Search results for: clinical trial optimization

Authors: Hasan Demiroğlu, Uğur Avcıbaşı, Serhan Sakarya, Perihan Ünak

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Implanted devices are progressively practiced in innovative medicine to relieve pain or improve a compromised function. Implant-associated infections represent an emerging complication, caused by organisms which adhere to the implant surface and grow embedded in a protective extracellular polymeric matrix, known as a biofilm. In addition, the microorganisms within biofilms enter a stationary growth phase and become phenotypically resistant to most antimicrobials, frequently causing treatment failure. In such cases, surgical removal of the implant is often required, causing high morbidity and substantial healthcare costs. Staphylococcus aureus is the most common pathogen causing implant-associated infections. Successful treatment of these infections includes early surgical intervention and antimicrobial treatment with bactericidal drugs that also act on the surface-adhering microorganisms. Linezolid is a promising anti-microbial with ant-staphylococcal activity, used for the treatment of MRSA infections. Linezolid is a synthetic antimicrobial and member of oxazolidinoni group, with a bacteriostatic or bactericidal dose-dependent antimicrobial mechanism against gram-positive bacteria. Intensive use of antibiotics, have emerged multi-resistant organisms over the years and major problems have begun to be experienced in the treatment of infections occurred with them. While new drugs have been developed worldwide, on the other hand infections formed with microorganisms which gained resistance against these drugs were reported and the scale of the problem increases gradually. Scientific studies about the production of bacterial biofilm increased in recent years. For this purpose, we investigated the activity of Lin, Lin radiolabeled with 131I (131I-Lin) and cold iodinated Lin (127I-Lin) against clinical strains of Staphylococcus aureus DSM 4910 in biofilm. In the first stage, radio and cold labeling studies were performed. Quality-control studies of Lin and iodo (radio and cold) Lin derivatives were carried out by using TLC (Thin Layer Radiochromatography) and HPLC (High Pressure Liquid Chromatography). In this context, it was found that the binding yield was obtained to be about 86±2 % for 131I-Lin. The minimal inhibitory concentration (MIC) of Lin, 127I-Lin and 131I-Lin for Staphylococcus aureus DSM 4910 strain were found to be 1µg/mL. In time-kill studies of Lin, 127I-Lin and 131I-Lin were producing ≥ 3 log10 decreases in viable counts (cfu/ml) within 6 h at 2 and 4 fold of MIC respectively. No viable bacteria were observed within the 24 h of the experiments. Biofilm eradication of S. aureus started with 64 µg/mL of Lin, 127I-Lin and 131I-Lin, and OD630 was 0.507±0.0.092, 0.589±0.058 and 0.266±0.047, respectively. The media control of biofilm producing Staphylococcus was 1.675±0,01 (OD630). 131I and 127I did not have any effects on biofilms. Lin and 127I-Lin were found less effectively than 131I-Lin at killing cells in biofilm and biofilm eradication. Our results demonstrate that the 131I-Lin have potent anti-biofilm activity against S. aureus compare to Lin, 127I-Lin and media control. This is suggested that, 131I may have harmful effect on biofilm structure.

Keywords: iodine-131, linezolid, radiolabeling, slime layer, Staphylococcus

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Authors: Panagiotis Gkekas, Christos Sougles, Dionysios Kehagias, Dimitrios Tzovaras

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This paper presents the architecture of the “Intelligent cooperative integrated system for road safety and road infrastructure maintenance towards 2020” (ODOS2020) advanced infrastructure, which implements a number of cooperative ITS applications based on Internet of Things and Infrastructure-to-Vehicle (V2I) technologies with the purpose to enhance the active road safety level of vehicles through the provision of a fully automated V2I environment. The primary objective of the ODOS2020 project is to contribute to increased road safety but also to the optimization of time for maintenance of road infrastructure. The integrated technological solution presented in this paper addresses all types of vehicles and requires minimum vehicle equipment. Thus, the ODOS2020 comprises a low-cost solution, which is one of its main benefits. The system architecture includes an integrated notification system to transmit personalized information on road, traffic, and environmental conditions, in order for the drivers to receive real-time and reliable alerts concerning upcoming critical situations. The latter include potential dangers on the road, such as obstacles or road works ahead, extreme environmental conditions, etc., but also informative messages, such as information on upcoming tolls and their charging policies. At the core of the system architecture lies an integrated sensorial network embedded in special road infrastructures (strips) that constantly collect and transmit wirelessly information about passing vehicles’ identification, type, speed, moving direction and other traffic information in combination with environmental conditions and road wear monitoring and predictive maintenance data. Data collected from sensors is transmitted by roadside infrastructure, which supports a variety of communication technologies such as ITS-G5 (IEEE-802.11p) wireless network and Internet connectivity through cellular networks (3G, LTE). All information could be forwarded to both vehicles and Traffic Management Centers (TMC) operators, either directly through the ITS-G5 network, or to smart devices with Internet connectivity, through cloud-based services. Therefore, through its functionality, the system could send personalized notifications/information/warnings and recommendations for upcoming events to both road users and TMC operators. In the course of the ODOS2020 project pilot operation has been conducted to allow drivers of both C-ITS equipped and non-equipped vehicles to experience the provided added value services. For non-equipped vehicles, the provided information is transmitted to a smartphone application. Finally, the ODOS2020 system and infrastructure is appropriate for installation on both urban, rural, and highway environments. The paper presents the various parts of the system architecture and concludes by outlining the various challenges that had to be overcome during its design, development, and deployment in a real operational environment. Acknowledgments: Work presented in this paper was co-financed by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation (call RESEARCH–CREATE–INNOVATE) under contract no. Τ1EDK-03081 (project ODOS2020).

Keywords: infrastructure to vehicle, intelligent transportation systems, internet of things, road safety

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Authors: S. Mamoucha, N. Tsafantakis, Α. Ioannidis, S. Chatzipanagiotou, C. Nikolaou, L. Skaltsounis, N. Fokialakis, N. Christodoulakis

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Introduction: Plant secondary metabolites (SM) can be grouped into three chemically distinct groups: terpenes, phenolics, and nitrogen-containing compounds. For many years the adaptive significance of SM was unknown. They were thought to be functionless end-products. Currently it is accepted that many secondary metabolites (also known as natural products) have important ecological roles in plants. For instance, they serve as attractants (odor, color, taste) for pollinators and seed-dispersing animals. Moreover, they protect plants from herbivores, microbial pathogens and from environmental stress (high and low temperatures, drought, alkalinity, salinity, radiation etc). It is well known that both biotic and abiotic stress often increase the accumulation of SM. The local climatic conditions, seasonal changes, external factors such as light, temperature, humidity affect the biosynthesis and composition of secondary metabolites. A well known dioecious evergreen plant, Pistacia lentiscus L. (mastic tree), was selected in order to study the metabolic variations occur in response to the different climate conditions, due to the seasonal variation and its effect on the biosynthesis of bioactive compounds. Materials-methods: Young and mature leaves were collected in January and July 2014, dried and extracted by accelerated solvent extraction (Dionex ASE™ 350) using solvents of increased polarity (DCM, MeOH, and H2O). GC-MS and UHPLC-HRMS analysis were carried out in order to define the nature and the relative abundance of SM. The antibacterial activity was evaluated by using the Agar Disc Diffusion Assay against ATCC and clinical isolates strains: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Streptococcus mutans and Klebsiella pneumoniae. All tests were carried out in duplicate and the average radii of the inhibition zones were calculated for each extract. Results: According to the phytochemical profile obtained from each extract, the biosynthesis of SM varied both qualitatively and quantitatively under the two different types of seasonal stress. With exception of the biologically inactive nonpolar DCM extract of July, all extracts inhibited the growth of most of the investigated microorganisms. A clear positive correlation has been observed between the relative abundance of SM and the bioactivity of the DCM extracts of January and July. Observed changes during phytochemical analysis were mainly focused on the triterpenoid content. On the other hand, the bioactivity of the polar extracts (MeOH and H2O) of January and July resulted practically invariable against most of the microorganisms, besides the significant variation of the SM content due to the seasonal variation. Conclusion: Our results clearly confirmed the hypothesis of abiotic stress as an important regulating factor that significantly affects the biosynthesis of secondary metabolites and thus the presence of bioactive compounds. Acknowledgment: This work was supported by IKY - State Scholarship Foundation, Athens, Greece.

Keywords: antibacterial screening, phytochemical profile, Pistacia lentiscus, abiotic stress

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Authors: Sanaz Moayer, Fang Huang, Scott Gardner

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In the highly leveraged business world of today, an organisation’s success depends on how it can manage and organize its traditional and intangible assets. In the knowledge-based economy, knowledge as a valuable asset gives enduring capability to firms competing in rapidly shifting global markets. It can be argued that ability to create unique knowledge assets by configuring ICT and human capabilities, will be a defining factor for international competitive advantage in the mid-21st century. The concept of KM is recognized in the strategy literature, and increasingly by senior decision-makers (particularly in large firms which can achieve scalable benefits), as an important vehicle for stimulating innovation and organisational performance in the knowledge economy. This thinking has been evident in professional services and other knowledge intensive industries for over a decade. It highlights the importance of social capital and the value of the intellectual capital embedded in social and professional networks, complementing the traditional focus on creation of intellectual property assets. Despite the growing interest in KM within professional services there has been limited discussion in relation to multinational resource based industries such as mining and petroleum where the focus has been principally on global portfolio optimization with economies of scale, process efficiencies and cost reduction. The Australian minerals and metals mining industry, although traditionally viewed as capital intensive, employs a significant number of knowledge workers notably- engineers, geologists, highly skilled technicians, legal, finance, accounting, ICT and contracts specialists working in projects or functions, representing potential knowledge silos within the organisation. This silo effect arguably inhibits knowledge sharing and retention by disaggregating corporate memory, with increased operational and project continuity risk. It also may limit the potential for process, product, and service innovation. In this paper the strategic application of knowledge management incorporating contemporary ICT platforms and data mining practices is explored as an important enabler for knowledge discovery, reduction of risk, and retention of corporate knowledge in resource based industries. With reference to the relevant strategy, management, and information systems literature, this paper highlights possible connections (currently undergoing empirical testing), between an Strategic Knowledge Management (SKM) framework incorporating supportive Data Mining (DM) practices and competitive advantage for multinational firms operating within the Australian resource sector. We also propose based on a review of the relevant literature that more effective management of soft and hard systems knowledge is crucial for major Australian firms in all sectors seeking to improve organisational performance through the human and technological capability captured in organisational networks.

Keywords: competitive advantage, data mining, mining organisation, strategic knowledge management

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Authors: Mustafa Metin Donma, Orkide Donma

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Childhood obesity is an important clinical problem because it may lead to chronic diseases during the adulthood period of the individual. Obesity is a metabolic disease associated with low-grade inflammation. The liver occurs at the center of metabolic pathways. Adropin, fibroblast growth factor-21 (FGF-21), and fetuin-A are hepatokines. Due to the immense participation of the liver in glucose metabolism, these liver-derived factors may be associated with insulin resistance (IR), which is a phenomenon discussed within the scope of obesity problems. The aim of this study is to determine the concentrations of adropin, FGF-21, and fetuin-A in childhood obesity, to point out possible differences between the obesity groups, and to investigate possible associations among these three hepatokines in obese and morbidly obese children. A total of one hundred and thirty-two children were included in the study. Two obese groups were constituted. The groups were matched in terms of mean ± SD values of ages. Body mass index values of obese and morbidly obese groups were 25.0 ± 3.5 kg/m² and 29.8 ± 5.7 kg/m², respectively. Anthropometric measurements including waist circumference, hip circumference, head circumference, and neck circumference were recorded. Informed consent forms were taken from the parents of the participants. The ethics committee of the institution approved the study protocol. Blood samples were obtained after overnight fasting. Routine biochemical tests, including glucose- and lipid-related parameters, were performed. Concentrations of the hepatokines (adropin, FGF-21, fetuin A) were determined by enzyme-linked immunosorbent assay. Insulin resistance indices such as homeostasis model assessment for IR (HOMA-IR), alanine transaminase-to aspartate transaminase ratio (ALT/AST), diagnostic obesity notation model assessment laboratory index, diagnostic obesity notation model assessment metabolic syndrome index as well as obesity indices such as diagnostic obesity notation model assessment-II index, and fat mass index were calculated using the previously derived formulas. Statistical evaluation of the study data as well as findings of the study was performed by SPSS for Windows. Statistical difference was accepted significant when p is smaller than 0.05. Statistically significant differences were found for insulin, triglyceride, high-density lipoprotein cholesterol levels of the groups. A significant increase was observed for FGF-21 concentrations in the morbidly obese group. Higher adropin and fetuin-A concentrations were observed in the same group in comparison with the values detected in the obese group (p > 0.05). There was no statistically significant difference between the ALT/AST values of the groups. In all of the remaining IR and obesity indices, significantly increased values were calculated for morbidly obese children. Significant correlations were detected between HOMA-IR and each of the hepatokines. The highest one was the association with fetuin-A (r=0.373, p=0.001). In conclusion, increased levels observed in adropin, FGF-21, and fetuin-A have shown that these hepatokines possess increasing potential going from obese to morbid obese state. Out of the correlations found with the IR index, the most affected hepatokine was fetuin-A, the parameter possibly used as the indicator of the advanced obesity stage.

Keywords: adropin, fetuin A, fibroblast growth factor-21, insulin resistance, pediatric obesity

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Authors: Irena Kostovska, Katerina Tosheska Trajkovska, Svetlana Cekovska, Julijana Brezovska Kavrakova, Hristina Ampova, Sonja Topuzovska, Ognen Kostovski, Goce Spasovski, Danica Labudovic

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Background: Proteinuria is an important feature of secondary nephropathies. The quantitative and qualitative analysis of proteinuria plays an important role in determining the types of proteinuria (glomerular, tubular and mixed), in the diagnosis and prognosis of secondary nephropathies. The damage of the glomerular basement membrane is responsible for a proteinuria characterized by the presence of large amounts of protein with high molecular weights such as albumin (69 kilo Daltons-kD), transferrin (78 kD) and immunoglobulin G (150 kD). An insufficiency of proximal tubular function is the cause of a proteinuria characterized by the presence of proteins with low molecular weight (LMW), such as retinol binding protein (21 kD) and α1-microglobulin (31 kD). In some renal diseases, a mixed glomerular and tubular proteinuria is frequently seen. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) is the most widely used method of analyzing urine proteins for clinical purposes. The main aim of the study is to determine the type of proteinuria in the most common secondary nephropathies such as diabetic, hypertensive nephropathy and preeclampsia. Material and methods: In this study were included 90 subjects: subjects with diabetic nephropathy (n=30), subjects with hypertensive nephropahty (n=30) and pregnant women with preeclampsia (n=30). We divided all subjects according to UM/CR into three subgroups: macroalbuminuric (UM/CR >300 mg/g), microalbuminuric (UM/CR 30-300 mg/g) and normolabuminuric (UM/CR<30 mg/g). In all subjects, we measured microalbumin and creatinine in urine with standard biochemical methods. Separation of urinary proteins was performed by SDS-PAGE, in several stages: linear gel preparation (4-22%), treatment of urinary samples before their application on the gel, electrophoresis, gel fixation, coloring with Coomassie blue, and identification of the separated protein fractions based on standards with exactly known molecular weight. Results: According to urinary microalbumin/creatinin ratio in group of subject with diabetic nephropathy, nine patients were macroalbuminuric, while 21 subject were microalbuminuric. In group of subjects with hypertensive nephropathy, we found macroalbuminuria (n=4), microalbuminuria (n=20) and normoalbuminuria (n=6). All pregnant women with preeclampsia were macroalbuminuric. Electrophoretic separation of urinary proteins showed that in macroalbuminric patients with diabetic nephropathy 56% have mixed proteinuria, 22% have glomerular proteinuria and 22% have tubular proteinuria. In subgroup of subjects with diabetic nephropathy and microalbuminuria, 52% have glomerular proteinuria, 8% have tubular proteinuria, and 40% of subjects have normal electrophoretic findings. All patients with maroalbuminuria and hypertensive nephropathy have mixed proteinuria. In subgroup of patients with microalbuminuria and hypertensive nephropathy, we found: 32% with mixed proteinuria, 27% with normal findings, 23% with tubular, and 18% with glomerular proteinuria. In all normoalbuminruic patiens with hypertensive nephropathy, we detected normal electrophoretic findings. In group of subjects pregnant women with preeclampsia, we found: 81% with mixed proteinuria, 13% with glomerular, and 8% with tubular proteinuria. Conclusion: By SDS PAGE method, we detected that in patients with secondary nephropathies the most common type of proteinuria is mixed proteinuria, indicating both loss of glomerular permeability and tubular function. We can conclude that SDS PAGE is high sensitive method for detection of renal impairment in patients with secondary nephropathies.

Keywords: diabetic nephropathy, preeclampsia, hypertensive nephropathy, SDS PAGE

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Authors: Ruth Goldschmidt, Vyacheslav Kalchenko, Lilah Agemy, Rachel Elmoalem, Avigdor Scherz

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Vascular Targeted Photodynamic therapy (VTP) is a new modality for selective cancer treatment that leads to the complete tumor ablation. A photosensitizer, a bacteriochlorophyll derivative in our case, is first administered to the patient and followed by the illumination of the tumor area, by a near-IR laser for its photoactivation. The photoactivated drug releases reactive oxygen species (ROS) in the circulation, which reacts with blood cells and the endothelium leading to the occlusion of the blood vasculature. If the blood vessels are only partially closed, the tumor may recover, and cancer cells could survive. On the other hand, excessive treatment may lead to toxicity of healthy tissues nearby. Simultaneous VTP monitoring and image processing independent of the photoexcitation laser has not yet been reported, to our knowledge. Here we present a method for blood flow monitoring, using a real-time laser speckle imaging (RTLSI) in the tumor during VTP. We have synthesized over the years a library of bacteriochlorophyll derivatives, among them WST11 and STL-6014. Both are water soluble derivatives that are retained in the blood vasculature through their partial binding to HSA. WST11 has been approved in Mexico for VTP treatment of prostate cancer at a certain drug dose, and time/intensity of illumination. Application to other bacteriochlorophyll derivatives or other cancers may require different treatment parameters (such as light/drug administration). VTP parameters for STL-6014 are still under study. This new derivative mainly differs from WST11 by its lack of the central Palladium, and its conjugation to an Arg-Gly-Asp (RGD) sequence. RGD is a tumor-specific ligand that is used for targeting the necrotic tumor domains through its affinity to αVβ3 integrin receptors. This enables the study of cell-targeted VTP. We developed a special RTLSI module, based on Labview software environment for data processing. The new module enables to acquire raw laser speckle images and calculate the values of the laser temporal statistics of time-integrated speckles in real time, without additional off-line processing. Using RTLSI, we could monitor the tumor’s blood flow following VTP in a CT26 colon carcinoma ear model. VTP with WST11 induced an immediate slow down of the blood flow within the tumor and a complete final flow arrest, after some sporadic reperfusions. If the irradiation continued further, the blood flow stopped also in the blood vessels of the surrounding healthy tissue. This emphasizes the significance of light dose control. Using our RTLSI system, we could prevent any additional healthy tissue damage by controlling the illumination time and restrict blood flow arrest within the tumor only. In addition, we found that VTP with STL-6014 was the most effective when the photoactivation was conducted 4h post-injection, in terms of tumor ablation success in-vivo and blood vessel flow arrest. In conclusion, RTSLI application should allow to optimize VTP efficacy vs. toxicity in both the preclinical and clinical arenas.

Keywords: blood vessel occlusion, cancer treatment, photodynamic therapy, real time imaging

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Authors: Innocent Atuhe, Babra Nalwadda, Grace Mulyowa, Annabella Habinka Ejiri

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Background: Atopic Dermatitis (AD) is one of the most prevalent and growing chronic inflammatory skin diseases in African prisons. AD care is limited in African due to a lack of information about the disease amongst primary care workers, limited access to dermatologists, lack of proper training of healthcare workers, and shortage of appropriate treatments. We designed and implemented the Prisons Telederma project based on the recommendations of the International Society of Atopic Dermatitis. We aimed at; i) increase awareness and understanding of teledermatology among prison health workers and ii) improve treatment outcomes of prisoners with atopic dermatitis through increased access to and utilization of consultant dermatologists through teledermatology in Uganda prisons. Approach: We used Store-and-forward Teledermatology (SAF-TD) to increase access to dermatologist-led care for prisoners and prison staff with AD. We conducted five days of training for prison health workers using an adapted WHO training guide on recognizing neglected tropical diseases through changes on the skin together with an adapted American Academy of Dermatology (AAD) Childhood AD Basic Dermatology Curriculum designed to help trainees develop a clinical approach to the evaluation and initial management of patients with AD. This training was followed by blended e-learning, webinars facilitated by consultant Dermatologists with local knowledge of medication and local practices, apps adjusted for pigmented skin, WhatsApp group discussions, and sharing pigmented skin AD pictures and treatment via zoom meetings. We hired a team of Ugandan Senior Consultant dermatologists to draft an iconographic atlas of the main dermatoses in pigmented African skin and shared this atlas with prison health staff for use as a job aid. We had planned to use MySkinSelfie mobile phone application to take and share skin pictures of prisoners with AD with Consultant Dermatologists, who would review the pictures and prescribe appropriate treatment. Unfortunately, the National Health Service withdrew the app from the market due to technical issues. We monitored and evaluated treatment outcomes using the Patient-Oriented Eczema Measure (POEM) tool. We held four advocacy meetings to persuade relevant stakeholders to increase supplies and availability of first-line AD treatments such as emollients in prison health facilities. Results: We have the very first iconographic atlas of the main dermatoses in pigmented African skin. We increased; i) the proportion of prison health staff with adequate knowledge of AD and teledermatology from 20% to 80%; ii) the proportion of prisoners with AD reporting improvement in disease severity (POEM scores) from 25% to 35% in one year; iii) increased proportion of prisoners with AD seen by consultant dermatologist through teledermatology from 0% to 20% in one year and iv)Increased the availability of AD recommended treatments in prisons health facilities from 5% to 10% in one year. Our study contributes to the use, evaluation, and verification of the use of teledermatology to increase access to specialist dermatology services to the most hard to reach areas and vulnerable populations such as that of prisoners.

Keywords: teledermatology, prisoners, reaching, un-reachable

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Authors: Chen Jiang, Eric Jordan, Maurice Gell, Balakrishnan Nair

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Nuclear fusion, one of the most promising options for reliably generating large amounts of carbon-free energy in the future, has seen a plethora of ground-breaking technological advances in recent years. An efficient and durable “breeding blanket”, needed to ensure a reactor’s self-sufficiency by maintaining the optimal coolant temperature as well as by minimizing radiation dosage behind the blanket, still remains a technological challenge for the various reactor designs for commercial fusion power plants. A relatively new dual-coolant lead-lithium (DCLL) breeder design has exhibited great potential for high-temperature (>700oC), high-thermal-efficiency (>40%) fusion reactor operation. However, the structural material, namely reduced activation ferritic-martensitic (RAFM) steel, is not chemically stable in contact with molten Pb-17%Li coolant. Thus, to utilize this new promising reactor design, the demand for effective corrosion-resistant coatings on RAFM steels represents a pressing need. Solution Spray Technologies LLC (SST) is developing a double-layer ceramic coating design to address the corrosion protection of RAFM steels, using a novel solution and solution/suspension plasma spray technology through a US Department of Energy-funded project. Plasma spray is a coating deposition method widely used in many energy applications. Novel derivatives of the conventional powder plasma spray process, known as the solution-precursor and solution/suspension-hybrid plasma spray process, are powerful methods to fabricate thin, dense ceramic coatings with complex compositions necessary for the corrosion protection in DCLL breeders. These processes can be used to produce ultra-fine molten splats and to allow fine adjustment of coating chemistry. Thin, dense ceramic coatings with chosen chemistry for superior chemical stability in molten Pb-Li, low activation properties, and good radiation tolerance, is ideal for corrosion-protection of RAFM steels. A key challenge is to accommodate its CTE mismatch with the RAFM substrate through the selection and incorporation of appropriate bond layers, thus allowing for enhanced coating durability and robustness. Systematic process optimization is being used to define the optimal plasma spray conditions for both the topcoat and bond-layer, and X-ray diffraction and SEM-EDS are applied to successfully validate the chemistry and phase composition of the coatings. The plasma-sprayed double-layer corrosion resistant coatings were also deposited onto simulated RAFM steel substrates, which are being tested separately under thermal cycling, high-temperature moist air oxidation as well as molten Pb-Li capsule corrosion conditions. Results from this testing on coated samples, and comparisons with bare RAFM reference samples will be presented and conclusions will be presented assessing the viability of the new ceramic coatings to be viable corrosion prevention systems for DCLL breeders in commercial nuclear fusion reactors.

Keywords: breeding blanket, corrosion protection, coating, plasma spray

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Authors: Jing Zhang, Yvonne Reinwald, Nick Poulson, Alicia El Haj, Chung See, Mike Somekh, Melissa Mather

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Biomedical imaging of native tissue using light offers the potential to obtain excellent structural and functional information in a non-invasive manner with good temporal resolution. Image contrast can be derived from intrinsic absorption, fluorescence, or scatter, or through the use of extrinsic contrast. A major challenge in applying optical microscopy to in vivo tissue imaging is the effects of light attenuation which limits light penetration depth and achievable imaging resolution. Recently Selective Plane Illumination Microscopy (SPIM) has been used to map the 3D distribution of fluorophores dispersed in biological structures. In this approach, a focused sheet of light is used to illuminate the sample from the side to excite fluorophores within the sample of interest. Images are formed based on detection of fluorescence emission orthogonal to the illumination axis. By scanning the sample along the detection axis and acquiring a stack of images, 3D volumes can be obtained. The combination of rapid image acquisition speeds with the low photon dose to samples optical sectioning provides SPIM is an attractive approach for imaging biological samples in 3D. To date all implementations of SPIM rely on the use of fluorescence reporters be that endogenous or exogenous. This approach has the disadvantage that in the case of exogenous probes the specimens are altered from their native stage rendering them unsuitable for in vivo studies and in general fluorescence emission is weak and transient. Here we present for the first time to our knowledge a label-free implementation of SPIM that has downstream applications in the clinical setting. The experimental set up used in this work incorporates both label-free and fluorescent illumination arms in addition to a high specification camera that can be partitioned for simultaneous imaging of both fluorescent emission and scattered light from intrinsic sources of optical contrast in the sample being studied. This work first involved calibration of the imaging system and validation of the label-free method with well characterised fluorescent microbeads embedded in agarose gel. 3D constructs of mammalian cells cultured in agarose gel with varying cell concentrations were then imaged. A time course study to track cell proliferation in the 3D construct was also carried out and finally a native tissue sample was imaged. For each sample multiple images were obtained by scanning the sample along the axis of detection and 3D maps reconstructed. The results obtained validated label-free SPIM as a viable approach for imaging cells in a 3D gel construct and native tissue. This technique has the potential use in a near-patient environment that can provide results quickly and be implemented in an easy to use manner to provide more information with improved spatial resolution and depth penetration than current approaches.

Keywords: bioimaging, optics, selective plane illumination microscopy, tissue imaging

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Authors: Pedro A. Marques, Francisco Monteiro, Alessandra Zumbo, Alessia Simonini, Miguel A. Mendez

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Cryogenic fuels such as Liquid Hydrogen (LH₂) must be transported and stored at extremely low temperatures. Without expensive active cooling solutions, preventing fuel boil-off over time is impossible. Hence, one must resort to venting systems at the cost of significant energy and fuel mass loss. These losses increase significantly in propellant tanks installed on vehicles, as the presence of external accelerations induces sloshing. Sloshing increases heat and mass transfer rates and leads to significant pressure oscillations, which might further trigger propellant venting. To make LH₂ economically viable, it is essential to minimize these factors by using advanced control techniques. However, these require accurate modelling and a full understanding of the tank's thermodynamics. The present research aims to implement a simple thermodynamic model capable of predicting the state of a cryogenic fuel tank under different operating conditions (i.e., filling, pressurization, fuel extraction, long-term storage, and sloshing). Since this model relies on a set of closure parameters to drive the system's transient response, it must be calibrated using experimental or numerical data. This work focuses on the former approach, wherein the model is calibrated through an experimental campaign carried out on a reduced-scale model of a cryogenic tank. The thermodynamic model of the system is composed of three control volumes: the ullage, the liquid, and the insulating walls. Under this lumped formulation, the governing equations are derived from energy and mass balances in each region, with mass-averaged properties assigned to each of them. The gas-liquid interface is treated as an infinitesimally thin region across which both phases can exchange mass and heat. This results in a coupled system of ordinary differential equations, which must be closed with heat and mass transfer coefficients between each control volume. These parameters are linked to the system evolution via empirical relations derived from different operating regimes of the tank. The derivation of these relations is carried out using an inverse method to find the optimal relations that allow the model to reproduce the available data. This approach extends classic system identification methods beyond linear dynamical systems via a nonlinear optimization step. Thanks to the data-driven assimilation of the closure problem, the resulting model accurately predicts the evolution of the tank's thermodynamics at a negligible computational cost. The lumped model can thus be easily integrated with other submodels to perform complete system simulations in real time. Moreover, by setting the model in a dimensionless form, a scaling analysis allowed us to relate the tested configurations to a representative full-size tank for naval applications. It was thus possible to compare the relative importance of different transport phenomena between the laboratory model and the full-size prototype among the different operating regimes.

Keywords: destratification, hydrogen, modeling, pressure-drop, pressurization, sloshing, thermodynamics

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Authors: Sigal Portnoy, Yael Kaufman-Cohen, Yafa Levanon

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Introduction: Rehabilitation following wrist fractures often includes exercising flexion-extension movements with a dynamic splint. However, during daily activities, we combine most of our wrist movements with radial and ulnar deviations. Also, the multi-plane wrist motion, named the ‘dart throw motion’ (DTM), was found to be a more stable motion in healthy individuals, in term of the motion of the proximal carpal bones, compared with sagittal wrist motion. The aim of this study was therefore to explore the pathomechanics of the wrist in a common multi-plane movement pattern (DTM) and design a novel splint for rehabilitation following distal radius fractures. Methods: First, a multi-axis electro-goniometer was used to quantify the plane angle of motion of the dominant and non-dominant wrists during various activities, e.g. drinking from a glass of water and answering a phone in 43 healthy individuals. The following protocols were then implemented with a population following distal radius fracture. Two dynamic scans were performed, one of the sagittal wrist motion and DTM, in a 3T magnetic resonance imaging (MRI) device, bilaterally. The scaphoid and lunate carpal bones, as well as the surface of the distal radius, were manually-segmented in SolidWorks and the angles of motion of the scaphoid and lunate bones were calculated. Subsequently, a patient-specific splint was designed using 3D scans of the hand. The brace design comprises of a proximal attachment to the arm and a distal envelope of the palm. An axle with two wheels is attached to the proximal part. Two wires attach the proximal part with the medial-palmar and lateral-ventral aspects of the distal part: when the wrist extends, the first wire is released and the second wire is strained towards the radius. The opposite occurs when the wrist flexes. The splint was attached to the wrist using Velcro and constrained the wrist movement to the desired calculated multi-plane of motion. Results: No significant differences were found between the multi-plane angles of the dominant and non-dominant wrists. The most common daily activities occurred at a plane angle of approximately 20° to 45° from the sagittal plane and the MRI studies show individual angles of the plane of motion. The printed splint fitted the wrist of the subjects and constricted movement to the desired multi-plane of motion. Hooks were inserted on each part to allow the addition of springs or rubber bands for resistance training towards muscle strengthening in the rehabilitation setting. Conclusions: It has been hypothesized that activation of the wrist in a multi-plane movement pattern following distal radius fractures will accelerate the recovery of the patient. Our results show that this motion can be determined from either the dominant or non-dominant wrists. The design of the patient-specific dynamic splint is the first step towards assessing whether splinting to induce combined movement is beneficial to the rehabilitation process, compared to conventional treatment. The evaluation of the clinical benefits of this method, compared to conventional rehabilitation methods following wrist fracture, are a part of a PhD work, currently conducted by an occupational therapist.

Keywords: distal radius fracture, rehabilitation, dynamic magnetic resonance imaging, dart throw motion

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Authors: Alaa Abdellatif, Gabrièle Breda

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Background. Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. ATMP includes gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (CTMP), and tissue-engineered therapies (TEP). Since legislation opened the way in 2007, 25 ATMPs have been approved in the EU, which is about the same amount as the U.S. Food and Drug Administration. However, not all of the ATMPs that have been approved have successfully reached the market and retained their approval. Objectives. We aim to understand all the factors limiting the market access to very promising therapies in a systemic approach, to be able to overcome these problems, in the future, with scientific, regulatory and commercial innovations. Further to recent reviews that focus either on specific countries, products, or dimensions, we will address all the challenges faced by ATMP development today. Methodology. We used mixed methods and a multi-level approach for data collection. First, we performed an updated academic literature review on ATMP development and their scientific and market access challenges (papers published between 2018 and April 2023). Second, we analyzed industry feedback from cell and gene therapy webinars and white papers published by providers and pharmaceutical industries. Finally, we established a comparative analysis of the regulatory guidelines published by EMA and the FDA for ATMP approval. Results: The main challenges in bringing these therapies to market are the high development costs. Developing ATMPs is expensive due to the need for specialized manufacturing processes. Furthermore, the regulatory pathways for ATMPs are often complex and can vary between countries, making it challenging to obtain approval and ensure compliance with different regulations. As a result of the high costs associated with ATMPs, challenges in obtaining reimbursement from healthcare payers lead to limited patient access to these treatments. ATMPs are often developed for orphan diseases, which means that the patient population is limited for clinical trials which can make it challenging to demonstrate their safety and efficacy. In addition, the complex manufacturing processes required for ATMPs can make it challenging to scale up production to meet demand, which can limit their availability and increase costs. Finally, ATMPs face safety and efficacy challenges: dangerous adverse events of these therapies like toxicity related to the use of viral vectors or cell therapy, starting material and donor-related aspects. Conclusion. As a result of our mixed method analysis, we found that ATMPs face a number of challenges in their development, regulatory approval, and commercialization and that addressing these challenges requires collaboration between industry, regulators, healthcare providers, and patient groups. This first analysis will help us to address, for each challenge, proper and innovative solution(s) in order to increase the number of ATMPs approved and reach the patients

Keywords: advanced therapy medicinal products (ATMPs), product development, market access, innovation

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Authors: Leen Al Kassab, Sarah Johns, Helen Noble, Nawal Nour, Elizabeth Janiak, Sarrah Shahawy

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Introduction: Immigrant and refugee women experience disparities in sexual and reproductive health (SRH) outcomes, partially as a result of barriers to SRH literacy and to regular healthcare access and engagement. Despite the existing data highlighting growing needs for culturally relevant and structurally competent care, interventions are scarce and not well-documented. Methods: In this IRB-approved study, we used a community-based participatory research approach, with the assistance of a community advisory board, to conduct a qualitative needs assessment of SRH knowledge and service engagement with immigrant and refugee women from Africa or the Middle East and currently residing in Boston. We conducted a total of nine focus group discussions (FGDs) in partnership with medical, community, and religious centers, in six languages: Arabic, English, French, Somali, Pashtu, and Dari. A total of 44 individuals participated. We explored migrant and refugee women’s current and evolving SRH care needs and gaps, specifically related to the development of interventions and clinical best practices targeting SRH literacy, healthcare engagement, and informed decision-making. Recordings of the FGDs were transcribed verbatim and translated by interpreter services. We used open coding with multiple coders who resolved discrepancies through consensus and iteratively refined our codebook while coding data in batches using Dedoose software. Results: Participants reported immigrant adaptation experiences, discrimination, and feelings of trust, autonomy, privacy, and connectedness to family, community, and the healthcare system as factors surrounding SRH knowledge and needs. The context of previously learned SRH knowledge was commonly noted to be in schools, at menstruation, before marriage, from family members, partners, friends, and online search engines. Common themes included empowering strength drawn from religious and cultural communities, difficulties bridging educational gaps with their US- born daughters, and a desire for more SRH education from multiple sources, including family, health care providers, and religious experts & communities. Regarding further SRH education, participants’ preferences varied regarding ideal platform (virtual vs. in-person), location (in religious and community centers or not), smaller group sizes, and the involvement of men. Conclusions: Based on these results, empowering SRH initiatives should include both community and religious center-based, as well as clinic-based, interventions. Interventions should be composed of frequent educational workshops in small groups involving age-grouped women, daughters, and (sometimes) men, tailored SRH messaging, and the promotion of culturally, religiously, and linguistically competent care.

Keywords: community, immigrant, religion, sexual & reproductive health, women's health

Procedia PDF Downloads 101

Authors: Ramanpreet, Gursatej Gandhi

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Background: Dependence on electromagnetic radiations involved in communication and information technologies has incredibly increased in the personal and professional world. Among the numerous radiations, sources are fixed site transmitters, mobile phone base stations, and power lines beside indoor devices like cordless phones, WiFi, Bluetooth, TV, radio, microwave ovens, etc. Rather there is the continuous emittance of radiofrequency radiations (RFR) even to those not using the devices from mobile phone base stations. The consistent and widespread usage of wireless devices has build-up electromagnetic fields everywhere. In fact, the radiofrequency electromagnetic field (RF-EMF) has insidiously become a part of the environment and like any contaminant may pose to be health-hazardous requiring assessment. Materials and Methods: In the present study, cytogenetic damage was assessed using the Buccal Micronucleus Cytome (BMCyt) assay as a function of radiation exposure after Institutional Ethics Committee clearance of the study and written voluntary informed consent from the participants. On a pre-designed questionnaire, general information lifestyle patterns (diet, physical activity, smoking, drinking, use of mobile phones, internet, Wi-Fi usage, etc.) genetic, reproductive (pedigrees) and medical histories were recorded. For this, 24 hour-personal exposimeter measurements (PEM) were recorded for unrelated 60 healthy adults (40 cases residing in the vicinity of mobile phone base stations since their installation and 20 controls residing in areas with no base stations). The personal exposimeter collects information from all the sources generating EMF (TETRA, GSM, UMTS, DECT, and WLAN) as total RF-EMF uplink and downlink. Findings: The cases (n=40; 23-90 years) and the controls (n=20; 19-65 years) matched for alcohol drinking, smoking habits, and mobile and cordless phone usage. The PEM in cases (149.28 ± 8.98 mV/m) revealed significantly higher (p=0.000) electric field strength compared to the recorded value (80.40 ± 0.30 mV/m) in controls. The GSM 900 uplink (p=0.000), GSM 1800 downlink (p=0.000),UMTS (both uplink; p=0.013 and downlink; p=0.001) and DECT (p=0.000) electric field strength were significantly elevated in the cases as compared to controls. The electric field strength in the cases was significantly from GSM1800 (52.26 ± 4.49mV/m) followed by GSM900 (45.69 ± 4.98mV/m), UMTS (25.03 ± 3.33mV/m), DECT (18.02 ± 2.14mV/m) and was least from WLAN (8.26 ± 2.35mV/m). The higher significantly (p=0.000) increased exposure to the cases was from GSM (97.96 ± 6.97mV/m) in comparison to UMTS, DECT, and WLAN. The frequencies of micronuclei (1.86X, p=0.007), nuclear buds (2.95X, p=0.002) and cell death parameter (condensed chromatin cells) were significantly (1.75X, p=0.007) elevated in cases compared to that in controls probably as a function of radiofrequency radiation exposure. Conclusion: In the absence of other exposure(s), any cytogenetic damage if unrepaired is a cause of concern as it can cause malignancy. Larger sample size with the clinical assessment will prove more insightful of such an effect.

Keywords: Buccal micronucleus cytome assay, cytogenetic damage, electric field strength, personal exposimeter

Procedia PDF Downloads 133

Authors: Merve Begum Terzi, Orhan Arikan, Adnan Abaci, Mustafa Candemir

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Acute myocardial infarction is a major cause of death in the world. Therefore, its fast and reliable diagnosis is a major clinical need. ECG is the most important diagnostic methodology which is used to make decisions about the management of the cardiovascular diseases. In patients with acute myocardial ischemia, temporary chest pains together with changes in ST segment and T wave of ECG occur shortly before the start of myocardial infarction. In this study, a technique which detects changes in ST/T sections of ECG is developed for the early diagnosis of acute myocardial ischemia. For this purpose, a database of real ECG recordings that contains a set of records from 75 patients presenting symptoms of chest pain who underwent elective percutaneous coronary intervention (PCI) is constituted. 12-lead ECG’s of the patients were recorded before and during the PCI procedure. Two ECG epochs, which are the pre-inflation ECG which is acquired before any catheter insertion and the occlusion ECG which is acquired during balloon inflation, are analyzed for each patient. By using pre-inflation and occlusion recordings, ECG features that are critical in the detection of acute myocardial ischemia are identified and the most discriminative features for the detection of acute myocardial ischemia are extracted. A classification technique based on support vector machine (SVM) approach operating with linear and radial basis function (RBF) kernels to detect ischemic events by using ST-T derived joint features from non-ischemic and ischemic states of the patients is developed. The dataset is randomly divided into training and testing sets and the training set is used to optimize SVM hyperparameters by using grid-search method and 10fold cross-validation. SVMs are designed specifically for each patient by tuning the kernel parameters in order to obtain the optimal classification performance results. As a result of implementing the developed classification technique to real ECG recordings, it is shown that the proposed technique provides highly reliable detections of the anomalies in ECG signals. Furthermore, to develop a detection technique that can be used in the absence of ECG recording obtained during healthy stage, the detection of acute myocardial ischemia based on ECG recordings of the patients obtained during ischemia is also investigated. For this purpose, a Gaussian mixture model (GMM) is used to represent the joint pdf of the most discriminating ECG features of myocardial ischemia. Then, a Neyman-Pearson type of approach is developed to provide detection of outliers that would correspond to acute myocardial ischemia. Neyman – Pearson decision strategy is used by computing the average log likelihood values of ECG segments and comparing them with a range of different threshold values. For different discrimination threshold values and number of ECG segments, probability of detection and probability of false alarm values are computed, and the corresponding ROC curves are obtained. The results indicate that increasing number of ECG segments provide higher performance for GMM based classification. Moreover, the comparison between the performances of SVM and GMM based classification showed that SVM provides higher classification performance results over ECG recordings of considerable number of patients.

Keywords: ECG classification, Gaussian mixture model, Neyman–Pearson approach, support vector machine

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Authors: Lauren G. Coggins

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Catheter-associated urinary tract infections (CAUTI) and central line-associated bloodstream infections (CLABSI) are among the most common healthcare-associated infections (HAI), contributing to prolonged lengths of stay, greater costs of patient care, and increased patient mortality. Evidence-based preventative care bundles exist to establish consistent, safe patient-care practices throughout an entire organization, helping to ensure the collective application of care strategies that aim to improve patient outcomes and minimize complications. The cardiac intensive care unit at a nationally ranked teaching and research hospital in the United States exceeded its annual CAUTI and CLABSI targets in the fiscal year 2019, prompting examination into the unit’s infection prevention efforts that included preventative care bundles for both HAIs. Adherence to the CAUTI and CLABSI preventative care bundles was evaluated through frequent audits conducted over three months, using standards and resources from The Joint Commission, a globally recognized leader in quality improvement in healthcare and patient care safety. The bundle elements with the lowest scores were identified as the most commonly missed elements. Three elements from both bundles, six elements in total, served as key content areas for the educational interventions targeted to bedside nurses. The CAUTI elements included appropriate urinary catheter order, appropriate continuation criteria, and urinary catheter care. The CLABSI elements included primary tubing compliance, needleless connector compliance, and dressing change compliance. An integrated, multi-platform education campaign featured content on each CAUTI and CLABSI preventative care bundle in its entirety, with additional reinforcement focused on the lowest scoring elements. One-on-one educational materials included an informational pamphlet, badge buddy, a presentation to reinforce nursing care standards, and real-time application through case studies and electronic health record demonstrations. A digital hub was developed on the hospital’s Intranet for quick access to unit resources, and a bulletin board helped track the number of days since the last CAUTI and CLABSI incident. Audits continued to be conducted throughout the education campaign, and staff were given real-time feedback to address any gaps in adherence. Nearly every nurse in the cardiac intensive care unit received all educational materials, and adherence to all six key bundle elements increased after the implementation of educational interventions. Recommendations from this implementation include providing consistent, comprehensive education across multiple teaching tools and regular audits to track adherence. The multi-platform education campaign brought focus to the evidence-based CAUTI and CLABSI bundles, which in turn will help to reduce CAUTI and CLABSI rates in clinical practice.

Keywords: education, healthcare-associated infections, infection, nursing, prevention

Procedia PDF Downloads 87

Authors: Abdou Elhendy

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Numerous study have shown the efficacy of the percutaneous intervention (PCI) and coronary stenting in improving left ventricular function and relieving exertional angina. Furthermore, PCI remains the main line of therapy in acute myocardial infarction. Improvement of procedural techniques and new devices have resulted in an increased number of PCI in those with difficult and extensive lesions, multivessel disease as well as total occlusion. Immediate and late outcome may be compromised by acute thrombosis or the development of fibro-intimal hyperplasia. In addition, progression of coronary artery disease proximal or distal to the stent as well as in non-stented arteries is not uncommon. As a result, complications can occur, such as acute myocardial infarction, worsened heart failure or recurrence of angina. In a stent, restenosis can occur without symptoms or with atypical complaints rendering the clinical diagnosis difficult. Routine invasive angiography is not appropriate as a follow up tool due to associated risk and cost and the limited functional assessment. Exercise and pharmacologic stress testing are increasingly used to evaluate the myocardial function, perfusion and adequacy of revascularization. Information obtained by these techniques provide important clues regarding presence and severity of compromise in myocardial blood flow. Stress echocardiography can be performed in conjunction with exercise or dobutamine infusion. The diagnostic accuracy has been moderate, but the results provide excellent prognostic stratification. Adding myocardial contrast agents can improve imaging quality and allows assessment of both function and perfusion. Stress radionuclide myocardial perfusion imaging is an alternative to evaluate these patients. The extent and severity of wall motion and perfusion abnormalities observed during exercise or pharmacologic stress are predictors of survival and risk of cardiac events. According to current guidelines, stress echocardiography and radionuclide imaging are considered to have appropriate indication among patients after PCI who have cardiac symptoms and those who underwent incomplete revascularization. Stress testing is not recommended in asymptomatic patients, particularly early after revascularization, Coronary CT angiography is increasingly used and provides high sensitive for the diagnosis of coronary artery stenosis. Average sensitivity and specificity for the diagnosis of in stent stenosis in pooled data are 79% and 81%, respectively. Limitations include blooming artifacts and low feasibility in patients with small stents or thick struts. Anatomical and functional cardiac imaging modalities are corner stone for the assessment of patients after PCI and provide salient diagnostic and prognostic information. Current imaging techniques cans serve as gate keeper for coronary angiography, thus limiting the risk of invasive procedures to those who are likely to benefit from subsequent revascularization. The determination of which modality to apply requires careful identification of merits and limitation of each technique as well as the unique characteristic of each individual patient.

Keywords: coronary artery disease, stress testing, cardiac imaging, restenosis

Procedia PDF Downloads 137

Authors: Giulia Fredi, Andrea Dorigato, Luca Fambri, Alessandro Pegoretti

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Thermal energy storage (TES) is the storage of heat for later use, thus filling the gap between energy request and supply. The most widely used materials for TES are the organic solid-liquid phase change materials (PCMs), such as paraffin. These materials store/release a high amount of latent heat thanks to their high specific melting enthalpy, operate in a narrow temperature range and have a tunable working temperature. However, they suffer from a low thermal conductivity and need to be confined to prevent leakage. These two issues can be tackled by confining PCMs with carbon nanotubes (CNTs). TES applications include the buildings industry, solar thermal energy collection and thermal management of electronics. In most cases, TES systems are an additional component to be added to the main structure, but if weight and volume savings are key issues, it would be advantageous to embed the TES functionality directly in the structure. Such multifunctional materials could be employed in the automotive industry, where the diffusion of lightweight structures could complicate the thermal management of the cockpit environment or of other temperature sensitive components. This work aims to produce epoxy/carbon structural laminates containing CNT-stabilized paraffin. CNTs were added to molten paraffin in a fraction of 10 wt%, as this was the minimum amount at which no leakage was detected above the melting temperature (45°C). The paraffin/CNT blend was cryogenically milled to obtain particles with an average size of 50 µm. They were added in various percentages (20, 30 and 40 wt%) to an epoxy/hardener formulation, which was used as a matrix to produce laminates through a wet layup technique, by stacking five plies of a plain carbon fiber fabric. The samples were characterized microstructurally, thermally and mechanically. Differential scanning calorimetry (DSC) tests showed that the paraffin kept its ability to melt and crystallize also in the laminates, and the melting enthalpy was almost proportional to the paraffin weight fraction. These thermal properties were retained after fifty heating/cooling cycles. Laser flash analysis showed that the thermal conductivity through the thickness increased with an increase of the PCM, due to the presence of CNTs. The ability of the developed laminates to contribute to the thermal management was also assessed by monitoring their cooling rates through a thermal camera. Three-point bending tests showed that the flexural modulus was only slightly impaired by the presence of the paraffin/CNT particles, while a more sensible decrease of the stress and strain at break and the interlaminar shear strength was detected. Optical and scanning electron microscope images revealed that these could be attributed to the preferential location of the PCM in the interlaminar region. These results demonstrated the feasibility of multifunctional structural TES composites and highlighted that the PCM size and distribution affect the mechanical properties. In this perspective, this group is working on the encapsulation of paraffin in a sol-gel derived organosilica shell. Submicron spheres have been produced, and the current activity focuses on the optimization of the synthesis parameters to increase the emulsion efficiency.

Keywords: carbon fibers, carbon nanotubes, lightweight materials, multifunctional composites, thermal energy storage

Procedia PDF Downloads 130

Authors: Brian Bacia, Esther Githaiga, Teresia Kabucho, Paul Moses Ndegwa, Lucy Gichohi

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Purpose: The aim of the study is to ensure an appropriate mix of evidence-based prevention strategies geared towards the reduction of new HIV infections and the incidence of Sexually transmitted Illnesses Background: In Nakuru County, more than 90% of all HIV-infected patients are adults and on a single-dose medication-one pill that contains a combination of several different HIV drugs. Nakuru town has been identified as the hardest hit by HIV/Aids in the County according to the latest statistics from the County Aids and STI group, with a prevalence rate of 5.7 percent attributed to the high population and an active urban center. Method: 2 key studies were carried out to provide evidence for the effectiveness of antiretroviral therapy (ART) when used optimally on preventing sexual transmission of HIV. Discussions based on an examination, assessments of successes in planning, program implementation, and ultimate impact of prevention and treatment were undertaken involving health managers, health workers, community health workers, and people living with HIV/AIDS between February -August 2021. Questionnaires were carried out by a trained duo on ethical procedures at 15 HIV treatment clinics targeting patients on ARVs and caregivers on ARV prevention and treatment of pediatric HIV infection. Findings: Levels of AIDS awareness are extremely high. Advances in HIV treatment have led to an enhanced understanding of the virus, improved care of patients, and control of the spread of drug-resistant HIV. There has been a tremendous increase in the number of people living with HIV having access to life-long antiretroviral drugs (ARV), mostly on generic medicines. Healthcare facilities providing treatment are stressed challenging the administration of the drugs, which require a clinical setting. Women find it difficult to take a daily pill which reduces the effectiveness of the medicine. ART adherence can be strengthened largely through the use of innovative digital technology. The case management approach is useful in resource-limited settings. The county has made tremendous progress in mother-to-child transmission reduction through enhanced early antenatal care (ANC) attendance and mapping of pregnant women Recommendations: Treatment reduces the risk of transmission to the child during pregnancy, labor, and delivery. Promote research of medicines through patients and community engagement. Reduce the risk of transmission through breastfeeding. Enhance testing strategies and strengthen health systems for sustainable HIV service delivery. Need exists for improved antenatal care and delivery by skilled birth attendants. Develop a comprehensive maternal reproductive health policy covering equitability, efficient and effective delivery of services. Put in place referral systems.

Keywords: evidence-based prevention strategies, service delivery, human management, integrated approach

Procedia PDF Downloads 67

Authors: G. Cunningham, E. Cantor, X. Wu, F. Shen, G. Jiang, S. Philips, C. Bales, Y. Xiao, T. R. Cummins, J. C. Fehrenbacher, B. P. Schneider

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Background: Taxane-induced peripheral neuropathy (TIPN) is the most devastating survivorship issue for patients receiving therapy. Dose reductions due to TIPN in the curative setting lead to inferior outcomes for African American patients, as prior research has shown that this group is more susceptible to developing severe neuropathy. The mechanistic underpinnings of TIPN, however, have not been entirely elucidated. While it would be appealing to use primary tissue to study the development of TIPN, procuring nerves from patients is not realistically feasible, as nerve biopsies are painful and may result in permanent damage. Therefore, our laboratory has investigated paclitaxel-induced neuronal morphological and molecular changes using an ex vivo model of human-induced pluripotent stem cell (iPSC)-derived neurons. Methods: iPSCs are undifferentiated and endlessly dividing cells that can be generated from a patient’s somatic cells, such as peripheral blood mononuclear cells (PBMCs). We successfully reprogrammed PBMCs into iPSCs using the Erythroid Progenitor Reprograming Kit (STEMCell Technologiesᵀᴹ); pluripotency was verified by flow cytometry analysis. iPSCs were then induced into neurons using a differentiation protocol that bypasses the neural progenitor stage and uses selected small-molecule modulators of key signaling pathways (SMAD, Notch, FGFR1 inhibition, and Wnt activation). Results: Flow cytometry analysis revealed expression of core pluripotency transcription factors Nanog, Oct3/4 and Sox2 in iPSCs overlaps with commercially purchased pluripotent cell line UCSD064i-20-2. Trilineage differentiation of iPSCs was confirmed with immunofluorescent imaging with germ-layer-specific markers; Sox17 and ExoA2 for ectoderm, Nestin, and Pax6 for mesoderm, and Ncam and Brachyury for endoderm. Sensory neuron markers, β-III tubulin, and Peripherin were applied to stain the cells for the maturity of iPSC-derived neurons. Patch-clamp electrophysiology and calcitonin gene-related peptide (CGRP) release data supported the functionality of the induced neurons and provided insight into the timing for which downstream assays could be performed (week 4 post-induction). We have also performed a cell viability assay and fluorescence-activated cell sorting (FACS) using four cell-surface markers (CD184, CD44, CD15, and CD24) to select a neuronal population. At least 70% of the cells were viable in the isolated neuron population. Conclusion: We have found that these iPSC-derived neurons recapitulate mature neuronal phenotypes and demonstrate functionality. Thus, this represents a patient-derived ex vivo neuronal model to investigate the molecular mechanisms of clinical TIPN.

Keywords: chemotherapy, iPSC-derived neurons, peripheral neuropathy, taxane, paclitaxel

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Authors: Duncan Wallace, M-Tahar Kechadi

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In recent years, Machine Learning (ML) approaches have been successfully applied to an analysis of patient symptom data in the context of disease diagnosis, at least where such data is well codified. However, much of the data present in Electronic Health Records (EHR) are unlikely to prove suitable for classic ML approaches. Furthermore, as scores of data are widely spread across both hospitals and individuals, a decentralized, computationally scalable methodology is a priority. The focus of this paper is to develop a method to predict outliers in an out-of-hours healthcare provision center (OOHC). In particular, our research is based upon the early identification of patients who have underlying conditions which will cause them to repeatedly require medical attention. OOHC act as an ad-hoc delivery of triage and treatment, where interactions occur without recourse to a full medical history of the patient in question. Medical histories, relating to patients contacting an OOHC, may reside in several distinct EHR systems in multiple hospitals or surgeries, which are unavailable to the OOHC in question. As such, although a local solution is optimal for this problem, it follows that the data under investigation is incomplete, heterogeneous, and comprised mostly of noisy textual notes compiled during routine OOHC activities. Through the use of Deep Learning methodologies, the aim of this paper is to provide the means to identify patient cases, upon initial contact, which are likely to relate to such outliers. To this end, we compare the performance of Long Short-Term Memory, Gated Recurrent Units, and combinations of both with Convolutional Neural Networks. A further aim of this paper is to elucidate the discovery of such outliers by examining the exact terms which provide a strong indication of positive and negative case entries. While free-text is the principal data extracted from EHRs for classification, EHRs also contain normalized features. Although the specific demographical features treated within our corpus are relatively limited in scope, we examine whether it is beneficial to include such features among the inputs to our neural network, or whether these features are more successfully exploited in conjunction with a different form of a classifier. In this section, we compare the performance of randomly generated regression trees and support vector machines and determine the extent to which our classification program can be improved upon by using either of these machine learning approaches in conjunction with the output of our Recurrent Neural Network application. The output of our neural network is also used to help determine the most significant lexemes present within the corpus for determining high-risk patients. By combining the confidence of our classification program in relation to lexemes within true positive and true negative cases, with an inverse document frequency of the lexemes related to these cases, we can determine what features act as the primary indicators of frequent-attender and non-frequent-attender cases, providing a human interpretable appreciation of how our program classifies cases.

Keywords: artificial neural networks, data-mining, machine learning, medical informatics

Procedia PDF Downloads 104

Authors: Kenneth A. Rostowsky, Alexander S. Maher, Nahian F. Chowdhury, Andrei Irimia

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The clinical significance of cerebral microbleeds (CMBs) due to mild traumatic brain injury (mTBI) remains unclear. Here we use magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and connectomic analysis to investigate the statistical association between mTBI-related CMBs, post-TBI changes to the human connectome and neurological/cognitive deficits. This study was undertaken in agreement with US federal law (45 CFR 46) and was approved by the Institutional Review Board (IRB) of the University of Southern California (USC). Two groups, one consisting of 26 (13 females) mTBI victims and another comprising 26 (13 females) healthy control (HC) volunteers were recruited through IRB-approved procedures. The acute Glasgow Coma Scale (GCS) score was available for each mTBI victim (mean µ = 13.2; standard deviation σ = 0.4). Each HC volunteer was assigned a GCS of 15 to indicate the absence of head trauma at the time of enrollment in our study. Volunteers in the HC and mTBI groups were matched according to their sex and age (HC: µ = 67.2 years, σ = 5.62 years; mTBI: µ = 66.8 years, σ = 5.93 years). MRI [including T1- and T2-weighted volumes, gradient recalled echo (GRE)/susceptibility weighted imaging (SWI)] and gradient echo (GE) DWI volumes were acquired using the same MRI scanner type (Trio TIM, Siemens Corp.). Skull-stripping and eddy current correction were implemented. DWI volumes were processed in TrackVis (http://trackvis.org) and 3D Slicer (http://www.slicer.org). Tensors were fit to DWI data to perform DTI, and tractography streamlines were then reconstructed using deterministic tractography. A voxel classifier was used to identify image features as CMB candidates using Microbleed Anatomic Rating Scale (MARS) guidelines. For each peri-lesional DTI streamline bundle, the null hypothesis was formulated as the statement that there was no neurological or cognitive deficit associated with between-scan differences in the mean FA of DTI streamlines within each bundle. The statistical significance of each hypothesis test was calculated at the α = 0.05 level, subject to the family-wise error rate (FWER) correction for multiple comparisons. Results: In HC volunteers, the along-track analysis failed to identify statistically significant differences in the mean FA of DTI streamline bundles. In the mTBI group, significant differences in the mean FA of peri-lesional streamline bundles were found in 21 out of 26 volunteers. In those volunteers where significant differences had been found, these differences were associated with an average of ~47% of all identified CMBs (σ = 21%). In 12 out of the 21 volunteers exhibiting significant FA changes, cognitive functions (memory acquisition and retrieval, top-down control of attention, planning, judgment, cognitive aspects of decision-making) were found to have deteriorated over the six months following injury (r = -0.32, p < 0.001). Our preliminary results suggest that acute post-TBI CMBs may be associated with cognitive decline in some mTBI patients. Future research should attempt to identify mTBI patients at high risk for cognitive sequelae.

Keywords: traumatic brain injury, magnetic resonance imaging, diffusion tensor imaging, connectomics

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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

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Authors: Laura Roe

Abstract:

This study draws on twelve months of ethnographic fieldwork conducted in 2017 with heroin and poly-substance users in Scotland and explores experiences of time and temporality as factors in continuing drug use. The research largely took place over the year in which drug-related deaths in Scotland reached a record high, and were statistically recorded as the highest in Europe. This qualitative research is therefore significant in understanding both evolving patterns of drug use and the experiential lifeworlds of those who use heroin and other substances in high doses. Methodologies included participant observation, structured and semi-structured interviews, and unstructured conversations with twenty-two regular participants. The fieldwork was conducted in two needle exchanges, a community recovery group and in the community. The initial aim of the study was to assess evolving patterns of drug preferences in order to explore a clinical and user-reported rise in the use of novel psychoactive substances (NPS), which are typically considered to be highly potent, synthetic substances, often available at a low cost. It was found, however, that while most research participants had experimented with NPS with varying intensity, those who used every day regularly consumed heroin, methadone, and alcohol with benzodiazepines such as diazepam or anticonvulsants such as gabapentin. The research found that many participants deliberately pursued the non-fatal effects of overdose, aiming to induce states of dissociation, detachment and uneven consciousness, and did so by both mixing substances and experimenting with novel modes of consumption. Temporality was significant in the decision to consume cocktails of substances, as users described wishing to sever themselves from time; entering into states of ‘non-time’ and insensibility through specific modes of intoxication. Time and temporality similarly impacted other aspects of addicted life. Periods of attempted abstinence witnessed a slowing of time’s passage that was tied to affective states of boredom and melancholy, in addition to a disruptive return of distressing and difficult memories. Abject past memories frequently dominated and disrupted the present, which otherwise could be highly immersive due to the time and energy-consuming nature of seeking drugs while in financial difficulty. There was furthermore a discordance between individual user temporalities and the strict time-based regimes of recovery services and institutional bodies, and the study aims to highlight the impact of such a disjuncture on the efficacy of treatment programs. Many participants had difficulty in adhering to set appointments or temporal frameworks due to their specific temporal situatedness. Overall, exploring increasing tendencies of heroin users in Scotland towards poly-substance use, this study draws on experiences and perceptions of time, analysing how temporality comes to bear on the ways drugs are sought and consumed, and how recovery is imagined and enacted. The study attempts to outline the experiential, intimate and subjective worlds of heroin and poly-substance users while explicating the structural and historical factors that shape them.

Keywords: addiction, poly-substance use, temporality, timelessness

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Authors: Mariia Karizhenskaia, Tanvi Nandani, Ali Tafazoli Moghadam

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Hospice palliative care (HPC) is one of the most complicated philosophies of care in which physical, social/cultural, and spiritual aspects of human life are intermingled with an undeniably significant role in every aspect. Among these dimensions of care, culture possesses an outstanding position in the process and goal determination of HPC. This study shows the importance of cultural elements in the establishment of effective and optimized structures of HPC in the Canadian healthcare environment. Our systematic search included Medline, Google Scholar, and St. Lawrence College Library, considering original, peer-reviewed research papers published from 1998 to 2023 to identify recent national literature connecting culture and palliative care delivery. The most frequently presented feature among the articles is the role of culture in the efficiency of the HPC. It has been shown frequently that including the culturespecific parameters of each nation in this system of care is vital for its success. On the other hand, ignorance about the exclusive cultural trends in a specific location has been accompanied by significant failure rates. Accordingly, implementing a culture-wise adaptable approach is mandatory for multicultural societies. The following outcome of research studies in this field underscores the importance of culture-oriented education for healthcare staff. Thus, all the practitioners involved in HPC will recognize the importance of traditions, religions, and social habits for processing the care requirements. Cultural competency training is a telling sample of the establishment of this strategy in health care that has come to the aid of HPC in recent years. Another complexity of the culturized HPC nowadays is the long-standing issue of racialization. Systematic and subconscious deprivation of minorities has always been an adversity of advanced levels of care. The last part of the constellation of our research outcomes is comprised of the ethical considerations of culturally driven HPC. This part is the most sophisticated aspect of our topic because almost all the analyses, arguments, and justifications are subjective. While there was no standard measure for ethical elements in clinical studies with palliative interventions, many research teams endorsed applying ethical principles for all the involved patients. Notably, interpretations and projections of ethics differ in varying cultural backgrounds. Therefore, healthcare providers should always be aware of the most respectable methodologies of HPC on a case-by-case basis. Cultural training programs have been utilized as one of the main tactics to improve the ability of healthcare providers to address the cultural needs and preferences of diverse patients and families. In this way, most of the involved health care practitioners will be equipped with cultural competence. Considerations for ethical and racial specifications of the clients of this service will boost the effectiveness and fruitfulness of the HPC. Canadian society is a colorful compilation of multiple nationalities; accordingly, healthcare clients are diverse, and this divergence is also translated into HPC patients. This fact justifies the importance of studying all the cultural aspects of HPC to provide optimal care on this enormous land.

Keywords: cultural competence, end-of-life care, hospice, palliative care

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Authors: Ksenia Volkova, Artur Petrosyan, Ignatii Dubyshkin, Alexei Ossadtchi

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Brain-computer interfaces are a growing research field producing many implementations that find use in different fields and are used for research and practical purposes. Despite the popularity of the implementations using non-invasive neuroimaging methods, radical improvement of the state channel bandwidth and, thus, decoding accuracy is only possible by using invasive techniques. Electrocorticography (ECoG) is a minimally invasive neuroimaging method that provides highly informative brain activity signals, effective analysis of which requires the use of machine learning methods that are able to learn representations of complex patterns. Deep learning is a family of machine learning algorithms that allow learning representations of data with multiple levels of abstraction. This study explores the potential of deep learning approaches for ECoG processing, decoding movement intentions and the perception of proprioceptive information. To obtain synchronous recording of kinematic movement characteristics and corresponding electrical brain activity, a series of experiments were carried out, during which subjects performed finger movements at their own pace. Finger movements were recorded with a three-axis accelerometer, while ECoG was synchronously registered from the electrode strips that were implanted over the contralateral sensorimotor cortex. Then, multichannel ECoG signals were used to track finger movement trajectory characterized by accelerometer signal. This process was carried out both causally and non-causally, using different position of the ECoG data segment with respect to the accelerometer data stream. The recorded data was split into training and testing sets, containing continuous non-overlapping fragments of the multichannel ECoG. A deep convolutional neural network was implemented and trained, using 1-second segments of ECoG data from the training dataset as input. To assess the decoding accuracy, correlation coefficient r between the output of the model and the accelerometer readings was computed. After optimization of hyperparameters and training, the deep learning model allowed reasonably accurate causal decoding of finger movement with correlation coefficient r = 0.8. In contrast, the classical Wiener-filter like approach was able to achieve only 0.56 in the causal decoding mode. In the noncausal case, the traditional approach reached the accuracy of r = 0.69, which may be due to the presence of additional proprioceptive information. This result demonstrates that the deep neural network was able to effectively find a representation of the complex top-down information related to the actual movement rather than proprioception. The sensitivity analysis shows physiologically plausible pictures of the extent to which individual features (channel, wavelet subband) are utilized during the decoding procedure. In conclusion, the results of this study have demonstrated that a combination of a minimally invasive neuroimaging technique such as ECoG and advanced machine learning approaches allows decoding motion with high accuracy. Such setup provides means for control of devices with a large number of degrees of freedom as well as exploratory studies of the complex neural processes underlying movement execution.

Keywords: brain-computer interface, deep learning, ECoG, movement decoding, sensorimotor cortex

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Authors: Huey-Yeu Yan, Ching-Ying Lee, Hung-Ru Lin

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Background: Physical assessment is a vital clinical nursing competence. The gap between conventional teaching method and the way e-generation students’ preferred could be bridged owing to the support of Internet technology, i.e. interacting with online media to manage learning works. Nursing instructors in the wake of new learning pattern of the e-generation students are challenged to actively adjust and make teaching contents and methods more versatile. Objective: The objective of this research is to explore the effects on teaching and learning with live webcast-assisted on a specific topic, Physical Assessment technique, on a designated group of young nursing majors. It’s hoped that, with a way of nursing instructing, more versatile learning resources may be provided to facilitate self-directed learning. Design: This research adopts a cross-sectional descriptive survey. The instructor demonstrated physical assessment techniques and operation procedures via live webcast broadcasted online to all students. It increased both the off-time interaction between teacher and students concerning teaching materials. Methods: A convenient sampling was used to recruit a total of 52 nursing-majors at a certain university. The nursing majors took two-hour classes of Physical Assessment per week for 18 weeks (36 hrs. in total). The instruction covered four units with live webcasting and then conducted an online anonymous survey of learning outcomes by questionnaire. The research instrument was the online questionnaire, covering three major domains—online media used, learning outcome evaluation and evaluation result. The data analysis was conducted via IBM SPSS Statistics Version 2.0. The descriptive statistics was undertaken to describe the analysis of basic data and learning outcomes. Statistical methods such as descriptive statistics, t-test, ANOVA, and Pearson’s correlation were employed in verification. Results: Results indicated the following five major findings. (1) learning motivation, about four fifth of the participants agreed the online instruction resources are very helpful in improving learning motivation and raising the learning interest. (2) learning needs, about four fifth of participants agreed it was helpful to plan self-directed practice after the instruction, and meet their needs of repetitive learning and/or practice at their leisure time. (3) learning effectiveness, about two third agreed it was helpful to reduce pre-exam anxiety, and improve their test scores. (4) course objects, about three fourth agreed that it was helpful to achieve the goal of ‘executing the complete Physical Assessment procedures with proper skills’. (5) finally, learning reflection, about all of participants agreed this experience of online instructing, learning, and practicing is beneficial to them, they recommend instructor to share with other nursing majors, and they will recommend it to fellow students too. Conclusions: Live webcasting is a low-cost, convenient, efficient and interactive resource to facilitate nursing majors’ motivation of learning, need of self-directed learning and practice, outcome of learning. When live webcasting is integrated into nursing teaching, it provides an opportunity of self-directed learning to promote learning effectiveness, as such to fulfill the teaching objective.

Keywords: innovative teaching, learning effectiveness, live webcasting, physical assessment technique

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Authors: Esther Friedlander, Philip Friedlander

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The use of immunotherapy that inhibits programmed death-1 (PD-1) or its ligand PD-L1 confers survival benefits in patients with non-small cell lung cancer (NSCLC). However, approximately 45% of patients experience primary treatment resistance, necessitating the development of strategies to improve efficacy. While the renin-angiotensin system (RAS) has systemic hemodynamic effects, tissue-specific regulation exists along with modulation of immune activity in part through regulation of myeloid cell activity, leading to the hypothesis that RAS inhibition may improve anti-PD-1/L-1 efficacy. A retrospective analysis was conducted that included 173 advanced solid tumor cancer patients treated at Valley Hospital, a community Hospital in New Jersey, USA, who were treated with a PD-1/L-1 inhibitor in a defined time period showing a statistically significant relationship between RAS pathway inhibition (RASi through concomitant treatment with an ACE inhibitor or angiotensin receptor blocker) and positive efficacy to the immunotherapy that was independent of age, gender and cancer type. Subset analysis revealed strong numerical benefit for efficacy in both patients with squamous and nonsquamous NSCLC as determined by documented clinician assessment of efficacy and by duration of therapy. A PUBMED literature search was now conducted to identify studies assessing the effect of RAS pathway inhibition on anti-PD-1/L1 efficacy in advanced solid tumor patients and compare these findings to those seen in the Valley Hospital retrospective study with a focus on NSCLC specifically. A total of 11 articles were identified assessing the effects of RAS pathway inhibition on the efficacy of checkpoint inhibitor immunotherapy in advanced cancer patients. Of the 11 studies, 10 assessed the effect on survival of RASi in the context of treatment with anti-PD-1/PD-L1, while one assessed the effect on CTLA-4 inhibition. Eight of the studies included patients with NSCLC, while the remaining 2 were specific to genitourinary malignancies. Of the 8 studies, two were specific to NSCLC patients, with the remaining 6 studies including a range of cancer types, of which NSCLC was one. Of these 6 studies, only 2 reported specific survival data for the NSCLC subpopulation. Patient characteristics, multivariate analysis data and efficacy data seen in the 2 NSLCLC specific studies and in the 2 basket studies, which provided data on the NSCLC subpopulation, were compared to that seen in the Valley Hospital retrospective study supporting a broader effect of RASi on anti-PD-1/L1 efficacy in advanced NSLCLC with the majority of studies showing statistically significant benefit or strong statistical trends but with one study demonstrating worsened outcomes. This comparison of studies extends published findings to the community hospital setting and supports prospective assessment through randomized clinical trials of efficacy in NSCLC patients with pharmacodynamic components to determine the effect on immune cell activity in tumors and on the composition of the tumor microenvironment.

Keywords: immunotherapy, cancer, angiotensin, efficacy, PD-1, lung cancer, NSCLC

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Authors: J. Ticona Chambi, E. A. De Almeida, C. A. Andrade Raymundo Gaiotto, A. M. Do Espírito Santo, L. Infantes, S. L. Cuffini

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The solubility of active pharmaceutical ingredients (APIs) is challenging for the pharmaceutical industry. The new multicomponent crystalline forms as cocrystal and solvates present an opportunity to improve the solubility of APIs. Commonly, the procedure to obtain multicomponent crystalline forms of a drug starts by screening the drug molecule with the different coformers/solvents. However, it is necessary to develop methods to obtain multicomponent forms in an efficient way and with the least possible environmental impact. The Hansen Solubility Parameters (HSPs) is considered a tool to obtain theoretical knowledge of the solubility of the target compound in the chosen solvent. H-Bond Propensity (HBP), Molecular Complementarity (MC), Coordination Values (CV) are tools used for statistical prediction of cocrystals developed by the Cambridge Crystallographic Data Center (CCDC). The HSPs and the CCDC tools are based on inter- and intra-molecular interactions. The curcumin (Cur), target molecule, is commonly used as an anti‐inflammatory. The demethoxycurcumin (Demcur) and bisdemethoxycurcumin (Bisdcur) are natural analogues of Cur from turmeric. Those target molecules have differences in their solubilities. In this way, the work aimed to analyze and compare different tools for multicomponent forms prediction (solvates) of Cur, Demcur and Biscur. The HSP values were calculated for Cur, Demcur, and Biscur using the chemical group contribution methods and the statistical optimization from experimental data. The HSPmol software was used. From the HSPs of the target molecules and fifty solvents (listed in the HSP books), the relative energy difference (RED) was determined. The probability of the target molecules would be interacting with the solvent molecule was determined using the CCDC tools. A dataset of fifty molecules of different organic solvents was ranked for each prediction method and by a consensus ranking of different combinations: HSP, CV, HBP and MC values. Based on the prediction, 15 solvents were selected as Dimethyl Sulfoxide (DMSO), Tetrahydrofuran (THF), Acetonitrile (ACN), 1,4-Dioxane (DOX) and others. In a starting analysis, the slow evaporation technique from 50°C at room temperature and 4°C was used to obtain solvates. The single crystals were collected by using a Bruker D8 Venture diffractometer, detector Photon100. The data processing and crystal structure determination were performed using APEX3 and Olex2-1.5 software. According to the results, the HSPs (theoretical and optimized) and the Hansen solubility sphere for Cur, Demcur and Biscur were obtained. With respect to prediction analyses, a way to evaluate the predicting method was through the ranking and the consensus ranking position of solvates already reported in the literature. It was observed that the combination of HSP-CV obtained the best results when compared to the other methods. Furthermore, as a result of solvent selected, six new solvates, Cur-DOX, Cur-DMSO, Bicur-DOX, Bircur-THF, Demcur-DOX, Demcur-ACN and a new Biscur hydrate, were obtained. Crystal structures were determined for Cur-DOX, Biscur-DOX, Demcur-DOX and Bicur-Water. Moreover, the unit-cell parameter information for Cur-DMSO, Biscur-THF and Demcur-ACN were obtained. The preliminary results showed that the prediction method is showing a promising strategy to evaluate the possibility of forming multicomponent. It is currently working on obtaining multicomponent single crystals.

Keywords: curcumin, HSPs, prediction, solvates, solubility

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