Search results for: clinically amyopathic dermatomyositis

Authors: M. Koksal, T. Ozyazici, E. Gurdal, M. Yarım, E. Demirpolat, M. B. Y. Aycan

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The discovery of new drugs in cancer chemotherapy is still a major topic because of severe side effects, selectivity problems and resistance development potential of existing drugs. In recent years, combined anticancer therapies or multi-acting drugs are clinically preferred over traditional cytotoxic treatment, with the aim of avoiding resistance and toxic side effects. Arrangement of multi-acting targets can be carried out either by combination of several drugs with different mechanisms or by usage of a single chemical compound capable of regulating several targets of a disease with multiple factors. In literature, several pyrimidine and piperazine derivatives have been involved in the structure of many compounds which have been used as chemotherapeutic agents along with wide clinical applications. The aim of this study is to combine pyrimidine and piperazine core structures to research and develop novel piperazinylpyrimidine derivatives with selective cytotoxicity over cancer cells. In this study, a group of novel 6-fluorophenyl-3-[2-(substitutedpiperazinyl)ethyl] hexahydropyrimidine-2,4-dione derivatives designed to observe the desired anticancer activity due to pyrimidine and piperazine based scaffolds. Target compounds were obtained by the reaction of appropriate piperazine derivatives and 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-dione. The synthetic pathway of 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-dione was started with Rodionov reaction using aldehyde, malonic acid and ammonium acetate in ethanol. Isolated β-fluorophenyl-β-amino acids were treated with 2-chloroethylisocyanate in the presence of an aqueous sodium hydroxide solution at room temperature to yield the sodium salts of the corresponding ureido acids. By addition of a mineral acid, ureido acids were precipitated. Later, these ureido acids were refluxed in thionyl chloride to give the 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-di-one which were furthermore treated with secondary amines. Structures of purified compounds were characterized with IR, 1H-NMR, 13C-NMR, mass spectroscopies and elemental analysis. All of the compounds gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structures. In IR spectra of the compounds, N-H group was seen at 3230-3213 cm⁻¹. C-H was seen at 3100-2820 cm⁻¹ and C=O vibrational peaks were observed approximately at 1725 and 1665 cm⁻¹ in accordance with literature. In the NMR spectra of target compounds, the methylene protons of piperazine give two separate multiplet peaks around 3.5 and 4.5 ppm representing the successful N-alkylation of the structure. The cytotoxic activity of the synthesized compounds was investigated on human bronchial epithelial (BEAS 2B), lung (A549), colon adenocarcinoma (COLO205) and breast (MCF7) cell lines, by means of sulphorhodamine B (SRB) assays in triplicate. IC₅₀ values of the screened derivatives were found in range of 11.8-78 µM. This project was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project no: 215S157).

Keywords: cytotoxicity, hexahydropyrimidine, piperazine, sulphorhodamine B assay

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Authors: Pauline Calleja, Brooke Alexander

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In 2010 the College of Emergency Nursing Australasia (CENA) undertook sole administration of the Trauma Nursing Program (TNP) across Australia. The original TNP was developed from recommendations by the Review of Trauma and Emergency Services-Victoria. While participant and faculty feedback about the program was positive, issues were identified that were common for industry training programs in Australia. These issues included didactic approaches, with many lectures and little interaction/activity for participants. Participants were not necessarily encouraged to undertake deep learning due to the teaching and learning principles underpinning the course, and thus participants described having to learn by rote, and only gain a surface understanding of principles that were not always applied to their working context. In Australia, a trauma or emergency nurse may work in variable contexts that impact on practice, especially where resources influence scope and capacity of hospitals to provide trauma care. In 2011, a program review was undertaken resulting in major changes to the curriculum, teaching, learning and assessment approaches. The aim was to improve learning including a greater emphasis on pre-program preparation for participants, the learning environment and clinically applicable contextualized outcomes participants experienced. Previously if participants wished to undertake assessment, they were given a take home examination. The assessment had poor uptake and return, and provided no rigor since assessment was not invigilated. A new assessment structure was enacted with an invigilated examination during course hours. These changes were implemented in early 2012 with great improvement in both faculty and participant satisfaction. This presentation reports on a comparison of participant evaluations collected from courses post implementation in 2012 and in 2015 to evaluate if positive changes were sustained. Methods: Descriptive statistics were applied in analyzing evaluations. Since all questions had more than 20% of cells with a count of <5, Fisher’s Exact Test was used to identify significance (p = <0.05) between groups. Results: A total of fourteen group evaluations were included in this analysis, seven CENA TNP groups from 2012 and seven from 2015 (randomly chosen). A total of 173 participant evaluations were collated (n = 81 from 2012 and 92 from 2015). All course evaluations were anonymous, and nine of the original 14 questions were applicable for this evaluation. All questions were rated by participants on a five-point Likert scale. While all items showed improvement from 2012 to 2015, significant improvement was noted in two items. These were in regard to the content being delivered in a way that met participant learning needs and satisfaction with the length and pace of the program. Evaluation of written comments supports these results. Discussion: The aim of redeveloping the CENA TNP was to improve learning and satisfaction for participants. These results demonstrate that initial improvements in 2012 were able to be maintained and in two essential areas significantly improved. Changes that increased participant engagement, support and contextualization of course materials were essential for CENA TNP evolution.

Keywords: emergency nursing education, industry training programs, teaching and learning, trauma education

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Authors: Andrew N. Saylor, James R. Peters

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Scoliosis is a complex 3D deformity of the thoracic and lumbar spines, clinically diagnosed by measurement of a Cobb angle of 10 degrees or more on a coronal X-ray. The Cobb angle is the angle made by the lines drawn along the proximal and distal endplates of the respective proximal and distal vertebrae comprising the curve. Traditionally, Cobb angles are measured manually using either a marker, straight edge, and protractor or image measurement software. The task of measuring the Cobb angle can also be represented by a function taking the spine geometry rendered using X-ray imaging as input and returning the approximate angle. Although the form of such a function may be unknown, it can be approximated using artificial neural networks (ANNs). The performance of ANNs is affected by many factors, including the choice of activation function and network architecture; however, the effects of these parameters on the accuracy of scoliotic deformity measurements are poorly understood. Therefore, the objective of this study was to systematically investigate the effect of ANN architecture and activation function on Cobb angle measurement from the coronal X-rays of scoliotic subjects. The data set for this study consisted of 609 coronal chest X-rays of scoliotic subjects divided into 481 training images and 128 test images. These data, which included labeled Cobb angle measurements, were obtained from the SpineWeb online database. In order to normalize the input data, each image was resized using bi-linear interpolation to a size of 500 × 187 pixels, and the pixel intensities were scaled to be between 0 and 1. A fully connected (dense) ANN with a fixed cost function (mean squared error), batch size (10), and learning rate (0.01) was developed using Python Version 3.7.3 and TensorFlow 1.13.1. The activation functions (sigmoid, hyperbolic tangent [tanh], or rectified linear units [ReLU]), number of hidden layers (1, 3, 5, or 10), and number of neurons per layer (10, 100, or 1000) were varied systematically to generate a total of 36 network conditions. Stochastic gradient descent with early stopping was used to train each network. Three trials were run per condition, and the final mean squared errors and mean absolute errors were averaged to quantify the network response for each condition. The network that performed the best used ReLU neurons had three hidden layers, and 100 neurons per layer. The average mean squared error of this network was 222.28 ± 30 degrees2, and the average mean absolute error was 11.96 ± 0.64 degrees. It is also notable that while most of the networks performed similarly, the networks using ReLU neurons, 10 hidden layers, and 1000 neurons per layer, and those using Tanh neurons, one hidden layer, and 10 neurons per layer performed markedly worse with average mean squared errors greater than 400 degrees2 and average mean absolute errors greater than 16 degrees. From the results of this study, it can be seen that the choice of ANN architecture and activation function has a clear impact on Cobb angle inference from coronal X-rays of scoliotic subjects.

Keywords: scoliosis, artificial neural networks, cobb angle, medical imaging

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Authors: Sahar El Shair, Laura Greco, William Reay, Murray Cairns

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Background: Rheumatoid arthritis (RA) is a chronic, systematic, inflammatory, autoimmune disease that involves damages to joints and erosions to the associated bones and cartilage, resulting in reduced physical function and disability. RA is a multifactorial disorder influenced by heterogenous genetic and environmental factors. Whilst different medications have proven successful in reducing inflammation associated with RA, they often come with significant side effects and limited efficacy. To address this, the novel pharmagenic enrichment score (PES) algorithm was tested in self-reported RA patients from the UK Biobank (UKBB), which is a cohort of predominantly European ancestry, and identified individuals with a high genetic risk in clinically actionable biological pathways to identify novel opportunities for precision interventions and drug repurposing to treat RA. Methods and materials: Genetic association data for rheumatoid arthritis was derived from publicly available genome-wide association studies (GWAS) summary statistics (N=97173). The PES framework exploits competitive gene set enrichment to identify pathways that are associated with RA to explore novel treatment opportunities. This data is then integrated into WebGestalt, Drug Interaction database (DGIdb) and DrugBank databases to identify existing compounds with existing use or potential for repurposed use. The PES for each of these candidates was then profiled in individuals with RA in the UKBB (Ncases = 3,719, Ncontrols = 333,160). Results A total of 209 pathways with known drug targets after multiple testing correction were identified. Several pathways, including interferon gamma signaling and TID pathway (which relates to a chaperone that modulates interferon signaling), were significantly associated with self-reported RA in the UKBB when adjusting for age, sex, assessment centre month and location, RA polygenic risk and 10 principal components. These pathways have a major role in RA pathogenesis, including autoimmune attacks against certain citrullinated proteins, synovial inflammation, and bone loss. Encouragingly, many also relate to the mechanism of action of existing RA medications. The analyses also revealed statistically significant association between RA polygenic scores and self-reported RA with individual PES scorings, highlighting the potential utility of the PES algorithm in uncovering additional genetic insights that could aid in the identification of individuals at risk for RA and provide opportunities for more targeted interventions. Conclusions In this study, pharmacologically annotated genetic risk was explored through the PES framework to overcome inter-individual heterogeneity and enable precision drug repurposing in RA. The results showed a statistically significant association between RA polygenic scores and self-reported RA and individual PES scorings for 3,719 RA patients. Interestingly, several enriched PES pathways were targeted by already approved RA drugs. In addition, the analysis revealed genetically supported drug repurposing opportunities for future treatment of RA with a relatively safe profile.

Keywords: rheumatoid arthritis, precision medicine, drug repurposing, system biology, bioinformatics

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Authors: Shelley Y. Hawkins

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Introduction/Background: As technology has grown exponentially in healthcare, nurse educators must prepare Advanced Practice Registered Nurse (APRN) graduates with the knowledge and skills in information systems/technology to support and improve patient care and health care systems. APRN’s are expected to lead in caring for populations who lack accessibility and availability through the use of technology, specifically telehealth. The capacity to effectively and efficiently use technology in patient care delivery is clearly delineated in the American Association of Colleges of Nursing (AACN) Doctor of Nursing Practice (DNP) and Master of Science in Nursing (MSN) Essentials. However, APRN’s have minimal, or no, exposure to formalized telehealth education and lack necessary technical skills needed to incorporate telehealth into their patient care. APRN’s must successfully master the technology using telehealth/telemedicine, electronic health records, health information technology, and clinical decision support systems to advance health. Furthermore, APRN’s must be prepared to lead the coordination and collaboration with other healthcare providers in their use and application. Aim/Goal/Purpose: The purpose of this presentation is to establish and operationalize telehealth-focused educational partnerships between one University School of Nursing and two health care systems in order to enhance the preparation of APRN NP students for practice, teaching, and/or scholarly endeavors. Methods: The proposed project was initially presented by the project director to selected multidisciplinary stakeholders including leadership, home telehealth personnel, primary care providers, and decision support systems within two major health care systems to garner their support for acceptance and implementation. Concurrently, backing was obtained from key university-affiliated colleagues including the Director of Simulation and Innovative Learning Lab and Coordinator of the Health Care Informatics Program. Technology experts skilled in design and production in web applications and electronic modules were secured from two local based technology companies. Results: Two telehealth-focused APRN Program academic/practice partnerships have been established. Students have opportunities to engage in clinically based telehealth experiences focused on: (1) providing patient care while incorporating various technology with a specific emphasis on telehealth; (2) conducting research and/or evidence-based practice projects in order to further develop the scientific foundation regarding incorporation of telehealth with patient care; and (3) participating in the production of patient-level educational materials related to specific topical areas. Conclusions: Evidence-based APRN student telehealth clinical experiences will assist in preparing graduates who can effectively incorporate telehealth into their clinical practice. Greater access for diverse populations will be available as a result of the telehealth service model as well as better care and better outcomes at lower costs. Furthermore, APRN’s will provide the necessary leadership and coordination through interprofessional practice by transforming health care through new innovative care models using information systems and technology.

Keywords: academic/practice partnerships, advanced practice nursing, nursing education, telehealth

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Authors: Pedro Llanos, Diego García

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This paper is addressed to expanding our understanding of the effects of hypoxia training on our bodies to better model its dynamics and leverage some of its implications and effects on human health. Hypoxia training is a recommended practice for military and civilian pilots that allow them to recognize their early hypoxia signs and symptoms, and Scientist Astronaut Candidates (SACs) who underwent hypobaric hypoxia (HH) exposure as part of a training activity for prospective suborbital flight applications. This observational-analytical study describes physiologic responses and symptoms experienced by a SAC group before, during and after HH exposure and proposes a model for assessing predicted versus observed physiological responses. A group of individuals with diverse Science Technology Engineering Mathematics (STEM) backgrounds conducted a hypobaric training session to an altitude up to 22,000 ft (FL220) or 6,705 meters, where heart rate (HR), breathing rate (BR) and core temperature (Tc) were monitored with the use of a chest strap sensor pre and post HH exposure. A pulse oximeter registered levels of saturation of oxygen (SpO₂), number and duration of desaturations during the HH chamber flight. Hypoxia symptoms as described by the SACs during the HH training session were also registered. This data allowed to generate a preliminary predictive model of the oxygen desaturation and O₂ pressure curve for each subject, which consists of a sixth-order polynomial fit during exposure, and a fifth or fourth-order polynomial fit during recovery. Data analysis showed that HR and BR showed no significant differences between pre and post HH exposure in most of the SACs, while Tc measures showed slight but consistent decrement changes. All subjects registered SpO₂ greater than 94% for the majority of their individual HH exposures, but all of them presented at least one clinically significant desaturation (SpO₂ < 85% for more than 5 seconds) and half of the individuals showed SpO₂ below 87% for at least 30% of their HH exposure time. Finally, real time collection of HH symptoms presented temperature somatosensory perceptions (SP) for 65% of individuals, and task-focus issues for 52.5% of individuals as the most common HH indications. 95% of the subjects experienced HH onset symptoms below FL180; all participants achieved full recovery of HH symptoms within 1 minute of donning their O₂ mask. The current HH study performed on this group of individuals suggests a rapid and fully reversible physiologic response after HH exposure as expected and obtained in previous studies. Our data showed consistent results between predicted versus observed SpO₂ curves during HH suggesting a mathematical function that may be used to model HH performance deficiencies. During the HH study, real-time HH symptoms were registered providing evidenced SP and task focusing as the earliest and most common indicators. Finally, an assessment of HH signs of symptoms in a group of heterogeneous, non-pilot individuals showed similar results to previous studies in homogeneous populations of pilots.

Keywords: slow onset hypoxia, hypobaric chamber training, altitude sickness, symptoms and altitude, pressure cabin

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Authors: I. N. Nwafia, U. C. Ozumba, M. E. Ohanu, S. O. Ebede

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Antibiotic resistance is increasing globally and has become a major health challenge. Extended-spectrum beta-lactamase is clinically important because the ESBL gene are mostly plasmid encoded and these plasmids frequently carry genes encoding resistance to other classes of antimicrobials thereby limiting antibiotic options in the treatment of infections caused by these organisms. The specific objectives of this study were to determine the prevalence of ESBLs production in Escherichia coli, to determine the antibiotic susceptibility pattern of ESBLs producing Escherichia coli, to detect TEM, SHV and CTX-M genes and the risk factors to acquisition of ESBL producing Escherichia coli. The protocol of the study was approved by Health Research and Ethics committee of the University of Nigeria Teaching Hospital (UNTH), Enugu. It was a descriptive cross-sectional study that involved all hospitalized patients in UNTH from whose specimens Escherichia coli was isolated during the period of the study. The samples analysed were urine, wound swabs, blood and cerebrospinal fluid. These samples were cultured in 5% sheep Blood agar and MacConkey agar (Oxoid Laboratories, Cambridge UK) and incubated at 35-370C for 24 hours. Escherichia coli was identified with standard biochemical tests and confirmed using API 20E auxanogram (bioMerieux, Marcy 1'Etoile, France). The antibiotic susceptibility testing was done by disc diffusion method and interpreted according to the Clinical and Laboratory Standard Institute guideline. ESBL production was confirmed using ESBL Epsilometer test strips (Liofilchem srl, Italy). The ESBL bla genes were detected with polymerase chain reaction, after extraction of DNA with plasmid mini-prep kit (Jena Bioscience, Jena, Germany). Data analysis was with appropriate descriptive and inferential statistics. One hundred and six isolates (53.00%) out of the 200 were from urine, followed by isolates from different swabs specimens 53(26.50%) and the least number of the isolates 4(2.00) were from blood (P value = 0.096). Seventy (35.00%) out of the 200 isolates, were confirmed positive for ESBL production. Forty-two (60.00%) of the isolates were from female patients while 28(40.00%) were from male patients (P value = 0.13). Sixty-eight (97.14%) of the isolates were susceptible to imipenem while all of the isolates were resistant to ampicillin, chloramphenicol and tetracycline. From the 70 positive isolates the ESBL genes detected with polymerase chain reaction were blaCTX-M (n=26; 37.14%), blaTEM (n=7; 10.00%), blaSHV (n=2; 2.86%), blaCTX-M/TEM (n=7; 10.0%), blaCTX-M/SHV (n=14; 20.0%) and blaCTX-M/TEM/SHV (n=10; 14.29%). There was no gene detected in 4(5.71%) of the isolates. The most associated risk factors to infections caused by ESBL producing Escherichia coli was previous antibiotics use for the past 3 months followed by admission in the intensive care unit, recent surgery, and urinary catheterization. In conclusion, ESBLs was detected in 4 of every 10 Escherichia coli with the predominant gene detected being CTX-M. This knowledge will enable appropriate measures towards improvement of patient health care, antibiotic stewardship, research and infection control in the hospital.

Keywords: antimicrobial, Escherichia coli, extended spectrum beta lactamase, resistance

Procedia PDF Downloads 269

Authors: Scott M. Black, Craig Maclean, Pauline Hall Barrientos, Konstantinos Ritos, Asimina Kazakidi

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Aortic aneurysms and dissections are leading causes of death in cardiovascular disease. Both inevitably lead to hemodynamic instability without surgical intervention in the form of vascular stent-graft deployment. An accurate description of the aortic geometry and blood flow in patient-specific cases is vital for treatment planning and long-term success of such grafts, as they must generate physiological branch perfusion and in-stent hemodynamics. The aim of this study was to create patient-specific computational fluid dynamics (CFD) models through a multi-modality, multi-dimensional approach with boundary condition optimization to predict branch flow rates and in-stent hemodynamics in custom stent-graft configurations. Three-dimensional (3D) thoracoabdominal aortae were reconstructed from four-dimensional flow-magnetic resonance imaging (4D Flow-MRI) and computed tomography (CT) medical images. The former employed a novel approach to generate and enhance vessel lumen contrast via through-plane velocity at discrete, user defined cardiac time steps post-hoc. To produce patient-specific boundary conditions (BCs), the aortic geometry was reduced to a one-dimensional (1D) model. Thereafter, a zero-dimensional (0D) 3-Element Windkessel model (3EWM) was coupled to each terminal branch to represent the distal vasculature. In this coupled 0D-1D model, the 3EWM parameters were optimized to yield branch flow waveforms which are representative of the 4D Flow-MRI-derived in-vivo data. Thereafter, a 0D-3D CFD model was created, utilizing the optimized 3EWM BCs and a 4D Flow-MRI-obtained inlet velocity profile. A sensitivity analysis on the effects of stent-graft configuration and BC parameters was then undertaken using multiple stent-graft configurations and a range of distal vasculature conditions. 4D Flow-MRI granted unparalleled visualization of blood flow throughout the cardiac cycle in both the pre- and postsurgical states. Segmentation and reconstruction of healthy and stented regions from retrospective 4D Flow-MRI images also generated 3D models with geometries which were successfully validated against their CT-derived counterparts. 0D-1D coupling efficiently captured branch flow and pressure waveforms, while 0D-3D models also enabled 3D flow visualization and quantification of clinically relevant hemodynamic parameters for in-stent thrombosis and graft limb occlusion. It was apparent that changes in 3EWM BC parameters had a pronounced effect on perfusion distribution and near-wall hemodynamics. Results show that the 3EWM parameters could be iteratively changed to simulate a range of graft limb diameters and distal vasculature conditions for a given stent-graft to determine the optimal configuration prior to surgery. To conclude, this study outlined a methodology to aid in the prediction post-surgical branch perfusion and in-stent hemodynamics in patient specific cases for the implementation of custom stent-grafts.

Keywords: 4D flow-MRI, computational fluid dynamics, vascular stent-grafts, windkessel

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Authors: Jatinder Pal Singh, Harpreet Singh, Gagandeep Singh Digra, Mandeep Kaur Sidhu, Pawan Kumar

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Introduction: Ganglion cyst is a benign condition in which there is a cystic lesion in relation to a joint or a tendon sheath arising from myxoid degeneration of fibrous connective tissue. These can be unilocular or multilocular. In rare cases, there may be multiple ganglion cysts, known as cystic ganglionosis. They can occur at any age but are commonly seen in adults. Clinically they may be asymptomatic or present as swelling or mass effect in adjacent structures. These are common in extremities such as hands and feet. Case Presentation: 11-year-old female child presented with slowly progressive painless swelling of her right hand since the age of 4. Antenatal and perinatal history was unremarkable. Her family history was negative. She denies fever, malaise, morning stiffness, weight loss, fatigue, restriction of joint movements, or any sensory and motor deficit. Lab parameters were negative for inflammatory or infectious etiology. No other joint or extremity involvement was present. On physical examination, the swelling was present on the dorsum and palmer aspect of the right hand and wrist. They were non-tender on palpation without any motor or sensory deficit. MRI hand revealed multiple well-defined fluid signal intensity cystic appearing lesions in periarticular/intraarticular locations in relation to distal radio-ulnar, radio-carpal, intercarpal, carpometacarpal, metacarpophalangeal and interphalangeal joints as well as peritendinous location around flexor tendons more so in the region of wrist, palm, 1st and 5th digit and along extensor tendons in the region of wrist, largest one noted along flexor pollicis longus tendon in thenar region and along 1st digit measuring approx. 4.6 x 1.2 x 1.2 centimeter. Pressure erosions and bone remodelling were noted in the bases of the 2nd to 5th metacarpals, capitate, trapezoid, the distal shaft of 1st metacarpal, and proximal phalanx of 1st digit. Marrow edema was noted in the base and proximal shaft of the 4th metacarpal and proximal shaft of the 3rd metacarpal – likely stress or pressure related. The patient was advised of aspiration, but the family refused the procedure. Therefore the patient was kept on conservative treatment. Conclusion: Cystic ganglionosis is a rare condition with very few cases reported in the medical literature. Its prevalence and association are not known because of the rarity of this condition. It should be considered as an important differential in patients presenting with soft tissue swelling in extremities. Treatment option includes conservative management, aspiration, and surgery. Aspiration has a high recurrence rate. Although surgery has a low recurrence rate, it carries a high rate of complications. Imaging with MRI is essential for confirmation of the cystic nature of lesions and their relation with the joint capsules or tendons. This helps in differentiating from other soft tissue lesions and presurgical planning.

Keywords: radiology, rare, cystic ganglionosis, child

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Authors: Martina I. Reinhold, Theresa Bacon-Baguley

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Background: Medical knowledge continuously evolves and to help health care providers to stay up-to-date, evidence-based medicine (EBM) has emerged as a model. The practice of EBM requires new skills of the health care provider, including directed literature searches, the critical evaluation of research studies, and the direct application of the findings to patient care. This paper describes the integration and evaluation of an evidence-based medicine course sequence into a Physician Assistant curriculum. This course sequence teaches students to manage and use the best clinical research evidence to competently practice medicine. A survey was developed to assess the outcomes of the EBM course sequence. Methodology: The cornerstone of the three-semester sequence of EBM are interactive small group discussions that are designed to introduce students to the most clinically applicable skills to identify, manage and use the best clinical research evidence to improve the health of their patients. During the three-semester sequence, the students are assigned each semester to participate in small group discussions that are facilitated by faculty with varying background and expertise. Prior to the start of the first EBM course in the winter semester, PA students complete a knowledge-based survey that was developed by the authors to assess the effectiveness of the course series. The survey consists of 53 Likert scale questions that address the nine objectives for the course series. At the end of the three semester course series, the same survey was given to all students in the program and the results from before, and after the sequence of EBM courses are compared. Specific attention is paid to overall performance of students in the nine course objectives. Results: We find that students from the Class of 2016 and 2017 consistently improve (as measured by percent correct responses on the survey tool) after the EBM course series (Class of 2016: Pre- 62% Post- 75%; Class of 2017: Pre- 61 % Post-70%). The biggest increase in knowledge was observed in the areas of finding and evaluating the evidence, with asking concise clinical questions (Class of 2016: Pre- 61% Post- 81%; Class of 2017: Pre- 61 % Post-75%) and searching the medical database (Class of 2016: Pre- 24% Post- 65%; Class of 2017: Pre- 35 % Post-66 %). Questions requiring students to analyze, evaluate and report on the available clinical evidence regarding diagnosis showed improvement, but to a lesser extend (Class of 2016: Pre- 56% Post- 77%; Class of 2017: Pre- 56 % Post-61%). Conclusions: Outcomes identified that students did gain skills which will allow them to apply EBM principles. In addition, the outcomes of the knowledge-based survey allowed the faculty to focus on areas needing improvement, specifically the translation of best evidence into patient care. To address this area, the clinical faculty developed case scenarios that were incorporated into the lecture and discussion sessions, allowing students to better connect the research studies with patient care. Students commented that ‘class discussion and case examples’ contributed most to their learning and that ‘it was helpful to learn how to develop research questions and how to analyze studies and their significance to a potential client’. As evident by the outcomes, the EBM courses achieved the goals of the course and were well received by the students. 

Keywords: evidence-based medicine, clinical education, assessment tool, physician assistant

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Authors: Clemens Bulitta, Sasan Sadrizadeh, Sebastian Buhl

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Introduction: Ventilation technology in operating theatres (OT)is internationally regulated by dif-ferent standards, which define basic specifications for technical equipment and many times also the necessary operating and performance parameters. This confronts the operators of healthcare facilities with the question of finding the best ventilation and air conditioning system for the OT in order to achieve the goal of a large and robust surgicalworkzone with appropriate air quality and climate for patient safety and occupational health. Additionally, energy consumption and the potential need for clothing that limits transmission of bacteria must be considered as well as the total life cycle cost. However, the evaluation methodology of ventilation systems regarding these matters are still a topic of discussion. To date, there are neither any uniform standardized specifications nor any common validation criteria established. Thus, this study aimed to review data in the literature and add ourown research results to compare and assess the performance of different ventilations systems regarding infection preventive effects, energy efficiency, and staff comfort. Methods: We have conducted a comprehensive literature review on OT ventilation-related topics to understand the strengths and limitations of different ventilation systems. Furthermore, data from experimental assessments on OT ventilation systems at the University of Amberg-Weidenin Germany were in-cluded to comparatively assess the performance of Laminar Airflow (LAF), Turbulent Mixing Air-flow(TMA), and Temperature-controlled Airflow (TcAF) with regards to patient and occupational safety as well as staff comfort including indoor climate.CFD simulations from the Royal Institute of Technology in Sweden (KTH) were also studied to visualize the differences between these three kinds of ventilation systems in terms of the size of the surgical workzone, resilience to obstacles in the airflow, and energy use. Results: A variety of ventilation concepts are in use in the OT today. Each has its advantages and disadvantages, and thus one may be better suited than another depend-ing on the built environment and clinical workflow. Moreover, the proper functioning of OT venti-lation is also affected by multiple external and internal interfering factors. Based on the available data TcAF and LAF seem to provide the greatest effects regarding infection control and minimizing airborne risks for surgical site infections without the need for very tight surgical clothing systems. Resilience to obstacles, staff comfort, and energy efficiency seem to be favourable with TcAF. Conclusion: Based on literature data in current publications and our studies at the Technical Uni-versity of Applied Sciences Amberg-Weidenand the Royal Institute of Technoclogy, LAF and TcAF are more suitable for minimizing the risk for surgical site infections leading to improved clin-ical outcomes. Nevertheless, regarding the best management of thermal loads, atmosphere, energy efficiency, and occupational safety, overall results and data suggest that TcAF systems could pro-vide the economically most efficient and clinically most effective solution under routine clinical conditions.

Keywords: ventilation systems, infection control, energy efficiency, operating theatre, airborne infection risks

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Authors: Meenakshi Barsaul Chauhan, Aastha Chauhan, Shilpa Hurmade, Rajeev Sen, Jyotsna Sen, Monika Dalal

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Introduction: Ovarian masses are common forms of neoplasm in women and represent 2/3rd of gynaecological malignancies. A pre-operative suggestion of malignancy can guide the gynecologist to refer women with suspected pelvic mass to a gynecological oncologist for appropriate therapy and optimized treatment, which can improve survival. In the younger age group preoperative differentiation into benign or malignant pathology can decide for conservative or radical surgery. Imaging modalities have a definite role in establishing the diagnosis. By using International Ovarian Tumor Analysis (IOTA) classification with sonography, costly radiological methods like Magnetic Resonance Imaging (MRI) / computed tomography (CT) scan can be reduced, especially in developing countries like India. Thus, this study is being undertaken to evaluate the role of clinical methods and sonography for diagnosis of the nature of the ovarian tumor. Material And Methods: This prospective observational study was conducted on 40 patients presenting with ovarian masses, in the Department of Obstetrics and Gynaecology, at a tertiary care center in northern India. Functional cysts were excluded. Ultrasonography and color Doppler were performed on all the cases.IOTA rules were applied, which take into account locularity, size, presence of solid components, acoustic shadow, dopper flow etc . Magnetic Resonance Imaging (MRI) / computed tomography (CT) scans abdomen and pelvis were done in cases where sonography was inconclusive. In inoperable cases, Fine needle aspiration cytology (FNAC) was done. The histopathology report after surgery and cytology report after FNAC was correlated statistically with the pre-operative diagnosis made clinically and sonographically using IOTA rules. Statistical Analysis: Descriptive measures were analyzed by using mean and standard deviation and the Student t-test was applied and the proportion was analyzed by applying the chi-square test. Inferential measures were analyzed by sensitivity, specificity, negative predictive value, and positive predictive value. Results: Provisional diagnosis of the benign tumor was made in 16(42.5%) and of the malignant tumor was made in 24(57.5%) patients on the basis of clinical findings. With IOTA simple rules on sonography, 15(37.5%) were found to be benign, while 23 (57.5%) were found to be malignant and findings were inconclusive in 2 patients (5%). FNAC/Histopathology reported that benign ovarian tumors were 14 (35%) and 26(65%) were malignant, which was taken as the gold standard. The clinical finding alone was found to have a sensitivity of 66.6% and a specificity of 90.9%. USG alone had a sensitivity of 86% and a specificity of 80%. When clinical findings and IOTA simple rules of sonography were combined (excluding inconclusive masses), the sensitivity and specificity were 83.3% and 92.3%, respectively. While including inconclusive masses, sensitivity came out to be 91.6% and specificity was 89.2. Conclusion: IOTA's simple sonography rules are highly sensitive and specific in the prediction of ovarian malignancy and also easy to use and easily reproducible. Thus, combining clinical examination with USG will help in the better management of patients in terms of time, cost and better prognosis. This will also avoid the need for costlier modalities like CT, and MRI.

Keywords: benign, international ovarian tumor analysis classification, malignant, ovarian tumours, sonography

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Authors: Leander Van Neste, Kirk Wojno

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The innate immune system reacts to foreign insult in several unique ways, one of which is phagocytosis of perceived threats such as cancer, bacteria, and viruses. The goal of this study was to look for evidence of phagocytosed RNA from tumor cells in circulating monocytes. While all monocytes possess phagocytic capabilities, the non-classical CD14+/FCGR3A+ monocytes and the intermediate CD14++/FCGR3A+ monocytes most actively remove threatening ‘external’ cellular materials. Purified CD14-positive monocyte samples from fourteen patients recently diagnosed with clinically localized prostate cancer (PCa) were investigated by single-cell RNA sequencing using the 10X Genomics protocol followed by paired-end sequencing on Illumina’s NovaSeq. Similarly, samples were processed and used as controls, i.e., one patient underwent biopsy but was found not to harbor prostate cancer (benign), three young, healthy men, and three men previously diagnosed with prostate cancer that recently underwent (curative) radical prostatectomy (post-RP). Sequencing data were mapped using 10X Genomics’ CellRanger software and viable cells were subsequently identified using CellBender, removing technical artifacts such as doublets and non-cellular RNA. Next, data analysis was performed in R, using the Seurat package. Because the main goal was to identify differences between PCa patients and ‘control’ patients, rather than exploring differences between individual subjects, the individual Seurat objects of all 21 patients were merged into one Seurat object per Seurat’s recommendation. Finally, the single-cell dataset was normalized as a whole prior to further analysis. Cell identity was assessed using the SingleR and cell dex packages. The Monaco Immune Data was selected as the reference dataset, consisting of bulk RNA-seq data of sorted human immune cells. The Monaco classification was supplemented with normalized PCa data obtained from The Cancer Genome Atlas (TCGA), which consists of bulk RNA sequencing data from 499 prostate tumor tissues (including 1 metastatic) and 52 (adjacent) normal prostate tissues. SingleR was subsequently run on the combined immune cell and PCa datasets. As expected, the vast majority of cells were labeled as having a monocytic origin (~90%), with the most noticeable difference being the larger number of intermediate monocytes in the PCa patients (13.6% versus 7.1%; p<.001). In men harboring PCa, 0.60% of all purified monocytes were classified as harboring PCa signals when the TCGA data were included. This was 3-fold, 7.5-fold, and 4-fold higher compared to post-RP, benign, and young men, respectively (all p<.001). In addition, with 7.91%, the number of unclassified cells, i.e., cells with pruned labels due to high uncertainty of the assigned label, was also highest in men with PCa, compared to 3.51%, 2.67%, and 5.51% of cells in post-RP, benign, and young men, respectively (all p<.001). It can be postulated that actively phagocytosing cells are hardest to classify due to their dual immune cell and foreign cell nature. Hence, the higher number of unclassified cells and intermediate monocytes in PCa patients might reflect higher phagocytic activity due to tumor burden. This also illustrates that small numbers (~1%) of circulating peripheral blood monocytes that have interacted with tumor cells might still possess detectable phagocytosed tumor RNA.

Keywords: circulating monocytes, phagocytic cells, prostate cancer, tumor immune response

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Authors: Dina Farran, Mark Ashworth, Fiona Gaughran

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Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is associated with an increased risk of stroke, contributing to heart failure and death. In this project, we aim to improve patient safety by screening for stroke risk among people with AF and co-morbid mental illness. To do so, we started by conducting a systematic review and meta-analysis on prevalence, management, and outcomes of AF in people with Serious Mental Illness (SMI) versus the general population. We then evaluated oral anticoagulation (OAC) prescription trends in people with AF and co-morbid SMI in King’s College Hospital. We also evaluated the association between mental illness severity and OAC prescription in eligible patients in South London and Maudsley (SLaM) NHS Foundation Trust. Next, we implemented an electronic clinical decision support system (eCDSS) consisting of a visual prompt on patient electronic Personal Health Records to screen for AF-related stroke risk in three Mental Health of Older Adults wards at SLaM. Finally, we assessed the feasibility and acceptability of the eCDSS by qualitatively investigating clinicians’ perspectives of the potential usefulness of the eCDSS (pre-intervention) and their experiences and their views regarding its impact on clinicians and patients (post-intervention). The systematic review showed that people with SMI had low reported rates of AF. AF patients with SMI were less likely to receive OAC than the general population. When receiving warfarin, people with SMI, particularly bipolar disorder, experienced poor anticoagulation control compared to the general population. Meta-analysis showed that SMI was not significantly associated with an increased risk of stroke or major bleeding when adjusting for underlying risk factors. The main findings of the first observational study were that among AF patients having a high stroke risk, those with co-morbid SMI were less likely than non-SMI to be prescribed any OAC, particularly warfarin. After 2019, there was no significant difference between the two groups. In the second observational study, patients with AF and co-morbid SMI were less likely to be prescribed any OAC compared to those with dementia, substance use disorders, or common mental disorders, adjusting for age, sex, stroke, and bleeding risk scores. Among AF patients with co-morbid SMI, warfarin was less likely to be prescribed to those having alcohol or substance dependency, serious self-injury, hallucinations or delusions, and activities of daily living impairment. In the intervention, clinicians were asked to confirm the presence of AF, clinically assess stroke and bleeding risks, record risk scores in clinical notes, and refer patients at high risk of stroke to OAC clinics. Clinicians reported many potential benefits for the eCDSS, including improving clinical effectiveness, better identification of patients at risk, safer and more comprehensive care, consistency in decision making and saving time. Identified potential risks included rigidity in decision-making, overreliance, reduced critical thinking, false positive recommendations, annoyance, and increased workload. This study presents a unique opportunity to quantify AF patients with mental illness who are at high risk of severe outcomes using electronic health records. This has the potential to improve health outcomes and, therefore patients' quality of life.

Keywords: atrial fibrillation, stroke, mental health conditions, electronic clinical decision support systems

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Authors: Angelis P. Barlampas

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An 89 years old woman came to the emergency department complaining of long-lasting headaches and nausea. A CT examination was performed, and a homogeneous midline anterior cranial fossa lesion was revealed, which was situated near the base and measured 2,4 cm in diameter. The patient was allergic, and an i.v.c injection could not be done on the spot, and neither could an MRI exam because of metallic implants. How could someone narrow down the differential diagnosis? The interhemispheric meningioma is usually a silent midline lesion with no edema, and most often presents as a homogeneous, solid type, isodense, or slightly hyperdense mass ( usually the smallest lesions as this one ). Of them, 20-30% have some calcifications. Hyperostosis is typical for meningiomas that abut the base of the skull but is absent in the current case, presumably of a more cephalad location that is borderline away from the bone. Because further investigation could not be done, as the patient was allergic to the contrast media, some other differential options should be considered. Regarding the site of the lesion, the most common other entities to keep in mind are the following: Metastasis, tumor of skull base, abscess, primary brain tumors, meningioma, giant aneurysm of the anterior cerebral artery, olfactory neuroblastoma, interhemispheric meningioma, giant aneurysm of the anterior cerebral artery, midline lesion. Appearance will depend on whether the aneurysm is non-thrombosed, or partially, or completely thrombosed. Non-contrast: slightly hyperdense, well-defined round extra-axial mass, may demonstrate a peripheral calcified rim, olfactory neuroblastoma, midline lesion. The mass is of soft tissue attenuation and is relatively homogeneous. Focal calcifications are occasionally present. When an intracranial extension is present, peritumoral cysts between it and the overlying brain are often present. Final diagnosis interhemispheric meningioma (Known from the previous patient’s history). Meningiomas come from the meningocytes or the arachnoid cells of the meninges. They are usually found incidentally, have an indolent course, and their most common location is extra-axial, parasagittal, and supratentorial. Other locations include the sphenoid ridge, olfactory groove, juxtasellar, infratentorial, intraventricular, pineal gland area, and optic nerve meningioma. They are clinically silent entities, except for large ones, which can present with headaches, changes in personality status, paresis, or symptomatology according to their specific site and may cause edema of the surrounding brain tissue. Imaging findings include the presence of calcifications, the CSF cleft sign, hyperostosis of adjacent bone, dural tail, and white matter buckling sign. After i.v.c. injection, they enhance brightly and homogenously, except for large ones, which may exhibit necrotic areas or may be heavily calcified. Malignant or cystic variants demonstrate more heterogeneity and less intense enhancement. Sometimes, it is inevitable that the needed CT protocol cannot be performed, especially in the emergency department. In these cases, the radiologist must focus on the characteristic imaging features of the unenhanced lesion, as well as in previous examinations or a known lesion history, in order to come to the right report conclusion.

Keywords: computed tomography, emergency radiology, metastasis, tumor of skull base, abscess, primary brain tumors, meningioma, giant aneurysm of the anterior cerebral artery, olfactory neuroblastoma, interhemispheric meningioma

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Authors: Mukul Sharma, Madhusmita Das, Sundeep Chaitanya Vedithi

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Leprosy is a chronic human disease caused by Mycobacterium leprae, that cannot be cultured in vitro. Though treatable with multidrug therapy (MDT), recently, bacteria reported resistance to multiple antibiotics. Targeting DNA replication and repair pathways can serve as the foundation of developing new anti-leprosy drugs. Due to the absence of an axenic culture medium for the propagation of M. leprae, studying cellular processes, especially those belonging to DNA repair pathways, is challenging. Genomic understanding of M. Leprae harbors several protein-coding genes with no previously assigned function known as 'hypothetical proteins'. Here, we report identification and expression of known and hypothetical DNA repair genes from a human skin biopsy and mouse footpads that are involved in base excision repair, direct reversal repair, and SOS response. Initially, a bioinformatics approach was employed based on sequence similarity, identification of known protein domains to screen the hypothetical proteins in the genome of M. leprae, that are potentially related to DNA repair mechanisms. Before testing on clinical samples, pure stocks of bacterial reference DNA of M. leprae (NHDP63 strain) was used to construct standard graphs to validate and identify lower detection limit in the qPCR experiments. Primers were designed to amplify the respective transcripts, and PCR products of the predicted size were obtained. Later, excisional skin biopsies of newly diagnosed untreated, treated, and drug resistance leprosy cases from SIHR & LC hospital, Vellore, India were taken for the extraction of RNA. To determine the presence of the predicted transcripts, cDNA was generated from M. leprae mRNA isolated from clinically confirmed leprosy skin biopsy specimen across all the study groups. Melting curve analysis was performed to determine the integrity of the amplification and to rule out primer‑dimer formation. The Ct values obtained from qPCR were fitted to standard curve to determine transcript copy number. Same procedure was applied for M. leprae extracted after processing a footpad of nude mice of drug sensitive and drug resistant strains. 16S rRNA was used as positive control. Of all the 16 genes involved in BER, DR, and SOS, differential expression pattern of the genes was observed in terms of Ct values when compared to human samples; this was because of the different host and its immune response. However, no drastic variation in gene expression levels was observed in human samples except the nth gene. The higher expression of nth gene could be because of the mutations that may be associated with sequence diversity and drug resistance which suggests an important role in the repair mechanism and remains to be explored. In both human and mouse samples, SOS system – lexA and RecA, and BER genes AlkB and Ogt were expressing efficiently to deal with possible DNA damage. Together, the results of the present study suggest that DNA repair genes are constitutively expressed and may provide a reference for molecular diagnosis, therapeutic target selection, determination of treatment and prognostic judgment in M. leprae pathogenesis.

Keywords: DNA repair, human biopsy, hypothetical proteins, mouse footpads, Mycobacterium leprae, qPCR

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Authors: Rachana Tank, Donald. M. Lyall, Kristin Flegal, Joey Ward, Jonathan Cavanagh

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Alzheimer’s research UK estimates by 2050, 2 million individuals will be living with Late Onset Alzheimer’s disease (LOAD). However, individuals experience considerable cognitive deficits and brain pathology over decades before reaching clinically diagnosable LOAD and studies have utilised gene candidate studies such as genome wide association studies (GWAS) and polygenic risk (PGR) scores to identify high risk individuals and potential pathways. This investigation aims to determine whether high genetic risk of LOAD is associated with worse brain MRI and cognitive performance in healthy older adults within the UK Biobank cohort. Previous studies investigating associations of PGR for LOAD and measures of MRI or cognitive functioning have focused on specific aspects of hippocampal structure, in relatively small sample sizes and with poor ‘controlling’ for confounders such as smoking. Both the sample size of this study and the discovery GWAS sample are bigger than previous studies to our knowledge. Genetic interaction between loci showing largest effects in GWAS have not been extensively studied and it is known that APOE e4 poses the largest genetic risk of LOAD with potential gene-gene and gene-environment interactions of e4, for this reason we  also analyse genetic interactions of PGR with the APOE e4 genotype. High genetic loading based on a polygenic risk score of 21 SNPs for LOAD is associated with worse brain MRI and cognitive outcomes in healthy individuals within the UK Biobank cohort. Summary statistics from Kunkle et al., GWAS meta-analyses (case: n=30,344, control: n=52,427) will be used to create polygenic risk scores based on 21 SNPs and analyses will be carried out in N=37,000 participants in the UK Biobank. This will be the largest study to date investigating PGR of LOAD in relation to MRI. MRI outcome measures include WM tracts, structural volumes. Cognitive function measures include reaction time, pairs matching, trail making, digit symbol substitution and prospective memory. Interaction of the APOE e4 alleles and PGR will be analysed by including APOE status as an interaction term coded as either 0, 1 or 2 e4 alleles. Models will be adjusted partially for adjusted for age, BMI, sex, genotyping chip, smoking, depression and social deprivation. Preliminary results suggest PGR score for LOAD is associated with decreased hippocampal volumes including hippocampal body (standardised beta = -0.04, P = 0.022) and tail (standardised beta = -0.037, P = 0.030), but not with hippocampal head. There were also associations of genetic risk with decreased cognitive performance including fluid intelligence (standardised beta = -0.08, P<0.01) and reaction time (standardised beta = 2.04, P<0.01). No genetic interactions were found between APOE e4 dose and PGR score for MRI or cognitive measures. The generalisability of these results is limited by selection bias within the UK Biobank as participants are less likely to be obese, smoke, be socioeconomically deprived and have fewer self-reported health conditions when compared to the general population. Lack of a unified approach or standardised method for calculating genetic risk scores may also be a limitation of these analyses. Further discussion and results are pending.

Keywords: Alzheimer's dementia, cognition, polygenic risk, MRI

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Authors: Jenee Gooden, Kevin Vasquez-monterroso, Lady Paula Dejesus, Sandra Wainwright, Daniel Kim, Mackenzie Walker

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Introduction: Pyoderma gangrenosum (PG) is a rare, rapidly progressive, neutrophilic ulcerative colitis condition with an incidence of 3 to 10 cases per year ¹ ². Due to the similar appearance, PG is often misdiagnosed as a diabetic ulcer in diabetic patients. Though they may clinically appear similar in appearance, the treatment protocol and diagnostic criteria differ. Also, end-stage renal disease (ESRD) is often a condition seen in diabetic patients, which can have a significant impact on wound healing due to the wide range of uremic toxins³. This case study demonstrates a multidisciplinary team and multimodal treatment approach by podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine for an uncontrolled diabetic with pyoderma gangrenosum of a significant circumferential wound, covering almost the entire right lower extremity. Methods:56 y.o male presents with multiple PG ulcerations, including the chest, right posterior lower extremity and sacrum. All ulcerations were previously managed by the same wound care specialist. His chief complaint was worsening PG ulcerations accompanied by a fever of 103 °F . This case study focuses on the wound to his RLE. Past medical history significant for diabetes mellitus type 2 with hemoglobin A1c of 10% and end stage renal disease (ESRD) on hemodialysis. A multidisciplinary team approach by podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine was successfully used to perform right lower extremity limb salvage. The patient was managed by rheumatology for the continuation of prior medication, as well as the mutual agreement with wound care for the addition of dapsone. A coronary CT angiogram was performed by interventional cardiology, but no significant disease was noted, and no further vascular workup was necessary. Multiple surgical sharp wide excisional debridements with application of allografts and split thickness skin grafts for the circumferential ulceration that encompassed almost the entire right lower extremity were performed by both podiatric surgery and general surgery. Wound cultures and soft tissue biopsies were performed, and infectious disease managed antibiotic therapy. Hyperbaric oxygen therapy and wound vac therapy by wound care were also completed as adjunct management. Results: Prevention of leg amputation by limb salvage of the RLE was accomplished by a multidisciplinary team approach, with the wound size decreasing over a total of 29 weeks from 600 cm² to 12.0 x 3.5 x 0.2 cm. Our multidisciplinary team included podiatric surgery, general surgery, rheumatology, infectious disease, interventional cardiology, wound care and hyperbaric medicine. Discussion: Wound healing, in general, can have its challenges, and those challenges are only magnified when accompanied by multiple systemic illnesses. Though the negative impact of diabetes on wound healing is well known, the compound impact of being a diabetic with ESRD and having pyoderma gangrenosum is not. This case demonstrates the necessity for a multidisciplinary team approach with a wide array of treatment modalities to optimize wound healing and perform limb salvage with prevention of lower extremity amputation.

Keywords: diabetes, podiatry, pyoderma gangrenosum, end stage renal disease

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Authors: Karlee J. Hall, Mark Laylor, Jessy Varghese, Paula Polastri, Karen Van Ooteghem, William McIlroy

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Balance training is a common part of physiotherapy treatment and often involves a set of proprioceptive exercises which the patient carries out in the clinic and as part of their exercise program. Understanding all contributing factors to altered balance is of utmost importance to the clinical success of treatment of balance dysfunctions. A critical role for the autonomic nervous system (ANS) in the control of balance reactions has been proposed previously, with evidence for potential involvement being inferred from the observation of phasic galvanic skin responses (GSR) evoked by external balance perturbations. The current study explored whether the coupling between ANS reactivity and balance reactions would be observed during spontaneously occurring instability while standing, including standard positions typical of physiotherapy balance assessments. It was hypothesized that time-varying changes in GSR (ANS reactivity) would be associated with time-varying changes in the mediolateral center of pressure (ML-COP) (somatomotor reactivity). Nine individuals (5 females, 4 males, aged 19-37 years) were recruited. To induce varying balance demands during standing, the study compared ML-COP and GSR data across different task conditions varying the availability of vision and width of the base of support. Subjects completed 3, 30-second trials for each of the following stance conditions: standard, narrow, and tandem eyes closed, tandem eyes open, tandem eyes open with dome to shield visual input, and restricted peripheral visual field. ANS activity was evaluated by measures of GSR recorded from Ag-AgCl electrodes on the middle phalanges of digits 2 and 4 on the left hand; balance measures include ML-COP excursion frequency and amplitude recorded from two force plates embedded in the floor underneath each foot. Subjects were instructed to stand as still as possible with arms crossed in front of their chest. When comparing mean task differences across subjects, there was an expected increase in postural sway from tasks with a wide stance and no sensory restrictions (least challenging) to those with a narrow stance and no vision (most challenging). The correlation analysis revealed a significant positive relationship between ML-COP variability and GSR variability when comparing across tasks (r=0.94, df=5, p < 0.05). In addition, correlations coincided within each subject and revealed a significant positive correlation in 7 participants (r= 0.47, 0.57, 0.62, 0.62, 0.81, 0.64, 0.69 respectively, df=19, p < 0.05) and no significant relationship in 2 participants (r=0.36, 0.29 respectively, df=19, p > 0.05). The current study revealed a significant relationship between ML-COP and GSR during balance tasks, revealing the ANS reactivity associated with naturally occurring instability when standing still, which is proportional to the degree of instability. Understanding the link between ANS activity and control of COP is an important step forward in the enhancement of assessment of contributing factors to poor balance and treatment of balance dysfunctions. The next steps will explore the temporal association between the time-varying changes in COP and GSR to establish if the ANS reactivity phase leads or lags the evoked motor reactions, as well as exploration of potential biomarkers for use in screening of ANS activity as a contributing factor to altered balance control clinically.

Keywords: autonomic nervous system, balance control, center of pressure, somatic nervous system

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Authors: Ali Baker, Russel Krawitz

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This paper describes a rare occurrence where a potentially fatal complication of COVID-19 infection (MIS-A) was misdiagnosed as an acute abdomen. As most patients with this syndrome present with fever and gastrointestinal symptoms, they may inadvertently fall under the care of the surgical unit. However, unusual imaging findings and a poor response to anti-microbial therapy should prompt clinicians to suspect a non-surgical etiology. More than half of MIS-A patients require ICU admission and vasopressor support. Prompt referral to a physician is key, as the cornerstone of treatment is IVIG and corticosteroid therapy. A 32 year old woman presented with right sided abdominal pain and fevers. She had also contracted COVID-19 two months earlier. Abdominal examination revealed generalised right sided tenderness. The patient had raised inflammatory markers, but other blood tests were unremarkable. CT scan revealed extensive lymphadenopathy along the ileocolic chain. The patient proved to be a diagnostic dilemma. She was reviewed by several surgical consultants and discussed with several inpatient teams. Although IV antibiotics were commenced, the right sided abdominal pain, and fevers persisted. Pan-culture returned negative. A mild cholestatic derangement developed. On day 5, the patient underwent preparation for colonoscopy to assess for a potential intraluminal etiology. The following day, the patient developed sinus tachycardia and hypotension that was refractory to fluid resuscitation. That patient was transferred to ICU and required vasopressor support. Repeat CT showed peri-portal edema and a thickened gallbladder wall. On re-examination, the patient was Murphy’s sign positive. Biliary ultrasound was equivocal for cholecystitis. The patient was planned for diagnostic laparoscopy. The following morning, a marked rise in cardiac troponin was discovered, and a follow-up echocardiogram revealed moderate to severe global systolic dysfunction. The impression was post-COVID MIS with myocardial involvement. IVIG and Methylprednisolone infusions were commenced. The patient had a great response. Vasopressor support was weaned, and the patient was discharged from ICU. The patient continued to improve clinically with oral prednisolone, and was discharged on day 17. Although MIS following COVID-19 infection is well-described syndrome in children, only recently has it come to light that it can occur in adults. The exact incidence is unknown, but it is thought to be rare. A recent systematic review found only 221 cases of MIS-A, which could be included for analysis. Symptoms vary, but the most frequent include fever, gastrointestinal, and mucocutaneous. Many patients progress to multi-organ failure and require vasopressor support. 7% succumb to the illness. The pathophysiology of MIS is only partly understood. It shares similarities with Kawasaki disease, macrophage activation syndrome, and cytokine release syndrome. Importantly, by definition, the patient must have an absence of severe respiratory symptoms. It is thought to be due to a dysregulated immune response to the virus. Potential mechanisms include reduced levels of neutralising antibodies and autoreactive antibodies that promote inflammation. Further research into MIS-A is needed. Although rare, this potentially fatal syndrome should be considered in the unwell surgical patient who has recently contracted COVID-19 and poses a diagnostic dilemma.

Keywords: acute-abdomen, MIS, COVID-19, ICU

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Authors: Chung-Ming Lo, Chung-Chien Lee

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In many countries, the lifetime prevalence of shoulder pain is up to 70%. In America, the health care system spends 7 billion per year about the healthy issues of shoulder pain. With respect to the origin, up to 70% of shoulder pain is attributed to rotator cuff lesions This study proposed a computer-aided diagnosis (CAD) system to assist radiologists classifying rotator cuff lesions with less operator dependence. Quantitative features were extracted from the shoulder ultrasound images acquired using an ALOKA alpha-6 US scanner (Hitachi-Aloka Medical, Tokyo, Japan) with linear array probe (scan width: 36mm) ranging from 5 to 13 MHz. During examination, the postures of the examined patients are standard sitting position and are followed by the regular routine. After acquisition, the shoulder US images were drawn out from the scanner and stored as 8-bit images with pixel value ranging from 0 to 255. Upon the sonographic appearance, the boundary of each lesion was delineated by a physician to indicate the specific pattern for analysis. The three lesion categories for classification were composed of 20 cases of tendon inflammation, 18 cases of calcific tendonitis, and 18 cases of supraspinatus tear. For each lesion, second-order statistics were quantified in the feature extraction. The second-order statistics were the texture features describing the correlations between adjacent pixels in a lesion. Because echogenicity patterns were expressed via grey-scale. The grey-scale co-occurrence matrixes with four angles of adjacent pixels were used. The texture metrics included the mean and standard deviation of energy, entropy, correlation, inverse different moment, inertia, cluster shade, cluster prominence, and Haralick correlation. Then, the quantitative features were combined in a multinomial logistic regression classifier to generate a prediction model of rotator cuff lesions. Multinomial logistic regression classifier is widely used in the classification of more than two categories such as the three lesion types used in this study. In the classifier, backward elimination was used to select a feature subset which is the most relevant. They were selected from the trained classifier with the lowest error rate. Leave-one-out cross-validation was used to evaluate the performance of the classifier. Each case was left out of the total cases and used to test the trained result by the remaining cases. According to the physician’s assessment, the performance of the proposed CAD system was shown by the accuracy. As a result, the proposed system achieved an accuracy of 86%. A CAD system based on the statistical texture features to interpret echogenicity values in shoulder musculoskeletal ultrasound was established to generate a prediction model for rotator cuff lesions. Clinically, it is difficult to distinguish some kinds of rotator cuff lesions, especially partial-thickness tear of rotator cuff. The shoulder orthopaedic surgeon and musculoskeletal radiologist reported greater diagnostic test accuracy than general radiologist or ultrasonographers based on the available literature. Consequently, the proposed CAD system which was developed according to the experiment of the shoulder orthopaedic surgeon can provide reliable suggestions to general radiologists or ultrasonographers. More quantitative features related to the specific patterns of different lesion types would be investigated in the further study to improve the prediction.

Keywords: shoulder ultrasound, rotator cuff lesions, texture, computer-aided diagnosis

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Authors: Ahmad Saad, Shuja Abbas, Breanna Marine

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Introduction: This study explores the potential applications of autologous pedal fat pad grafting as a minimally invasive therapeutic strategy for addressing pedal fat pad loss. Without adequate shock absorbing tissue, a patient can experience functional deficits, ulcerations, loss of quality of life, and significant limitations with ambulation. This study details a novel technique involving autologous adipose grafting from the abdomen to enhance plantar fat pad thickness in a patient involved in a severe motor vehicle accident which resulted in total fat pad loss of the heel. Autologous adipose grafting (AAG) was used following adipose allografting in an effort to recreate a normal shock absorbing surface to allow return to activities of daily living and painless ambulation. Methods: A 46-year-old male sustained multiple open pedal fractures and necrosis to the heel fat pad after a motorcycle accident, which resulted in complete loss of the calcaneal fat pad. The patient underwent serial debridement’s, utilization of wound vac therapy and split thickness skin grafting to accomplish complete closure, despite complete loss of adipose to area. Patient presented with complaints of pain on ambulation, inability to bear weight on the heel, recurrent ulcerations, admitted had not been ambulating for two years. Clinical exam demonstrated complete loss of the plantar fat pad with a thin layer of epithelial tissue overlying the calcaneal bone, allowing visibility of the osseous contour of the calcaneus. Scar tissue had formed in place of the fat pad, with thickened epithelial tissue extending from the midfoot to the calcaneus. After conservative measures were exhausted, the patient opted for initial management by adipose allograft matrix (AAM) injections. Post operative X-ray imaging revealed noticeable improvement in calcaneal fat pad thickness. At 1 year follow up, the patient was able to ambulate without assistive devices. The fat pad at this point was significantly thicker than it was pre-operatively, but the thickness did not restore to pre-accident thickness. In order to compare the take of allograft versus autografting of adipose tissue, the decision to use adipose autograft through abdominal liposuction harvesting was deemed suitable. A general surgeon completed harvesting of adipose cells from the patient’s abdomen via liposuction, and a podiatric surgeon performed the AAG injection into the heel. Total of 15 cc’s of autologous adipose tissue injected to the calcaneus. Results: There was a visual increase in the calcaneal fat pad thickness both clinically and radiographically. At the 6-week follow up, imaging revealed retention of the calcaneal fat pad thickness. Three months postop, patient returned to activities of daily living and increased quality of life due to their increased ability to ambulate. Discussion: AAG is a novel treatment for pedal fat pad loss. These treatments may be viable and reproducible therapeutic choices for patients suffering from fat pad atrophy, fat pad loss, and/or plantar ulcerations. Both treatments of AAM and AAG exhibited similar therapeutic results by providing pain relief for ambulation and allowing for patients to return to their quality of life.

Keywords: podiatry, wound, adipose, allograft, autograft, wound care, limb reconstruction, injection, limb salvage

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Authors: Patricia Shirley Almeida Prado, Liz Brito, Selma Paixão Argollo, Gracie Moreira, Leticia Matos Sobrinho

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Diffuse idiopathic skeletal hyperostosis (DISH) is a degenerative bone disease also known as Forestier´s disease and ankylosing hyperostosis of the spine is characterized by a tendency toward ossification of half the anterior longitudinal spinal ligament without intervertebral disc disease. DISH is not considered to be osteoarthritis, although the two conditions commonly occur together. Diagnostic criteria include fusion of at least four vertebrae by bony bridges arising from the anterolateral aspect of the vertebral bodies. These vertebral bodies have a 'dripping candle wax' appearance, also can be seen periosteal new bone formation on the anterior surface of the vertebral bodies and there is no ankylosis at zygoapophyseal facet joint. Clinically, patients with DISH tend to be asymptomatic some patients mention moderate pain and stiffness in upper back. This disease is more common in man, uncommon in patients younger than 50 years and rare in patients under 40 years old. In modern populations, DISH is found in association with obesity, (type II) diabetes; abnormal vitamin A metabolism and also associated with higher levels of serum uric acid. There is also some association between the increase of risk of stroke or other cerebrovascular disease. The DISH condition can be confused with Heterotopic Ossification, what is the bone formation in the soft tissues as the result of trauma, wounding, surgery, burnings, prolonged immobility and some central nervous system disorder. All these conditions have been described extensively as myositis ossificans which can be confused with the fibrodysplasia (myositis) ossificans progressive. As in the DISH symptomatology it can be asymptomatic or extensive enough to impair joint function. A third confusion osteoarthritis disease that can bring confusion are the enthesopathies that occur in the entire skeleton being common on the ischial tuberosities, iliac crests, patellae, and calcaneus. Ankylosis of the sacroiliac joint by bony bridges may also be found. CASE 1: this case is skeletal remains presenting skull, some vertebrae and scapulae. This case remains unidentified and due to lack of bone remains. Sex, age and ancestry profile was compromised, however the DISH pathognomonic findings and diagnostic helps to estimate sex and age characteristics. Moreover to presenting DISH these skeletal remains also showed some bone alterations and non-metrics as fusion of the first vertebrae with occipital bone, maxillae and palatine torus and scapular foramen on the right scapulae. CASE 2: this skeleton remains shows an extensive bone heterotopic ossification on the great trochanter area of left femur, right fibula showed a healed fracture in its body however in its inteosseous crest there is an extensive bone growth, also in the Ilium at the region of inferior gluteal line can be observed some pronounced bone growth and the skull presented a pronounced mandibular, maxillary and palatine torus. Despite all these pronounced heterotopic ossification the whole skeleton presents moderate bone overgrowth that is not linked with aging, since the skeleton belongs to a young unidentified individual. The appropriate osteopathological diagnosis support the human identification process through medical reports and also assist with epidemiological data that can strengthen vulnerable anthropological estimates.

Keywords: bone disease, DISH, human identification, human remains

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Authors: Viviana Manzulli, Luigina Serrecchia, Adelia Donatiello, Valeria Rondinone, Sabine Zange, Alina Tscherne, Antonio Parisi, Antonio Fasanella

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Anthrax is a zoonotic disease that affects a wide range of animal species (primarily ruminant herbivores), and can be transmitted to humans through consumption or handling of contaminated animal products. The etiological agent B.anthracis is able to survive in unfavorable environmental conditions by forming endospore which remain viable in the soil for many decades. Furthermore, B.anthracis is considered as one of the most feared agents to be potentially misused as a biological weapon and the importance of the disease and its treatment in humans has been underscored before the bioterrorism events in the United States in 2001. Due to the often fatal outcome of human cases, antimicrobial susceptibility testing plays especially in the management of anthrax infections an important role. In Italy, animal anthrax is endemic (predominantly found in the southern regions and on islands) and is characterized by sporadic outbreaks occurring mainly during summer. Between 2012 and 2017 single human cases of cutaneous anthrax occurred. In this study, 90 diverse strains of B.anthracis, isolated in Italy from 2001 to 2017, were screened to their susceptibility to sixteen clinically relevant antimicrobial agents by using the broth microdilution method. B.anthracis strains selected for this study belong to the strain collection stored at the Anthrax Reference Institute of Italy located inside the Istituto Zooprofilattico Sperimentale of Puglia and Basilicata. The strains were isolated at different time points and places from various matrices (human, animal and environmental). All strains are a representative of over fifty distinct MLVA 31 genotypes. The following antibiotics were used for testing: gentamicin, ceftriaxone, streptomycin, penicillin G, clindamycin, chloramphenicol, vancomycin, linezolid, cefotaxime, tetracycline, erythromycin, rifampin, amoxicillin, ciprofloxacin, doxycycline and trimethoprim. A standard concentration of each antibiotic was prepared in a specific diluent, which were then twofold serial diluted. Therefore, each wells contained: bacterial suspension of 1–5x104 CFU/mL in Mueller-Hinton Broth (MHB), the antibiotic to be tested at known concentration and resazurin, an indicator of cell growth. After incubation overnight at 37°C, the wells were screened for color changes caused by the resazurin: a change from purple to pink/colorless indicated cell growth. The lowest concentration of antibiotic that prevented growth represented the minimal inhibitory concentration (MIC). This study suggests that B.anthracis remains susceptible in vitro to many antibiotics, in addition to doxycycline (MICs ≤ 0,03 µg/ml), ciprofloxacin (MICs ≤ 0,03 µg/ml) and penicillin G (MICs ≤ 0,06 µg/ml), recommend by CDC for the treatment of human cases and for prophylactic use after exposure to the spores. In fact, the good activity of gentamicin (MICs ≤ 0,25 µg/ml), streptomycin (MICs ≤ 1 µg/ml), clindamycin (MICs ≤ 0,125 µg/ml), chloramphenicol(MICs ≤ 4 µg/ml), vancomycin (MICs ≤ 2 µg/ml), linezolid (MICs ≤ 2 µg/ml), tetracycline (MICs ≤ 0,125 µg/ml), erythromycin (MICs ≤ 0,25 µg/ml), rifampin (MICs ≤ 0,25 µg/ml), amoxicillin (MICs ≤ 0,06 µg/ml), towards all tested B.anthracis strains demonstrates an appropriate alternative choice for prophylaxis and/or treatment. All tested B.anthracis strains showed intermediate susceptibility to the cephalosporins (MICs ≥ 16 µg/ml) and resistance to trimethoprim (MICs ≥ 128 µg/ml).

Keywords: Bacillus anthracis, antibiotic susceptibility, treatment, minimum inhibitory concentration

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Authors: Dilek Ozturk, Narin Ozturk, Zeliha Pala Kara, Engin Kaptan, Serap Sancar Bas, Nurten Ozsoy, Alper Okyar

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Most physiological processes oscillate in a rhythmic manner in mammals including metabolism and energy homeostasis, locomotor activity, hormone secretion, immune and endocrine system functions. Endocrine body rhythms are tightly regulated by the circadian timing system. The hypothalamic-pituitary-thyroid (HPT) axis is under circadian control at multiple levels from hypothalamus to thyroid gland. Since circadian timing system controls a variety of biological functions in mammals, circadian rhythms of biological functions may modify the drug tolerability/toxicity depending on the dosing time. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer agent that is active against many cancers. It was also found to be active in medullary thyroid cancer. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus on the thyroid gland and hormones in mice. Healthy C57BL/6J mice were synchronized with 12h:12h Light-Dark cycle (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding to Light onset). Everolimus was administered to male (5 mg/kg/day) and female mice (15 mg/kg/day) orally at ZT1-rest period- and ZT13-activity period- for 4 weeks; body weight loss, clinical signs and possible changes in serum thyroid hormone levels (TSH and free T4) were examined. Histological alterations in the thyroid gland were evaluated according to the following criteria: follicular size, colloid density and viscidity, height of the follicular epithelium and the presence of necrotic cells. The statistical significance between differences was analyzed with ANOVA. Study findings included everolimus-related diarrhea, decreased activity, decreased body weight gains, alterations in serum TSH levels, and histopathological changes in thyroid gland. Decreases in mean body weight gains were more evident in mice treated at ZT1 as compared to ZT13 (p < 0.001, for both sexes). Control tissue sections of thyroid glands exhibited well-organized histoarchitecture when compared to everolimus-treated groups. Everolimus caused histopathological alterations in thyroid glands in male (5 mg/kg, slightly) and female mice (15 mg/kg; p < 0.01 for both ZT as compared to their controls) irrespective of dosing-time. TSH levels were slightly decreased upon everolimus treatment at ZT13 in both males and females. Conversely, increases in TSH levels were observed when everolimus treated at ZT1 in both males (5 mg/kg; p < 0.05) and females (15 mg/kg; slightly). No statistically significant alterations in serum free T4 levels were observed. TSH and free T4 is clinically important thyroid hormones since a number of disease states have been linked to alterations in these hormones. Serum free T4 levels within the normal ranges in the presence of abnormal serum TSH levels in everolimus treated mice may suggest subclinical thyroid disease which may have repercussions on the cardiovascular system, as well as on other organs and systems. Our study has revealed the histological damage on thyroid gland induced by subacute everolimus administration, this effect was irrespective of dosing time. However, based on the body weight changes and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13 in both male and females. Yet, effects of everolimus on thyroid functions may deserve further studies regarding their clinical importance and chronotoxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, thyroid gland, thyroid hormones

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Authors: Pauline Nyssen, Ange Mouithys-Mickalad, Maryse Hoebeke

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Inflammation is a complex physiological phenomenon involving chemical and enzymatic mechanisms. Polymorphonuclear neutrophil leukocytes (PMNs) play an important role by producing reactive oxygen species (ROS) and releasing myeloperoxidase (MPO), a pro-oxidant enzyme. Released both in the phagolysosome and the extracellular medium, MPO produces during its peroxidase and halogenation cycles oxidant species, including hypochlorous acid, involved in the destruction of pathogen agents, like bacteria or viruses. Inflammatory pathologies, like rheumatoid arthritis, atherosclerosis induce an excessive stimulation of the PMNs and, therefore, an uncontrolled release of ROS and MPO in the extracellular medium, causing severe damages to the surrounding tissues and biomolecules such as proteins, lipids, and DNA. The treatment of chronic inflammatory pathologies remains a challenge. For many years, MPO has been used as a target for the development of effective treatments. Numerous studies have been focused on the design of new drugs presenting more efficient MPO inhibitory properties. However, some designed inhibitors can be toxic. An alternative consists of assessing the potential inhibitory action of clinically-known molecules, having antioxidant activity. Propofol, 2,6-diisopropyl phenol, which is used as an intravenous anesthetic agent, meets these requirements. Besides its anesthetic action employed to induce a sedative state during surgery or in intensive care units, propofol and its injectable form Diprivan indeed present antioxidant properties and act as ROS and free radical scavengers. A study has also evidenced the ability of propofol to inhibit the formation of the neutrophil extracellular traps fibers, which are important to trap pathogen microorganisms during the inflammation process. The aim of this study was to investigate the potential inhibitory action mechanism of propofol and Diprivan on MPO activity. To go into the anti-inflammatory action of propofol in-depth, two of its oxidative derivatives, 2,6-diisopropyl-1,4-p-benzoquinone (PPFQ) and 3,5,3’,5’-tetra isopropyl-(4,4’)-diphenoquinone (PPFDQ), were studied regarding their inhibitory action. Specific immunological extraction followed by enzyme detection (SIEFED) and molecular modeling have evidenced the low anti-catalytic action of propofol. Stopped-flow absorption spectroscopy and direct MPO activity analysis have proved that propofol acts as a reversible MPO inhibitor by interacting as a reductive substrate in the peroxidase cycle and promoting the accumulation of redox compound II. Overall, Diprivan exhibited a weaker inhibitory action than the active molecule propofol. In contrast, PPFQ seemed to bind and obstruct the enzyme active site, preventing the trigger of the MPO oxidant cycles. PPFQ induced a better chlorination cycle inhibition at basic and neutral pH in comparison to propofol. PPFDQ did not show any MPO inhibition activity. The three interest molecules have also demonstrated their inhibition ability on an important step of the inflammation pathway, the PMNs superoxide anions production, thanks to EPR spectroscopy and chemiluminescence. In conclusion, propofol presents an interesting immunomodulatory activity by acting as a reductive substrate in the peroxidase cycle of MPO, slowing down its activity, whereas PPFQ acts more as an anti-catalytic substrate. Although PPFDQ has no impact on MPO, it can act on the inflammation process by inhibiting the superoxide anions production by PMNs.

Keywords: Diprivan, inhibitor, myeloperoxidase, propofol, spectroscopy

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Authors: Manuel I. Capel, Antonio Tomeu, Alberto Salguero

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Tumor growth from a transformed cancer-cell up to a clinically apparent mass spans through a range of spatial and temporal magnitudes. Through computer simulations, Cellular Automata (CA) can accurately describe the complexity of the development of tumors. Tumor development prognosis can now be made -without making patients undergo through annoying medical examinations or painful invasive procedures- if we develop appropriate CA-based software tools. In silico testing mainly refers to Computational Biology research studies of application to clinical actions in Medicine. To establish sound computer-based models of cellular behavior, certainly reduces costs and saves precious time with respect to carrying out experiments in vitro at labs or in vivo with living cells and organisms. These aim to produce scientifically relevant results compared to traditional in vitro testing, which is slow, expensive, and does not generally have acceptable reproducibility under the same conditions. For speeding up computer simulations of cellular models, specific literature shows recent proposals based on the CA approach that include advanced techniques, such the clever use of supporting efficient data structures when modeling with deterministic stochastic cellular automata. Multiparadigm and multiscale simulation of tumor dynamics is just beginning to be developed by the concerned research community. The use of stochastic cellular automata (SCA), whose parallel programming implementations are open to yield a high computational performance, are of much interest to be explored up to their computational limits. There have been some approaches based on optimizations to advance in multiparadigm models of tumor growth, which mainly pursuit to improve performance of these models through efficient memory accesses guarantee, or considering the dynamic evolution of the memory space (grids, trees,…) that holds crucial data in simulations. In our opinion, the different optimizations mentioned above are not decisive enough to achieve the high performance computing power that cell-behavior simulation programs actually need. The possibility of using multicore and GPU parallelism as a promising multiplatform and framework to develop new programming techniques to speed-up the computation time of simulations is just starting to be explored in the few last years. This paper presents a model that incorporates parallel processing, identifying the synchronization necessary for speeding up tumor growth simulations implemented in Java and C++ programming environments. The speed up improvement that specific parallel syntactic constructs, such as executors (thread pools) in Java, are studied. The new tumor growth parallel model is proved using implementations with Java and C++ languages on two different platforms: chipset Intel core i-X and a HPC cluster of processors at our university. The parallelization of Polesczuk and Enderling model (normally used by researchers in mathematical oncology) proposed here is analyzed with respect to performance gain. We intend to apply the model and overall parallelization technique presented here to solid tumors of specific affiliation such as prostate, breast, or colon. Our final objective is to set up a multiparadigm model capable of modelling angiogenesis, or the growth inhibition induced by chemotaxis, as well as the effect of therapies based on the presence of cytotoxic/cytostatic drugs.

Keywords: cellular automaton, tumor growth model, simulation, multicore and manycore programming, parallel programming, high performance computing, speed up

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Authors: Jan F. Talts, Amit Saxena, Kåre Engkilde

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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by anti-neoplastic agents, with a prevalence from 19 % to 85 %. Clinically, CIPN is a mostly sensory neuropathy leading to pain and to motor and autonomic changes. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors, especially because currently, there is no single effective method of preventing CIPN. Hearing loss is the most common form of sensory impairment in humans and can be caused by ototoxic chemical compounds such as chemotherapy (platinum-based antineoplastic agents).In rodents, single or repeated cisplatin injections induce peripheral neuropathy and hearing impairment mimicking human disorder, allowing studying the efficacy of new pharmacological candidates in chemotherapy-induced hearing loss and peripheral neuropathy. RNA sequencing data from full term amniotic fluid (TAF) mesenchymal stemcell (MSC) clones was used to identify neural-specific markers present on TAF-MSC. Several prospective neural markers were tested by flow cytometry on cultured TAF-MSC. One of these markers was used for cell-sorting using Tyto MACSQuant cell sorter, and the neural marker positive cell population was expanded for several passages to the final therapeutic product stage. Peripheral neuropathy and hearing loss was induced in mice by administration of cisplatin in three week-long cycles. The efficacy of neural-specific TAF-MSC in treating hearing loss and pain perception was evaluated by administration of three injections of 3 million cells/kg by intravenous route or three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment. Auditory brainstem responses (ABR) are electric potentials recorded from scalp electrodes, and the first ABR wave represents the summed activity of the auditory nerve fibers contacting the inner hair cells. For ABR studies, mice were anesthetized, then earphones were placed in the left ear of each mouse, an active electrode was placed in the vertex of the skull, a reference electrode under the skin of the mastoid bone, and a ground electrode in the neck skin. The stimuli consisted of tone pips of five frequencies (2, 4, 6, 12, 16, and 24 kHz) at various sound levels (from 0 to 90 dB) ranging to cover the mouse auditory frequency range. The von Frey test was used to assess the onset and maintenance of mechanical allodynia over time. Mice were placed in clear plexiglass cages on an elevated mesh floor and tested after 30 min of habituation. Mechanical paw withdrawal threshold was examined using an electronic von Frey anesthesiometer. Cisplatin groups treated with three injections of 3 million cells/kg by intravenous route and three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment presented, a significant increase of hearing acuity characterized by a decrease of ABR threshold and a decrease of neuropathic pain characterized by an increase of von Frey paw withdrawal threshold compared to controls only receiving cisplatin. This study shows that treatment with MSCselected for neural specificity presents significant positive efficacy on the chemotherapy-induced neuropathic pain and the chemotherapy-induced hearing loss.

Keywords: mesenchymal stem cell, peripheral neuropathy, amniotic fluid, regenerative medicine

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Authors: Michael R. Shurin, Galina Shurin, Vladimir A. Kirichenko

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Background. Visibility of hepatic malignancies is poor on non-contrast imaging for daily verification of liver malignancies prior to radiation therapy on MRI-guided Linear Accelerators (MR-Linac). Ferumoxytol® (Feraheme, AMAG Pharmaceuticals, Waltham, MA) is a SPION agent that is increasingly utilized off-label as hepatic MRI contrast. This agent has the advantage of providing a functional assessment of the liver based upon its uptake by hepatic Kupffer cells proportionate to vascular perfusion, resulting in strong T1, T2 and T2* relaxation effects and enhanced contrast of malignant tumors, which lack Kupffer cells. The latter characteristic has been recently utilized for MRI-guided radiotherapy planning with precision targeting of liver malignancies. However potential radiotoxicity of SPION has never been addressed for its safe use as an MRI-contrast agent during liver radiotherapy on MRI-Linac. This study defines the radiomodulating properties of SPIONs in vitro on human monocyte and macrophage cell lines exposed to 60Go gamma-rays within clinical radiotherapy dose range. Methods. Human monocyte and macrophages cell line in cultures were loaded with a clinically relevant concentration of Ferumoxytol (30µg/ml) for 2 and 24 h and irradiated to 3Gy, 5Gy and 10Gy. Cells were washed and cultured for additional 24 and 48 h prior to assessing their phenotypic activation by flow cytometry and function, including viability (Annexin V/PI assay), proliferation (MTT assay) and cytokine expression (Luminex assay). Results. Our results reveled that SPION affected both human monocytes and macrophages in vitro. Specifically, iron oxide nanoparticles decreased radiation-induced apoptosis and prevented radiation-induced inhibition of human monocyte proliferative activity. Furthermore, Ferumoxytol protected monocytes from radiation-induced modulation of phenotype. For instance, while irradiation decreased polarization of monocytes to CD11b+CD14+ and CD11bnegCD14neg phenotype, Ferumoxytol prevented these effects. In macrophages, Ferumoxytol counteracted the ability of radiation to up-regulate cell polarization to CD11b+CD14+ phenotype and prevented radiation-induced down-regulation of expression of HLA-DR and CD86 molecules. Finally, Ferumoxytol uptake by human monocytes down-regulated expression of pro-inflammatory chemokines MIP-1α (Macrophage inflammatory protein 1α), MIP-1β (CCL4) and RANTES (CCL5). In macrophages, Ferumoxytol reversed the expression of IL-1RA, IL-8, IP-10 (CXCL10) and TNF-α, and up-regulates expression of MCP-1 (CCL2) and MIP-1α in irradiated macrophages. Conclusion. SPION agent Ferumoxytol increases resistance of human monocytes to radiation-induced cell death in vitro and supports anti-inflammatory phenotype of human macrophages under radiation. The effect is radiation dose-dependent and depends on the duration of Feraheme uptake. This study also finds strong evidence that SPIONs reversed the effect of radiation on the expression of pro-inflammatory cytokines involved in initiation and development of radiation-induced liver damage. Correlative translational work at our institution will directly assess the cyto-protective effects of Ferumoxytol on human Kupfer cells in vitro and ex vivo analysis of explanted liver specimens in a subset of patients receiving Feraheme-enhanced MRI-guided radiotherapy to the primary liver tumors as a bridge to liver transplant.

Keywords: superparamagnetic iron oxide nanoparticles, radioprotection, magnetic resonance imaging, liver

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Authors: Georgina Cherry, Taranpreet Rai, Luke Boyden, Sitira Williams, Andrea Wright, Richard Brown, Viva Chu, Alasdair Cook, Kevin Wells

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Estimating population-level burden, abilities of pet-parents to identify disease and demand for veterinary services worldwide is challenging. The purpose of this study is to compare a feline pruritus survey with social media listening (SML) data discussing this condition. Surveys are expensive and labour intensive to analyse, but SML data is freeform and requires careful filtering for relevancy. This study considers data from a survey of owner-observed symptoms of 156 pruritic cats conducted using Pet Parade® and SML posts collected through web-scraping to gain insights into the characterisation and management of feline pruritus. SML posts meeting a feline body area, behaviour and symptom were captured and reviewed for relevance representing 1299 public posts collected from 2021 to 2023. The survey involved 1067 pet-parents who reported on pruritic symptoms in their cats. Among the observed cats, approximately 18.37% (n=196) exhibited at least one symptom. The most frequently reported symptoms were hair loss (9.2%), bald spots (7.3%) and infection, crusting, scaling, redness, scabbing, scaling, or bumpy skin (8.2%). Notably, bald spots were the primary symptom reported for short-haired cats, while other symptoms were more prevalent in medium and long-haired cats. Affected body areas, according to pet-parents, were primarily the head, face, chin, neck (27%), and the top of the body, along the spine (22%). 35% of all cats displayed excessive behaviours consistent with pruritic skin disease. Interestingly, 27% of these cats were perceived as non-symptomatic by their owners, suggesting an under-identification of itch-related signs. Furthermore, a significant proportion of symptomatic cats did not receive any skin disease medication, whether prescribed or over the counter (n=41). These findings indicate a higher incidence of pruritic skin disease in cats than recognized by pet owners, potentially leading to a lack of medical intervention for clinically symptomatic cases. The comparison between the survey and social media listening data revealed bald spots were reported in similar proportions in both datasets (25% in the survey and 28% in SML). Infection, crusting, scaling, redness, scabbing, scaling, or bumpy skin accounted for 31% of symptoms in the survey, whereas it represented 53% of relevant SML posts (excluding bumpy skin). Abnormal licking or chewing behaviours were mentioned by pet-parents in 40% of SML posts compared to 38% in the survey. The consistency in the findings of these two disparate data sources, including a complete overlap in affected body areas for the top 80% of social media listening posts, indicates minimal biases in each method, as significant biases would likely yield divergent results. Therefore, the strong agreement across pruritic symptoms, affected body areas, and reported behaviours enhances our confidence in the reliability of the findings. Moreover, the small differences identified between the datasets underscore the valuable insights that arise from utilising multiple data sources. These variations provide additional depth in characterising and managing feline pruritus, allowing for more comprehensive understanding of the condition. By combining survey data and social media listening, researchers can obtain a nuanced perspective and capture a wider range of experiences and perspectives, supporting informed decision-making in veterinary practice.

Keywords: social media listening, feline pruritus, surveys, felines, cats, pet owners

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