Search results for: Govind S. Gupta

Authors: Vikrant Gupta, Amrit Goswami

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The fixed income market forms the basis of the modern financial market. All other assets in financial markets derive their value from the bond market. Owing to its over-the-counter nature, corporate bonds have relatively less data publicly available and thus is researched upon far less compared to Equities. Bond price prediction is a complex financial time series forecasting problem and is considered very crucial in the domain of finance. The bond prices are highly volatile and full of noise which makes it very difficult for traditional statistical time-series models to capture the complexity in series patterns which leads to inefficient forecasts. To overcome the inefficiencies of statistical models, various machine learning techniques were initially used in the literature for more accurate forecasting of time-series. However, simple machine learning methods such as linear regression, support vectors, random forests fail to provide efficient results when tested on highly complex sequences such as stock prices and bond prices. hence to capture these intricate sequence patterns, various deep learning-based methodologies have been discussed in the literature. In this study, a recurrent neural network-based deep learning model using long short term networks for prediction of corporate bond prices has been discussed. Long Short Term networks (LSTM) have been widely used in the literature for various sequence learning tasks in various domains such as machine translation, speech recognition, etc. In recent years, various studies have discussed the effectiveness of LSTMs in forecasting complex time-series sequences and have shown promising results when compared to other methodologies. LSTMs are a special kind of recurrent neural networks which are capable of learning long term dependencies due to its memory function which traditional neural networks fail to capture. In this study, a simple LSTM, Stacked LSTM and a Masked LSTM based model has been discussed with respect to varying input sequences (three days, seven days and 14 days). In order to facilitate faster learning and to gradually decompose the complexity of bond price sequence, an Empirical Mode Decomposition (EMD) has been used, which has resulted in accuracy improvement of the standalone LSTM model. With a variety of Technical Indicators and EMD decomposed time series, Masked LSTM outperformed the other two counterparts in terms of prediction accuracy. To benchmark the proposed model, the results have been compared with traditional time series models (ARIMA), shallow neural networks and above discussed three different LSTM models. In summary, our results show that the use of LSTM models provide more accurate results and should be explored more within the asset management industry.

Keywords: bond prices, long short-term memory, time series forecasting, empirical mode decomposition

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Authors: Vinod Kumar Tewari, Mazhar Husain, Hari Kishan Das Gupta

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Background: Primary or secondary brain death is also accompanied with vasospasm of the perforators other than tissue disruption & further exaggerates the anoxic damage, in the form of neuropraxia. In normal conditions the excitatory impulse propagates as anterograde neurotransmission (ANT) and at the level of synapse, glutamate activates NMDA receptors on postsynaptic membrane. Nitric oxide (NO) is produced by Nitric oxide Synthetase (NOS) in postsynaptic dendride or cell body and travels backwards across a chemical synapse to bind to the axon terminal of a presynaptic neuron for regulation of ANT this process is called as the retrograde neurotransmission (RNT). Thus the primary function of NO is RNT and the purpose of RNT is regulation of chemical neurotransmission at synapse. For this reason, RNT allows neural circuits to create feedback loops. The haem is the ligand binding site of NO receptor (sGC) at presynaptic membrane. The affinity of haem exhibits > 10,000-fold excess for NO than Oxygen (THE 10,000 FOLD EFFECT). In pathological conditions ANT, normal synaptic activity including RNT is absent. NO donors like sodium nitroprusside (SNP) releases NO by activating NOS at the level of postsynaptic area. NO now travels backwards across a chemical synapse to bind to the haem of NO receptor at axon terminal of a presynaptic neuron as in normal condition. NO now acts as impulse generator (at presynaptic membrane) thus bypasses the normal ANT. Also the arteriolar perforators are having Nitric Oxide Synthetase (NOS) at the adventitial side (outer border) on which sodium nitroprusside (SNP) acts; causing release of Nitric Oxide (NO) which vasodilates the perforators causing gush of blood in brain’s tissue and reversal of brain death. Objective: In brain death cases we only think for various transplantations but this study being a pilot study reverses some criteria of brain death by vasodilating the arteriolar perforators. To study the effect of intrathecal sodium nitroprusside (IT SNP) in cases of brain death in which: 1. Retrograde transmission = assessed by the hyperacute timings of reversal 2. The arteriolar perforator vasodilatation caused by NO and the maintenance of reversal of brain death reversal. Methods: 35 year old male, who became brain death after head injury and has not shown any signs of improvement after every maneuver for 6 hours, a single superfusion done by SNP via transoptic canal route for quadrigeminal cistern and cisternal puncture for IV ventricular with SNP done. Results: He showed spontaneous respiration (7 bouts) with TCD studies showing start of pulsations of various branches of common carotid arteries. Conclusions: In future we can give this SNP via transoptic canal route and in IV ventricle before declaring the body to be utilized for transplantations or dead or in broader way we can say that in near future it is possible to revert back from brain death or we have to modify our criterion.

Keywords: brain death, intrathecal sodium nitroprusside, TCD studies, perforators, vasodilatations, retrograde transmission, 10, 000 fold effect

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Authors: Kamal Tolani, Sandeep Kumar, Rohit Luthra, Ankit Dadhania, Krishnaprasad K., Ram Gupta, Deepa Joshi

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Background: Post-operative analgesia remains a clinical challenge, with central and peripheral sensitization playing a pivotal role in treatment-related complications and impaired quality of life. Centrally acting opioids offer poor risk benefit profile with increased intensity of gastrointestinal or central side effects and slow onset of clinical analgesia. The objective of this study was to assess the clinical feasibility of induction and maintenance therapy with Tapentadol Nasal Spray (NS) in moderate to severe acute post-operative pain. Methods: Phase III, randomized, active-controlled, non-inferiority clinical trial involving 294 cases who had undergone surgical procedures under general anesthesia or regional anesthesia. Post-surgery patients were randomized to receive either Tapentadol NS 45 mg or Tramadol 100mg IV as a bolus and subsequent 50 mg or 100 mg dose over 2-3 minutes. The frequency of administration of NS was at every 4-6 hours. At the end of 24 hrs, patients in the tramadol group who had a pain intensity score of ≥4 were switched to oral tramadol immediate release 100mg capsule until the pain intensity score reduced to <4. All patients who had achieved pain intensity ≤ 4 were shifted to a lower dose of either Tapentadol NS 22.5 mg or oral Tramadol immediate release 50mg capsule. The statistical analysis plan was envisaged as a non-inferiority trial involving comparison with Tramadol for Pain intensity difference at 60 minutes (PID60min), Sum of Pain intensity difference at 60 minutes (SPID60min), and Physician Global Assessment at 24 hrs (PGA24 hrs). Results: The per-protocol analyses involved 255 hospitalized cases undergoing surgical procedures. The median age of patients was 38.0 years. For the primary efficacy variables, Tapentadol NS was non-inferior to Inj/Oral Tramadol in relief of moderate to severe post-operative pain. On the basis of SPID60min, no clinically significant difference was observed between Tapentadol NS and Tramadol IV (1.73±2.24 vs. 1.64± 1.92, -0.09 [95% CI, -0.43, 0.60]). In the co-primary endpoint PGA24hrs, Tapentadol NS was non–inferior to Tramadol IV (2.12 ± 0.707 vs. 2.02 ±0.704, - 0.11[95% CI, -0.07, 0.28). However, on further assessment at 48hr, 72 hrs, and 120hrs, clinically superior pain relief was observed with the Tapentadol NS formulation that was statistically significant (p <0.05) at each of the time intervals. Secondary efficacy measures, including the onset of clinical analgesia and TOTPAR, showed non-inferiority to Tramadol. The safety profile and need for rescue medication were also similar in both the groups during the treatment period. The most common concomitant medications were anti-bacterial (98.3%). Conclusion: Tapentadol NS is a clinically feasible option for improved compliance as induction and maintenance therapy while offering a sustained and persistent patient response that is clinically meaningful in post-surgical settings.

Keywords: tapentadol nasal spray, acute pain, tramadol, post-operative pain

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Authors: Abha Gupta, Deepak K. Mishra

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Food security issue in India has surrounded over availability and accessibility of cereal which is regarded as the only food group to check hunger and improve nutrition. Significance of fruits, vegetables, meat and other food products have totally been neglected given the fact that they provide essential nutrients to the body. There is a need to shift the emphasis from cereal-based approach to a more diverse diet so that aim of achieving food security may change from just reducing hunger to an overall health. This paper attempts to analyse how far dietary diversity level has been achieved across different socio-economic groups in India. For this purpose, present paper sets objectives to determine (a) percentage share of different food groups to total food expenditure and consumption by background characteristics (b) source of and preference for all food items and, (c) diversity of diet across socio-economic groups. A cross sectional survey covering 304 households selected through proportional stratified random sampling was conducted in six villages of Aligarh district of Uttar Pradesh, India. Information on amount of food consumed, source of consumption and expenditure on food (74 food items grouped into 10 major food groups) was collected with a recall period of seven days. Per capita per day food consumption/expenditure was calculated through dividing consumption/expenditure by household size and number seven. Food variety score was estimated by giving 0 values to those food groups/items which had not been eaten and 1 to those which had been taken by households in last seven days. Addition of all food group/item score gave result of food variety score. Diversity of diet was computed using Herfindahl-Hirschman index. Findings of the paper show that cereal, milk, roots and tuber food groups contribute a major share in total consumption/expenditure. Consumption of these food groups vary across socio-economic groups whereas fruit, vegetables, meat and other food consumption remain low and same. Estimation of dietary diversity show higher concentration of diet due to higher consumption of cereals, milk, root and tuber products and dietary diversity slightly varies across background groups. Muslims, Scheduled caste, small farmers, lower income class, food insecure, below poverty line and labour families show higher concentration of diet as compared to their counterpart groups. These groups also evince lower mean intake of number of food item in a week due to poor economic constraints and resultant lower accessibility to number of expensive food items. Results advocate to make a shift from cereal based diet to dietary diversity which not only includes cereal and milk products but also nutrition rich food items such as fruits, vegetables, meat and other products. Integrating a dietary diversity approach in food security programmes of the country would help to achieve nutrition security as hidden hunger is widespread among the Indian population.

Keywords: dietary diversity, food Security, India, socio-economic groups

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Authors: Shyam Sunder Gupta

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The current theory for the creation of the universe, the Big Bang theory, is widely accepted but leaves some unanswered questions. It does not explain the origin of the singularity or what causes the Big Bang. The theory of the Big Bang also does not explain why there is such a huge amount of dark energy and dark matter in our universe. Also, there is a question related to one universe or multiple universes which needs to be answered. This research addresses these questions using the Bhagvat Puran and other Vedic scriptures as the basis. There is a Unique Pure Energy Field that is eternal, infinite, and finest of all and never transforms when in its original form. The Carrier Particles of Unique Pure Energy are Param-anus- Fundamental Energy Particles. Param-anus and a combination of these particles create bigger particles from which the Universe gets created. For creation to initiate, Unique Pure Energy is represented in three phases: positive phase energy, neutral phase eternal time energy and negative phase energy. Positive phase energy further expands in three forms of creative energies (CE1, CE2andCE3). From CE1 energy, three energy modes, mode of activation, mode of action, and mode of darkness, were created. From these three modes, 16 Principles, subtlest forms of energies, namely Pradhan, Mahat-tattva, Time, Ego, Intellect, Mind, Sound, Space, Touch, Air, Form, Fire, Taste, Water, Smell, and Earth, get created. In the Mahat-tattva, dominant in the Mode of Darkness, CE1 energy creates innumerable primary singularities from seven principles: Pradhan, Mahat-tattva, Ego, Sky, Air, Fire, and Water. CE1 energy gets divided as CE2 and enters, along with three modes and time, in each singularity, and primary Big Bang takes place, and innumerable Invisible Universes get created. Each Universe has seven coverings of 7 principles, and each layer is 10 times thicker than the previous layer. By energy CE2, space in Invisible Universe under the coverings is divided into two halves. In the lower half, the process of evolution gets initiated, and seeds of 24 elements get created, out of which 5 fundamental elements, building blocks of matter, Sky, Air, Fire, Water and Earth, create seeds of stars, planets, galaxies and all other matter. Since 5 fundamental elements get created out of the mode of darkness, it explains why there is so much dark energy and dark matter in our Universe. This process of creation, in the lower half of Invisible universe continues for 2.16 billion years. Further, in the lower part of the energy field, exactly at the Centre of Invisible Universe, Secondary Singularity is created, through which, by force of Mode of Action, Secondary Big Bang takes place and Visible Universe gets created in the shape of Lotus Flower, expanding into upper part. Visible matter starts appearing after a gap of 360,000 years. Within the Visible Universe, a small part gets created known as the Phenomenal Material World, which is our Solar System, the sun being in the Centre. Diameter of Solar planetary system is 6.4 billion km.

Keywords: invisible universe, phenomenal material world, primary Big Bang, secondary Big Bang, singularities, visible universe

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Authors: Diane Ghanem, Arjun Gupta, Rohan Vijayan, Ali Uneri, Babar Shafiq

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Introduction: Ankle sprains and fractures often result in syndesmosis injuries. Unstable syndesmotic injuries result from relative motion between the distal ends of the tibia and fibula, anatomic juncture which should otherwise be rigid, and warrant operative management. Clinical and radiological evaluations of intraoperative syndesmosis stability remain a challenging task as traditional 2D fluoroscopy is limited to a uniplanar translational displacement. The purpose of this pilot cadaveric study is to compare the 2D fluoroscopy and 3D cone beam computed tomography (CBCT) stress-induced syndesmosis displacements. Methods: Three fresh-frozen lower legs underwent 2D fluoroscopy and 3D CIOS CBCT to measure syndesmosis position before dissection. Syndesmotic injury was simulated by resecting the (1) anterior inferior tibiofibular ligament (AITFL), the (2) posterior inferior tibiofibular ligament (PITFL) and the inferior transverse ligament (ITL) simultaneously, followed by the (3) interosseous membrane (IOM). Manual external rotation and Cotton stress test were performed after each of the three resections and 2D and 3D images were acquired. Relevant 2D and 3D parameters included the tibiofibular overlap (TFO), tibiofibular clear space (TCS), relative rotation of the fibula, and anterior-posterior (AP) and medial-lateral (ML) translations of the fibula relative to the tibia. Parameters were measured by two independent observers. Inter-rater reliability was assessed by intraclass correlation coefficient (ICC) to determine measurement precision. Results: Significant mismatches were found in the trends between the 2D and 3D measurements when assessing for TFO, TCS and AP translation across the different resection states. Using 3D CBCT, TFO was inversely proportional to the number of resected ligaments while TCS was directly proportional to the latter across all cadavers and ‘resection + stress’ states. Using 2D fluoroscopy, this trend was not respected under the Cotton stress test. 3D AP translation did not show a reliable trend whereas 2D AP translation of the fibula was positive under the Cotton stress test and negative under the external rotation. 3D relative rotation of the fibula, assessed using the Tang et al. ratio method and Beisemann et al. angular method, suggested slight overall internal rotation with complete resection of the ligaments, with a change < 2mm - threshold which corresponds to the commonly used buffer to account for physiologic laxity as per clinical judgment of the surgeon. Excellent agreement (>0.90) was found between the two independent observers for each of the parameters in both 2D and 3D (overall ICC 0.9968, 95% CI 0.995 - 0.999). Conclusions: The 3D CIOS CBCT appears to reliably depict the trend in TFO and TCS. This might be due to the additional detection of relevant rotational malpositions of the fibula in comparison to the standard 2D fluoroscopy which is limited to a single plane translation. A better understanding of 3D imaging may help surgeons identify the precise measurements planes needed to achieve better syndesmosis repair.

Keywords: 2D fluoroscopy, 3D computed tomography, image processing, syndesmosis injury

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Authors: Rajinder Kumar Gupta, Rajni Kant Agrawal, Jaganniwas

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One of the most frightening phenomena of nature is the occurrence of earthquake as it has terrible and disastrous effects. Many earthquakes occur every day worldwide. There is need to have knowledge regarding the trends in earthquake occurrence worldwide. The recoding and interpretation of data obtained from the establishment of the worldwide system of seismological stations made this possible. From the analysis of recorded earthquake data, the earthquake parameters and source parameters can be computed and the earthquake catalogues can be prepared. These catalogues provide information on origin, time, epicenter locations (in term of latitude and longitudes) focal depths, magnitude and other related details of the recorded earthquakes. Theses catalogues are used for seismic hazard estimation. Manual interpretation and analysis of these data is tedious and time consuming. A geographical information system is a computer based system designed to store, analyzes and display geographic information. The implementation of integrated GIS technology provides an approach which permits rapid evaluation of complex inventor database under a variety of earthquake scenario and allows the user to interactively view results almost immediately. GIS technology provides a powerful tool for displaying outputs and permit to users to see graphical distribution of impacts of different earthquake scenarios and assumptions. An endeavor has been made in present study to compile the earthquake data for the whole world in visual Basic on ARC GIS Plate form so that it can be used easily for further analysis to be carried out by earthquake engineers. The basic data on time of occurrence, location and size of earthquake has been compiled for further querying based on various parameters. A preliminary analysis tool is also provided in the user interface to interpret the earthquake recurrence in region. The user interface also includes the seismic hazard information already worked out under GHSAP program. The seismic hazard in terms of probability of exceedance in definite return periods is provided for the world. The seismic zones of the Indian region are included in the user interface from IS 1893-2002 code on earthquake resistant design of buildings. The City wise satellite images has been inserted in Map and based on actual data the following information could be extracted in real time: • Analysis of soil parameters and its effect • Microzonation information • Seismic hazard and strong ground motion • Soil liquefaction and its effect in surrounding area • Impacts of liquefaction on buildings and infrastructure • Occurrence of earthquake in future and effect on existing soil • Propagation of earth vibration due of occurrence of Earthquake GIS based earthquake information system has been prepared for whole world in Visual Basic on ARC GIS Plate form and further extended micro level based on actual soil parameters. Individual tools has been developed for liquefaction, earthquake frequency etc. All information could be used for development of infrastructure i.e. multi story structure, Irrigation Dam & Its components, Hydro-power etc in real time for present and future.

Keywords: GIS based earthquake information system, microzonation, analysis and real time information about liquefaction, infrastructure development

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Authors: Mayank Gupta, Siba Prasad Samal, Vasu Kakkirala

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The internet world and its priorities have changed considerably in the last decade. Browsing on smart phones has increased manifold and is set to explode much more. Users spent considerable time browsing different websites, that gives a great deal of insight into user’s preferences. Instead of plain information classifying different aspects of browsing like Bookmarks, History, and Download Manager into useful categories would improve and enhance the user’s experience. Most of the classification solutions are server side that involves maintaining server and other heavy resources. It has security constraints and maybe misses on contextual data during classification. On device, classification solves many such problems, but the challenge is to achieve accuracy on classification with resource constraints. This on device classification can be much more useful in personalization, reducing dependency on cloud connectivity and better privacy/security. This approach provides more relevant results as compared to current standalone solutions because it uses content rendered by browser which is customized by the content provider based on user’s profile. This paper proposes a Naive Bayes based lightweight classification engine targeted for a resource constraint devices. Our solution integrates with Web Browser that in turn triggers classification algorithm. Whenever a user browses a webpage, this solution extracts DOM Tree data from the browser’s rendering engine. This DOM data is a dynamic, contextual and secure data that can’t be replicated. This proposal extracts different features of the webpage that runs on an algorithm to classify into multiple categories. Naive Bayes based engine is chosen in this solution for its inherent advantages in using limited resources compared to other classification algorithms like Support Vector Machine, Neural Networks, etc. Naive Bayes classification requires small memory footprint and less computation suitable for smartphone environment. This solution has a feature to partition the model into multiple chunks that in turn will facilitate less usage of memory instead of loading a complete model. Classification of the webpages done through integrated engine is faster, more relevant and energy efficient than other standalone on device solution. This classification engine has been tested on Samsung Z3 Tizen hardware. The Engine is integrated into Tizen Browser that uses Chromium Rendering Engine. For this solution, extensive dataset is sourced from dmoztools.net and cleaned. This cleaned dataset has 227.5K webpages which are divided into 8 generic categories ('education', 'games', 'health', 'entertainment', 'news', 'shopping', 'sports', 'travel'). Our browser integrated solution has resulted in 15% less memory usage (due to partition method) and 24% less power consumption in comparison with standalone solution. This solution considered 70% of the dataset for training the data model and the rest 30% dataset for testing. An average accuracy of ~96.3% is achieved across the above mentioned 8 categories. This engine can be further extended for suggesting Dynamic tags and using the classification for differential uses cases to enhance browsing experience.

Keywords: chromium, lightweight engine, mobile computing, Naive Bayes, Tizen, web browser, webpage classification

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Authors: Neerja Gupta

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Objective-Reconstruction of large cavities of the breast without contralateral symmetrisation Background- Reconstruction of breast includes a wide spectrum of procedures from displacement to regional and distant flaps. The pedicled Perforator flaps cover a wide spectrum of reconstruction surgery for all quadrants of the breast, especially in patients with comorbidities. These axial flaps singly or adjunct are based on a near constant perforator vessel, a ratio of 2:1 at its entry in a flap is good to maintain vascularity. The perforators of lateral chest wall viz LICAP, LTAP have overlapping perfurosomes without clear demarcation. LTAP is localized in the narrow zone between the lateral breast fold and anterior axillary line,2.5-3.8cm from the fold. MICAP are localized at 1-2 cm from sternum. Being 1-2mm in diameter, a Single perforator is good to maintain the flap. LICAP has a dominant perforator in 6th-11th spaces, while LTAP has higher placed dominant perforators in 4th and 5th spaces. Methodology-Six consecutive patients who underwent reconstruction of the breast with pedicled perforator flaps were retrospectively analysed. Selections of the flap was done based on the size and locations of the tumour, anticipated volume loss, willingness to undergo contralateral symmetrisation, cosmetic expectations, and finances available.3 patients underwent vertical LTAP, the distal limit of the flap being the inframammary crease. 3 patients underwent MICAP, oriented along the axis of rib, the distal limit being the anterior axillary line. Preoperative identification was done using a unidirectional hand held doppler. The flap was raised caudal to cranial, the pivot point of rotation being the vessel entry into the skin. The donor area is determined by the skin pinch. Flap harvest time was 20-25 minutes. Intra operative vascularity was assessed with dermal bleed. The patient immediate pre, post-operative and follow up pics were compared independently by two breast surgeons. Patients were given a breast Q questionnaire (licensed) for scoring. Results-The median age of six patients was 46. Each patient had a hospital stay of 24 hours. None of the patients was willing for contralateral symmetrisation. The specimen dimensions were from 8x6.8x4 cm to 19x16x9 cm. The breast volume reconstructed range was 30 percent to 45 percent. All wide excision had free margins on frozen. The mean flap dimensions were 12x5x4.5 cm. One LTAP underwent marginal necrosis and delayed wound healing due to seroma. Three patients were phyllodes, of which one was borderline, and 2 were benign on final histopathology. All other 3 patients were invasive ductal cancer and have completed their radiation. The median follow up is 7 months the satisfaction scores at median follow of 7 months are 90 for physical wellbeing and 85 for surgical results. Surgeons scored fair to good in Harvard score. Conclusion- Pedicled perforator flaps are a valuable option for 3/8th volume of breast defects. LTAP is preferred for tumours at the Central, upper, and outer quadrants of the breast and MICAP for the inner and lower quadrant. The vascularity of the flap is dependent on the angiosomalterritories; adequate venous and cavity drainage.

Keywords: breast, oncoplasty, pedicled, perforator

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Authors: V. K. Tewari, M. Hussain, H. K. D. Gupta

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Background: Nitric Oxide Donars (NODs) (intrathecal sodium nitroprusside (ITSNP) and oral tadalafil 20mg post ITSNP) has been studied in this context in cerebral palsy patients for fast recovery. This work proposes two mechanisms for acute cases and one mechanism for chronic cases, which are interrelated, for physiological recovery. a) Retrograde Neurotransmission (acute cases): 1) Normal excitatory impulse: at the synaptic level, glutamate activates NMDA receptors, with nitric oxide synthetase (NOS) on the postsynaptic membrane, for further propagation by the calcium-calmodulin complex. Nitric oxide (NO, produced by NOS) travels backward across the chemical synapse and binds the axon-terminal NO receptor/sGC of a presynaptic neuron, regulating anterograde neurotransmission (ANT) via retrograde neurotransmission (RNT). Heme is the ligand-binding site of the NO receptor/sGC. Heme exhibits > 10,000-fold higher affinity for NO than for oxygen (the 10,000-fold effect) and is completed in 20 msec. 2) Pathological conditions: normal synaptic activity, including both ANT and RNT, is absent. A NO donor (SNP) releases NO from NOS in the postsynaptic region. NO travels backward across a chemical synapse to bind to the heme of a NO receptor in the axon terminal of a presynaptic neuron, generating an impulse, as under normal conditions. b) Vasopasm: (acute cases) Perforators show vasospastic activity. NO vasodilates the perforators via the NO-cAMP pathway. c) Long-Term Potentiation (LTP): (chronic cases) The NO–cGMP-pathway plays a role in LTP at many synapses throughout the CNS and at the neuromuscular junction. LTP has been reviewed both generally and with respect to brain regions specific for memory/learning. Aims/Study Design: The principles of “generation of impulses from the presynaptic region to the postsynaptic region by very potent RNT (10,000-fold effect)” and “vasodilation of arteriolar perforators” are the basis of the authors’ hypothesis to treat cerebral palsy cases. Case-control prospective study. Materials and Methods: The experimental population included 82 cerebral palsy patients (10 patients were given control treatments without NOD or with 5% dextrose superfusion, and 72 patients comprised the NOD group). The mean time for superfusion was 5 months post-cerebral palsy. Pre- and post-NOD status was monitored by Gross Motor Function Classification System for Cerebral Palsy (GMFCS), MRI, and TCD studies. Results: After 7 days in the NOD group, the mean change in the GMFCS score was an increase of 1.2 points mean; after 3 months, there was an increase of 3.4 points mean, compared to the control-group increase of 0.1 points at 3 months. MRI and TCD documented the improvements. Conclusions: NOD (ITSNP boosts up the recovery and oral tadalafil maintains the recovery to a well-desired level) acts swiftly in the treatment of CP, acting within 7 days on 5 months post-cerebral palsy either of the three mechanisms.

Keywords: cerebral palsy, intrathecal sodium nitroprusside, oral tadalafil, perforators, vasodilations, retrograde transmission, the 10, 000-fold effect, long-term potantiation

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Authors: Prashant Gupta

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Throughout India, temples have served as cultural centers, commerce hubs, art galleries, educational institutions, and social centers in addition to being places of worship since centuries. Across the country, there are over two million temples, which are crucial economic hubs, attracting devotees and tourists worldwide. In India, we have 53 temples per each 100,000 Indians. As per NSSO survey, the temple economy is worth about $40 billion and 2.32 per cent of GDP based on major temple’s survey, which only includes formal sector. It could be much larger as an actual estimation has not been done yet. In India, 43.1% of total economy represents informal sector. Over 10 billion domestic tourists visit to new destinations every year within India. Even 20 per cent of the 90 million foreign tourists visited Madurai and Mahabalipuram temples which became the most visited tourist spot in 2022. Recently the current central government in power have started revitalizing the ancient Indian civilization by reconstructing and beautifying the major temples of India i.e., Kashi Vishwanath Corridor, Mahakaleshwara Temple, Kedarnath, Ayodhya etc. The reason researcher chose Kashi as a case study because it is known as a Spiritual Capital of India, which is also the abode for the spread of Hinduism, Buddhism, Jainism and Sikkism, which are core Sanatan Dharmic practices. 17,800 Million INR Amount was spend to redevelop Kashi Vishwanath Corridor since 2019. RESEARCH OBJECTIVES 1. To assess historical contribution of temples in socio economic development and revival of Indic Civilization. 2. To examine the role of temples redevelopment for informal sector businesses. 3. To identify the sub-sectors of informal sector businesses 4. To identify products and services of informal businesses for investigation of marketing strategies and business development. PROPOSED METHODS AND PROCEDURES This study will follow a mixed approach, employing both qualitative and quantitative methods of research. To conduct the study, data will be collected from 500 informal business owners through structured questionnaire and interview instruments. The informal business owners will be selected using a systematic random sampling technique. In addition, documents from government offices of the last 10 years of tax collection will be reviewed to substantiate the study. To analyze the study, descriptive and econometric analysis techniques will be employed. EXPECTED CONTRIBUTION OF THE PROPOSED STUDY By studying the contribution of temple re-development on informal business creation and growth, the study will be beneficial to the informal business owners and the government. For the government, scientific and empirical evidence on the contribution of temple re-development for informal business creation and growth to give evidence the study will give based infrastructural development and boosting tax collection. For informal businesses, the study will give them a detailed insight on the nature of their business and the possible future growth potential of their business, and the alternative products and services supplying to their customers in the future. Studying informal businesses will help to identify the key products and services which are majorly profitable and possess potential to multiply and grow through correct product marketing strategies and business development.

Keywords: business development, informal sector businesses, services and products marketing, temple economics

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Authors: Ved Vrat Verma, Rani Gupta, Manisha Goel

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γ-glutamyltranspeptidase (GGT: EC 2.3.2.2) is an N-terminal nucleophile hydrolase conserved in all three domains of life. GGT plays a key role in glutathione metabolism where it catalyzes the breakage of the γ-glutamyl bonds and transfer of γ-glutamyl group to water (hydrolytic activity) or amino acids or short peptides (transpeptidase activity). GGTs from bacteria, archaea, and eukaryotes (human, rat and mouse) are homologous proteins sharing >50% sequence similarity and conserved four layered αββα sandwich like three dimensional structural fold. These proteins though similar in their structure to each other, are quite diverse in their enzyme activity: some GGTs are better at hydrolysis reactions but poor in transpeptidase activity, whereas many others may show opposite behaviour. GGT is known to be involved in various diseases like asthma, parkinson, arthritis, and gastric cancer. Its inhibition prior to chemotherapy treatments has been shown to sensitize tumours to the treatment. Microbial GGT is known to be a virulence factor too, important for the colonization of bacteria in host. However, all known inhibitors (mimics of its native substrate, glutamate) are highly toxic because they interfere with other enzyme pathways. However, a few successful efforts have been reported previously in designing species specific inhibitors. We aim to leverage the diversity seen in GGT family (pathogen vs. eukaryotes) for designing specific inhibitors. Thus, in the present study, we have used DIVERGE software to identify sites in GGT proteins, which are crucial for the functional and structural divergence of these proteins. Since, type II divergence sites vary in clade specific manner, so type II divergent sites were our focus of interest throughout the study. Type II divergent sites were identified for pathogen vs. eukaryotes clusters and sites were marked on clade specific representative structures HpGGT (2QM6) and HmGGT (4ZCG) of pathogen and eukaryotes clade respectively. The crucial divergent sites within 15 A radii of the binding cavity were highlighted, and in-silico mutations were performed on these sites to delineate the role of these sites on the mechanism of catalysis and protein folding. Further, the amino acid network (AAN) analysis was also performed by Cytoscape to delineate assortative mixing for cavity divergent sites which could strengthen our hypothesis. Additionally, molecular dynamics simulations were performed for wild complexes and mutant complexes close to physiological conditions (pH 7.0, 0.1 M ionic strength and 1 atm pressure) and the role of putative divergence sites and structural integrities of the homologous proteins have been analysed. The dynamics data were scrutinized in terms of RMSD, RMSF, non-native H-bonds and salt bridges. The RMSD, RMSF fluctuations of proteins complexes are compared, and the changes at protein ligand binding sites were highlighted. The outcomes of our study highlighted some crucial divergent sites which could be used for novel inhibitors designing in a species-specific manner. Since, for drug development, it is challenging to design novel drug by targeting similar protein which exists in eukaryotes, so this study could set up an initial platform to overcome this challenge and help to deduce the more effective targets for novel drug discovery.

Keywords: γ-glutamyltranspeptidase, divergence, species-specific, drug design

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Authors: Sakshi Gupta, Kavita Sardana

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Management of a forest catchment involves diverse dimensions, multiple stakeholders, and conflicting interests, primarily due to the wide variety of valuable ecosystem services offered by it. Often, the coordination among different levels of formal institutions governing the catchment, local communities, as well as societal norms, taboos, customs and practices, happens to be amiss, leading to conflicting policy interventions which prove detrimental for such resources. In the case of Ala Catchment, which is a protected forest located at a distance of 9 km North-East of the town of Dalhousie, within district Chamba of Himachal Pradesh, India, and serves as one of the primary sources of public water supply for the downstream town of Dalhousie and nearby areas, several policy measures have been adopted for the restoration of the forest catchment, as well as for the improvement of public water supply. These catchment forest restoration measures include; the installation of a fence along the perimeter of the catchment, plantation of trees in the empty patches of the forest, construction of check dams, contour trenches, contour bunds, issuance of grazing permits, and installation of check posts to keep track of trespassers. While the measures adopted to address the acute shortage of public water supply in the Dalhousie region include; building and maintenance of large capacity water storage tanks, laying of pipelines, expanding public water distribution infrastructure to include water sources other than Ala Catchment Forest and introducing of five new water supply schemes for drinking water as well as irrigation. However, despite these policy measures, the degradation of the Ala catchment and acute shortage of water supply continue to distress the region. This study attempts to conduct an institutional analysis to assess the impact of policy measures for the restoration of the Ala Catchment in the Chamba district of Himachal Pradesh in India. For this purpose, the theoretical framework of Ostrom’s Institutional Assessment and Development (IAD) Framework was used. Snowball sampling was used to conduct private interviews and focused group discussions. A semi-structured questionnaire was administered to interview a total of 184 respondents across stakeholders from both formal and informal institutions. The central hypothesis of the study is that the interplay of formal and informal institutions facilitates the implementation of policy measures for ameliorating Ala Catchment, in turn improving the livelihood of people depending on this forest catchment for direct and indirect benefits. The findings of the study suggest that leakages in the successful implementation of policy measures occur at several nodes of decision-making, which adversely impact the catchment and the ecosystem services provided by it. Some of the key reasons diagnosed by the immediate analysis include; ad-hoc assignment of property rights, rise in tourist inflow increasing the pressures on water demand, illegal trespassing by local and nomadic pastoral communities for grazing and unlawful extraction of forest products, and rent-seeking by a few influential formal institutions. Consequently, it is indicated that the interplay of formal and informal institutions may be obscuring the consequentiality of the policy measures on the restoration of the catchment.

Keywords: catchment forest restoration, institutional analysis and development framework, institutional interplay, protected forest, water supply management

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Authors: Vivek Garg, Brajendra S. Sengar, Gaurav Siddharth, Nisheka Anadkat, Amitesh Kumar, Shailendra Kumar, Shaibal Mukherjee

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CuInGaSe (CIGSe) is the dominant thin film solar cell technology. The band alignment of Buffer/CIGSe interface is one of the most crucial parameters for solar cell performance. In this article, the valence band offset (VBOff) and conduction band offset (CBOff) values of Cu(In0.70Ga0.30)Se/ 1 at.% Ga: Mg0.25Zn0.75O (GMZO) heterojunction, grown by dual ion beam sputtering system (DIBS), are calculated to understand the carrier transport mechanism at the heterojunction for the realization of all sputtered buffer-less solar cells. To determine the valence band offset (VBOff), ∆E_V at GMZO/CIGSe heterojunction interface, the standard method based on core-level photoemission is utilized. The value of ∆E_V can be evaluated by considering common core-level peaks. In our study, the values of (Valence band onset)VBOn, obtained by linear extrapolation method for GMZO and CIGSe films are calculated to be 2.86 and 0.76 eV. In the UPS spectra peak positions of Se 3d is observed in UPS spectra at 54.82 and 54.7 eV for CIGSe film and GMZO/CIGSe interface respectively, while the peak position of Mg 2p is observed at 50.09 and 50.12 eV for GMZO and GMZO/CIGSe interface respectively. The optical band gap of CIGSe and GMZO are obtained from absorption spectra procured from spectroscopic ellipsometry are 1.26 and 3.84 eV respectively. The calculated average values of ∆E_v and ∆E_C are estimated to be 2.37 and 0.21 eV, respectively, at room temperature. The calculated positive conduction band offset termed as a spike at the absorber junction is the required criterion for the high-efficiency solar cells for the efficient charge extraction from the junction. So we can conclude that the above study confirms GMZO thin films grown by the dual ion beam sputtering system are the suitable candidate for the CIGSe thin films based ultra-thin buffer-less solar cells. We investigated the band-offset properties at the GMZO/CIGSe heterojunction to verify the suitability of the GMZO for the realization of the buffer-less solar cells. The calculated average values of ∆E_V and ∆E_C are estimated to be 2.37 and 0.21 eV, respectively, at room temperature. The calculated positive conduction band offset termed as a spike at the absorber junction is the required criterion for the high-efficiency solar cells for the efficient charge extraction from the junction. So we can conclude that the above study confirms GMZO thin films grown by the dual ion beam sputtering system are the suitable candidate for the CIGSe thin films based ultra-thin buffer-less solar cells. Acknowledgment: We are thankful to DIBS, EDX, and XRD facility equipped at Sophisticated Instrument Centre (SIC) at IIT Indore. The authors B.S.S and A.K acknowledge CSIR and V.G acknowledge UGC, India for their fellowships. B.S.S is thankful to DST and IUSSTF for BASE Internship Award. Prof. Shaibal Mukherjee is thankful to DST and IUSSTF for BASE Fellowship and MEITY YFRF award. This work is partially supported by DAE BRNS, DST CERI, and DST-RFBR Project under India-Russia Programme of Cooperation in Science and Technology. We are thankful to Mukul Gupta for SIMS facility equipped at UGC-DAE Indore.

Keywords: CIGSe, DIBS, GMZO, solar cells, UPS

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Authors: Abha Gupta, Deepak K. Mishra

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The focus of food security studies in India has been on the adequacy of calories and its linkage with poverty level. India currently being undergoing a massive demographic and epidemiological transition has demonstrated a decline in average physical activity with improved mechanization and urbanization. Food consumption pattern is also changing with decreasing intake of coarse cereals and a marginal increase in the consumption of fruits, vegetables and meat products resulting into a nutrition transition in the country. However, deficiency of essential micronutrients such as vitamins and minerals is rampant despite their growing importance in fighting back with lifestyle and other modern diseases. The calorie driven studies can hardly tackle the complex problem of malnutrition. This paper fills these research lacuna and analyses mean intake of different major and micro-nutrients among different socio-economic groups and adequacy of these nutrients from recommended dietary allowance. For the purpose, a cross-sectional survey covering 304 households selected through proportional stratified random sampling was conducted in six villages of Aligarh district of the state of Uttar Pradesh, India. Data on quantity consumed of 74 food items grouped into 10 food categories with a recall period of seven days was collected from the households and converted into energy, protein, fat, carbohydrate, calcium, iron, thiamine, riboflavin, niacin and vitamin C using standard guidelines of National Institute of Nutrition. These converted nutrients were compared with recommended norms given by National Nutrition Monitoring Bureau. Per capita nutrient adequacy was calculated by dividing mean nutrient intake by the household size and then by comparing it with recommended norm. Findings demonstrate that source of both macro and micro-nutrients are mainly cereals followed by milk, edible oil and sugar items. Share of meat in providing essential nutrients is very low due to vegetarian diet. Vegetables, pulses, nuts, fruits and dry fruits are a poor source for most of the nutrients. Further analysis evinces that intake of most of the nutrients is higher than the recommended norm. Riboflavin is the only vitamin whose intake is less than the standard norm. Poor group, labour, small farmers, Muslims, scheduled caste demonstrate comparatively lower intake of all nutrients than their counterpart groups, though, they get enough macro and micro-nutrients significantly higher than the norm. One of the major reasons for higher intake of most of the nutrients across all socio-economic groups is higher consumption of monotonous diet based on cereals and milk. Most of the nutrients get their major share from cereals particularly wheat and milk intake. It can be concluded from the analysis that although there is adequate intake of most of the nutrients in the diet of rural population yet their source is mainly cereals and milk products depicting a monotonous diet. Hence, more efforts are needed to diversify the diet by giving more focus to the production of other food items particularly fruits, vegetables and pulse products. Awareness among the population, more accessibility and incorporating food items other than cereals in government social safety programmes are other measures to improve food security in India.

Keywords: hidden hunger, India, nutrients, recommended norm

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Authors: Sugandha Gupta, Arun Kumar Jha

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A large number of ferroelectric materials have been intensely investigated for applications in non-volatile ferroelectric random access memories (FeRAMs), piezoelectric transducers, actuators, pyroelectric sensors, high dielectric constant capacitors, etc. Bismuth layered ferroelectric materials such as Strontium Bismuth Tantalate (SBT) has attracted a lot of attention due to low leakage current, high remnant polarization and high fatigue endurance up to 1012 switching cycles. However, pure SBT suffers from various major limitations such as high dielectric loss, low remnant polarization values, high processing temperature, bismuth volatilization, etc. Significant efforts have been made to improve the dielectric and ferroelectric properties of this compound. Firstly, it has been reported that electrical properties vary with the Sr/ Bi content ratio in the SrBi2Ta2O9 compsition i.e. non-stoichiometric compositions with Sr-deficient / Bi excess content have higher remnant polarization values than stoichiometic SBT compositions. With the objective to improve structural, dielectric, ferroelectric and piezoelectric properties of SBT compound, rare earth holmium (Ho3+) was chosen as a donor cation for substitution onto the Bi2O2 layer. Moreover, hardly any report on holmium substitution in stoichiometric SrBi2Ta2O9 and non-stoichiometric Sr0.8Bi2.2Ta2O9 compositions were available in the literature. The holmium substituted SrBi2-xHoxTa2O9 (x= 0.00-2.0) and Sr0.8Bi2.2Ta2O9 (x=0.0 and 0.01) compositions were synthesized by the solid state reaction method. The synthesized specimens were characterized for their structural and electrical properties. X-ray diffractograms reveal single phase layered perovskite structure formation for holmium content in stoichiometric SBT samples up to x ≤ 0.1. The granular morphology of the samples was investigated using scanning electron microscope (Hitachi, S-3700 N). The dielectric measurements were carried out using a precision LCR meter (Agilent 4284A) operating at oscillation amplitude of 1V. The variation of dielectric constant with temperature shows that the Curie temperature (Tc) decreases on increasing the holmium content. The specimen with x=2.0 i.e. the bismuth free specimen, has very low dielectric constant and does not show any appreciable variation with temperature. The dielectric loss reduces significantly with holmium substitution. The polarization–electric field (P–E) hysteresis loops were recorded using a P–E loop tracer based on Sawyer–Tower circuit. It is observed that the ferroelectric property improve with Ho substitution. Holmium substituted specimen exhibits enhanced value of remnant polarization (Pr= 9.22 μC/cm²) as compared to holmium free specimen (Pr= 2.55 μC/cm²). Piezoelectric co-efficient (d33 values) was measured using a piezo meter system (Piezo Test PM300). It is observed that holmium substitution enhances piezoelectric coefficient. Further, the optimized holmium content (x=0.01) in stoichiometric SrBi2-xHoxTa2O9 composition has been substituted in non-stoichiometric Sr0.8Bi2.2Ta2O9 composition to obtain further enhanced structural and electrical characteristics. It is expected that a new class of ferroelectric materials i.e. Rare Earth Layered Structured Ferroelectrics (RLSF) derived from Bismuth Layered Structured Ferroelectrics (BLSF) will generate which can be used to replace static (SRAM) and dynamic (DRAM) random access memories with ferroelectric random access memories (FeRAMS).

Keywords: dielectrics, ferroelectrics, piezoelectrics, strontium bismuth tantalate

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Authors: Parth Gupta, Ujjawal Singh, Shashank Kumar, Mansi Chandra, Arnab Sarkar

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Microfluidic devices have emerged as indispensable tools across various scientific disciplines, offering precise control and manipulation of fluids at the microscale. Their efficacy in flow-based research, spanning engineering, chemistry, and biology, relies heavily on the geometric design of microfluidic channels. This work introduces a novel approach to optimise these channels through Response Surface Methodology (RSM), departing from the conventional practice of addressing one parameter at a time. Traditionally, optimising microfluidic channels involved isolated adjustments to individual parameters, limiting the comprehensive understanding of their combined effects. In contrast, our approach considers the simultaneous impact of multiple parameters, employing RSM to efficiently explore the complex design space. The outcome is an innovative microfluidic channel that consumes an optimal sample volume and minimises flow time, enhancing overall efficiency. The relevance of geometric parameter optimization in microfluidic channels extends significantly in biomedical engineering. The flow characteristics of porous materials within these channels depend on many factors, including fluid viscosity, environmental conditions (such as temperature and humidity), and specific design parameters like sample volume, channel width, channel length, and substrate porosity. This intricate interplay directly influences the performance and efficacy of microfluidic devices, which, if not optimized, can lead to increased costs and errors in disease testing and analysis. In the context of biomedical applications, the proposed approach addresses the critical need for precision in fluid flow. it mitigate manufacturing costs associated with trial-and-error methodologies by optimising multiple geometric parameters concurrently. The resulting microfluidic channels offer enhanced performance and contribute to a streamlined, cost-effective process for testing and analyzing diseases. A key highlight of our methodology is its consideration of the interconnected nature of geometric parameters. For instance, the volume of the sample, when optimized alongside channel width, length, and substrate porosity, creates a synergistic effect that minimizes errors and maximizes efficiency. This holistic optimization approach ensures that microfluidic devices operate at their peak performance, delivering reliable results in disease testing. A key highlight of our methodology is its consideration of the interconnected nature of geometric parameters. For instance, the volume of the sample, when optimized alongside channel width, length, and substrate porosity, creates a synergistic effect that minimizes errors and maximizes efficiency. This holistic optimization approach ensures that microfluidic devices operate at their peak performance, delivering reliable results in disease testing. A key highlight of our methodology is its consideration of the interconnected nature of geometric parameters. For instance, the volume of the sample, when optimized alongside channel width, length, and substrate porosity, creates a synergistic effect that minimizes errors and maximizes efficiency. This holistic optimization approach ensures that microfluidic devices operate at their peak performance, delivering reliable results in disease testing.

Keywords: microfluidic device, minitab, statistical optimization, response surface methodology

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Authors: Amber Dhoot, Tarush Gupta, Andrea Gurr, William Jenkins, Sandro Pietrunti, Alexis Tang

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Background: The COVID-19 pandemic has driven pharmacovigilance towards a new paradigm. Nowadays, more people than ever before are recognising and reporting adverse reactions from medications, treatments, and vaccines. In the modern era, with over 3.8 billion users, social media has become the most accessible medium for people to voice their opinions and so provides an opportunity to engage with more patient-centric and accessible pharmacovigilance. However, the pharmaceutical industry has been slow to incorporate social media into its modern pharmacovigilance strategy. This project aims to make social media a more effective tool in pharmacovigilance, and so reduce drug costs, improve drug safety and improve patient outcomes. This will be achieved by firstly uncovering and categorising the barriers facing the widespread adoption of social media in pharmacovigilance. Following this, the potential opportunities of social media will be explored. We will then propose realistic, practical recommendations to make social media a more effective tool for pharmacovigilance. Methodology: A comprehensive systematic literature review was conducted to produce a categorised summary of these barriers. This was followed by conducting 11 semi-structured interviews with pharmacovigilance experts to confirm the literature review findings whilst also exploring the unpublished and real-life challenges faced by those in the pharmaceutical industry. Finally, a survey of the general public (n = 112) ascertained public knowledge, perception, and opinion regarding the use of their social media data for pharmacovigilance purposes. This project stands out by offering perspectives from the public and pharmaceutical industry that fill the research gaps identified in the literature review. Results: Our results gave rise to several key analysis points. Firstly, inadequacies of current Natural Language Processing algorithms hinder effective pharmacovigilance data extraction from social media, and where data extraction is possible, there are significant questions over its quality. Social media also contains a variety of biases towards common drugs, mild adverse drug reactions, and the younger generation. Additionally, outdated regulations for social media pharmacovigilance do not align with new, modern General Data Protection Regulations (GDPR), creating ethical ambiguity about data privacy and level of access. This leads to an underlying mindset of avoidance within the pharmaceutical industry, as firms are disincentivised by the legal, financial, and reputational risks associated with breaking ambiguous regulations. Conclusion: Our project uncovered several barriers that prevent effective pharmacovigilance on social media. As such, social media should be used to complement traditional sources of pharmacovigilance rather than as a sole source of pharmacovigilance data. However, this project adds further value by proposing five practical recommendations that improve the effectiveness of social media pharmacovigilance. These include: prioritising health-orientated social media; improving technical capabilities through investment and strategic partnerships; setting clear regulatory guidelines using multi-stakeholder processes; creating an adverse drug reaction reporting interface inbuilt into social media platforms; and, finally, developing educational campaigns to raise awareness of the use of social media in pharmacovigilance. Implementation of these recommendations would speed up the efficient, ethical, and systematic adoption of social media in pharmacovigilance.

Keywords: adverse drug reaction, drug safety, pharmacovigilance, social media

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Authors: Veenu Bala, Yashpal S. Chhonker, Bhavana Kushwaha, Rabi S. Bhatta, Gopal Gupta, Vishnu L. Sharma

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According to UNAIDS 2013 estimate nearly 52% of all individuals living with HIV are now women of reproductive age (15–44 years). Seventy-five percent cases of HIV acquisition are through heterosexual contacts and sexually transmitted infections (STIs), attributable to unsafe sexual behaviour. Each year, an estimated 500 million people acquire atleast one of four STIs: chlamydia, gonorrhoea, syphilis and trichomoniasis. Trichomonas vaginalis (TV) is exclusively sexually transmitted in adults, accounting for 30% of STI cases and associated with pelvic inflammatory disease (PID), vaginitis and pregnancy complications in women. TV infection resulted in impaired vaginal milieu, eventually favoring HIV transmission. In the absence of an effective prophylactic HIV vaccine, prevention of new infections has become a priority. It was thought worthwhile to integrate HIV prevention and reproductive health services including unintended pregnancy protection for women as both are related with unprotected sex. Initially, nonoxynol-9 (N-9) had been proposed as a spermicidal agent with microbicidal activity but on the contrary it increased HIV susceptibility due to surfactant action. Thus, to accomplish an urgent need of novel woman controlled non-detergent microbicidal spermicides benzenepropanamine analogues have been synthesized. At first, five benzenepropanamine-dithiocarbamate hybrids have been synthesized and evaluated for their spermicidal, anti-Trichomonas and anti-fungal activities along with safety profiling to cervicovaginal cells. In order to further enhance the scope of above study benzenepropanamine was hybridized with thiourea as to introduce anti-HIV potential. The synthesized hybrid molecules were evaluated for their reverse transcriptase (RT) inhibition, spermicidal, anti-Trichomonas and antimicrobial activities as well as their safety against vaginal flora and cervical cells. simulated vaginal fluid (SVF) stability and pharmacokinetics of most potent compound versus N-9 was examined in female Newzealand (NZ) rabbits to observe its absorption into systemic circulation and subsequent exposure in blood plasma through vaginal wall. The study resulted in the most promising compound N-butyl-4-(3-oxo-3-phenylpropyl) piperazin-1-carbothioamide (29) exhibiting better activity profile than N-9 as it showed RT inhibition (72.30 %), anti-Trichomonas (MIC, 46.72 µM against MTZ susceptible and MIC, 187.68 µM against resistant strain), spermicidal (MEC, 0.01%) and antifungal activity (MIC, 3.12–50 µg/mL) against four fungal strains. The high safety against vaginal epithelium (HeLa cells) and compatibility with vaginal flora (lactobacillus), SVF stability and least vaginal absorption supported its suitability for topical vaginal application. Docking study was performed to gain an insight into the binding mode and interactions of the most promising compound, N-butyl-4-(3-oxo-3-phenylpropyl) piperazin-1-carbothioamide (29) with HIV-1 Reverse Transcriptase. The docking study has revealed that compound (29) interacted with HIV-1 RT similar to standard drug Nevirapine. It may be concluded that hybridization of benzenepropanamine and thiourea moiety resulted into novel lead with multiple activities including RT inhibition. A further lead optimization may result into effective vaginal microbicides having spermicidal, anti-Trichomonas, antifungal and anti-HIV potential altogether with enhanced safety to cervico-vaginal cells in comparison to Nonoxynol-9.

Keywords: microbicidal, nonoxynol-9, reverse transcriptase, spermicide

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Authors: Varinder Kaur Gambhir, Neema Gupta, Sonal Tickoo Chaudhuri

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Bengaluru, a rapidly growing metropolis in India, with a population of 12.5 million citizens, generates 5,757 metric tonnes of solid waste per day. Despite their invaluable contribution to waste management, society and the economy, waste pickers face significant stigma, suspicion and contempt and are left with a sense of shame about their work. In this context, BBC Media Action was funded by the H&M Foundation to develop a 3-year multi-phase social media campaign to shift perceptions of waste picking and informal waste pickers amongst the Bengaluru population. Research has been used to inform project strategy and adaptation, at all stages. Formative research to inform campaign strategy used mixed methods– 14 focused group discussions followed by 406 online surveys – to explore people’s knowledge of, and attitudes towards waste pickers, and identify potential barriers and motivators to changing perceptions. Use of qualitative techniques like metaphor maps (using bank of pictures rather than direct questions to understand mindsets) helped establish the invisibility of informal waste pickers, and the quantitative research enabled audience segmentation based on attitudes towards informal waste pickers. To pretest the campaign idea, eight I-GDs (individual interaction followed by group discussions) were conducted to allow interviewees to first freely express their feelings individually, before discussing in a group. Robert Plucthik’s ‘wheel of emotions’ was used to understand audience’s emotional response to the content. A robust monitoring and evaluation is being conducted (baseline and first phase of monitoring already completed) using a rotating longitudinal panel of 1,800 social media users (exposed and unexposed to the campaign), recruited face to face and representative of the social media universe of Bengaluru city. In addition, qualitative in-depth interviews are being conducted after each phase to better understand change drivers. The research methodology and ethical protocols for impact evaluation have been independently reviewed by an Institutional Review Board. Formative research revealed that while waste on the streets is visible and is of concern to the public, informal waste pickers are virtually ‘invisible’, for most people in Bengaluru Pretesting research revealed that the creative outputs evoked emotions like acceptance and gratitude towards waste-pickers, suggesting that the content had the potential to encourage attitudinal change. After the first phase of campaign, social media analytics show that #Invaluables content reached at least 2.6 million unique people (21% of the Bengaluru population) through Facebook and Instagram. Further, impact monitoring results show significant improvements in spontaneous awareness of different segments of informal waste pickers ( such as sorters at scrap shops or dry waste collection centres -from 10% at baseline to 16% amongst exposed and no change amongst unexposed), recognition that informal waste pickers help the environment (71% at baseline to 77% among exposed and no change among unexposed) and greater discussion about informal waste pickers among those exposed (60%) as against not exposed (49%). Using the insights from this research, the planned social media intervention is designed to increase the visibility of and appreciation for the work of waste pickers in Bengaluru, supporting a more inclusive society.

Keywords: awareness, discussion, discrimination, informal waste pickers, invisibility, social media campaign, waste management

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Authors: Kartik Gupta, Virendra Kumar, Sanjeev Sinha, N. Jagannathan

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Introduction: A significant number of patients having human immunodeficiency virus (HIV) infection show a neurocognitive decline (NCD) ranging from minor cognitive impairment to severe dementia. The possible causes of NCD in HIV-infected patients include brain injury by HIV before cART, neurotoxic viral proteins and metabolic abnormalities. In the present study, we compared the level of NCD in asymptomatic HIV-infected patients with changes in brain metabolites measured by using magnetic resonance spectroscopy (MRS). Methods: 43 HIV-positive patients (30 males and 13 females) coming to ART center of the hospital and HIV-seronegative healthy subjects were recruited for the study. All the participants completed MRI and MRS examination, detailed clinical assessments and a battery of neuropsychological tests. All the MR investigations were carried out at 3.0T MRI scanner (Ingenia/Achieva, Philips, Netherlands). MRI examination protocol included the acquisition of T2-weighted imaging in axial, coronal and sagittal planes, T1-weighted, FLAIR, and DWI images in the axial plane. Patients who showed any apparent lesion on MRI were excluded from the study. T2-weighted images in three orthogonal planes were used to localize the voxel in left frontal lobe white matter (FWM) and left basal ganglia (BG) for single voxel MRS. Single voxel MRS spectra were acquired with a point resolved spectroscopy (PRESS) localization pulse sequence at an echo time (TE) of 35 ms and a repetition time (TR) of 2000 ms with 64 or 128 scans. Automated preprocessing and determination of absolute concentrations of metabolites were estimated using LCModel by water scaling method and the Cramer-Rao lower bounds for all metabolites analyzed in the study were below 15\%. Levels of total N-acetyl aspartate (tNAA), total choline (tCho), glutamate + glutamine (Glx), total creatine (tCr), were measured. Cognition was tested using a battery of tests validated for Indian population. The cognitive domains tested were the memory, attention-information processing, abstraction-executive, simple and complex perceptual motor skills. Z-scores normalized according to age, sex and education standard were used to calculate dysfunction in these individual domains. The NCD was defined as dysfunction with Z-score ≤ 2 in at least two domains. One-way ANOVA was used to compare the difference in brain metabolites between the patients and healthy subjects. Results: NCD was found in 23 (53%) patients. There was no significant difference in age, CD4 count and viral load between the two groups. Maximum impairment was found in the domains of memory and simple motor skills i.e., 19/43 (44%). The prevalence of deficit in attention-information processing, complex perceptual motor skills and abstraction-executive function was 37%, 35%, 33% respectively. Subjects with NCD had a higher level of Glutamate in the Frontal region (8.03 ± 2.30 v/s. 10.26 ± 5.24, p-value 0.001). Conclusion: Among newly diagnosed, ART-naïve retroviral disease patients from India, cognitive decline was found in 53\% patients using tests validated for this population. Those with neurocognitive decline had a significantly higher level of Glutamate in the left frontal region. There was no significant difference in age, CD4 count and viral load at initiation of ART between the two groups.

Keywords: HIV, neurocognitive decline, neurometabolites, magnetic resonance spectroscopy

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Authors: Kashima Arora, Monika Tomar, Vinay Gupta

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Biosensors have found potential applications ranging from environmental testing and biowarfare agent detection to clinical testing, health care, and cell analysis. This is driven in part by the desire to decrease the cost of health care and to obtain precise information more quickly about the health status of patient by the development of various biosensors, which has become increasingly prevalent in clinical testing and point of care testing for a wide range of biological elements. Uric acid is an important byproduct in human body and a number of pathological disorders are related to its high concentration in human body. In past few years, rapid growth in the development of new materials and improvements in sensing techniques have led to the evolution of advanced biosensors. In this context, metal oxide thin film based matrices due to their bio compatible nature, strong adsorption ability, high isoelectric point (IEP) and abundance in nature have become the materials of choice for recent technological advances in biotechnology. In the past few years, wide band-gap metal oxide semiconductors including ZnO, SnO₂ and CeO₂ have gained much attention as a matrix for immobilization of various biomolecules. Tin oxide (SnO₂), wide band gap semiconductor (Eg =3.87 eV), despite having multifunctional properties for broad range of applications including transparent electronics, gas sensors, acoustic devices, UV photodetectors, etc., it has not been explored much for biosensing purpose. To realize a high performance miniaturized biomolecular electronic device, rf sputtering technique is considered to be the most promising for the reproducible growth of good quality thin films, controlled surface morphology and desired film crystallization with improved electron transfer property. Recently, iron oxide and its composites have been widely used as matrix for biosensing application which exploits the electron communication feature of Fe, for the detection of various analytes using urea, hemoglobin, glucose, phenol, L-lactate, H₂O₂, etc. However, to the authors’ knowledge, no work is being reported on modifying the electronic properties of SnO₂ by implanting with suitable metal (Fe) to induce the redox couple in it and utilizing it for reagentless detection of uric acid. In present study, Fe implanted SnO₂ based matrix has been utilized for reagentless uric acid biosensor. Implantation of Fe into SnO₂ matrix is confirmed by energy-dispersive X-Ray spectroscopy (EDX) analysis. Electrochemical techniques have been used to study the response characteristics of Fe modified SnO₂ matrix before and after uricase immobilization. The developed uric acid biosensor exhibits a high sensitivity to about 0.21 mA/mM and a linear variation in current response over concentration range from 0.05 to 1.0 mM of uric acid besides high shelf life (~20 weeks). The Michaelis-Menten kinetic parameter (Km) is found to be relatively very low (0.23 mM), which indicates high affinity of the fabricated bioelectrode towards uric acid (analyte). Also, the presence of other interferents present in human serum has negligible effect on the performance of biosensor. Hence, obtained results highlight the importance of implanted Fe:SnO₂ thin film as an attractive matrix for realization of reagentless biosensors towards uric acid.

Keywords: Fe implanted tin oxide, reagentless uric acid biosensor, rf sputtering, thin film

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Authors: Vipin Bhandari, Anupama Singh, Kopal Gupta

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Solid state fermentation, an eminent bioconversion technique for converting many biological substrates into a value-added product, has proven its role in the biotransformation of crops by nutritionally enriching them. Hence, an effort was made for nutritional enhancement of underutilized crops viz. barnyard millet, amaranthus and horse gram based composite flour using SSF. The grains were given pre-treatments before fermentation and these pre-treatments proved quite effective in diminishing the level of antinutrients in grains and in improving their nutritional characteristics. The present study deals with the enhancement of nutritional characteristics of underutilized crops viz. barnyard millet, amaranthus and horsegram based composite flour using solid state fermentation (SSF) as the principle bioconversion technique to convert the composite flour substrate into a nutritionally enriched value added product. Response surface methodology was used to design the experiments. The variables selected for the fermentation experiments were substrate particle size, substrate blend ratio, fermentation time, fermentation temperature and moisture content having three levels of each. Seventeen designed experiments were conducted randomly to find the effect of these variables on microbial count, reducing sugar, pH, total sugar, phytic acid and water absorption index. The data from all experiments were analyzed using Design Expert 8.0.6 and the response functions were developed using multiple regression analysis and second order models were fitted for each response. Results revealed that pretreatments proved quite handful in diminishing the level of antinutrients and thus enhancing the nutritional value of the grains appreciably, for instance, there was about 23% reduction in phytic acid levels after decortication of barnyard millet. The carbohydrate content of the decorticated barnyard millet increased to 81.5% from initial value of 65.2%. Similarly popping and puffing of horsegram and amaranthus respectively greatly reduced the trypsin inhibitor activity. Puffing of amaranthus also reduced the tannin content appreciably. Bacillus subtilis was used as the inoculating specie since it is known to produce phytases in solid state fermentation systems. These phytases remarkably reduce the phytic acid content which acts as a major antinutritional factor in food grains. Results of solid state fermentation experiments revealed that phytic acid levels reduced appreciably when fermentation was allowed to continue for 72 hours at a temperature of 35°C. Particle size and substrate blend ratio also affected the responses positively. All the parameters viz. substrate particle size, substrate blend ratio, fermentation time, fermentation temperature and moisture content affected the responses namely microbial count, reducing sugar, pH, total sugar, phytic acid and water absorption index but the effect of fermentation time was found to be most significant on all the responses. Statistical analysis resulted in the optimum conditions (particle size 355µ, substrate blend ratio 50:20:30 of barnyard millet, amaranthus and horsegram respectively, fermentation time 68 hrs, fermentation temperature 35°C and moisture content 47%) for maximum reduction in phytic acid. The model F- value was found to be highly significant at 1% level of significance in case of all the responses. Hence, second order model could be fitted to predict all the dependent parameters. The effect of fermentation time was found to be most significant as compared to other variables.

Keywords: composite flour, solid state fermentation, underutilized crops, cereals, fermentation technology, food processing

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Authors: Richa Jaiswal, Vidisha Sharma, Amulya Rattan, Sushma Sagar, Subodh Kumar, Amit Gupta, Biplab Mishra, Maneesh Singhal

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Background: Adequate nutritional support and daily patient monitoring have an independent therapeutic role in the successful management of high output fistulae and early recovery after abdominal trauma. Case presentation: An 18-year-old girl was brought to AIIMS emergency with alleged history of fall of a heavy weight (electric motor) over abdomen. She was evaluated as per Advanced Trauma Life Support(ATLS) protocols and diagnosed to have significant abdominal trauma. After stabilization, she was referred to Trauma center. Abdomen was guarded and focused assessment with sonography for trauma(FAST) was found positive. Complete duodenojejunal(DJ) junction transection was found at laparotomy, and end-to-end repair was done. However, patient was re-explored in view of biliary peritonitis on post-operative day3, and anastomotic leak was found with sloughing of duodenal end. Resection of non-viable segments was done followed by side-to-side anastomosis. Unfortunately, the anastomosis leaked again, this time due to a post-anastomotic kink, diagnosed on dye study. Due to hostile abdomen, the patient was planned for supportive care, with plan of build-up and delayed definitive surgery. Percutaneous transheptic biliary drainage (PTBD) and STSG were required in the course as well. Nutrition: In intensive care unit (ICU), major goals of nutritional therapy were to improve wound healing, optimize nutrition, minimize enteral feed associated complications, reduce biliary fistula output, and prepare the patient for definitive surgeries. Feeding jejunostomy (FJ) was started from day 4 at the rate of 30ml/h along with total parenteral nutrition (TPN) and intra-venous (IV) micronutrients support. Due to high bile output, bile refeed started from day 13.After 23 days of ICU stay, patient was transferred to general ward with body mass index (BMI)<11kg/m2 and serum albumin –1.5gm%. Patient was received in the ward in catabolic phase with high risk of refeeding syndrome. Patient was kept on FJ bolus feed at the rate of 30–50 ml/h. After 3–4 days, while maintaining patient diet book log it was observed that patient use to refuse feed at night and started becoming less responsive with every passing day. After few minutes of conversation with the patient for a couple of days, she complained about enteral feed discharge in urine, mild pain and sign of dumping syndrome. Dye study was done, which ruled out any enterovesical fistula and conservative management were planned. At this time, decision was taken for continuous slow rate feeding through commercial feeding pump at the rate of 2–3ml/min. Drastic improvement was observed from the second day in gastro-intestinal symptoms and general condition of the patient. Nutritional composition of feed, TPN and diet ranged between 800 and 2100 kcal and 50–95 g protein. After STSG, TPN was stopped. Periodic diet counselling was given to improve oral intake. At the time of discharge, serum albumin level was 2.1g%, weight – 38.6, BMI – 15.19 kg/m2. Patient got discharge on an oral diet. Conclusion: Successful management of post-traumatic proximal high output fistulae is a challenging task, due to impaired nutrient absorption and enteral feed associated complications. Strategic- and goal-based nutrition support can salvage such critically ill patients, as demonstrated in the present case.

Keywords: nutritional monitoring, nutritional support, duodenal fistula, abdominal trauma

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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: Anjula Negi, Sanjay Gupta

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Paradigms studied inform inadequacies of financial resources, be it to finance metro rails for construction or to meet operational revenues or to derive profits in the long term. Funding sustainability is far and wide for much-needed public transport modes, like urban rail or metro rails, to be successfully operated. India embarks upon a sustainable transport journey and has proposed metro rail systems countrywide. As an emerging economic leader, its fiscal constraints are paramount, and the land value capture (LVC) mechanism provides necessary support and innovation toward development. India’s metro rail policy promotes multiple methods of financing, including private-sector investments and public-private-partnership. The critical question that remains to be addressed is what factors can make such mechanisms work. Globally, urban rail is a revolution noted by many researchers as future mobility. Researchers in this study deep dive by way of literature review and empirical assessments into factors that can lead to the adoption of LVC mechanisms. It is understood that the adoption of LVC methods is in the nascent stages in India. Research posits numerous challenges being faced by metro rail agencies in raising funding and for incremental value capture. A few issues pertaining to land-based financing, inter alia: are long-term financing, inter-institutional coordination, economic/ market suitability, dedicated metro funds, land ownership issues, piecemeal approach to real estate development, property development legal frameworks, etc. The question under probe is what are the parameters that can lead to success in the adoption of land value capture (LVC) as a financing mechanism. This research provides insights into key parameters crucial to the adoption of LVC in the context of Indian metro rails. Researchers have studied current forms of LVC mechanisms at various metro rails of the country. This study is significant as little research is available on the adoption of LVC, which is applicable to the Indian context. Transit agencies, State Government, Urban Local Bodies, Policy makers and think tanks, Academia, Developers, Funders, Researchers and Multi-lateral agencies may benefit from this research to take ahead LVC mechanisms in practice. The study deems it imperative to explore and understand key parameters that impact the adoption of LVC. Extensive literature review and ratification by experts working in the metro rails arena were undertaken to arrive at parameters for the study. Stakeholder consultations in the exploratory factor analysis (EFA) process were undertaken for principal component extraction. 43 seasoned and specialized experts participated in a semi-structured questionnaire to scale the maximum likelihood on each parameter, represented by various types of stakeholders. Empirical data was collected on chosen eighteen parameters, and significant correlation was extracted for output descriptives and inferential statistics. Study findings reveal these principal components as institutional governance framework, spatial planning features, legal frameworks, funding sustainability features and fiscal policy measures. In particular, funding sustainability features highlight sub-variables of beneficiaries to pay and use of multiple revenue options towards success in LVC adoption. Researchers recommend incorporation of these variables during early stage in design and project structuring for success in adoption of LVC. In turn leading to improvements in revenue sustainability of a public transport asset and help in undertaking informed transport policy decisions.

Keywords: Exploratory factor analysis, land value capture mechanism, financing metro rails, revenue sustainability, transport policy

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

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Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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