked questions, enrolment rates were higher, while providing reassurance and optimism could lead to non-attendance if patients had a high degree of worry. In qualitative studies, support to overcome barriers and knowledge about health benefits from participation in cardiac rehabilitation facilitated enrolment. Feeling reassured that the cardiac condition was good could lead to non-attendance. DISCUSSION AND CONCLUSION: To support patients' enrolment in cardiac rehabilitation, it is recommended that interventions integrate a person-centered dialogue. Individual worries and barriers to cardiac rehabilitation should be jointly explored. When talking with patients for whom worries predominate, the recommendation is to focus on the patients' perspectives and avoid too much focus on reassurance and problem-solving. The patients' perspectives, the mechanisms of change, and the process evaluation of the intervention including person-centeredness are relevant to include in future studies.

Keywords: ischemic heart disease, cardiac rehabilitation, enrolment, person-centered, in-hospital interventions

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Authors: Aneal Khan, Elleine Allapitan, Desmond Koo, Katherine-Ann Piedalue, Shaneel Pathak, Utkarsh Subnis

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Background: Disease management of metabolic, genetic disorders is long-term and can be cumbersome to patients and caregivers. Patient-Reported Outcome Measures (PROMs) have been a useful tool in capturing patient perspectives to help enhance treatment compliance and engagement with health care providers, reduce utilization of emergency services, and increase satisfaction with their treatment choices. Currently, however, PROMs are collected during infrequent and decontextualized clinic visits, which makes translation of patient experiences challenging over time. The GRIT study aims to evaluate a digital health journal application called Zamplo that provides a personalized health diary to record self-reported health outcomes accurately and efficiently in patients with metabolic, genetic disorders. Methods: This is a randomized controlled trial (RCT) (1:1) that assesses the efficacy of Zamplo to increase patient activation (primary outcome), improve healthcare satisfaction and confidence to manage medications (secondary outcomes), and reduce costs to the healthcare system (exploratory). Using standardized online surveys, assessments will be collected at baseline, 1 month, 3 months, 6 months, and 12 months. Outcomes will be compared between patients who were given access to the application versus those with no access. Results: Seventy-seven patients were recruited as of November 30, 2021. Recruitment for the study commenced in November 2020 with a target of n=150 patients. The accrual rate was 50% from those eligible and invited for the study, with the majority of patients having Fabry disease (n=48) and the remaining having Pompe disease and mitochondrial disease. Real-time clinical responses, such as pain, are being measured and correlated to disease-modifying therapies, supportive treatments like pain medications, and lifestyle interventions. Engagement with the application, along with compliance metrics of surveys and journal entries, are being analyzed. An interim analysis of the engagement data along with preliminary findings from this pilot RCT, and qualitative patient feedback will be presented. Conclusions: The digital self-care journal provides a unique approach to disease management, allowing patients direct access to their progress and actively participating in their care. Findings from the study can help serve the virtual care needs of patients with metabolic, genetic disorders in North America and the world over.

Keywords: eHealth, mobile health, rare disease, patient outcomes, quality of life (QoL), pain, Fabry disease, Pompe disease

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Authors: Zahra Mohajer, Afsaneh Soltani

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Doping is a major issue in competitive sports and is favored by vast groups of athletes. The feeling of being higher-ranking than others and gaining fame has caused many athletes to misuse drugs. The definition of doping is to use prohibited substances and/or methods that help physical or mental performances or both. Doping counts as the illegal use of chemical substances or drugs, excessive amounts of physiological substances to increase the performance at or out of competition or even the use of inappropriate medications to treat an injury to gain the ability to participate in a competition. The International Olympic Committee (IOC) and World Anti-Doping Agency (WADA) have forbidden these substances to ensure fair and equal competition and also the health of the competitors. As of 2004 WADA has published an international list of illegal substances used for doping, which is updated annually. In the process of the Genome Project scientists have gained the ability to treat numerous diseases by gene therapy, which may result in bodily performance increase and therefore a potential opportunity to misuse by some athletes. Gene doping is defined as the non-therapeutic direct and indirect genetic modifications using genetic materials that can improve the performances in sports events. Biosynthetic drugs are a form of indirect genetic engineering. The method can be performed in three ways such as injecting the DNA directly into the muscle, inserting the genetically engineered cells, or transferring the DNA using a virus as a vector. Erythropoietin is a hormone majorly released by the kidney and in small amounts by the liver. Its function is to stimulate the erythropoiesis and therefore the more production of red blood cells (RBC) which causes an increase in Hemoglobin (Hb). During this process, the oxygen delivery to muscles will increase, which will improve athletic performance and postpone exhaustion. There are ways to increase the oxygen transferred to muscles such as blood transfusion, stimulating the production of red blood cells by using Erythropoietin (EPO), and also using allosteric effectors of Hemoglobin. EPO can either be injected as a protein or can be inserted into the cells as the gene which encodes EPO. Adeno-associated viruses have been employed to deliver the EPO gene to the cells. Employing the genes that naturally exist in the human body such as the EPO gene can reduce the risk of detecting gene doping. The first research about blood doping was conducted in 1947. The study has shown that an increase in hematocrit (HCT) up to 55% following homologous transfusion makes it more unchallenging for the body to perform the exercise at the altitude. Thereafter athletes’ attraction to blood infusion escalated. Also, a study has demonstrated that by reinfusing their own blood 4 weeks after being drawn, three men have shown a rise in Hb level which improved the oxygen uptake, and a delay in exhaustion. The list of performance-enhancing drugs is published by WADA annually and includes the following drugs: anabolic agents, hormones, Beta-2 agonists, Beta-blockers, Diuretics, Stimulants, narcotics, cannabinoids, and corticosteroids.

Keywords: doping, PEDs, sports, WADA

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Authors: Rahaba Marima, Clement Penny

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The Health-related quality of life (HRQoL) for HIV positive patients has improved since the introduction of the highly active antiretroviral treatment (HAART). However, in the present HAART era, HIV co-morbidities such as lung cancer, a non-AIDS (NAIDS) defining cancer have been documented to be on the rise. Under normal physiological conditions, cells grow, repair and proliferate through the cell-cycle as cellular homeostasis is important in the maintenance and proper regulation of tissues and organs. Contrarily, the deregulation of the cell-cycle is a hallmark of cancer, including lung cancer. The association between lung cancer and the use of HAART components such as Efavirenz (EFV) is poorly understood. This study aimed at elucidating the effects of EFV on the cell-cycle genes’ expression in lung cancer. For this purpose, the human cell-cycle gene array composed of 84 genes was evaluated on both normal lung fibroblasts (MRC-5) cells and adenocarcinoma (A549) lung cells, in response to 13µM EFV or 0.01% vehicle. The ±2 up or down fold change was used as a basis of target selection, with p < 0.05. Additionally, RT-qPCR was done to validate the gene array results. Next, In-silico bio-informatics tools, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Ingenuity Pathway Analysis (IPA) were used for gene/gene interaction studies as well as to map the molecular and biological pathways influenced by the identified targets. Interestingly, the DNA damage response (DDR) pathway genes such as p53, Ataxia telangiectasia mutated and Rad3 related (ATR), Growth arrest and DNA damage inducible alpha (GADD45A), HUS1 checkpoint homolog (HUS1) and Role of radiation (RAD) genes were shown to be upregulated following EFV treatment, as revealed by STRING analysis. Additionally, functional enrichment analysis by the KEGG pathway revealed that most of the differentially expressed gene targets function at the cell-cycle checkpoint such as p21, Aurora kinase B (AURKB) and Mitotic Arrest Deficient-Like 2 (MAD2L2). Core analysis by IPA revealed that p53 downstream targets such as survivin, Bcl2, and cyclin/cyclin dependent kinases (CDKs) complexes are down-regulated, following exposure to EFV. Furthermore, Reactome analysis showed a significant increase in cellular response to stress genes, DNA repair genes, and apoptosis genes, as observed in both normal and cancerous cells. These findings implicate the genotoxic effects of EFV on lung cells, provoking the DDR pathway. Notably, the constitutive expression of this pathway (DDR) often leads to uncontrolled cell proliferation and eventually tumourigenesis, which could be the attribute of HAART components’ (such as EFV) effect on human cancers. Targeting the cell-cycle and its regulation holds a promising therapeutic intervention to the potential HAART associated carcinogenesis, particularly lung cancer.

Keywords: cell-cycle, DNA damage response, Efavirenz, lung cancer

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Authors: Patrícia Pires, Renata Vaz, Bárbara Teles, Marco Pato, Pedro Beckert

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Introduction: The management of lateral third clavicle fractures can be challenging due to difficulty in distinguishing subtle variations in the fracture pattern, which may be suggestive of potential fracture instability. They occur most often in men between 30 and 50 years of age, and in individuals over 70 years of age, its distribution is equal between both men and women. These fractures account for 10%–30% of all clavicle fractures and roughly 30%–45% of all clavicle nonunion fractures. Lateral third clavicle fractures may be treated conservatively or surgically, and there is no gold standard, although the risk of nonunion or pseudoarthrosis impacts the recommendation of surgical treatment when these fractures are unstable. There are many strategies for surgical treatment, including locking plates, hook plates fixation, coracoclavicular fixation using suture anchors, devices or screws, tension band fixation with suture or wire, transacromial Kirschner wire fixation and arthroscopically assisted techniques. Whenever taking the hardware into consideration, we must not disregard that obtaining adequate lateral fixation of small fragments is a difficult task, and plates are more associated to local irritation. The aim of the appropriate treatment is to ensure fracture healing and a rapid return to preinjury activities of daily living but, as explained, definitive treatment strategies have not been established and the variety of techniques avalilable add up to the discussion of this topic. Methods and Results: We present a clinical case of a 43-year-old man with the diagnosis of a lateral third clavicle fracture (Neer IIC) in the sequence of a fall on his right shoulder after a bicycle fall. He was operated three days after the injury, and through K-wire temporary fixation and indirect reduction using a ZipTight, he underwent osteosynthesis with an interfragmentary figure-of-eight tension band with polydioxanone suture (PDS). Two weeks later, there was a good aligment. He kept the sling until 6 weeks pos-op, avoiding efforts. At 7-weeks pos-op, there was still a good aligment, starting the physiotherapy exercises. After 10 months, he had no limitation in mobility or pain and returned to work with complete recovery in strength. Conclusion: Some distal clavicle fractures may be conservatively treated, but it is widely accepted that unstable fractures require surgical treatment to obtain superior clinical outcomes. In the clinical case presented, the authors chose an osteosuture technique due to the fracture pattern, its location. Since there isn´t a consensus on the prefered fixation method, it is important for surgeons to be skilled in various techniques and decide with their patient which approach is most appropriate for them, weighting the risk-benefit of each method. For instance, with the suture technique used, there is no wire migration or breakage, and it doesn´t require a reoperation for hardware removal; there is also less tissue exposure since it requires a smaller approach in comparison to the plate fixation and avoids cuff tears like the hook plate. The good clinical outcome on this case report serves the purpose of expanding the consideration of this method has a therapeutic option.

Keywords: lateral third, clavicle, suture, fixation

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Authors: Jason Blair, Adeboye Adebayo, Mohamed Saad, Jeannette M. Byrne, Fabien A. Basset

Abstract:

Running economy is a key physiological parameter of an individual’s running efficacy and a valid tool for predicting performance outcomes. Of the many factors known to influence running economy (RE), footwear certainly plays a role owing to its characteristics that vary substantially from model to model. Although minimalist footwear is believed to enhance RE and thereby endurance performance, conclusive research reports are scarce. Indeed, debates remain as to which footwear characteristics most alter RE. The purposes of this study were, therefore, two-fold: (a) to determine whether wearing minimalist shoes results in better RE compared to shod and to identify relationships with kinematic and muscle activation patterns; (b) to determine whether changes in RE with minimalist shoes are still evident following a fatiguing bout of exercise. Well-trained male distance runners (n=10; 29.0 ± 7.5 yrs; 71.0 ± 4.8 kg; 176.3 ± 6.5 cm) partook first in a maximal O₂ uptake determination test (VO₂ₘₐₓ = 61.6 ± 7.3 ml min⁻¹ kg⁻¹) 7 days prior to the experimental sessions. Second, in a fully randomized fashion, an RE test consisting of three 8-min treadmill runs in shod and minimalist footwear were performed prior to and following exercise induced fatigue (EIF). The minimalist and shod conditions were tested with a minimum of 7-day wash-out period between conditions. The RE bouts, interspaced by 2-min rest periods, were run at 2.79, 3.33, and 3.89 m s⁻¹ with a 1% grade. EIF consisted of 7 times 1000 m at 94-97% VO₂ₘₐₓ interspaced with 3-min recovery. Cardiorespiratory, electromyography (EMG), kinematics, rate of perceived exertion (RPE) and blood lactate were measured throughout the experimental sessions. A significant main speed effect on RE (p=0.001) and stride frequency (SF) (p=0.001) was observed. The pairwise comparisons showed that running at 2.79 m s⁻¹ was less economic compared to 3.33, and 3.89 m s⁻¹ (3.56 ± 0.38, 3.41 ± 0.45, 3.40 ± 0.45 ml O₂ kg⁻¹ km⁻¹; respectively) and that SF increased as a function of speed (79 ± 5, 82 ± 5, 84 ± 5 strides min⁻¹). Further, EMG analyses revealed that root mean square EMG significantly increased as a function of speed for all muscles (Biceps femoris, Gluteus maximus, Gastrocnemius, Tibialis anterior, Vastus lateralis). During EIF, the statistical analysis revealed a significant main effect of time on lactate production (from 2.7 ± 5.7 to 11.2 ± 6.2 mmol L⁻¹), RPE scores (from 7.6 ± 4.0 to 18.4 ± 2.7) and peak HR (from 171 ± 30 to 181 ± 20 bpm), expect for the recovery period. Surprisingly, a significant main footwear effect was observed on running speed during intervals (p=0.041). Participants ran faster with minimalist shoes compared to shod (3:24 ± 0:44 min [95%CI: 3:14-3:34] vs. 3:30 ± 0:47 min [95%CI: 3:19-3:41]). Although EIF altered lactate production and RPE scores, no other effect was noticeable on RE, EMG, and SF pre- and post-EIF, except for the expected speed effect. The significant footwear effect on running speed during EIF was unforeseen but could be due to shoe mass and/or heel-toe-drop differences. We also cannot discard the effect of speed on foot-strike pattern and therefore, running performance.

Keywords: exercise-induced fatigue, interval training, minimalist footwear, running economy

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Authors: Angeliki Gkiouzeli, Christine Rotonda, Elise Eby, Claire Touchet, Marie-Jo Brennstuhl, Cyril Tarquinio

Abstract:

Resilience is a psychological concept of possible relevance to the development and maintenance of chronic pain (CP). It refers to the ability of individuals to maintain reasonably healthy levels of physical and psychological functioning when exposed to an isolated and potentially highly disruptive event. Extensive research in recent years has supported the importance of this concept in the CP literature. Increased levels of resilience were associated with lower levels of perceived pain intensity and better mental health outcomes in adults with persistent pain. The ongoing project seeks to include the concept of pain-specific resilience in the French literature in order to provide more appropriate measures for assessing and understanding the complexities of CP in the near future. To the best of our knowledge, there is currently no validated version of the pain-specific resilience measure, the Pain Resilience scale (PRS), for French-speaking populations. Therefore, the present work aims to address this gap, firstly by performing a linguistic and cultural translation of the scale into French and secondly by studying the internal validity and reliability of the PRS for French CP populations. The forward-translation-back translation methodology was used to achieve as perfect a cultural and linguistic translation as possible according to the recommendations of the COSMIN (Consensus-based Standards for the selection of health Measurement Instruments) group, and an online survey is currently conducted among a representative sample of the French population suffering from CP. To date, the survey has involved one hundred respondents, with a total target of around three hundred participants at its completion. We further seek to study the metric properties of the French version of the PRS, ''L’Echelle de Résilience à la Douleur spécifique pour les Douleurs Chroniques'' (ERD-DC), in French patients suffering from CP, assessing the level of pain resilience in the context of CP. Finally, we will explore the relationship between the level of pain resilience in the context of CP and other variables of interest commonly assessed in pain research and treatment (i.e., general resilience, self-efficacy, pain catastrophising, and quality of life). This study will provide an overview of the methodology used to address our research objectives. We will also present for the first time the main findings and further discuss the validity of the scale in the field of CP research and pain management. We hope that this tool will provide a better understanding of how CP-specific resilience processes can influence the development and maintenance of this disease. This could ultimately result in better treatment strategies specifically tailored to individual needs, thus leading to reduced healthcare costs and improved patient well-being.

Keywords: chronic pain, pain measure, pain resilience, questionnaire adaptation

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Authors: Anisur Rahman, Sabyasachi Behera, Pawan Pathak, Benazir Patil, Rajesh Khanna

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Background: Nearly half of India’s population is expected to reside in urban areas by 2030. The extent to which India's health system can provide for this large and growing city-based population will determine the country's success in achieving universal health coverage and improved national health indices. National Urban Health Mission (NUHM) strive for improving access to primary health care in urban areas. Implementation of NUHM solicits sensitive, effective and sustainable strategies to strengthen the service delivery mechanisms. The Challenge Initiative for Healthy Cities (TCIHC) is working with the Government of India and three provincial states to develop effective service delivery mechanisms for reproductive, maternal, newborn and child health (RMNCH) through a health systems approach for the urban poor. Method: A rapid assessment study was conceptualized and executed to generate evidence in order to address the challenges impeding in functioning of urban health facilities to deliver effective, efficient and equitable health care services in 7 cities spread across two project States viz. Madhya Pradesh and Odisha. Results: The findings of the assessment reflect: 1. The overall ecosystem pertaining to planning and management of public health interventions is not conducive. 2. The challenges regarding population dynamics like migration keeps on influencing the demand-supply-enabling environment triangle for both public and private service providers. 3. Lack of norms for planning and benchmark for service delivery further impedes urban health system as a whole. 4. Operationalization of primary level services have enough potential to meet the demand of slum dwellers at large. 5. Lack of policy driven strategies on how to integrate the NUHM with other thematic areas of Maternal, Newborn & Child Health (MNCH) and Family Planning (FP). 5. The inappropriate capacity building and acute shortage of Human Resources has huge implication on service provisioning and adherence to the service delivery protocols. Conclusion: The findings from rapid assessment are aimed to inform pertinent stakeholders to develop a multiyear city health action plan to strengthen the health systems in order to improve the efficacy of service delivery mechanism in urban settings.

Keywords: city health plan, health system, rapid assessment, urban mission

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Authors: Bakytzhan Bimbetov, Abay Zhangabilov, Saule Aitbaeva, Galymzhan Meirambekov

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Mare’s milk (saumal) contains in total about 40 biological components necessary for the human body. The most significant among them are amino acids, fats, carbohydrates, enzymes (lysozyme, amylase), more minerals and vitamins which are well balanced with each other. In Kazakhstan, Company "Eurasia Invest Ltd.” produces a freeze-dried saumal in form of powder by the use of modern German innovative technology by means of evaporating at low temperature (-35°C) with an appropriate pasteurization. Research of freeze-dried biomilk for the qualitative content showed that main ingredients of freshly drown milk are being preserved. We are currently studying medical and dietary properties of freeze-dried mare's milk for diseases of the digestive system, including for nonalcoholic steatohepatitis (NASH) and liver cirrhosis (LC) viral etiology. The studied group consisted of 14 patients with NASH, and 7 patients with LC viral etiology of Class A severity degree as per Child-Pugh. Patients took freeze-dried saumal, preliminary dissolved in boiled warm water (24 g. powder per 200 ml water) 3-4 times a day for a month in conjunction with basic therapy. The results were compared to a control group (11 patients with NASH and LC) who received only basic therapy without mare’s milk. Results of preliminary research showed an improvement of subjective and objective conditions of all patients, but more significant improvement of clinical symptoms and syndromes were observed in the treatment group compared to the control one. Patients with NASH significantly over time compared to the beginning of therapy decreased asthenic and dyspeptic syndromes (p<0,01). Hepatomegaly, identified on the basis of ultrasound prior to treatment was observed in 92,8±2,4% of patients, and after combination therapy hepatomegaly the rate decreased by 14,3%, amounting to 78,5±2,8%. Patients with LC also noted the improvement of asthenic (p<0,01) and dyspeptic (p<0,05) syndromes and hemorrhagic syndrome (nosebleeds and bleeding gums when brushing your teeth, p<0,05), and jaundice. Laboratory study also showed improvement in the research group, but more significant changes were observed in the experimental group. Group of patients with NASH showed a significant improvement of index in cytolysis in conjunction with a combination therapy (p<0,05). In the control group, these indicators were also improved, but they were not statistically reliable (p>0,05). Markers of liver failure were additionally studied during the study of laboratory parameters in patients with liver cirrhosis, in particular, bilirubin, albumin and prothrombin index (PTI). Combined therapy with the use of basic treatment and mare's milk showed a significant improvement in cytolysis and bilirubin (p<0,05). In our opinion, a very important and interesting fact is that, in conjunction with basic therapy, the use of mare's milk revealed an improvement of liver function in the form of normalized PTI and albumin in patients with liver cirrhosis viral etiology. Results of this work have shown therapeutic efficiency of the use of mare's milk in complex treatment of patients with liver disease and require further in-depth study.

Keywords: liver cirrhosis, non-alcohol steatohepatitis, saumal, mare’s milk

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Authors: Meenu S. Babu, K. Jayasankara Reddy

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Depression is a serious mental health concern that leads to significant distress and dysfunction in an individual. Due to the high physical, psychological, social, and economic burden it causes, it is important to study various bio-psycho-social factors that influence the onset, course, duration, intensity of depressive symptoms. The study aims to explore relationship between autobiographical memory (AM) functions, perceived control over stressful events and depressive symptoms. AM functions and perceived control were both found to be protective factors for individuals against depression and were both modifiable to predict better behavioral and affective outcomes. An extensive review of literatur, with a systematic search on Google Scholar, JSTOR, Science Direct and Springer Journals database, was conducted for the purpose of this review paper. These were used for all the aforementioned databases. The time frame used for the search was 2010-2021. An additional search was conducted with no time bar to map the development of the theoretical concepts. The relevant studies with quantitative, qualitative, experimental, and quasi- experimental research designs were included for the review. Studies including a sample with a DSM- 5 or ICD-10 diagnosis of depressive disorders were excluded from the study to focus on the behavioral patterns in a non-clinical population. The synthesis of the findings that were obtained from the review indicates there is a significant relationship between cognitive variables of AM functions and perceived control and depressive symptoms. AM functions were found to be have significant effects on once sense of self, interpersonal relationships, decision making, self- continuity and were related to better emotion regulation and lower depressive symptoms. Not all the components of AM function were equally significant in their relationships with various depressive symptoms. While self and directive functions were more related to emotion regulation, anhedonia, motivation and hence mood and affect, the social function was related to perceived social support and social engagement. Perceived control was found to be another protective cognitive factor that provides individuals a sense of agency and control over one’s life outcomes which was found to be low in individuals with depression. This was also associated to the locus of control, competency beliefs, contingency beliefs and subjective well being in individuals and acted as protective factors against depressive symptoms. AM and perceived control over stressful events serve adaptive functions, hence it is imperative to study these variables more extensively. They can be imperative in planning and implementing therapeutic interventions to foster these cognitive protective factors to mitigate or alleviate depressive symptoms. Exploring AM as a determining factor in depressive symptoms along with perceived control over stress creates a bridge between biological and cognitive factors underlying depression and increases the scope of developing a more eclectic and effective treatment plan for individuals. As culture plays a crucial role in AM functions as well as certain aspects of control such as locus of control, it is necessary to study these variables keeping in mind the cultural context to tailor culture/community specific interventions for depression.

Keywords: autobiographical memories, autobiographical memory functions, perceived control, depressive symptoms, depression, young adults

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Authors: John T. Leman, James Gibson, Peter J. Bonitatibus

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There have been no potential clinically translatable developments of intravenous CT contrast materials over decades, and iodinated contrast agents (ICA) remain the only FDA-approved media for CT. Small molecule ICA used to highlight vascular anatomy have weak CT signals in large-to-obese patients due to their rapid redistribution from plasma into interstitial fluid, thereby diluting their intravascular concentration, and because of a mismatch of iodine’s K-edge and the high kVp settings needed to image this patient population. The use of ICA is also contraindicated in a growing population of renally impaired patients who are hypersensitive to these contrast agents; a transformative intravenous contrast agent with improved capabilities is urgently needed. Tantalum oxide nanoparticles (TaO NPs) with zwitterionic siloxane polymer coatings have high potential as clinically translatable general-purpose CT contrast agents because of (1) substantially improved imaging efficacy compared to ICA in swine/phantoms emulating medium-sized and larger adult abdomens and superior thoracic vascular contrast enhancement of thoracic arteries and veins in rabbit, (2) promising biological safety profiles showing near-complete renal clearance and low tissue retention at 3x anticipated clinical dose (ACD), and (3) clinically acceptable physiochemical parameters as concentrated bulk solutions(250-300 mgTa/mL). Here, we review requirements for general-purpose intravenous CT contrast agents in terms of patient safety, X-ray attenuating properties and contrast-producing capabilities, and physicochemical and pharmacokinetic properties. We report the current status of a TaO NP-based contrast agent, including chemical process technology developments and results of newly defined scaled-up processes for NP synthesis and purification, yielding reproducible formulations with appropriate size and concentration specifications. We discuss recent results of recent pre-clinical in vitro immunology, non-GLP high dose tolerability in rats (10x ACD), non-GLP long-term biodistribution in rats at 3x ACD, and non-GLP repeat dose in rats at ACD. We also include a discussion of NP characterization, in particular size-stability testing results under accelerated conditions (37C), and insights into TaO NP purity, surface structure, and bonding of the zwitterionic siloxane polymer coating by multinuclear (1H, 13C, 29Si) and multidimensional (2D) solution NMR spectroscopy.

Keywords: nanoparticle, imaging, diagnostic, process technology, nanoparticle characterization

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