Search results for: seismic evaluation

Authors: Keshari Shrestha, Philip Vatterott

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Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially fatal drug-related syndrome. DRESS classically presents with a diffuse maculopapular rash, fevers, and eosinophilia more than three weeks after drug exposure. DRESS can present with multi-organ involvement, with liver damage being the most common and severe. Pulmonary involvement is a less common manifestation and is associated with poor clinical outcomes. Chest imaging is often nonspecific, and symptoms can range from mild cough to acute respiratory distress syndrome (ARDS) . This is a case of a 49-year-old female with a history of recent clostridium difficile colitis status post treatment with oral vancomycin who presented with rash, acute liver and kidney failure, as well as diffuse nodular alveolar lung opacities concerning for DRESS syndrome with multi-organ involvement. Clinical Course: This patient initially presented to an outside hospital with clostridium difficile colitis, acute liver injury, and acute kidney injury. She developed a desquamating maculopapular rash in the setting of recent oral vancomycin, meloxicam, and furosemide initiation. She was hospitalized on two additional occasions with worsening altered mental status, liver injury, and acute kidney injury and was initiated on intermittent hemodialysis. Notably, she was found to have systemic eosinophilia (4100 cells/microliter) several weeks prior. She was transferred to this institution for further management where she was found to have encephalopathy, jaundice, lower extremity edema, and diffuse bilateral rhonchorous breath sounds on pulmonary examination. The patient was started on methylprednisolone for suspected DRESS syndrome. She underwent an evaluation for alternative causes of her organ failure. Her workup included a negative infectious, autoimmune, metabolic, toxic, and malignant work-up. Abdominal computed tomography (CT) and ultrasound were remarkable for evidence of hepatic steatosis and possible cirrhotic morphology. Additionally, a chest CT demonstrated diffuse and symmetric nodular alveolar lung opacities with peripheral sparing not consistent with acute respiratory distress syndrome or edema. Ultimately, her condition continued to decline, and she required intubation on several occasions. On hospital day 25 she succumbed to distributive shock in the setting of probable sepsis and multi-organ failure. Discussion: DRESS syndrome occurs in 1 in 1,000 to 10,000 patients with a mortality rate of around 10%. Anti-convulsant, anti-bacterial, anti-viral, and sulfonamide drugs are the most common drugs implicated in the development of DRESS syndrome; however, the list of offending agents is extensive . The diagnosis of DRESS syndrome is made after excluding other causes of disease such as infectious and autoimmune etiologies. The RegiSCAR scoring system is used to diagnose DRESS syndrome with 2-3 points indicating possible disease, 4-5 probable disease, and >5 definite disease. This patient scored a 7 on the RegiSCAR scale for eosinophilia, rash, organ involvement, and exclusion of other causes (infectious and autoimmune). While the pharmacologic trigger in this case is unknown, it is speculated to be caused by vancomycin, meloxicam, or furosemide due to the favorable timeline of initiation. Despite aggressive treatment, DRESS syndrome can often be fatal. Because of this, early diagnosis and treatment of patients with suspected DRESS syndrome is imperative.

Keywords: drug reaction with eosinophilia and systemic symptoms, multi-organ failure, pulmonary involvement, renal failure

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Authors: Ananya Barui, Provas Banerjee, Jyotirmoy Chatterjee

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Application of optical technology in medicine and biology has a long track-record. In this endeavor, OCT is able to attract both engineers and biologists to work together in the field of photonics for establishing a striking non-invasive imaging technology. In contrast to other in vivo imaging modalities like Raman imaging, confocal imaging, two-photon microscopy etc. which can perform in vivo imaging upto 100-200 micron depth due to limitation in numerical aperture or scattering, however, OCT can achieve high-resolution imaging upto few millimeters of tissue structures depending on their refractive index in different anatomical location. This tomographic system depends on interference of two light waves in an interferometer to produce a depth profile of specimen. In wound healing, frequent collection of biopsies for follow-up of repair process could be avoided by such imaging technique. Real time skin OCT (the optical biopsy) has efficacy in deeper and faster illumination of cutaneou tissue to acquire high resolution cross sectional images of their internal micro-structure. Swept Source-OCT (SS-OCT), a novel imaging technique, can generate high-speed depth profile (~ 2 mm) of wound at a sweeping rate of laser with micron level resolution and optimum coherent length of 5-6 mm. Normally multi-layered skin tissue depicts different optical properties along with variation in thickness, refractive index and composition (i.e. keratine layer, water, fat etc.) according to their anatomical location. For instance, stratum corneum, the upper-most and relatively dehydrated layer of epidermis reflects more light and produces more lucid and a sharp demarcation line with rest of the hydrated epidermal region. During wound healing or regeneration, optical properties of cutaneous tissue continuously altered with maturation of wound bed. More mature and less hydrated tissue component reflects more light and becomes visible as a brighter area in comparison to immature region which content higher amount water or fat that depicts as a darker area in OCT image. Non-healing wound possess prolonged inflammation and inhibits nascent proliferative stage. Accumulation of necrotic tissues also prevents the repair of non-healing wounds. Due to high resolution and potentiality to reflect the compositional aspects of tissues in terms of their optical properties, this tomographic method may facilitate in differentiating non-healing and acute wounds in addition to clinical observations. Non-invasive OCT offers better insight regarding specific biological status of tissue in health and pathological conditions, OCT images could be associated with histo-pathological ‘gold standard’. This correlated SS-OCT and microscopic evaluation of the wound edges can provide information regarding progressive healing and maturation of the epithelial components. In the context of searching analogy between two different imaging modalities, their relative performances in imaging of healing bed were estimated for probing an alternative approach. Present study validated utility of SS-OCT in revealing micro-anatomic structure in the healing bed with newer information. Exploring precise correspondence of OCT images features with histo-chemical findings related to epithelial integrity of the regenerated tissue could have great implication. It could establish the ‘optical biopsy’ as a potent non-invasive diagnostic tool for cutaneous pathology.

Keywords: histo-pathology, non invasive imaging, OCT, wound healing

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Authors: Juliet Sorensen, Anna Maitland

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Introduction: Characterized by lack of water and sanitation, food insecurity, and low access to hospitals and clinics, informal urban settlements in Lagos, Nigeria have very poor health outcomes. With little education and a general inability to demand basic rights, these communities are often disempowered and isolated from understanding, claiming, or owning their health needs. Utilizing community-based participatory research characterized by interdisciplinary, cross-cultural partnerships, evidence-based assessments, and both primary and secondary source research, a holistic health education and advocacy program was developed in Lagos to address health barriers for targeted communities. This includes a first of its kind guide formulated to teach community-based health educators how to transmit health information to low-literacy Nigerian audiences while supporting behavior change models and social support mechanisms. This paper discusses the interdisciplinary contributions to developing a health education program while also looking at the need for greater beneficiary ownership and implementation of health justice and access. Methods: In March 2016, an interdisciplinary group of medical, legal, and business graduate students and faculty from Northwestern University conduced a Health Needs Assessment (HNA) in Lagos with a partner and a local non-governmental organization. The HNA revealed that members of informal urban communities in Lagos were lacking basic health literacy, but desired to remedy this lacuna. Further, the HNA revealed that even where the government mandates specific services, many vulnerable populations are unable to access these services. The HNA concluded that a program focused on education, advocacy, and organizing around anatomy, maternal and sexual health, infectious disease and malaria, HIV/AIDS, emergency care, and water and sanitation would respond to stated needs while also building capacity in communities to address health barriers. Results: Based on the HNA, including both primary and secondary source research on integrated health education approaches and behavior change models and responsive, adaptive material development, a holistic program was developed for the Lagos partners and first implemented in November 2016. This program trained community-nominated health educators in adult, low-literacy, knowledge exchange approaches, utilizing information identified by communities as a priority. After a second training in March 2017, these educators will teach community-based groups and will support and facilitate behavior change models and peer-support methods around basic issues like hand washing and disease transmission. They will be supported by community paralegals who will help ensure that newly trained community groups can act on education around access, such as receiving free vaccinations, maternal health care, and HIV/AIDS medicines. Materials will continue to be updated as needs and issues arise, with a focus on identifying best practices around health improvements that can be shared across these partner communities. Conclusion: These materials are the first of their kind, and address a void of health information and understanding pervasive in informal-urban Lagos communities. Initial feedback indicates high levels of commitment and interest, as well as investment by communities in these materials, largely because they are responsive, targeted, and build community capacity. This methodology is an important step in dignity-based health justice solutions, albeit in the process of refinement.

Keywords: community health educators, interdisciplinary and cross cultural partnerships, health justice and access, Nigeria

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Authors: Chusit Apirumanekul, Chayanis Krittasudthacheewa, Ratchapat Ratanavaraha, Yanyong Inmuong

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Rapid economic development in the Lower Mekong region is leading to changes in water quantity and quality. Changes in land- and forest-use, infrastructure development, increasing urbanization, migration patterns and climate risks are increasing demands for water, within various sectors, placing pressure on scarce water resources. Appropriate policies, strategies, and planning are urgently needed for improved water resource management. Over the last decade, Thailand has experienced more frequent and intense drought situations, affecting the level of water storage in reservoirs along with insufficient water allocation for agriculture during the dry season. The Huay Saibat River Basin, one of the well-known water-scarce areas in the northeastern region of Thailand, is experiencing ongoing water scarcity that affects both farming livelihoods and household consumption. Drought management in Thailand mainly focuses on emergency responses, rather than advance preparation and mitigation for long-term solutions. Despite many efforts from local authorities to mitigate the drought situation, there is yet no long-term comprehensive water management strategy, that integrates climate risks alongside other uncertainties. This paper assesses the application in the Huay Saibat River Basin, of the Robust Decision Support framework, to explore the feasibility of multiple drought management policies; including a shift in cropping season, in crop changes, in infrastructural operations and in the use of groundwater, under a wide range of uncertainties, including climate and land-use change. A series of consultative meetings were organized with relevant agencies and experts at the local level, to understand and explore plausible water resources strategies and identify thresholds to evaluate the performance of those strategies. Three different climate conditions were identified (dry, normal and wet). Other non-climatic factors influencing water allocation were further identified, including changes from sugarcane to rubber, delaying rice planting, increasing natural retention storage and using groundwater to supply demands for household consumption and small-scale gardening. Water allocation and water use in various sectors, such as in agriculture, domestic, industry and the environment, were estimated by utilising the Water Evaluation And Planning (WEAP) system, under various scenarios developed from the combination of climatic and non-climatic factors mentioned earlier. Water coverage (i.e. percentage of water demand being successfully supplied) was defined as a threshold for water resource strategy assessment. Thresholds for different sectors (agriculture, domestic, industry, and environment) were specified during multi-stakeholder engagements. Plausible water strategies (e.g. increasing natural retention storage, change of crop type and use of groundwater as an alternative source) were evaluated based on specified thresholds in 4 sectors (agriculture, domestic, industry, and environment) under 3 climate conditions. 'Business as usual' was evaluated for comparison. The strategies considered robust, emerge when performance is assessed as successful, under a wide range of uncertainties across the river basin. Without adopting any strategy, the water scarcity situation is likely to escalate in the future. Among the strategies identified, the use of groundwater as an alternative source was considered a potential option in combating water scarcity for the basin. Further studies are needed to explore the feasibility for groundwater use as a potential sustainable source.

Keywords: climate change, robust decision support, scenarios, water resources management

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Authors: Kumar Satyam Das, Murali Raghunathan

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This note discusses the feasibility of field development of a challenging shallow offshore field in South East Asia and how its learnings can be applied to marginal field development across the world especially developing marginal fields in this low oil price world. The field was found to be economically challenging even during high oil prices and the project was put on hold. Shell started development study with the aim to significantly reduce cost through competitively scoping and revive stranded projects. The proposed strategy to achieve this involved Improve Per platform recovery and Reduction in CAPEX. Methodology: Based on various Benchmarking Tool such as Woodmac for similar projects in the region and economic affordability, a challenging target of 50% reduction in unit development cost (UDC) was set for the project. Technical scope was defined to the minimum as to be a wellhead platform with minimum functionality to ensure production. The evaluation of key project decisions like Well location and number, well design, Artificial lift methods and wellhead platform type under different development concept was carried out through integrated multi-discipline approach. Key elements influencing per platform recovery were Wellhead Platform (WHP) location, Well count, well reach and well productivity. Major Findings: Reservoir being shallow posed challenges in well design (dog-leg severity, casing size and the achievable step-out), choice of artificial lift and sand-control method. Integrated approach amongst relevant disciplines with challenging mind-set enabled to achieve optimized set of development decisions. This led to significant improvement in per platform recovery. It was concluded that platform recovery largely depended on the reach of the well. Choice of slim well design enabled designing of high inclination and better productivity wells. However, there is trade-off between high inclination Gas Lift (GL) wells and low inclination wells in terms of long term value, operational complexity, well reach, recovery and uptime. Well design element like casing size, well completion, artificial lift and sand control were added successively over the minimum technical scope design leading to a value and risk staircase. Logical combinations of options (slim well, GL) were competitively screened to achieve 25% reduction in well cost. Facility cost reduction was achieved through sourcing standardized Low Cost Facilities platform in combination with portfolio execution to maximizing execution efficiency; this approach is expected to reduce facilities cost by ~23% with respect to the development costs. Further cost reductions were achieved by maximizing use of existing facilities nearby; changing reliance on existing water injection wells and utilizing existing water injector (W.I.) platform for new injectors. Conclusion: The study provides a spectrum of technically feasible options. It also made clear that different drivers lead to different development concepts and the cost value trade off staircase made this very visible. Scoping of the project through competitive way has proven to be valuable for decision makers by creating a transparent view of value and associated risks/uncertainty/trade-offs for difficult choices: elements of the projects can be competitive, whilst other parts will struggle, even though contributing to significant volumes. Reduction in UDC through proper scoping of present projects and its benchmarking paves as a learning for the development of marginal fields across the world, especially in this low oil price scenario. This way of developing a field has on average a reduction of 40% of cost for the Shell projects.

Keywords: benchmarking, full field development, CAPEX, feasibility

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Authors: Justin Woulfe

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Siloed logistics and supply chain management systems throughout the Department of Defense (DOD) has led to disparate approaches to modeling and simulation (M&S), a lack of understanding of how one system impacts the whole, and issues with “optimal” solutions that are good for one organization but have dramatic negative impacts on another. Many different systems have evolved to try to understand and account for uncertainty and try to reduce the consequences of the unknown. As the DoD undertakes expansive digital transformation initiatives, there is an opportunity to fuse and leverage traditionally disparate data into a centrally hosted source of truth. With a streamlined process incorporating machine learning (ML) and artificial intelligence (AI), advanced M&S will enable informed decisions guiding program success via optimized operational readiness and improved mission success. One of the current challenges is to leverage the terabytes of data generated by monitored systems to provide actionable information for all levels of users. The implementation of a cloud-based application analyzing data transactions, learning and predicting future states from current and past states in real-time, and communicating those anticipated states is an appropriate solution for the purposes of reduced latency and improved confidence in decisions. Decisions made from an ML and AI application combined with advanced optimization algorithms will improve the mission success and performance of systems, which will improve the overall cost and effectiveness of any program. The Systecon team constructs and employs model-based simulations, cutting across traditional silos of data, aggregating maintenance, and supply data, incorporating sensor information, and applying optimization and simulation methods to an as-maintained digital twin with the ability to aggregate results across a system’s lifecycle and across logical and operational groupings of systems. This coupling of data throughout the enterprise enables tactical, operational, and strategic decision support, detachable and deployable logistics services, and configuration-based automated distribution of digital technical and product data to enhance supply and logistics operations. As a complete solution, this approach significantly reduces program risk by allowing flexible configuration of data, data relationships, business process workflows, and early test and evaluation, especially budget trade-off analyses. A true capability to tie resources (dollars) to weapon system readiness in alignment with the real-world scenarios a warfighter may experience has been an objective yet to be realized to date. By developing and solidifying an organic capability to directly relate dollars to readiness and to inform the digital twin, the decision-maker is now empowered through valuable insight and traceability. This type of educated decision-making provides an advantage over the adversaries who struggle with maintaining system readiness at an affordable cost. The M&S capability developed allows program managers to independently evaluate system design and support decisions by quantifying their impact on operational availability and operations and support cost resulting in the ability to simultaneously optimize readiness and cost. This will allow the stakeholders to make data-driven decisions when trading cost and readiness throughout the life of the program. Finally, sponsors are available to validate product deliverables with efficiency and much higher accuracy than in previous years.

Keywords: artificial intelligence, digital transformation, machine learning, predictive analytics

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Authors: Agman Gupta, Rajashekar Badam, Noriyoshi Matsumi

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Introduction: Recently, silicon has been recognized as one of the potential alternatives as anode active material in Li-ion batteries (LIBs) to replace the conventionally used graphite anodes. Silicon is abundantly present in the nature, it can alloy with lithium metal, and has a higher theoretical capacity (~4200 mAhg-1) that is approximately 10 times higher than graphite. However, because of a large volume expansion (~400%) upon repeated de-/alloying, the pulverization of Si particles causes the exfoliation of electrode laminate leading to the loss of electrical contact and adversely affecting the formation of solid-electrolyte interface (SEI).1 Functional polymers as binders have emerged as a competitive strategy to mitigate these drawbacks and failure mechanism of silicon anodes.1 A variety of aqueous/non-aqueous polymer binders like sodium carboxy-methyl cellulose (CMC-Na), styrene butadiene rubber (SBR), poly(acrylic acid), and other variants like mussel inspired binders have been investigated to overcome these drawbacks.1 However, there are only a few reports that mention the attempt of addressing all the drawbacks associated with silicon anodes effectively using a single novel functional polymer system as a binder. In this regard, here, we report a novel highly robust n-type bisiminoacenaphthenequinone (BIAN)-paraphenylene-based crosslinked polymer as a binder for Si anodes in lithium-ion batteries (Fig. 1). On its application, crosslinked-BIAN binder was evaluated to provide mechanical robustness to the large volume expansion of Si particles, maintain electrical conductivity within the electrode laminate, and facilitate in the formation of a thin SEI by restricting the extent of electrolyte decomposition on the surface of anode. The fabricated anodic half-cells were evaluated electrochemically for their rate capability, cyclability, and discharge capacity. Experimental: The polymerized BIAN (P-BIAN) copolymer was synthesized as per the procedure reported by our group.2 The synthesis of crosslinked P-BIAN: a solution of P-BIAN copolymer (1.497 g, 10 mmol) in N-methylpyrrolidone (NMP) (150 ml) was set-up to stir under reflux in nitrogen atmosphere. To this, 1,6-dibromohexane (5 mmol, 0.77 ml) was added dropwise. The resultant reaction mixture was stirred and refluxed at 150 °C for 24 hours followed by refrigeration for 3 hours at 5 °C. The product was obtained by evaporating the NMP solvent under reduced pressure and drying under vacuum at 120 °C for 12 hours. The obtained product was a black colored sticky compound. It was characterized by 1H-NMR, XPS, and FT-IR techniques. Results and Discussion: The N 1s XPS spectrum of the crosslinked BIAN polymer showed two characteristic peaks corresponding to the sp2 hybridized nitrogen (-C=N-) at 399.6 eV of the diimine backbone in the BP and quaternary nitrogen at 400.7 eV corresponding to the crosslinking of BP via dibromohexane. The DFT evaluation of the crosslinked BIAN binder showed that it has a low lying lowest unoccupied molecular orbital (LUMO) that enables it to get doped in the reducing environment and influence the formation of a thin (SEI). Therefore, due to the mechanically robust crosslinked matrices as well as its influence on the formation of a thin SEI, the crosslinked BIAN binder stabilized the Si anode-based half-cell for over 1000 cycles with a reversible capacity of ~2500 mAhg-1 and ~99% capacity retention as shown in Fig. 2. The dynamic electrochemical impedance spectroscopy (DEIS) characterization of crosslinked BIAN-based anodic half-cell confirmed that the SEI formed was thin in comparison with the conventional binder-based anodes. Acknowledgement: We are thankful to the financial support provided by JST-Mirai Program, Grant Number: JP18077239

Keywords: self-healing binder, n-type binder, thin solid-electrolyte interphase (SEI), high-capacity silicon anodes, low-LUMO

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Authors: Lilia Edit Aparicio Pico, Paulo Cesar Coronado Sánchez, Roberto Ferro Escobar

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This paper presents the implementation of telemedicine services for physiotherapy, occupational therapy, and speech therapy rehabilitation, utilizing telebroadcasting of audiovisual content to enhance comprehensive patient recovery in rural areas of San Vicente del Caguán municipality, characterized by high levels of social conflict in Colombia. The region faces challenges such as dysfunctional problems, physical rehabilitation needs, and a high prevalence of hearing diseases, leading to neglect and substandard health services. Limited access to healthcare due to communication barriers and transportation difficulties exacerbates these issues. To address these challenges, a research initiative was undertaken to leverage information and communication technologies (ICTs) to improve healthcare quality and accessibility for this vulnerable population. The primary objective was to develop a tele-rehabilitation system to provide asynchronous online therapies and teleconsultation services for patient follow-up during the recovery process. The project comprises two components: Communication systems and human development. A technological component involving the establishment of a wireless network connecting rural centers and the development of a mobile application for video-based therapy delivery. Communications systems will be provided by a radio link that utilizes internet provided by the Colombian government, located in the municipality of San Vicente del Caguán to connect two rural centers (Pozos and Tres Esquinas) and a mobile application for managing videos for asynchronous broadcasting in sidewalks and patients' homes. This component constitutes an operational model integrating information and telecommunications technologies. The second component involves pedagogical and human development. The primary focus is on the patient, where performance indicators and the efficiency of therapy support were evaluated for the assessment and monitoring of telerehabilitation results in physical, occupational, and speech therapy. They wanted to implement a wireless network to ensure audiovisual content transmission for tele-rehabilitation, design audiovisual content for tele-rehabilitation based on services provided by the ESE Hospital San Rafael in physiotherapy, occupational therapy, and speech therapy, develop a software application for fixed and mobile devices enabling access to tele-rehabilitation audiovisual content for healthcare personnel and patients and finally to evaluate the technological solution's contribution to the ESE Hospital San Rafael community. The research comprised four phases: wireless network implementation, audiovisual content design, software application development, and evaluation of the technological solution's impact. Key findings include the successful implementation of virtual teletherapy, both synchronously and asynchronously, and the assessment of technological performance indicators, patient evolution, timeliness, acceptance, and service quality of tele-rehabilitation therapies. The study demonstrated improved service coverage, increased care supply, enhanced access to timely therapies for patients, and positive acceptance of teletherapy modalities. Additionally, the project generated new knowledge for potential replication in other regions and proposed strategies for short- and medium-term improvement of service quality and care indicators

Keywords: e-health, medical informatics, telemedicine, telerehabilitation, virtual therapy

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Authors: Tim Crocker-Buque, Sandra Mounier-Jack, Natasha Howard

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Background: Due to both the increasing scale and speed of urbanisation, urban areas in low and middle-income countries (LMICs) host increasingly large populations of under-immunized children, with the additional associated risks of rapid disease transmission in high-density living environments. Multiple interdependent factors are associated with these coverage disparities in urban areas and most evidence comes from relatively few countries, e.g., predominantly India, Kenya, Nigeria, and some from Pakistan, Iran, and Brazil. This study aimed to identify, describe, and assess the main tools used to measure or improve coverage of immunisation services in poor urban areas. Methods: Authors used a qualitative review design, including academic and non-academic literature, to identify tools used to improve coverage of public health interventions in urban areas. Authors selected and extracted sources that provided good examples of specific tools, or categories of tools, used in a context relevant to urban immunization. Diagnostic (e.g., for data collection, analysis, and insight generation) and programme tools (e.g., for investigating or improving ongoing programmes) and interventions (e.g., multi-component or stand-alone with evidence) were selected for inclusion to provide a range of type and availability of relevant tools. These were then prioritised using a decision-analysis framework and a tool selection guide for programme managers developed. Results: Authors reviewed tools used in urban immunisation contexts and tools designed for (i) non-immunization and/or non-health interventions in urban areas, and (ii) immunisation in rural contexts that had relevance for urban areas (e.g., Reaching every District/Child/ Zone). Many approaches combined several tools and methods, which authors categorised as diagnostic, programme, and intervention. The most common diagnostic tools were cross-sectional surveys, key informant interviews, focus group discussions, secondary analysis of routine data, and geographical mapping of outcomes, resources, and services. Programme tools involved multiple stages of data collection, analysis, insight generation, and intervention planning and included guidance documents from WHO (World Health Organisation), UNICEF (United Nations Children's Fund), USAID (United States Agency for International Development), and governments, and articles reporting on diagnostics, interventions, and/or evaluations to improve urban immunisation. Interventions involved service improvement, education, reminder/recall, incentives, outreach, mass-media, or were multi-component. The main gaps in existing tools were an assessment of macro/policy-level factors, exploration of effective immunization communication channels, and measuring in/out-migration. The proposed framework uses a problem tree approach to suggest tools to address five common challenges (i.e. identifying populations, understanding communities, issues with service access and use, improving services, improving coverage) based on context and available data. Conclusion: This study identified many tools relevant to evaluating urban LMIC immunisation programmes, including significant crossover between tools. This was encouraging in terms of supporting the identification of common areas, but problematic as data volumes, instructions, and activities could overwhelm managers and tools are not always suitably applied to suitable contexts. Further research is needed on how best to combine tools and methods to suit local contexts. Authors’ initial framework can be tested and developed further.

Keywords: health equity, immunisation, low and middle-income countries, poverty, urban health

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Authors: Nazym Zhumabayeva, Aleksandr Mezin, Alexandra Knysheva

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Women's underrepresentation in STEM is critical, worsened by ineffective engagement in educational practices. UNICEF Kazakhstan and GameLab KBTU's collaborative initiatives aim to enhance female STEM participation by fostering an inclusive environment. Learning from LEVEL UP's 2023 program, which featured a hackathon, the 2024 strategy pivots towards non-competitive gamification. Although the data from last year's project showed higher than average student engagement, observations and in-depth interviews with participants showed that the format was stressful for the girls, making them focus on points rather than on other values. This study presents a gamified educational system, DPG Lab, aimed at incentivizing young women's participation in STEM through the development of digital public goods (DPGs). By prioritizing collaborative gamification elements, the project seeks to create an inclusive learning environment that increases engagement and interest in STEM among young women. The DPG Lab aims to find a solution to minimize competition and support collaboration. The project is designed to motivate female participants towards the development of digital solutions through an introduction to the concept of DPGs. It consists of a short online course, a simulation videogame, and a real-time online quest with an offline finale at the KBTU campus. The online course offers short video lectures on open-source development and DPG standards. The game facilitates the practical application of theoretical knowledge, enriching the learning experience. Learners can also participate in a quest that encourages participants to develop DPG ideas in teams by choosing missions throughout the quest path. At the offline quest finale, the participants will meet in person to exchange experiences and accomplishments without engaging in comparative assessments: the quest ensures that each team’s trajectory is distinct by design. This marks a shift from competitive hackathons to a collaborative format, recognizing the unique contributions and achievements of each participant. The pilot batch of students is scheduled to commence in April 2024, with the finale anticipated in June. It is projected that this group will comprise 50 female high-school students from various regions across Kazakhstan. Expected outcomes include increased engagement and interest in STEM fields among young female participants, positive emotional and psychological impact through an emphasis on collaborative learning environments, and improved understanding and skills in DPG development. GameLab KBTU intends to undertake a hypothesis evaluation, employing a methodology similar to that utilized in the preceding LEVEL UP project. This approach will encompass the compilation of quantitative metrics (conversion funnels, test results, and surveys) and qualitative data from in-depth interviews and observational studies. For comparative analysis, a select group of participants from the previous year's project will be recruited to engage in the DPG Lab. By developing and implementing a gamified framework that emphasizes inclusion, engagement, and collaboration, the study seeks to provide practical knowledge about effective gamification strategies for promoting gender diversity in STEM. The expected outcomes of this initiative can contribute to the broader discussion on gamification in education and gender equality in STEM by offering a replicable and scalable model for similar interventions around the world.

Keywords: collaborative learning, competitive learning, digital public goods, educational gamification, emerging regions, STEM, underprivileged groups

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Authors: Volker Wannack

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Regional, national, and international strategies focusing on hydrogen (H₂) and blockchain are driving significant advancements in hydrogen and blockchain technology worldwide. These strategies lay the foundation for the groundbreaking "Blockchain Based Hydrogen Market (BBH₂)" project. The primary goal of this project is to develop a functional Blockchain Minimum Viable Product (B-MVP) for the hydrogen market. The B-MVP will leverage blockchain as an enabling technology with a common database and platform, facilitating secure and automated transactions through smart contracts. This innovation will revolutionize logistics, trading, and transactions within the hydrogen market. The B-MVP has transformative potential across various sectors. It benefits renewable energy producers, surplus energy-based hydrogen producers, hydrogen transport and distribution grid operators, and hydrogen consumers. By implementing standardized, automated, and tamper-proof processes, the B-MVP enhances cost efficiency and enables transparent and traceable transactions. Its key objective is to establish the verifiable integrity of climate-friendly "green" hydrogen by tracing its supply chain from renewable energy producers to end users. This emphasis on transparency and accountability promotes economic, ecological, and social sustainability while fostering a secure and transparent market environment. A notable feature of the B-MVP is its cross-border operability, eliminating the need for country-specific data storage and expanding its global applicability. This flexibility not only broadens its reach but also creates opportunities for long-term job creation through the establishment of a dedicated blockchain operating company. By attracting skilled workers and supporting their training, the B-MVP strengthens the workforce in the growing hydrogen sector. Moreover, it drives the emergence of innovative business models that attract additional company establishments and startups and contributes to long-term job creation. For instance, data evaluation can be utilized to develop customized tariffs and provide demand-oriented network capacities to producers and network operators, benefitting redistributors and end customers with tamper-proof pricing options. The B-MVP not only brings technological and economic advancements but also enhances the visibility of national and international standard-setting efforts. Regions implementing the B-MVP become pioneers in climate-friendly, sustainable, and forward-thinking practices, generating interest beyond their geographic boundaries. Additionally, the B-MVP serves as a catalyst for research and development, facilitating knowledge transfer between universities and companies. This collaborative environment fosters scientific progress, aligns with strategic innovation management, and cultivates an innovation culture within the hydrogen market. Through the integration of blockchain and hydrogen technologies, the B-MVP promotes holistic innovation and contributes to a sustainable future in the hydrogen industry. The implementation process involves evaluating and mapping suitable blockchain technology and architecture, developing and implementing the blockchain, smart contracts, and depositing certificates of origin. It also includes creating interfaces to existing systems such as nomination, portfolio management, trading, and billing systems, testing the scalability of the B-MVP to other markets and user groups, developing data formats for process-relevant data exchange, and conducting field studies to validate the B-MVP. BBH₂ is part of the "Technology Offensive Hydrogen" funding call within the research funding of the Federal Ministry of Economics and Climate Protection in the 7th Energy Research Programme of the Federal Government.

Keywords: hydrogen, blockchain, sustainability, innovation, structural change

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Authors: Tianqiao Zhang, Ye Tian, Yanliang Yin, Yichao Tian, Suzhai Tian, Weige Sun, Shuhui Gong, Limei Tang, Ruoliang Tang

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Introduction: Healthcare workers, especially the nurses all over the world, are highly vulnerable to work-related musculoskeletal disorders (WMSDs), experiencing high rates of neck, shoulder, and low back injuries, due to the unfavorable working conditions. To reduce WMSDs among nursing personnel, many workplace interventions have been developed and implemented. Unfortunately, the ongoing Covid-19 (SARS-CoV-2) pandemic has posed great challenges to the ergonomic practices and interventions in healthcare facilities, particularly the hospitals, since current Covid-19 mitigation measures, such as social distancing and working remotely, has substantially minimized in-person gatherings and trainings. On the other hand, hospitals throughout the world have been short-staffed, resulting in disturbance of shift scheduling and more importantly, the increased job demand among the available caregivers, particularly the doctors and nurses. With the latest development in communication technology, remote intervention measures have been developed as an alternative, without the necessity of in-person meetings. The Omaha System (OS) is a standardized classification system for nursing practices, including a problem classification system, an intervention system, and an outcome evaluation system. This paper describes the development of an OS-based ergonomic intervention program. Methods: First, a comprehensive literature search was performed among worldwide electronic databases, including PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), between journal inception to May 2020, resulting in a total of 1,418 scientific articles. After two independent screening processes, the final knowledge pool included eleven randomized controlled trial studies to develop the draft of the intervention program with Omaha intervention subsystem as the framework. After the determination of sample size needed for statistical power and the potential loss to follow-up, a total of 94 nurses from eight clinical departments agreed to provide written, informed consent to participate in the study, which were subsequently assigned into two random groups (i.e., intervention vs. control). A subgroup of twelve nurses were randomly selected to participate in a semi-structured interview, during which their general understanding and awareness of musculoskeletal disorders and potential interventions was assessed. Then, the first draft was modified to reflect the findings from these interviews. Meanwhile, the tentative program schedule was also assessed. Next, two rounds of consultation were conducted among experts in nursing management, occupational health, psychology, and rehabilitation, to further adjust and finalize the intervention program. The control group had access to all the information and exercise modules at baseline, while an interdisciplinary research team was formed and supervised the implementation of the on-line intervention program through multiple social media groups. Outcome measures of this comparative study included biomechanical load assessed by the Quick Exposure Check and stresses due to awkward body postures. Results and Discussion: Modification to the draft included (1) supplementing traditional Chinese medicine practices, (2) adding the use of assistive patient handling equipment, and (3) revising the on-line training method. Information module should be once a week, lasting about 20 to 30 minutes, for a total of 6 weeks, while the exercise module should be 5 times a week, each lasting about 15 to 20 minutes, for a total of 6 weeks.

Keywords: ergonomic interventions, musculoskeletal disorders (MSDs), omaha system, nurses, Covid-19

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Authors: Joanna Szymanska, Paulina Wawulska-Marek, Jaroslaw Mizera

Abstract:

Nowadays, the rapid growth of global energy consumption and uncontrolled depletion of natural resources become a serious problem. Shale rocks are the largest and potential global basins containing hydrocarbons, trapped in closed pores of the shale matrix. Regardless of the shales origin, mining conditions are extremely unfavourable due to high reservoir pressure, great depths, increased clay minerals content and limited permeability (nanoDarcy) of the rocks. Taking into consideration such geomechanical barriers, effective extraction of natural gas from shales with plastic zones demands effective operations. Actually, hydraulic fracturing is the most developed technique based on the injection of pressurized fluid into a wellbore, to initiate fractures propagation. However, a rapid drop of pressure after fluid suction to the ground induces a fracture closure and conductivity reduction. In order to minimize this risk, proppants should be applied. They are solid granules transported with hydraulic fluids to locate inside the rock. Proppants act as a prop for the closing fracture, thus gas migration to a borehole is effective. Quartz sands are commonly applied proppants only at shallow deposits (USA). Whereas, ceramic proppants are designed to meet rigorous downhole conditions to intensify output. Ceramic granules predominate with higher mechanical strength, stability in strong acidic environment, spherical shape and homogeneity as well. Quality of ceramic proppants is conditioned by raw materials selection. Aim of this study was to obtain the proppants from aluminosilicates (the kaolinite subgroup) and mix of minerals with a high alumina content. These loamy minerals contain a tubular and platy morphology that improves mechanical properties and reduces their specific weight. Moreover, they are distinguished by well-developed surface area, high porosity, fine particle size, superb dispersion and nontoxic properties - very crucial for particles consolidation into spherical and crush-resistant granules in mechanical granulation process. The aluminosilicates were mixed with water and natural organic binder to improve liquid-bridges and pores formation between particles. Afterward, the green proppants were subjected to sintering at high temperatures. Evaluation of the minerals utility was based on their particle size distribution (laser diffraction study) and thermal stability (thermogravimetry). Scanning Electron Microscopy was useful for morphology and shape identification combined with specific surface area measurement (BET). Chemical composition was verified by Energy Dispersive Spectroscopy and X-ray Fluorescence. Moreover, bulk density and specific weight were measured. Such comprehensive characterization of loamy materials confirmed their favourable impact on the proppants granulation. The sintered granules were analyzed by SEM to verify the surface topography and phase transitions after sintering. Pores distribution was identified by X-Ray Tomography. This method enabled also the simulation of proppants settlement in a fracture, while measurement of bulk density was essential to predict their amount to fill a well. Roundness coefficient was also evaluated, whereas impact on mining environment was identified by turbidity and solubility in acid - to indicate risk of the material decay in a well. The obtained outcomes confirmed a positive influence of the loamy minerals on ceramic proppants properties with respect to the strict norms. This research is perspective for higher quality proppants production with costs reduction.

Keywords: aluminosilicates, ceramic proppants, mechanical granulation, shale gas

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Authors: Faruk Ozdemir, Roy Kalawsky, Peter Hubbard

Abstract:

Accurate estimation of RUL provides a basis for effective predictive maintenance, reducing unexpected downtime for industrial equipment. However, while models such as the Random Forest have effective predictive capabilities, they are the so-called ‘black box’ models, where interpretability is at a threshold to make critical diagnostic decisions involved in industries related to aviation. The purpose of this work is to present a prognostic framework that embeds Explainable Artificial Intelligence (XAI) techniques in order to provide essential transparency in Machine Learning methods' decision-making mechanisms based on sensor data, with the objective of procuring actionable insights for the aviation industry. Sensor readings have been gathered from critical equipment such as turbofan jet engine and landing gear, and the prediction of the RUL is done by a Random Forest model. It involves steps such as data gathering, feature engineering, model training, and evaluation. These critical components’ datasets are independently trained and evaluated by the models. While suitable predictions are served, their performance metrics are reasonably good; such complex models, however obscure reasoning for the predictions made by them and may even undermine the confidence of the decision-maker or the maintenance teams. This is followed by global explanations using SHAP and local explanations using LIME in the second phase to bridge the gap in reliability within industrial contexts. These tools analyze model decisions, highlighting feature importance and explaining how each input variable affects the output. This dual approach offers a general comprehension of the overall model behavior and detailed insight into specific predictions. The proposed framework, in its third component, incorporates the techniques of causal analysis in the form of Granger causality tests in order to move beyond correlation toward causation. This will not only allow the model to predict failures but also present reasons, from the key sensor features linked to possible failure mechanisms to relevant personnel. The causality between sensor behaviors and equipment failures creates much value for maintenance teams due to better root cause identification and effective preventive measures. This step contributes to the system being more explainable. Surrogate Several simple models, including Decision Trees and Linear Models, can be used in yet another stage to approximately represent the complex Random Forest model. These simpler models act as backups, replicating important jobs of the original model's behavior. If the feature explanations obtained from the surrogate model are cross-validated with the primary model, the insights derived would be more reliable and provide an intuitive sense of how the input variables affect the predictions. We then create an iterative explainable feedback loop, where the knowledge learned from the explainability methods feeds back into the training of the models. This feeds into a cycle of continuous improvement both in model accuracy and interpretability over time. By systematically integrating new findings, the model is expected to adapt to changed conditions and further develop its prognosis capability. These components are then presented to the decision-makers through the development of a fully transparent condition monitoring and alert system. The system provides a holistic tool for maintenance operations by leveraging RUL predictions, feature importance scores, persistent sensor threshold values, and autonomous alert mechanisms. Since the system will provide explanations for the predictions given, along with active alerts, the maintenance personnel can make informed decisions on their end regarding correct interventions to extend the life of the critical machinery.

Keywords: predictive maintenance, explainable artificial intelligence, prognostic, RUL, machine learning, turbofan engines, C-MAPSS dataset

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Authors: Ali Kazemi

Abstract:

Those within the volatile and interconnected international economic markets, appropriately predicting market trends, hold substantial fees for traders and financial establishments. Traditional device mastering strategies have made full-size strides in forecasting marketplace movements; however, monetary data's complicated and networked nature calls for extra sophisticated processes. This observation offers a groundbreaking method for monetary marketplace prediction that leverages the synergistic capability of Graph Convolutional Networks (GCNs) and Long Short-Term Memory (LSTM) networks. Our suggested algorithm is meticulously designed to forecast the traits of inventory market indices and cryptocurrency costs, utilizing a comprehensive dataset spanning from January 1, 2015, to December 31, 2023. This era, marked by sizable volatility and transformation in financial markets, affords a solid basis for schooling and checking out our predictive version. Our algorithm integrates diverse facts to construct a dynamic economic graph that correctly reflects market intricacies. We meticulously collect opening, closing, and high and low costs daily for key inventory marketplace indices (e.g., S&P 500, NASDAQ) and widespread cryptocurrencies (e.g., Bitcoin, Ethereum), ensuring a holistic view of marketplace traits. Daily trading volumes are also incorporated to seize marketplace pastime and liquidity, providing critical insights into the market's shopping for and selling dynamics. Furthermore, recognizing the profound influence of the monetary surroundings on financial markets, we integrate critical macroeconomic signs with hobby fees, inflation rates, GDP increase, and unemployment costs into our model. Our GCN algorithm is adept at learning the relational patterns amongst specific financial devices represented as nodes in a comprehensive market graph. Edges in this graph encapsulate the relationships based totally on co-movement styles and sentiment correlations, enabling our version to grasp the complicated community of influences governing marketplace moves. Complementing this, our LSTM algorithm is trained on sequences of the spatial-temporal illustration discovered through the GCN, enriched with historic fee and extent records. This lets the LSTM seize and expect temporal marketplace developments accurately. Inside the complete assessment of our GCN-LSTM algorithm across the inventory marketplace and cryptocurrency datasets, the version confirmed advanced predictive accuracy and profitability compared to conventional and opportunity machine learning to know benchmarks. Specifically, the model performed a Mean Absolute Error (MAE) of 0.85%, indicating high precision in predicting day-by-day charge movements. The RMSE was recorded at 1.2%, underscoring the model's effectiveness in minimizing tremendous prediction mistakes, which is vital in volatile markets. Furthermore, when assessing the model's predictive performance on directional market movements, it achieved an accuracy rate of 78%, significantly outperforming the benchmark models, averaging an accuracy of 65%. This high degree of accuracy is instrumental for techniques that predict the course of price moves. This study showcases the efficacy of mixing graph-based totally and sequential deep learning knowledge in economic marketplace prediction and highlights the fee of a comprehensive, records-pushed evaluation framework. Our findings promise to revolutionize investment techniques and hazard management practices, offering investors and economic analysts a powerful device to navigate the complexities of cutting-edge economic markets.

Keywords: financial market prediction, graph convolutional networks (GCNs), long short-term memory (LSTM), cryptocurrency forecasting

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Authors: Oluwaseun Adeleke, Samuel O. Ikani, Fidelis Edet, Anthony Nwala, Mopelola Raji, Simeon Christian Chukwu

Abstract:

Background The Delivering Innovations in Selfcare (DISC) project promotes universal access to quality selfcare services beginning with subcutaneous depot medroxy progesterone acetate (DMPA-SC) contraceptive self-injection (SI) option. Self-inject (SI) offers women a highly effective and convenient option that saves them frequent trips to providers. Its increased use has the potential to improve the efficiency of an overstretched healthcare system by reducing provider workloads. State Social and Behavioral Change Communications (SBCC) Officers lead project demand creation and service delivery innovations that have resulted in significant increases in SI uptake among women who opt for injectables. Strategies Service Delivery Innovations The implementation of the "Moment of Truth (MoT)" innovation helped providers overcome biases and address client fear and reluctance to self-inject. Bi-annual program audits and supportive mentoring visits helped providers retain their competence and motivation. Proper documentation, tracking, and replenishment of commodities were ensured through effective engagement with State Logistics Units. The project supported existing state monitoring and evaluation structures to effectively record and report subcutaneous depot medroxy progesterone acetate (DMPA-SC) service utilization. Demand creation Innovations SBCC Officers provide oversight, routinely evaluate performance, trains, and provides feedback for the demand creation activities implemented by community mobilizers (CMs). The scope and intensity of training given to CMs affect the outcome of their work. The project operates a demand creation model that uses a schedule to inform the conduct of interpersonal and group events. Health education sessions are specifically designed to counter misinformation, address questions and concerns, and educate target audience in an informed choice context. The project mapped facilities and their catchment areas and enlisted the support of identified influencers and gatekeepers to enlist their buy-in prior to entry. Each mobilization event began with pre-mobilization sensitization activities, particularly targeting male groups. Context-specific interventions were informed by the religious, traditional, and cultural peculiarities of target communities. Mobilizers also support clients to engage with and navigate online digital Family Planning (FP) online portals such as DiscoverYourPower website, Facebook page, digital companion (chat bot), interactive voice response (IVR), radio and television (TV) messaging. This improves compliance and provides linkages to nearby facilities. Results The project recorded 136,950 self-injection (SI) visits and a self-injection (SI) proportion rate that increased from 13 percent before the implementation of interventions in 2021 to 62 percent currently. The project cost-effectively demonstrated catalytic impact by leveraging state and partner resources, institutional platforms, and geographic scope to scale up interventions. The project also cost effectively demonstrated catalytic impact by leveraging on the state and partner resources, institutional platforms, and geographic scope to sustainably scale-up these strategies. Conclusion Using evidence-informed iterations of service delivery and demand creation models have been useful to significantly drive self-injection (SI) uptake. It will be useful to consider this implementation model during program design. Contemplation should also be given to systematic and strategic execution of strategies to optimize impact.

Keywords: family planning, contraception, DMPA-SC, self-care, self-injection, innovation, service delivery, demand creation.

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Authors: David J. Foran, Nhan Do, Samuel Ajjarapu, Wenjin Chen, Tahsin Kurc, Joel H. Saltz

Abstract:

The large-scale data and computational requirements of investigators throughout the clinical and research communities demand an informatics infrastructure that supports both existing and new investigative and translational projects in a robust, secure environment. In some subspecialties of medicine and research, the capacity to generate data has outpaced the methods and technology used to aggregate, organize, access, and reliably retrieve this information. Leading health care centers now recognize the utility of establishing an enterprise-wide, clinical data warehouse. The primary benefits that can be realized through such efforts include cost savings, efficient tracking of outcomes, advanced clinical decision support, improved prognostic accuracy, and more reliable clinical trials matching. The overarching objective of the work presented here is the development and implementation of a flexible Intelligent Retrieval and Interrogation System (IRIS) that exploits the combined use of computational imaging, genomics, and data-mining capabilities to facilitate clinical assessments and translational research in oncology. The proposed System includes a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide insight into the underlying tumor characteristics that are not be apparent by human inspection alone. A key distinguishing feature of the System is a configurable Extract, Transform and Load (ETL) interface that enables it to adapt to different clinical and research data environments. This project is motivated by the growing emphasis on establishing Learning Health Systems in which cyclical hypothesis generation and evidence evaluation become integral to improving the quality of patient care. To facilitate iterative prototyping and optimization of the algorithms and workflows for the System, the team has already implemented a fully functional Warehouse that can reliably aggregate information originating from multiple data sources including EHR’s, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology PAC systems, Digital Pathology archives, Unstructured Clinical Documents, and Next Generation Sequencing services. The System enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information about patient tumors individually or as part of large cohorts to identify patterns that may influence treatment decisions and outcomes. The CRDW core system has facilitated peer-reviewed publications and funded projects, including an NIH-sponsored collaboration to enhance the cancer registries in Georgia, Kentucky, New Jersey, and New York, with machine-learning based classifications and quantitative pathomics, feature sets. The CRDW has also resulted in a collaboration with the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at the U.S. Department of Veterans Affairs to develop algorithms and workflows to automate the analysis of lung adenocarcinoma. Those studies showed that combining computational nuclear signatures with traditional WHO criteria through the use of deep convolutional neural networks (CNNs) led to improved discrimination among tumor growth patterns. The team has also leveraged the Warehouse to support studies to investigate the potential of utilizing a combination of genomic and computational imaging signatures to characterize prostate cancer. The results of those studies show that integrating image biomarkers with genomic pathway scores is more strongly correlated with disease recurrence than using standard clinical markers.

Keywords: clinical data warehouse, decision support, data-mining, intelligent databases, machine-learning.

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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