Search results for: Rajat Dhawan

Authors: Rajat Dhawan, Hitendra K. Malik

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Electronegative plasmas comprising electrons, positive ions, and negative ions are advantageous for their expanding applications in industries. In plasma cleaning, plasma etching, and plasma deposition process, electronegative plasmas are preferred because of relatively less potential developed on the surface of the material under investigation. Also, the presence of negative ions avoid the irregularity in etching shapes and also enhance the material working during the fabrication process. The interaction of metallic conducting surface with plasma becomes mandatory to understand these applications. A metallic conducting probe immersed in a plasma results in the formation of a thin layer of charged species around the probe called as a sheath. The density of the ions embedded on the surface of the material and the sheath thickness are the important parameters for the surface-plasma interaction. Sheath thickness will give rise to the information of affected plasma region due to conducting surface/probe. The knowledge of the density of ions in the sheath region is advantageous in plasma nitriding, and their temperature is equally important as it strongly influences the thickness of the modified layer during surface plasma interaction. In the present work, we considered a negatively biased metallic probe immersed in a warm electronegative plasma. For this system, we adopted the continuity equation and momentum transfer equation for both the positive and negative ions, whereas electrons are described by Boltzmann distribution. Finally, we use the Poisson’s equation. Here, we assumed the spherical geometry for small probe radius. Poisson’s equation reveals the behaviour of potential surrounding a conducting metallic probe along with the use of the continuity and momentum transfer equations, with the help of proper boundary conditions. In turn, it gives rise to the information about the density profile of charged species and most importantly the thickness of the sheath. By keeping in mind, the well-known Bohm-Sheath criterion, all calculations are done. We found that positive ion density decreases with an increase in positive ion temperature, whereas it increases with the higher temperature of the negative ions. Positive ion density decreases as we move away from the center of the probe and is found to show a discontinuity at a particular distance from the center of the probe. The distance where discontinuity occurs is designated as sheath edge, i.e., the point where sheath ends. These results are beneficial for industrial applications, as the density of ions embedded on material surface is strongly affected by the temperature of plasma species. It has a drastic influence on the surface properties, i.e., the hardness, corrosion resistance, etc. of the materials.

Keywords: electronegative plasmas, plasma surface interaction positive ion density, sheath thickness

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Authors: Rajat Kapoor

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India is a developing country and has experienced a rapid and tumultuous urban growth in the 20th century. The total urban population of the city increased ten-fold between 1901 and 2001. The share of urban population to the total population increased from less than 11 percent to over 28 percent in the same period. Except few examples, most of the Indian cities have grown in a haphazard manner; concentration of population followed by the planning exercises. In this era of global competitiveness and rapid urbanization there is no scope for malpractices in development strategies. It is expected that the Indian cities shall be planned comprehensively and holistically. The study reveals the land transformations the city of Faridabad is witnessing due to development which is largely boosted by the virtue of its location in the Delhi NCR.

Keywords: Delhi NCR, Faridabad, urban growth patterns, India

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Authors: Sehijpal Singh Khangura, Jai Inder Preet Singh, Vikas Dhawan

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Global warming, growing awareness of the environment, waste management issues, dwindling fossil resources, and rising oil prices resulted to increase the research in the materials that are friendly to our health and environment. Due to these reasons, green products are increasingly being promoted for sustainable development. In this work, fully biodegradable green composites have been developed using jute fibers as reinforcement and poly lactic acid as matrix material by film stacking technique. The effect of curing temperature during development of composites ranging from 160 °C, 170 °C, 180 °C and 190 °C was investigated for various mechanical properties. Results obtained from various tests indicate that impact strength decreases with an increase in curing temperature, but tensile and flexural strength increases till 180 °C, thereafter both the properties decrease. This study gives an optimum curing temperature for the development of jute/PLA composites.

Keywords: natural fibers, polymer matrix composites, jute, compression molding, biodegradation

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Authors: Saurav Dhawan, Sanchit Bansal

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Background T-MACS is a computer-based decision aid that ‘rules in’ and ‘rules out’ ACS using a combination of the presence or absence of six clinical features with only one biomarker measured on arrival: hs-cTnT. T-MACS had 99.3% negative predictive value and 98.7% sensitivity for ACS, ‘ruling out’ ACS in 40% of patients while ‘ruling in’ 5% at the highest risk. We aim at benchmarking the use of T-MACS which could help to conserve healthcare resources, facilitate early discharges, and ensure safe practice. Methodology Randomized retrospective data collection (n=300) was done from ED electronic records across 3 hospital sites within MFT over a period of 2 months. Data was analysed and compared by percentage for the usage of T-MACS, number of admissions/discharges, and in days for length of stay in hospital. Results MRI A&E had the maximum compliance with the use of T-MACS in the trust at 66%, with minimum admissions (44%) and an average length of stay of 1.825 days. NMG A&E had an extremely low compliance rate (8 %), with 75% admission and 3.387 days as the average length of stay. WYT A&E had no TMACS recorded, with a maximum of 79% admissions and the longest average length of stay at 5.07 days. Conclusion All three hospital sites had a RAG rating of ‘RED’ as per the compliance levels. The assurance level was calculated as ‘Very Limited’ across all sites. There was a positive correlation observed between compliance with TMACS and direct discharges from ED, thereby reducing the average length of stay for patients in the hospital.

Keywords: ACS, discharges, ED, T-MACS

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Authors: Gagan Dhawan

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Mycobacterium tuberculosis was described as ‘captain of death’ with an inherent property of multiple drug resistance majorly caused by the competent mechanism of efflux pumps. In this study, various open source tools combining chemo-informatics with bioinformatics were used for efficient in-silico drug designing. The efflux pump, Rv1218c, belonging to the ABC transporter superfamily, which is predicted to be a tetronasin-transporter in M. tuberculosis was targeted. Recent studies have shown that Rv1218c forms a complex with two more efflux pumps (Rv1219c and Rv1217c) to provide multidrug resistance to the bacterium. The 3D structure of the protein was modeled (as the structure was unavailable in the previously collected databases on this gene). The TMHMM analysis of this protein in TubercuList has shown that this protein is present in the outer membrane of the bacterium. Virtual screening of compounds from various publically available chemical libraries was performed on the M. tuberculosis protein using various open source tools. These ligands were further assessed where various physicochemical properties were evaluated and analyzed. On comparison of different physicochemical properties, toxicity and docking, the ligand 2-(hydroxymethyl)-6-[4, 5, 6-trihydroxy-2-(hydroxymethyl) tetrahydropyran-3-yl] oxy-tetrahydropyran-3, 4, 5-triol was found to be best suited for further studies.

Keywords: drug resistance, efflux pump, molecular docking, virtual screening

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Authors: Hina Verma, Karine Le Guen, Mohammed H. Modi, Rajnish Dhawan, Philippe Jonnard

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Periodic multilayer mirrors have potential application as optical components in X-ray microscopy, particularly working in the water window region. The water window range, located between the absorption edges of carbon (285 eV) and oxygen (530eV), along with the presence of nitrogen K absorption edge (395 eV), makes it a powerful method for imaging biological samples due to the natural optical contrast between water and carbon. We characterized bilayer, trilayer, quadrilayer, and multilayer systems of Mg/Sc with ZrC thin layers introduced as a barrier layer and capping layer prepared by ion beam sputtering. The introduction of ZrC as a barrier layer is expected to improve the structure of the Mg/Sc system. The ZrC capping layer also prevents the stack from oxidation. The structural analysis of the Mg/Sc systems was carried out by using grazing incidence X-ray reflectivity (GIXRR) to obtain non-destructively a first description of the structural parameters, thickness, roughness, and density of the layers. Resonant soft X-ray reflectivity measurements in the vicinity of Sc L-absorption edge were performed to investigate and quantify the atomic distribution of deposited layers. Near absorption edge, the atomic scattering factor of an element changes sharply depending on its chemical environment inside the structure.

Keywords: buried interfaces, resonant soft X-ray reflectivity, X-ray optics, X-ray reflectivity

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Authors: Rajat Mittal, Harshal Raut, Jung Hee Seo

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Wave-assisted propulsion (WAP) systems convert wave energy into thrust using elastically mounted hydrofoils. We employ sharp-interface immersed boundary simulations to examine the effect of two key parameters on the flow physics, the fluid-structure interaction, as well as thrust performance of these systems - the stiffness of the torsional spring and the location of the rotational center. The variation in spring stiffness leads to different amplitude of pitch motion, phase difference with respect to heaving motion and thrust coefficient and we show the utility of ‘maps’ of energy exchange between the flow and the hydrofoil system, as a way to understand and predict this behavior. The Force Partitioning Method (FPM) is used to decompose the pressure forces into individual components and understand the mechanism behind increase in thrust. Next, a scaling law is presented for the thrust coefficient generated by heaving and pitching foil. The parameters within the scaling law are calculated based on direct-numerical simulations based parametric study utilized to generate the energy maps. The predictions of the proposed scaling law are then compared with those of a similar model from the literature, showing a noticeable improvement in the prediction of the thrust coefficient.

Keywords: propulsion, flapping foils, hydrodynamics, wave power

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Authors: Rajat Kapoor

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Indian Real Estate sector is the second largest employer after agriculture and is slated to grow at 30 percent over the next decade. Indian cities have shown tumultuous growth since last two decades. With the growing need of infrastructure, it has become inevitable for real estate sector to adopt more organized and transparent system of investment. SPVs such as REITs ensure transparency facilitating accessibility to invest in real estate for those who find it difficult to purchase real estate as an investment option with a realistic income expectation from their investment. RIETs or real estate investment trusts is an instrument of pooling funds similar to that of mutual funds. In a simpler term REIT is an Investment Vehicle in the form a trust which holds & manages large commercial rent¬ earning properties on behalf of investors and distributes most of its profit as dividends. REIT enables individual investors to invest their money in commercial real estate assets in a diversified portfolio and on the other hand provides fiscal liquidity to developers as easy exit option and channel funds for new projects. However, the success REIT is very much dependent on the taxation structure making such models attractive and adaptive enough for both developers and investors to opt for such investment option. This paper is intended to capture an overview of REITs with context to Indian real estate scenario.

Keywords: Indian real estate, real estate infrastructure trusts, urban finance, infrastructure investment trusts

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Authors: Rajat Raj, Rohini S. Hallikar

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The ever-increasing integration of renewable energy sources in the power grid necessitates the development of efficient and reliable microgrid systems. Photovoltaic (PV) systems coupled with energy storage technologies, such as batteries, offer promising solutions for sustainable and resilient power generation. This paper proposes an adaptive power control topology for a PV-battery microgrid system, aiming to optimize the utilization of available solar energy and enhance the overall system performance. In order to provide a smooth transition between the OFF-GRID and ON-GRID modes of operation with proportionate power sharing, a self-adaptive control method for a microgrid is proposed. Three different modes of operation are discussed in this paper, i.e., GRID connected, the transition between Grid-connected and Islanded State, and changing the irradiance of PVs and doing the transitioning. The simulation results show total harmonic distortion to be 0.08, 1.43 and 2.17 for distribution generation-1 and 4.22,3.92 and 2.10 for distribution generation-2 in the three modes, respectively which helps to maintain good power quality. The simulation results demonstrate the superiority of the adaptive power control topology in terms of maximizing renewable energy utilization, improving system stability and ensuring a seamless transition between grid-connected and islanded modes.

Keywords: islanded modes, microgrids, photo voltaic, total harmonic distortion

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Authors: Rajat Mittal, Jung Hee Seo, Jacob Turner, Harshal Raut

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The perpetual advancement in computational capabilities, coupled with the continuous evolution of software tools and numerical algorithms, is creating novel avenues for research, exploration, and application at the nexus of computational fluid and structural mechanics. Fish leverage their remarkably flexible bodies and fins to harness energy from vortices, propelling themselves with an elegance and efficiency that captivates engineers. Bats fly with unparalleled agility and speed by using their flexible membrane wings. Wave-assisted propulsion (WAP) systems, utilizing elastically mounted hydrofoils, convert wave energy into thrust. Each of these problems involves a complex and elegant interplay between fluid dynamics and structural mechanics. Historically, investigations into such phenomena were constrained by available tools, but modern computational advancements now facilitate exploration of these multi-physics challenges with an unprecedented level of fidelity, precision, and realism. In this work, the author will discuss projects that harness the capabilities of high-fidelity sharp-interface immersed boundary methods to address a spectrum of engineering and biological challenges involving fluid-structure interaction.

Keywords: immersed boundary methods, CFD, bioflight, fluid structure interaction

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Authors: Dipali Dhawan

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Cancerous epithelial cells are confined to a primary site by the continued expression of adhesion molecules and the intact basal lamina. However, as the cancer progresses some cells are believed to undergo an epithelial-mesenchymal transition (EMT) event, leading to increased motility, invasion and, ultimately, metastasis of the cells from the primary tumour to secondary sites within the body. These disseminated cancer cells need the ability to self-renew, as stem cells do, in order to establish and maintain a heterogeneous metastatic tumour mass. Identification of the specific subpopulation of cancer stem cells amenable to the process of metastasis is highly desirable. In this study, we have isolated and characterized cancer stem cells from luminal and basal breast cancer cell lines (MDA-MB-231, MDA-MB-453, MDA-MB-468, MCF7 and T47D) on the basis of cell surface markers CD44 and CD24; as well as Side Populations (SP) using Hoechst 33342 dye efflux. The isolated populations were analysed for epithelial and mesenchymal markers like E-cadherin, N-cadherin, Sfrp1 and Vimentin by Western blotting and Immunocytochemistry. MDA-MB-231 cell lines contain a major population of CD44+CD24- cells whereas MCF7, T47D and MDA-MB-231 cell lines show a side population. We observed higher expression of N-cadherin in MCF-7 SP cells as compared to MCF-7NSP (Non-side population) cells suggesting that the SP cells are mesenchymal like cells and hence express increased N-cadherin with stem cell-like properties. There was an expression of Sfrp1 in the MCF7- NSP cells as compared to no expression in MCF7-SP cells, which suggests that the Wnt pathway is expressed in the MCF7-SP cells. The mesenchymal marker Vimentin was expressed only in MDA-MB-231 cells. Hence, understanding the breast cancer heterogeneity would enable a better understanding of the disease progression and therapeutic targeting.

Keywords: cancer stem cells, epithelial to mesenchymal transition, biomarkers, breast cancer

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Authors: Rupesh K. Chaudhary, Narinder P. Jain, Rajesh Mahajan, Rajat Manchanda

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Introduction: Delirium is a complex, multifactorial neuropsychiatric syndrome comprising a broad range of cognitive and neurobehavioral symptoms. In critically ill patients, it may develop secondary to multiple predisposing factors. Although it can be transient and irreversible but if left untreated may lead to long term cognitive dysfunction. Early identification and assessment of risk factors usually help in appropriate management of delirium which in turn leads to decreased hospital stay, cost of therapy and mortality. Aim and Objective: Aim of the present study was to estimate the incidence of delirium using a validated scale in medical ICU patients and to determine the associated risk factors and outcomes. Material and Method: A prospective study in an 18-bed medical-intensive care unit (ICU) was undertaken. A total of 357 consecutive patients admitted to ICU for more than 24 hours were assessed. These patients were screened with the help of Confusion Assessment Method for Intensive Care Unit -CAM-ICU, Richmond Agitation and Sedation Scale, Screening Checklist for delirium and APACHE II. Appropiate statistical analysis was done to evaluate the risk factors influencing mortality in delirium. Results: Delirium occurred in 54.6% of 194 patients. Risk of delirium was independently associated with a history of hypertension, diabetes but not with severity of illness APACHE II score. Delirium was linked to longer ICU stay 13.08 ± 9.6 ver 7.07 ± 4.98 days, higher ICU mortality (35.8% % vs. 17.0%). Conclusion: Our study concluded that delirium poses a great risk factor in the outcome of the patient and carries high mortality, so a timely intervention helps in addressing these issues.

Keywords: delirium, risk factors, outcome, intervention

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Authors: Repaul Kanji, Rajat Agrawal

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In this era where issues like climate change and disasters are the topics of discussion at national and international forums, it is very often that humanity questions the causative role of corporates in such events. It is beyond any doubt that rapid industrialisation and development has taken a toll in the form of climate change and even disasters, in some case. Thus, demanding to fulfill a corporate's responsibilities in the form of rescue and relief in times of disaster, rehabilitation and even mitigation and preparedness to adapt to the oncoming changes is obvious. But how can the responsibilities of the corporates be channelised to ensure all this, i.e., develop a resilient society? More than that, which factors, when emphasised upon, can lead to the holistic development of the society. To answer this query, an extensive literature review was done to identify several enablers like legislations of a nation, the role of brand and reputation, ease of doing Corporate Social Responsibility, mission and vision of an organisation, religion and culture, etc. as a tool for building disaster resilience. A questionnaire survey, interviews with experts and academicians followed by interpretive structural modelling (ISM) were used to construct a multi-hierarchy model depicting the contextual relationship among the identified enablers. The study revealed that culture and religion are the most powerful driver, which affects other enablers either directly or indirectly. Taking cognisance of the fact that an idea of separation between religion and workplace (business) resides subconsciously within the society, the study tries to interpret the outcome of the ISM through the lenses of past researches (The Integrating Box) and explores how it can be leveraged to build a resilient society.

Keywords: corporate social responsibility, interpretive structural modelling, disaster resilience and risk reduction, the integration box (TIB)

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Authors: Rigved Chandrashekhar Nimkhedkar, Rajat Agrawal, Vinay Sharma

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Architects need help with a demand for an expanded skill set to effectively navigate a landscape of evolving opportunities and challenges in the dynamic realm of the architectural profession. This literature and survey-based study investigates the reasons behind architects’ choices of careers, as well as the effects of the evolving architectural scenario. The traditional role of architects in construction projects evolves as they explore diverse career motivations, face financial constraints due to an oversupply of professionals, and experience specialisation and upskilling trends. Architects inherently derive numerous value chains as more and more disciplines have been introduced into the design-construction-operation supply chain. This insight emphasizes the importance of integrating management and entrepreneurial education into architectural education rather than keeping them separate entities. The study reveals the complex nature of the entrepreneurially challenging architectural profession, including cash flow management, market competition, environmental sustainability, and innovation opportunities. Loyal to their professional identity, architects express dissatisfaction while envisioning a future in which they play a more significant role in shaping reputable brands and contributing to education. The study emphasizes the importance of dovetailing management and entrepreneurial education in architecture education in preparing graduates for the industry’s changing nature, emphasising the need for real-world skills. This research contributes insights into the architectural profession’s transformative trajectory, emphasising adaptability, upskilling, and educational enhancements as critical success factors.

Keywords: architects, career path, education, management, specialisation

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Authors: Rajat Jain, Himanshu Pandey, Somesh Mehta, Pravin P. Patil

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Formula SAE cars are the student designed and fabricated formula prototype cars, designed according to SAE INTERNATIONAL design rules which compete in the various national and international events. This paper shows a FEM based comparative study of free vibration analysis of different mode shapes of a formula prototype car chassis frame. Tubing sections of different diameters as per the design rules are designed in such a manner that the desired strength can be achieved. Natural frequency of first five mode was determined using finite element analysis method. SOLIDWORKS is used for designing the frame structure and SOLIDWORKS SIMULATION and ANSYS WORKBENCH 16.2 are used for the modal analysis. Mode shape results of ANSYS and SOLIDWORKS were compared. Fixed –fixed boundary conditions are used for fixing the A-arm wishbones. The simulation results were compared for the validation of the study. First five modes were compared and results were found within the permissible limits. The AISI4130 (CROMOLY- chromium molybdenum steel) material is used and the chassis frame is discretized with fine quality QUAD mesh followed by Fixed-fixed boundary conditions. The natural frequency of the chassis frame is 53.92-125.5 Hz as per the results of ANSYS which is found within the permissible limits. The study is concluded with the light weight and compact chassis frame without compensation with strength. This design allows to fabricate an extremely safe driver ergonomics, compact, dynamically stable, simple and light weight tubular chassis frame with higher strength.

Keywords: FEM, modal analysis, formula SAE cars, chassis frame, Ansys

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Authors: Ji Zhou, Jung Hee Seo, Rajat Mittal

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Fish move in groups for foraging, reproduction, predator protection, and hydrodynamic efficiency. Schooling's predator protection involves the "many eyes" theory, which increases predator detection probability in a group. Reduced visual signature in a group scales with school size, offering per-capita protection. The ‘confusion effect’ makes it hard for predators to target prey in a group. These benefits, however, all focus on vision-based sensing, overlooking sound-based detection. Fish, including predators, possess sophisticated sensory systems for pressure waves and underwater sound. The lateral line system detects acoustic waves, while otolith organs sense infrasound, and sharks use an auditory system for low-frequency sounds. Among sound generation mechanisms of fish, the mechanism of dipole sound relates to hydrodynamic pressure forces on the body surface of the fish and this pressure would be affected by group swimming. Thus, swimming within a group could affect this hydrodynamic noise signature of fish and possibly serve as an additional protection afforded by schooling, but none of the studies to date have explored this effect. BAUVs with fin-like propulsors could reduce acoustic noise without compromising performance, addressing issues of anthropogenic noise pollution in marine environments. Therefore, in this study, we used our in-house immersed-boundary method flow and acoustic solver, ViCar3D, to simulate fish schools consisting of four swimmers in the classic ‘diamond’ configuration and discussed the feasibility of yielding higher swimming efficiency and controlling far-field sound signature of the school. We examine the effects of the relative phase of fin flapping of the swimmers and the simulation results indicate that the phase of the fin flapping is a dominant factor in both thrust enhancement and the total sound radiated into the far-field by a group of swimmers. For fish in the “diamond” configuration, a suitable combination of the relative phase difference between pairs of leading fish and trailing fish can result in better swimming performance with significantly lower hydroacoustic noise.

Keywords: fish schooling, biopropulsion, hydrodynamics, hydroacoustics

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Authors: Vijayabhaskar Reddy Kandula, Peter Provost Taillac, Balasubramanya M. A., Ram Krishnan Nair, Gokul Toshnival, Vibhu Dhawan, Vijaya Karanam, Buffy Cramer

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Introduction: The lack of Emergency Care Services (ECS) is a cause of extensive and serious public health problems in low- and middle-income countries (LMIC), Many LMIC countries have ambulance services that allow timely transfer of ill patients but due to poor care during the ‘Golden Hour’ many deaths occur which are otherwise preventable. Lack of adequate training as evidenced by a study in India is a major reason for poor care during the ‘Golden Hour’. Adapting developed country models which includes staffing specialty-trained doctors in emergency care, is neither feasible nor guarantees cost-effective ECS. Methods: Based on our assessment and felt needs by first-line doctors providing emergency care in 2014, Rajiv Gandhi Health Sciences University’s JeevaRaksha Trust in partnership with the University of Utah, USA, designed, piloted and successfully implemented a 4-day Comprehensive-Emergency Care and Life Support course (C-ECLS) for allopathic doctors. 1730 doctors completed the 4-day course between June 2014 and December- 2020. Subsequently, we conducted a survey to investigate the utilization rates and usefulness of the training. 1662 were contacted but only 309 completed the survey. The respondents had the following designations: Senior faculty (33%), junior faculty (25), Resident (16%), Private-Practitioners (8%), Medical-Officer (16%) and not-working (11%). 51% were generalists (51%) and the rest were specialists (>30 specialties). Results: 97% (271/280) felt they are better doctors because of C-ECLS. 79% (244/309) reported that training helped to save life- specialists more likely than generalists (91% v/s 68%. P<0.05). 64% agreed that they were confident of managing COVID-19 symptomatic patients better because of C-ECLS. 27% (77) were neutral; 9% (24) disagreed. 66% agreed that training helps to be confident in managing COVID-19 critically ill patients. 26% (72) were neutral; 8% (23) disagreed. Frequency of use of C-ECLS skills: Hemorrhage-control (70%), Airway (67%), circulation skills (62%), Safe-transport and communication (60%), managing critically ill patients (58%), cardiac arrest (51%), Trauma (49%), poisoning/animal bites/stings (44%), neonatal-resuscitation (39%), breathing (36%), post-partum-hemorrhage and eclampsia (35%). Among those who used the skills, the majority (ranging from (88%-94%) reported that they were able to apply the skill more effectively because of ECLS training. Conclusion: JeevaRaksha’s C-ECLS is the world’s first comprehensive training. It improves the confidence of front-line doctors and enables them to provide quality care during the ‘Golden Hour’ of emergency. It also prepares doctors to manage unknown emergencies (e.g., COVID-19). C-ECLS was piloted in Morocco, and Uzbekistan and implemented countrywide in Bhutan. C-ECLS is relevant to most settings and offers a replicable model across LMIC.

Keywords: comprehensive emergency care and life support, training, capacity building, low- and middle-income countries, developing countries

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Authors: Aastha Arora, Vikas Bhuria, Saurabh Singh, Uma Pathak, Shweta Mathur, Puja P. Hazari, Rajat Sandhir, Ravi Soni, Anant N. Bhatt, Bilikere S. Dwarakanath

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Radiotherapy is an effective curative and palliative option for patients with thoracic malignancies. However, lung injury, comprising of pneumonitis and fibrosis, remains a significant clin¬ical complication of thoracic radiation, thus making it a dose-limiting factor. Also, injury to the lung is often reported as part of multi-organ failure in victims of accidental radiation exposures. Radiation induced inflammatory response in the lung, characterized by leukocyte infiltration and vascular changes, is an important contributing factor for the injury. Therefore, countermeasure agents to attenuate radiation induced inflammatory response are considered as an important approach to prevent chronic lung damage. Although Amifostine, the widely used, FDA approved radio-protector, has been found to reduce the radiation induced pneumonitis during radiation therapy of non-small cell lung carcinoma, its application during mass and field exposure is limited due to associated toxicity and ineffectiveness with the oral administration. The amifostine analogue (DRDE-30) overcomes this limitation as it is orally effective in reducing the mortality of whole body irradiated mice. The current study was undertaken to investigate the potential of DRDE-30 to ameliorate radiation induced lung damage. DRDE-30 was administered intra-peritoneally, 30 minutes prior to 13.5 Gy thoracic (60Co-gamma) radiation in C57BL/6 mice. Broncheo- alveolar lavage fluid (BALF) and lung tissues were harvested at 12 and 24 weeks post irradiation for studying inflammatory and fibrotic markers. Lactate dehydrogenase (LDH) leakage, leukocyte count and protein content in BALF were used as parameters to evaluate lung vascular permeability. Inflammatory cell signaling (p38 phosphorylation) and anti-oxidant status (MnSOD and Catalase level) was assessed by Western blot, while X-ray CT scan, H & E staining and trichrome staining were done to study the lung architecture and collagen deposition. Irradiation of the lung increased the total protein content, LDH leakage and total leukocyte count in the BALF, reflecting endothelial barrier dysfunction. These disruptive effects were significantly abolished by DRDE-30, which appear to be linked to the DRDE-30 mediated abrogation of activation of the redox-sensitive pro- inflammatory signaling cascade, the MAPK pathway. Concurrent administration of DRDE-30 with radiation inhibited radiation-induced oxidative stress by strengthening the anti-oxidant defense system and abrogated p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and macrophage recruitment to the lungs. Histopathological examination (by H & E staining) of the lung showed radiation-induced inflammation of the lungs, characterized by cellular infiltration, interstitial oedema, alveolar wall thickening, perivascular fibrosis and obstruction of alveolar spaces, which were all reduced by pre-administration of DRDE-30. Structural analysis with X-ray CT indicated lung architecture (linked to the degree of opacity) comparable to un-irradiated mice that correlated well with the lung morphology and reduced collagen deposition. Reduction in the radiation-induced inflammation and fibrosis brought about by DRDE-30 resulted in a profound increase in animal survival (72 % in the combination vs 24% with radiation) observed at the end of 24 weeks following irradiation. These findings establish the potential of the Amifostine analogue, DRDE-30, in reducing radiation induced pulmonary injury by attenuating the inflammatory and fibrotic responses.

Keywords: amifostine, fibrosis, inflammation, lung injury radiation

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