Search results for: orphan drug production

Authors: Trina Isabel D. Santiago, Juan Raphael M. Perez, Maria Angelica O. Soriano, Teresita B. Suing, Jumee F. Tayaban

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To achieve universal healthcare for everyone, the World Health Organization has emphasized the importance of National Medicines Policies for increased accessibility and utilization of high-quality and affordable medications. In the Philippines, significant challenges have been identified surrounding the sustainability of essential medicines, resulting in limited access such as high cost and dominance and market dominance and monopoly of multinational companies (MNCs) in the Philippine pharmaceutical industry. These identified challenges have been addressed by several initiatives, such as the Philippine National Drug Policy and Generics Act of 1988 (Republic Act 6675), to attempt to reduce drug prices. Despite these efforts, the concerns with drug accessibility and affordability continue to persist; hence, Republic Act 9502 was enacted. This paper attempts to review RA 9502 in the pursuit of making medicines more affordable for Filipinos, analyze and critique the problems and challenges associated with the law, and provide recommendations to address identified problems and challenges. A literature search and review, as well as an analysis of the law, has been done to evaluate the policy. RA 9502 recognizes the importance of market competition in drug price reduction and quality medicine accessibility. Contentious issues prior to enactment of the law include 1) parallel importation, pointing out that the drug price will depend on the global market price, 2) contrasting approaches in the drafting of the law as the House version focused on medicine price control while the Senate version prioritized market competition, and 3) MNCs opposing the amendments with concerns on discrimination, constitutional violations, and noncompliance with international treaty obligations. There are also criticisms and challenges with the implementation of the law in terms of content or modeling, interpretation and implementation, and other external factors or hindrances. The law has been criticized for its narrow scope as it only covers specific essential medicines with no cooperation with the national health insurance program. Moreover, the law has sections taking advantage of the TRIPS flexibilities, which disallow smaller countries to reap the benefits of flexibilities. The sanctions and penalties have an insignificant role in implementation as they only ask for a small portion of the income of MNCs. Proposed recommendations for policy improvement include aligning existing legislation through strengthened price regulation and expanded law coverage, strengthening penalties to promote law adherence, and promoting research and development to encourage and support local initiatives. Through these comprehensive recommendations, the issues surrounding the policy can be addressed, and the goal of enhancing the affordability and accessibility of medicines in the country can be achieved.

Keywords: drug accessibility, drug affordability, price regulation, Republic Act 9502

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Authors: Rady A., Elsheshai A., Eltawel M.

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Introduction and Aim of work: Literature suggest that antipsychotic medications may decrease cortisol level, an effect that seems to be more present with second generation antipsychotic. Our study aims at assessing effect of long term use of antipsychotics on cortisol level Subjects and Methods: 30 chronic schizophrenic patients on antipsychotics compared to 20 drug naive schizophrenic patients as regards serum cortisol level Results: Cortisol level was significantly lower in chronic schizophrenic patients receiving antipsychotics compared to drug naive patients (P=0.002 <0.05) Conclusion: Antipsychotic medications seem to have the potential to decrease cortisol level in blood. Among hypothesis proposed in literature is the good control of pseudo stress due to psychotic features.

Keywords: schizophrenia, antipsychotic, cortisol, HPA

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Authors: Yoftahe Nigussie Worku

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This research focuses on advancing fire tube boiler technology by systematically optimizing design parameters to achieve efficient saturated steam production. The main objective is to design a high-performance boiler with a production capacity of 2000kg/h at a 12-bar design pressure while minimizing costs. The methodology employs iterative analysis, utilizing relevant formulas, and considers material selection and production methods. The study successfully results in a boiler operating at 85.25% efficiency, with a fuel consumption rate of 140.37kg/hr and a heat output of 1610kW. Theoretical importance lies in balancing efficiency, safety considerations, and cost minimization. The research addresses key questions on parameter optimization, material choices, and safety-efficiency balance, contributing valuable insights to fire tube boiler design.

Keywords: safety consideration, efficiency, production methods, material selection

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Authors: Leandra Prempeh, Emily Malugen

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Prenatal drug exposure can have a molecular impact on the hypothalamic and reward genes that regulate feeding behavior. This can impact feeding regulation, resulting in feeding difficulties and growth failure. This was potentially seen in “McKayla,” a 19- month old girl with a history of in-utero drug exposure, patent ductus arteriosus, and gastroesophageal reflux disease who presented for intensive day treatment feeding therapy. She was diagnosed with Avoidant Restrictive Food Intake Disorder, described as total food refusal and meeting 100% of her caloric needs from a gastrostomy tube. The primary goals during intensive feeding therapy were to increase her oral intake and decrease her reliance on supplementation with formula. Several behavioral antecedent manipulations were implemented to establish consistent responding and make progress towards treatment goals. This included multiple modified bolus placements (using underloaded and Nuk brush), reinforcement contingencies, and variety fading before stability was finally achieved. Following, increasing retention of bites then increasing volume and variety were goals targeted. From treatment onset to the last 3 days of treatment, McKayla's rate of rapid acceptance of bite presentations increased significantly from 33.33% to 93.13%, rapid swallowing went from 0.00% to 92.32%, and her percentage of inappropriate mealtime behavior and expels decreased from 58.33% and 100% to 2.31% and 7.68%, respectively. Overall, the treatment team successfully introduced and increased the bite size of 7 pureed foods, generalize the treatment to caregivers with high integrity, and began facilitating tube weaning. She was receiving about 33.42% of her needs by mouth at the time of discharge. Other nutritional concerns addressed during treatment included drinking a nutritionally complete drink out of an open cup and age appropriate growth. McKayla continued to have emesis almost daily, as was her baseline before starting treatment; however, the frequency during mealtime decreased. Overall, McKayla responded well to treatment. She had a very slow response to treatment and required a lot of antecedent manipulations to establish consistent responding. As the literature suggests, [drug]-exposed neonates, like McKayla, may be at increased risk for nutritional and growth challenges that may persist throughout development. This supports the need for longterm follow-up of infant growth.

Keywords: behavioral intervention, feeding problems, in-utero drug exposure, intensive multidisciplinary intervention

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Authors: Maryam Beiranvand

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Multi-drug resistance in various microorganisms has increased globally in many healthcare facilities. Less effective antimicrobial activity of drug therapies for infection control becomes trouble. Since 1980, no new type of antimicrobial drug has been identified, even though combinations of antibiotic drugs have been discovered almost every decade. Between 1981 and 2006, over 70% of novel pharmaceuticals and chemical agents came from natural sources. Microorganisms have yielded almost 22,000 natural compounds. The identification of antimicrobial components from endophytes bacteria could help overcome the threat posed by multi-drug resistant strains. The project aims to analyze and identify antimicrobial peptides isolated from entophytic bacteria and their activity against multidrug-resistant Gram-negative bacteria in South Korea. Endophytic Paenibacillus polymyxa. 4G3 isolated from the plant, Gynura procumbery exhibited considerable antimicrobial activity against Methicillin-resistant Staphylococcus aureus, and Escherichia coli. The Rapid Annotations using Subsystems Technology showed that the total size of the draft genome was 5,739,603bp, containing 5178 genes with 45.8% G+C content. Genome annotation using antiSMASH version 6.0.0 was performed, which predicted the most common types of non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS). In this study, diethyl aminoethyl cellulose (DEAEC) resin was used as the first step in purifying for unknown peptides, and then the target protein was identified using hydrophilic and hydrophobic solutions, optimal pH, and step-by-step tests for antimicrobial activity. This crude was subjected to C18 chromatography and elution with 0, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% methanol, respectively. Only the fraction eluted with 20% -60% methanol demonstrated good antimicrobial activity against MDR E. coli. The concentration of the active fragment was measured by the Brad-ford test, and Protein A280 - Thermo Fisher Scientific at the end by examining the SDS PAGE Resolving Gel, 10% Acrylamide and purity were confirmed. Our study showed that, based on the combined results of the analysis and purification. P polymyxa. 4G3 has a high potential exists for producing novel functions of polymyxin E and bacitracin against bacterial pathogens.

Keywords: endophytic bacteria, antimicrobial activity, antimicrobial peptide, whole genome sequencing analysis, multi -drug resistance gram negative bacteria

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Authors: Randa Ismail Sharafeddine

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The Islamic economic system is distinctive in that it implicitly recognizes money as a separate, independent component of production capable of assuming risk and so entitled to the same reward as other Entrepreneurial Factors of Production (EFP). Conventional theory does not identify money capital explicitly as a component of production; rather, interest is recognized as a reward for capital, the interest rate is the cost of money capital, and it is also seen as a cost of physical capital. The conventional theory of production examines how diverse non-entrepreneurial resources (Land, Labor, and Capital) are selected; however, the economic theory community is largely unaware of the reasons why these resources choose to remain as non-entrepreneurial resources as opposed to becoming entrepreneurial resources. Should land, labor, and financial asset owners choose to work for others in return for rent, income, or interest, or should they engage in entrepreneurial risk-taking in order to profit. This is a decision made often in the actual world, but it has never been effectively treated in economic theory. This article will conduct a critical analysis of the conventional classification of factors of production and propose a classification for resource allocation and income distribution (Rent, Wages, Interest, and Profits) that is more rational, even within the conventional theoretical framework for evaluating and developing production and distribution theories. Money is an essential component of production in an Islamic economy, and it must be used to sustain economic activity.

Keywords: financial capital, production theory, distribution theory, economic activity, riba avoidance, institution of participation

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Authors: Mahmut Genc, Seda Genc

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Wine is the most popular alcoholic drink in the World with 274.4 million of hectoliter annual production in the year of 2015. The wine industry is very important for some regions as well as creating significant value in their economies. This industry is very sensitive to the global warming since viticulture highly depends on climate and geographical region. Sustainability concept is a crucial issue for the wine industry and sustainability performances of wine production processes should be determined. Although wine production industry is an energy intensive sector as a whole, the most energy intensive products are widely used both in the viti and vinicultural process. In this study, gate-to-gate LCA approach in energy resource utilization and global warming potential impacts for white wine production line were attempted and carbon footprint and exergy destruction footprint were calculated, accordingly. As a result, carbon footprint and exergy destruction footprint values were calculated to be 1.75 kg CO2eq and 365.3kW, respectively.

Keywords: carbon footprint, exergy analysis, exergy destruction footprint, white wine

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Authors: Atinkut Atinafu Yilma, Eyob Messele Sefene

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Anomaly detection is one of the essential mechanisms to control and reduce production loss, especially in today's smart manufacturing. Quick anomaly detection aids in reducing the cost of production by minimizing the possibility of producing defective products. However, developing an anomaly detection model that can rapidly detect a production change is challenging. This paper proposes Gated Recurrent Unit (GRU) combined with Random Forest (RF) to detect anomalies in the production process in real-time quickly. The GRU is used as a feature detector, and RF as a classifier using the input features from GRU. The model was tested using various synthesis and real-world datasets against benchmark methods. The results show that the proposed GRU-RF outperforms the benchmark methods with the shortest time taken to detect anomalies in the production process. Based on the investigation from the study, this proposed model can eliminate or reduce unnecessary production costs and bring a competitive advantage to manufacturing industries.

Keywords: anomaly detection, multivariate time series data, smart manufacturing, gated recurrent unit network, random forest

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Authors: Yose Rizal, Nuraini, Mirnawati, Maria Endo Mahata, Rio Darman, Dendi Kurniawan

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An experiment had been conducted to determine the effects of several levels of Neurospora crassa- fermented palm kernel cake in the diet on the production performance and egg-yolk quality of Arab laying-hens, and to obtain the appropriate level of this fermented palm kernel cake for reducing the utilization of concentrated feed in the diet. Three hundred Arab laying-hens of 72 weeks old were employed in this experiment, and randomly assigned to four treatments (0, 7.25, 10.15, and 13.05% fermented palm kernel cake in diets) in a completely randomized design with five replicates. Measured variables were production performance (feed consumption, egg-mass production, feed conversion, egg weight and hen-day egg production), and egg-yolk quality (ether extract and cholesterol contents, and egg-yolk color index). Results of experiment indicated that feed consumption, egg-mass production, feed conversion, egg weight, hen-day egg production and egg-yolk color index were not influenced (P>0.05) by diets. However, the ether extract and cholesterol contents of egg-yolk were very significantly reduced (P<0.01) by diets. In conclusion, Neurospora crassa-fermented palm kernel cake could be included up to 13.05% to effectively replace 45% concentrated feed in Arab laying-hens diet without adverse effect on the production performance.

Keywords: neurospora crassa-fermented palm kernel cake, Arab laying-hens, production performance, ether extract, cholesterol, egg-yolk color index

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Authors: Sarah Crawford, Gerry Lesley

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This research is a pre-clinical assessment of anti-cancer effects of novel non-steroidal diethyl stilbestrol-like estrogen analogs in estrogen-receptor positive/ progesterone-receptor positive human breast cancer microtumors of MCF 7 cell line. Tamoxifen analog formulation (Tam A1) was used as a single agent or in combination with therapeutic concentrations of 4-hydroxytamoxifen, currently used as a long-term treatment for the prevention of breast cancer recurrence in women with estrogen receptor positive/ progesterone receptor positive malignancies. At concentrations ranging from 30-50 microM, Tam A1 induced microtumor disaggregation and cell death. Incremental cytotoxic effects correlated with increasing concentrations of Tam A1. Live tumor microscopy showed that microtumos displayed diffuse borders and substrate-attached cells were rounded-up and poorly adherent. A complete cytotoxic effect was observed using 40-50 microM Tam A1 with time course kinetics similar to 4-hydroxytamoxifen. Combined treatment with TamA1 (30-50 microM) and 4-hydroxytamoxifen (10-15 microM) induced a highly cytotoxic, synergistic combined treatment response that was more rapid and complete than using 4-hydroxytamoxifen as a single agent therapeutic. Microtumors completely dispersed or formed necrotic foci indicating a highly cytotoxic combined treatment response. Moreover, breast cancer microtumors treated with both 4-hydroxytamoxifen and Tam A1 displayed lower levels of long-term post-treatment regrowth, a critical parameter of primary drug resistance, than observed for 4-hydroxytamoxifen when used as a single agent therapeutic. Tumor regrowth at 6 weeks post-treatment with either single agent 4-hydroxy tamoxifen, Tam A1 or a combined treatment was assessed for the development of drug resistance. Breast cancer cells treated with both 4-hydroxytamoxifen and Tam A1 displayed significantly lower levels of post-treatment regrowth, indicative of decreased drug resistance, than observed for either single treatment modality. The preclinical data suggest that combined treatment involving the use of tamoxifen analogs may be a novel clinical approach for long-term maintenance therapy in patients with estrogen-receptor positive/progesterone-receptor positive breast cancer receiving hormonal therapy to prevent disease recurrence. Detailed data on time-course, IC50 and tumor regrowth assays post- treatment as well as a proposed mechanism of action to account for observed synergistic drug effects will be presented.

Keywords: 4-hydroxytamoxifen, tamoxifen analog, drug-resistance, microtumors

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Authors: Sudhir Kumar, V. R. Sinha

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Background: The topical and systemic toxicity associated with present nonmelanoma skin cancer (NMSC) treatment therapy using 5-Fluorouracil (5-FU) make it necessary to develop a novel delivery system having lesser toxicity and better control over drug release. Solid lipid nanoparticles offer many advantages like: controlled and localized release of entrapped actives, nontoxicity, and better tolerance. Aim:-To investigate safety and efficacy of 5-FU loaded solid lipid nanoparticles as a topical delivery system for the treatment of nonmelanoma skin cancer. Method: Topical solid lipid nanoparticles of 5-FU were prepared using Compritol 888 ATO (Glyceryl behenate) as lipid component and pluronic F68 (Poloxamer 188), Tween 80 (Polysorbate 80), Tyloxapol (4-(1,1,3,3-Tetramethylbutyl) phenol polymer with formaldehyde and oxirane) as surfactants. The SLNs were prepared with emulsification method. Different formulation parameters viz. type and ratio of surfactant, ratio of lipid and ratio of surfactant:lipid were investigated on particle size and drug entrapment efficiency. Results: Characterization of SLNs like–Transmission Electron Microscopy (TEM), Differential Scannig calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Particle size determination, Polydispersity index, Entrapment efficiency, Drug loading, ex vivo skin permeation and skin retention studies, skin irritation and histopathology studies were performed. TEM results showed that shape of SLNs was spherical with size range 200-500nm. Higher encapsulation efficiency was obtained for batches having higher concentration of surfactant and lipid. It was found maximum 64.3% for SLN-6 batch with size of 400.1±9.22 nm and PDI 0.221±0.031. Optimized SLN batches and marketed 5-FU cream were compared for flux across rat skin and skin drug retention. The lesser flux and higher skin retention was obtained for SLN formulation in comparison to topical 5-FU cream, which ensures less systemic toxicity and better control of drug release across skin. Chronic skin irritation studies lacks serious erythema or inflammation and histopathology studies showed no significant change in physiology of epidermal layers of rat skin. So, these studies suggest that the optimized SLN formulation is efficient then marketed cream and safer for long term NMSC treatment regimens. Conclusion: Topical and systemic toxicity associated with long-term use of 5-FU, in the treatment of NMSC, can be minimized with its controlled release with significant drug retention with minimal flux across skin. The study may provide a better alternate for effective NMSC treatment.

Keywords: 5-FU, topical formulation, solid lipid nanoparticles, non melanoma skin cancer

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Authors: Omar Bataineh

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Total productive maintenance (TPM) is a principle-based method that aims to get a high-level production with no breakdowns, no slow running and no defects. Key principles of TPM were applied in this work to improve the performance of the glass production line at United Beverage Company in Kuwait, which is producing bottles of soft drinks. Principles such as 5S as a foundation for TPM implementation, developing a program for equipment management, Cause and Effect Analysis (CEA), quality improvement, training and education of employees were employed. After the completion of TPM implementation, it was possible to increase the Overall Equipment Effectiveness (OEE) from 23% to 40%.

Keywords: OEE, TPM, FMEA, CEA

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Authors: Shiva Abdoli, Daniel T.Semere

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Several researches have been conducted to study consumption of energy in cutting process. Most of these researches are focusing to measure the consumption and propose consumption reduction methods. In this work, the relation between the cutting parameters and the consumption is investigated in order to establish a generalized energy consumption model that can be used for process and production planning in real production lines. Using the generalized model, the process planning will be carried out by taking into account the energy as a function of the selected process parameters. Similarly, the generalized model can be used in production planning to select the right operational parameters like batch sizes, routing, buffer size, etc. in a production line. The description and derivation of the model as well as a case study are given in this paper to illustrate the applicability and validity of the model.

Keywords: process parameters, cutting process, energy efficiency, Material Removal Rate (MRR)

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Authors: Ranjot Kaur, Om P. Katare, Anupama Sharma, Sarah R. Dennison, Kamalinder K. Singh, Bhupinder Singh

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Respiratory microbial infections being among the top leading cause of death worldwide are difficult to treat as the microbes reside deep inside the airways, where only a small fraction of drug can access after traditional oral or parenteral routes. As a result, high doses of drugs are required to maintain drug levels above minimum inhibitory concentrations (MIC) at the infection site, unfortunately leading to severe systemic side-effects. Therefore, delivering antimicrobials directly to the respiratory tract provides an attractive way out in such situations. In this context, current study embarks on the systematic development of lung lia pid-modified chitosan nanoparticles for inhalation of voriconazole. Following the principles of quality by design, the chitosan nanoparticles were prepared by ionic gelation method and further coated with major lung lipid by precipitation method. The factor screening studies were performed by fractional factorial design, followed by optimization of the nanoparticles by Box-Behnken Design. The optimized formulation has a particle size range of 170-180nm, PDI 0.3-0.4, zeta potential 14-17, entrapment efficiency 45-50% and drug loading of 3-5%. The presence of a lipid coating was confirmed by FESEM, FTIR, and X-RD. Furthermore, the nanoparticles were found to be safe upto 40µg/ml on A549 and Calu-3 cell lines. The quantitative and qualitative uptake studies also revealed the uptake of nanoparticles in lung epithelial cells. Moreover, the data from Spraytec and next-generation impactor studies confirmed the deposition of nanoparticles in lower airways. Also, the interaction of nanoparticles with DPPC monolayers signifies its biocompatibility with lungs. Overall, the study describes the methodology and potential of lipid-coated chitosan nanoparticles in futuristic inhalation nanomedicine for the management of pulmonary aspergillosis.

Keywords: dipalmitoylphosphatidylcholine, nebulization, DPPC monolayers, quality-by-design

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Authors: Li-Wei Wu, Chung-Yu Wang

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Recently, interest has been generated in the search for a new reference framework for value creation that is centered on the co-creation process. Co-creation implies cooperative value creation between service firms and customers and requires the building of experiences as well as the resolution of problems through the combined effort of the parties in the relationship. For customers, values are always co-created through their participation in services. Customers can ultimately determine the value of the service in use. This new approach emphasizes that a customer’s participation in the service process is considered indispensable to value co-creation. An important feature of service in the context of exchange is co-production, which implies that a certain amount of participation is needed from customers to co-produce a service and hence co-create value. Co-production no doubt helps customers better understand and take charge of their own roles in the service process. Thus, this proposal is to encourage co-production, thus facilitating value co-creation of that is reflected in both customers and service firms. Four determinants of co-production are identified in this study, namely, commitment, trust, asset specificity, and decision-making uncertainty. Commitment is an essential dimension that directly results in successful cooperative behaviors. Trust helps establish a relational environment that is fundamental to cross-border cooperation. Asset specificity motivates co-production because this determinant may enhance return on asset investment. Decision-making uncertainty prompts customers to collaborate with service firms in making decisions. In other words, customers adjust their roles and are increasingly engaged in co-production when commitment, trust, asset specificity, and decision-making uncertainty are enhanced. Although studies have examined the preceding effects, to our best knowledge, none has empirically examined the simultaneous effects of all the curvilinear relationships in a single study. When these determinants are excessive, however, customers will not engage in co-production process. In brief, we suggest that the relationships of commitment, trust, asset specificity, and decision-making uncertainty with co-production are curvilinear or are inverse U-shaped. These new forms of curvilinear relationships have not been identified in existing literature on co-production; therefore, they complement extant linear approaches. Most importantly, we aim to consider both the bright and the dark sides of the determinants of co-production.

Keywords: co-production, commitment, trust, asset specificity, decision-making uncertainty

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Authors: Ilham Zaidi, P. Sankara Sarma, Quazi Taufique Ahmed, V. Raman Kutty, Khalid Umer Khayyam, Gurpreet Singh, Abhishek Royal

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Introduction: Tuberculosis is a global public health emergency, but it is particularly acute in India, which has the world's highest tuberculosis burden. Due to overpopulation, lack of sanitation, malnutrition, low living standards, and poor socioeconomic status, among other factors, it is India's most common infectious disease. The long period of treatment is one of the main reasons for considering it as a public health emergency. Consequently, there is an increase in patient noncompliance, which leads to treatment failure, adverse treatment outcomes, and deaths. This could lead to the growth of anti-TB drug resistance. According to the WHO, approximately 558 thousand new cases of Multi-Drug Resistance Tuberculosis were diagnosed worldwide, with 8.5 percent developed Extensively Drug Resistance Tuberculosis. Methodology: This study is a program-based cross-sectional descriptive survey of adult tuberculosis patients enrolled in the Delhi-based Revised National Tuberculosis Program. The study setting was 27 NTEP districts of Delhi. (N=65,893) and Sample size- was 200; the sampling method which is used in the study was the systemic random sampling method. Results: Most of the demographic factors (age, gender, residence, and family type) were not significantly associated with adherence; marital status was found statistically significant with the treatment compliance. Hesitation while telling people about the disease and motivation to strictly follow drug schedule by healthcare workers were other factors where a significant association with drug adherence was observed. The study findings also suggest that provision of food, minimal financial and other moral support from family, counseling, discussion and politeness by healthcare providers might also facilitate adherence. Discussion and Conclusions: For TB treatment, adherence, age, sex, socioeconomic status, types of accommodations, malnutrition, and personal hygiene should all be considered; similar results were observed in previous studies. In the care of TB patients, DOTS services, health workers, and family support play a significant role. According to the country's National Strategic Plan, the Indian government has set a goal of eliminating tuberculosis by 2025 and patients' compliance with TB care and treatment adherence is very crucial to achieve this aim. A cohort study will be able to give a better understanding of factors associated with adherence since this study may have missed some defaulters who were absconding and could not be reached. Important Terms: RNTCP, NTEP, DOTS, DS-TB, DR-TB, RR-TB, MDR-TB, XDR-TB, Treatment failure, Treatment relapse, Treatment adherence.

Keywords: treatment adherence, treatment relapse, treatment failure, drug resistance tuberculosis

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Authors: Shazia Mannan, Zunera Khalid, Hammad-Ul-Mubeen

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Wingless type Mouse mammary tumor virus (MMTV) Integration site-10B (Wnt10B) is an important member of the Wnt protein family that functions as cellular messenger in paracrine manner. Aberrant Wnt10B activity is the cause of several abnormalities including cancers of breast, cervix, liver, gastric tract, esophagus, pancreas as well as physiological problems like obesity, and osteoporosis. The objective of this study was to determine the possible inhibitors against aberrant expression of Wnt10B in order to prevent and treat the physiological disorders associated with it. Wnt10B3D structure was predicted by using comparative modeling and then analyzed by PROCHECK, Verify3D, and Errat. The model having 84.54% quality value was selected and acylated to satisfy the hydrophobic nature of Wnt10B. For search of inhibitors, virtual screening was performed on Natural Products (NP) database. The compounds were filtered and ligand-based screening was performed using the antagonist for mouse Wnt-3A. This resulted in a library of 272 unique compounds having most potent drug like activities for Wnt-4. Out of the 271 molecules analyzed three small molecules ZINC35442871, ZINC85876388, and ZINC00754234 having activity against Wnt4 abbarent expression were found common through docking experiment of Wnt10B. It is concluded that the three molecules ZINC35442871, ZINC85876388, and ZINC00754234 can be considered as lead compounds for performing further drug designing experiments against aberrant Wnt expressions.

Keywords: Wnt10B inhibitors, comparative computational studies, proto-oncogene, molecular docking

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Authors: Innocent Pangapanga-Phiri, Eric Dada Mungatana

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This study estimates the effect of climate-induced rural-urban migrants (RUM) on maize productivity. It uses panel data gathered by the National Statistics Office and the World Bank to understand the effect of RUM on the technical efficiency of maize production in rural Malawi. The study runs the two-stage Tobit regression to isolate the real effect of rural-urban migration on the technical efficiency of maize production. The results show that RUM significantly reduces the technical efficiency of maize production. However, the interaction of RUM and climate-smart agriculture has a positive and significant influence on the technical efficiency of maize production, suggesting the need for re-investing migrants’ remittances in agricultural activities.

Keywords: climate-smart agriculture, farm productivity, rural-urban migration, panel stochastic frontier models, two-stage Tobit regression

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Authors: Rosa Tsegaye Aga, Xuan Jiang, Pavel Vazquez Faci, Siqing Liu, Simon Rayner, Endalkachew Alemu, Markos Abebe

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Tuberculosis (TB) is a major cause of disease globally. In most cases, TB is treatable and curable, but only with the proper treatment. There is a time when drug-resistant TB occurs when bacteria become resistant to the drugs that are used to treat TB. Current strategies to identify drug-resistant TB bacteria are laboratory-based, and it takes a longer time to identify the drug-resistant bacteria and treat the patient accordingly. But machine learning (ML) and data science approaches can offer new approaches to the problem. In this study, we propose to develop an ML-based model to predict the antibiotic resistance phenotypes of TB isolates in minutes and give the right treatment to the patient immediately. The study has been using the whole genome sequence (WGS) of TB isolates as training data that have been extracted from the NCBI repository and contain different countries’ samples to build the ML models. The reason that different countries’ samples have been included is to generalize the large group of TB isolates from different regions in the world. This supports the model to train different behaviors of the TB bacteria and makes the model robust. The model training has been considering three pieces of information that have been extracted from the WGS data to train the model. These are all variants that have been found within the candidate genes (F1), predetermined resistance-associated variants (F2), and only resistance-associated gene information for the particular drug. Two major datasets have been constructed using these three information. F1 and F2 information have been considered as two independent datasets, and the third information is used as a class to label the two datasets. Five machine learning algorithms have been considered to train the model. These are Support Vector Machine (SVM), Random forest (RF), Logistic regression (LR), Gradient Boosting, and Ada boost algorithms. The models have been trained on the datasets F1, F2, and F1F2 that is the F1 and the F2 dataset merged. Additionally, an ensemble approach has been used to train the model. The ensemble approach has been considered to run F1 and F2 datasets on gradient boosting algorithm and use the output as one dataset that is called F1F2 ensemble dataset and train a model using this dataset on the five algorithms. As the experiment shows, the ensemble approach model that has been trained on the Gradient Boosting algorithm outperformed the rest of the models. In conclusion, this study suggests the ensemble approach, that is, the RF + Gradient boosting model, to predict the antibiotic resistance phenotypes of TB isolates by outperforming the rest of the models.

Keywords: machine learning, MTB, WGS, drug resistant TB

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Authors: Fabian Saptouw

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In the past decade there was a resurgence of interest in the value of ‘process’ and ‘craft’ within the social and artistic community. Theorist like Barbara Bolt and Paul Carter have eloquently argued for the importance of ‘theorizing out of practice’ and ‘material thinking’ in response to this trend. Time and labour intensive artistic production processes are however not generally included in this bracket and often labelled as either obsessive or absurd. Neither of these terms adequately conveys the conceptual importance of labour in relation to ‘process’ as manifested through this production method. This issue will be addressed by critically assessing the work of eight South African artists through the lens of contemporary process-based production. This will result in a more integrated view of the art-object, its art-historical trajectory, its materialisation as well as its production process. This paper will conclude by tying the characteristics of these artworks to international trends and provide a platform for the overall reconsideration of unalienated artistic labour.

Keywords: materiality, process art, practice-led research, unalienated labour

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Authors: Mostafa Sefidgar, Sohrab Zendehboudi, Hossein Bazmara, Madjid Soltani

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Based on findings from clinical applications, most drug treatments fail to eliminate malignant tumors completely even though drug delivery through systemic administration may inhibit their growth. Therefore, better understanding of tumor formation is crucial in developing more effective therapeutics. For this purpose, nowadays, solid tumor modeling and simulation results are used to predict how therapeutic drugs are transported to tumor cells by blood flow through capillaries and tissues. A solid tumor is investigated as a porous media for fluid flow simulation. Most of the studies use Darcy model for porous media. In Darcy model, the fluid friction is neglected and a few simplified assumptions are implemented. In this study, the effect of these assumptions is studied by considering Brinkman model. A multi scale mathematical method which calculates fluid flow to a solid tumor is used in this study to investigate how neglecting fluid friction affects the solid tumor simulation. In this work, the mathematical model in our previous studies is developed by considering two model of momentum equation for porous media: Darcy and Brinkman. The mathematical method involves processes such as fluid flow through solid tumor as porous media, extravasation of blood flow from vessels, blood flow through vessels and solute diffusion, convective transport in extracellular matrix. The sprouting angiogenesis model is used for generating capillary network and then fluid flow governing equations are implemented to calculate blood flow through the tumor-induced capillary network. Finally, the two models of porous media are used for modeling fluid flow in normal and tumor tissues in three different shapes of tumors. Simulations of interstitial fluid transport in a solid tumor demonstrate that the simplifications used in Darcy model affect the interstitial velocity and Brinkman model predicts a lower value for interstitial velocity than the values that Darcy model does.

Keywords: solid tumor, porous media, Darcy model, Brinkman model, drug delivery

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Authors: Farzad Jafarpour Taher, Maghsud Solimanpur

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Production planning is one of the complex tasks in multi-product firms that produce a wide range of products. Since resources in mass production companies are limited and different products use common resources, there must be a careful plan so that firms can respond to customer needs efficiently. Azar-battery Company is a firm that provides twenty types of products for its customers. Therefore, careful planning must be performed in this company. In this research, the current conditions of Azar-battery Company were investigated to provide a mathematical programming model to determine the optimum production rate of the products in this company. The production system of this company is multi-stage, multi-product and multi-period. This system is studied in terms of a one-year planning horizon regarding the capacity of machines and warehouse space limitation. The problem has been modeled as a linear programming model with deterministic demand in which shortage is not allowed. The objective function of this model is to minimize costs (including raw materials, assembly stage, energy costs, packaging, and holding). Finally, this model has been solved by Lingo software using the branch and bound approach. Since the computation time was very long, the solver interrupted, and the obtained feasible solution was used for comparison. The proposed model's solution costs have been compared to the company’s real data. This non-optimal solution reduces the total production costs of the company by about %35.

Keywords: multi-period, multi-product production, multi-stage, production planning

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Authors: X. Li, J. Sundquist, C. Sjöstedt, M. Winkleby, K. S. Kendler, K. Sundquist

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Aims: This study examines the association between the incidence of drug abuse (DA) and linking (communal) social capital, a theoretical concept describing the amount of trust between individuals and societal institutions. Methods: We present results from an 8-year population-based cohort study that followed all residents in Sweden, aged 15-44, from 2003 through 2010, for a total of 1,700,896 men and 1,642,798 women. Social capital was conceptualized as the proportion of people in a geographically defined neighborhood who voted in local government elections. Multilevel logistic regression was used to estimate odds ratios (ORs) and between-neighborhood variance. Results: We found robust associations between linking social capital (scored as a three level variable) and DA in men and women. For men, the OR for DA in the crude model was 2.11 [95% confidence interval (CI) 2.02-2.21] for those living in areas with the lowest vs. highest level of social capital. After accounting for neighborhood-level deprivation, the OR fell to 1.59 (1.51-1-68), indicating that neighborhood deprivation lies in the pathway between linking social capital and DA. The ORs remained significant after accounting for age, sex, family income, marital status, country of birth, education level, and region of residence, and after further accounting for comorbidities and family history of comorbidities and family history of DA. For women, the OR decreased from 2.15 (2.03-2.27) in the crude model to 1.31 (1.22-1.40) in the final model, adjusted for multiple neighborhood-level and individual-level variables. Conclusions: Our study suggests that low linking social capital may have important independent effects on DA.

Keywords: drug abuse, social linking capital, environment, family

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Authors: Kaleb Shiferaw, Berhanu Geberemedhin, Dereje Legesse

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Access to credit is often viewed as a key to transform semi-subsistence smallholders into market oriented producers. However, only a few studies have examined factors that affect farmers’ decision to allocate credit on farm activities in general and livestock production in particular. A trivariate probit model with double selection is employed to identify factors that affect farmers’ decision to allocate credit on livestock production using data collected from smallholder farmers in Ethiopia. After controlling for two sample selection bias – taking credit for the production season and decision to allocate credit on farm activities – land ownership and access to a livestock centered extension service are found to have a significant (p<0.001) effect on farmers decision to use credit for livestock production. The result showed farmers with large land holding, and access to a livestock centered extension services are more likely to utilize credit for livestock production. However since the effect of land ownership squared is negative the effect of land ownership for those who own a large plot of land lessens. The study highlights the fact that improving access to credit does not automatically translate into more productive households. Improving farmers’ access to credit should be followed by a focused extension services.

Keywords: livestock production, credit access, credit allocation, household decision, double sample selection

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Authors: Ravi Patel, Ravisinh Solanki, Dignesh Khunt

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A stability-indicating reverse phase high performance liquid chromatography (RP-HPLC) method was developed and validated for estimating Nirmatrelvir in its self-emulsifying drug delivery system (SEDDS). The separation of Nirmatrelvir and its degradation products was accomplished by employing an Agilent Zorbax Eclipse plus C18 (250 mm x 4.6 mm, 5 µm) column, through which the mobile phase 5 mM phosphate buffer (pH 4.0) as mobile phase A and Acetonitrile as mobile phase B in a ratio of (40:60 % v/v) was pumped at a flow rate of 1.0 mL/min, through the HPLC system. Chromatographic separation and elution were monitored by a photo-diode array detector at 210 nm. Stress studies have been employed to evaluate this method's ability to indicate stability. Nirmatrelvir was exposed to several stress conditions, such as acid, alkali, oxidative, photolytic, and thermal degradations. Significant degradation was observed during acid and alkali hydrolysis, and the resulting degradation product was successfully separated from the Nirmatrelvir peak, preventing any interference. Furthermore, the primary degradant produced under alkali degradation conditions was identified using UPLC-ESI-TQ-MS/MS. The method was validated in accordance with the International Council on Harmonization (ICH) and found to be selective, precise, accurate, linear, and robust. The apparent permeability of Nirmatrelvir SEDDS was 4.20 ± 0.21×10-6 cm/sec, and the average proportion of free drug recovered was 0.5%. The method developed in this study was feasible and accurate for routine quality control evaluation of Nirmatrelvir SEDDS.

Keywords: Nirmatrelvir, SEDDS, degradation study, HPLC, LC-MS/MS

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Authors: M. Goerke, J. Gehrmann

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Caused by shorter product life cycles and higher product variety the importance of production ramp ups is increasing. Even though companies are aware of that fact, up to 40% of the ramp up projects still miss technical and economical requirements. The success of a ramp up depends on the planning of human factors, organizational aspects and technological solutions. Since only partly considered in scientific literature, this paper lays its focus on the human factor during production ramp up. There are only incoherent methods which address the problems in this area. A systematic and holistic method to improve the capabilities of the employees during ramp up is missing. The Harada Method is a relatively young approach for developing highly-skilled workers. It consists of different worksheets which help employees to set guidelines and reach overall objectives. This approach is going to be transferred into a tool for ramp up management.

Keywords: employee development, Harada, production ramp up, organizational aspects

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Authors: Adel A. S. Al-Gheethi, M. O. Abdul-Monem

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Cellulase-producing bacteria were isolated from wastewater and sludge, and identified as Bacillus megaterium 1295S, Sporosarcina pasteurii 586S, Bacillus subtilis 117S, Burkholderia cepacia 120S and Staphylococcus xylosus 222W. Among bacteria, B. megaterium 1295S was the best cellulase producer under the catabolic repression and was therefore selected to study the factors affecting cellulase production. The optimum conditions for cellulase production were observed in CMC-Yeast Extract (CYE) agar medium (pH 6.5) inoculated with 0.4 mL of bacterial culture and incubated at 45˚C for 72 h. Twenty amino acids were introduced into the production medium as nitrogen source to investigate the production of cellulase in presence of amino acids in comparison to peptone (as an organic source) and sodium nitrate (as an inorganic source). The results found that the maximum production of cellulase was recorded at 50 ppm when L-hydroxy proline, L-arginine, glycine, L-histidine, L-leucine, DL-isoleucine, DL-β-phenylalanine were used as sole nitrogen sources and at 100 ppm when DL-threonine, L-ornithine 12.29, L-proline were used as sole nitrogen sources. The highest biomass yield was found when glycine 5 ppm and DL-serine 100 ppm used as a nitrogen source.

Keywords: CMCase, Bacillus megaterium 1295S, factors, amino acids

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Authors: Magno Enrique Mendoza Meza

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This paper deals with the comparison of three control techniques: the hysteresis on-off control (HyOOC), the hybrid on-off control (HOOC) and the simple Structured Treatment Interruptions (sSTI). These techniques are applied to the mathematical model developed by Kirschner and Webb. To compare these techniques we use a cost functional that minimize the wild-type virus population and the mutant virus population, but the main objective is to minimize the systemic cost of treatment and maximize levels of healthy CD4+ T cells. HyOOC, HOOC, and sSTI are applied to the drug therapies using a reverse transcriptase and protease inhibitors; simulations show that these controls maintain the uninfected cells in a small, bounded neighborhood of a pre-specified level. The controller HyOOC and HOOC are designed by appropriate choice of virtual equilibrium points.

Keywords: virus dynamics, on-off control, hysteresis, multi-drug therapies

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Authors: Francisco Espinosa, Juan Chavarría

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Glycerol is a byproduct of biodiesel production that can be used for aqueous-phase reforming to obtain hydrogen. Iridium is a material that has high activity and hydrogen selectivity for steam phase reforming. Nevertheless, a drawback for the use of iridium in aqueous-phase reforming is the low activity in water-gas shift reaction. Therefore, in this work, it is proposed the use of nickel and copper as a second metal in the catalyst to reach a synergetic effect. Iridium, iridium-nickel and iridium-copper catalysts were prepared by incipient wetness impregnation and evaluated in the aqueous-phase reforming of glycerol using CeO₂ or La₂O₃ as support. The catalysts were characterized by XRD, XPS, and EDX. The reactions were carried out in a fixed bed reactor feeding a solution of glycerol 10 wt% in water at 270°C, and reaction products were analyzed by gas chromatography. It was found that IrNi/CeO₂ reached highest glycerol conversion and hydrogen production, slightly above 70% and 43 vol% respectively. In terms of conversion, iridium is a promising metal, and its activity for hydrogen production can be enhanced when adding a second metal.

Keywords: aqueous-phase reforming, glycerol, hydrogen production, iridium

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Authors: Keaghan Brown

Abstract:

The prioritization of drug resistance mutations impacting protein folding or protein-drug and protein-DNA interactions within macromolecular systems is critical to the success of treatment regimens. With a continual increase in computational tools to assess these impacts, the need for scalability and reproducibility became an essential component of computational analysis and experimental research. Here it introduce a bioinformatics pipeline that combines several structural analysis tools in a simplified workflow, by optimizing the present computational hardware and software to automatically ease the flow of data transformations. Utilizing preestablished software tools, it was possible to develop a pipeline with a set of pre-defined functions that will automate mutation introduction into the HIV-1 Integrase protein structure, calculate the gain and loss of polar interactions and calculate the change in energy of protein fold. Additionally, an automated molecular dynamics analysis was implemented which reduces the constant need for user input and output management. The resulting pipeline, Automated Mutation Introduction and Analysis (AMIA) is an open source set of scripts designed to introduce and analyse the effects of mutations on the static protein structure as well as the results of the multi-conformational states from molecular dynamic simulations. The workflow allows the user to visualize all outputs in a user friendly manner thereby successfully enabling the prioritization of variant systems for experimental validation.

Keywords: automated workflow, variant prioritization, drug resistance, HIV Integrase

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