Search results for: drug therapy problem

Authors: Temesgen Sidamo, Prakruti S. Rao, Eleni Akllilu, Workineh Shibeshi, Yumi Park, Yong-Soon Cho, Jae-Gook Shin, Scott K. Heysell, Stellah G. Mpagama, Ephrem Engidawork

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The fluoroquinolones (FQs) are used off-label for the treatment of multidrug-resistant tuberculosis (MDR-TB), and for evaluation in shortening the duration of drug-susceptible TB in recently prioritized regimens. Within the class, levofloxacin (LFX) and moxifloxacin (MXF) play a substantial role in ensuring success in treatment outcomes. However, sub-therapeutic plasma concentrations of either LFX or MXF may drive unfavorable treatment outcomes. To the best of our knowledge, the pharmacokinetics of LFX and MXF in Ethiopian patients with MDR-TB have not yet been investigated. Therefore, the aim of this study was to develop a population pharmacokinetic (PopPK) model of levofloxacin (LFX) and moxifloxacin (MXF) and assess the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24-h (AUC0-24) and the in vitro minimum inhibitory concentration (MIC) (AUC0-24/MIC) in Ethiopian MDR-TB patients. Steady-state plasma was collected from 39 MDR-TB patients enrolled in the programmatic treatment course and the drug concentrations were determined using optimized liquid chromatography-tandem mass spectrometry. In addition, the in vitro MIC of the patients' pretreatment clinical isolates was determined. PopPK and simulations were run at various doses, and PK parameters were estimated. The effect of covariates on the PK parameters and the PTA for maximum mycobacterial kill and resistance prevention was also investigated. LFX and MXF both fit in a one-compartment model with adjustments. The apparent volume of distribution (V) and clearance (CL) of LFX were influenced by serum creatinine (Scr), whereas the absorption constant (Ka) and V of MXF were influenced by Scr and BMI, respectively. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L was 29%, 62%, and 95% with the simulated 750 mg, 1000 mg, and 1500 mg doses, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no difference in the PTA (94.4%) for maximum bacterial kill among the simulated doses of MXF (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention improved proportionately with dose. Standard LFX and MXF doses may not provide adequate drug exposure. LFX PopPK is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Scr and BMI are likely to be important covariates in dose optimization or therapeutic drug monitoring (TDM) studies in Ethiopian patients.

Keywords: population PK, PTA, moxifloxacin, levofloxacin, MDR-TB patients, ethiopia

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Authors: Saad Khalid Niaz, Arif Mahmood Siddiqui, Afzal Haqi

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Background: Estimated prevalence of Hepatitis C in Pakistan is 5% of which 78 % are Genotype 3, in which Response to conventional interferon is reported to be 70%. Objective: To determine the efficacy of pegylated interferon 20 kDa (Unipeg) plus ribavirin (Ribazole) in HCV genotype 3 patients who relapsed to conventional interferon. Methods: This is an ongoing study of 20 enrolled patients. Pegylated interferon alfa-2a 20 kDa 180 mcg weekly with ribavirin, were administered for a period of 24 weeks. Virological Responses were measured by Qualitative HCV RNA at weeks 4, 12, 24 and 48 to determine Rapid Virological Response (RVR), Early Virological Response (EVR), End of Treatment (ETR) and Sustained Virological Response (SVR), respectively. EVR was done for those who didn’t achieve RVR. Results: Males were 12 (60%) and mean age was 38.5 ±7.62 years. Out of 20 recruited patients, all completed 4 weeks therapy; RVR was achieved in 8 (40%) patients. One patient was lost to follow up and one yet to visit at 12 weeks. From 10 patients, 8 (80%) patients achieved EVR. Out of intent-to-treat patients, 15 completed 24 weeks therapy, ETR was achieved in 14 (93%) patients and 9 patients completed post therapy follow-up, of which, 8 (89%) patients achieved SVR. Conclusion: Our interim data demonstrates that Pegylated Interferon alfa-2a 20 kDa 180 mcg (Unipeg) in combination with Ribavirin (Ribazole) has shown promising results in treating HCV Genotype 3 patients who relapsed to conventional interferon. We recommend use of Pegylated Interferon in Relapsers with Genotype 3 when financial constraints limit the use of oral antivirals.

Keywords: pegylated interferon (unipeg), hepatitis c, relapsers, Pakistan

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Authors: Maryamsadat Habibi

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Objective: pharmaceutical errors are avoidable occurrences that can result in inappropriate pharmaceutical use, patient harm, treatment failure, increased hospital costs and length of stay, and other outcomes that affect both the individual receiving treatment and the healthcare provider. This study aimed to perform a reconciliation of medications in the cardiovascular ward of Imam Reza Hospital in Mashhad, Iran, and evaluate the prevalence of medication discrepancies between the best medication list created for the patient by the pharmacist and the medication order of the treating physician there. Materials & Methods: The 97 patients in the cardiovascular ward of the Imam Reza Hospital in Mashhad were the subject of a cross-sectional study from June to September of 2021. After giving their informed consent and being admitted to the ward, all patients with at least one underlying condition and at least two medications being taken at home were included in the study. A medical reconciliation form was used to record patient demographics and medical histories during the first 24 hours of admission, and the information was contrasted with the doctors' orders. The doctor then discovered medication inconsistencies between the two lists and double-checked them to separate the intentional from the accidental anomalies. Finally, using SPSS software version 22, it was determined how common medical discrepancies are and how different sorts of discrepancies relate to various variables. Results: The average age of the participants in this study was 57.6915.84 years, with 57.7% of men and 42.3% of women. 95.9% of the patients among these people encountered at least one medication discrepancy, and 58.9% of them suffered at least one unintentional drug cessation. Out of the 659 medications registered in the study, 399 cases (60.54%) had inconsistencies, of which 161 cases (40.35%) involved the intentional stopping of a medication, 123 cases (30.82%) involved the stopping of a medication unintentionally, and 115 cases (28.82%) involved the continued use of a medication by adjusting the dose. Additionally, the category of cardiovascular pharmaceuticals and the category of gastrointestinal medications were found to have the highest medical inconsistencies in the current study. Furthermore, there was no correlation between the frequency of medical discrepancies and the following variables: age, ward, date of visit, type, and number of underlying diseases (P=0.13), P=0.61, P=0.72, P=0.82, P=0.44, and so forth. On the other hand, there was a statistically significant correlation between the number of medications taken at home (P=0.037) and the prevalence of medical discrepancies with gender (P=0.029). The results of this study revealed that 96% of patients admitted to the cardiovascular unit at Imam Reza Hospital had at least one medication error, which was typically an intentional drug discontinuance. According to the study's findings, patients admitted to Imam Reza Hospital's cardiovascular ward have a great potential for identifying and correcting various medication discrepancies as well as for avoiding prescription errors when the medication reconciliation method is used. As a result, it is essential to carry out a precise assessment to achieve the best treatment outcomes and avoid unintended medication discontinuation, unwanted drug-related events, and drug interactions between the patient's home medications and those prescribed in the hospital.

Keywords: drug combination, drug side effects, drug incompatibility, cardiovascular department

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Authors: Vladimir Berezin, Aizhan Turmagambetova, Andrey Bogoyavlenskiy, Pavel Alexyuk, Madina Alexyuk, Irina Zaitceva, Nadezhda Sokolova

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Introduction: Influenza viruses could infect approximately 5% to 10% of the global human population annually, resulting in serious social and economic damage. Vaccination and etiotropic antiviral drugs are used for the prevention and treatment of influenza. Vaccination is important; however, antiviral drugs represent the second line of defense against new emerging influenza virus strains for which vaccines may be unsuccessful. However, the significant drawback of commercial synthetic anti-flu drugs is the appearance of drug-resistant influenza virus strains. Therefore, the search and development of new anti-flu drugs efficient against drug-resistant strains is an important medical problem for today. The aim of this work was a study of four phenolic acids of plant origin (Gallic, Syringic, Vanillic, and Protocatechuic acids) as a possible tool for treatment against influenza virus. Methods: Phenolic acids; gallic, syringic, vanillic, and protocatechuic have been prepared by extraction from plant tissues and purified using high-performance liquid chromatography fractionation. Avian influenza virus, strain A/Tern/South Africa/1/1961 (H5N3) and human epidemic influenza virus, strain A/Almaty/8/98 (H3N2) resistant to commercial anti-flu drugs (Rimantadine, Oseltamivir) were used for testing antiviral activity. Viruses were grown in the allantoic cavity of 10 days old chicken embryos. The chemotherapeutic index (CTI), determined as the ratio of an average toxic concentration of the tested compound (TC₅₀) to the average effective virus-inhibition concentration (EC₅₀), has been used as a criteria of specific antiviral action. Results: The results of study have shown that the structure of phenolic acids significantly affected their ability to suppress the reproduction of tested influenza virus strains. The highest antiviral activity among tested phenolic acids was detected for gallic acid, which contains three hydroxyl groups in the molecule at C3, C4, and C5 positions. Antiviral activity of gallic acid against A/H5N3 and A/H3N2 influenza virus strains was higher than antiviral activity of Oseltamivir and Rimantadine. gallic acid inhibited almost 100% of the infection activity of both tested viruses. Protocatechuic acid, which possesses 2 hydroxyl groups (C3 and C4) have shown weaker antiviral activity in comparison with gallic acid and inhibited less than 10% of virus infection activity. Syringic acid, which contains two hydroxyl groups (C3 and C5), was able to suppress up to 12% of infection activity. Substitution of two hydroxyl groups by methoxy groups resulted in the complete loss of antiviral activity. Vanillic acid, which is different from protocatechuic acid by replacing of C3 hydroxyl group to methoxy group, was able to suppress about 30% of infection activity of tested influenza viruses. Conclusion: For pronounced antiviral activity, the molecular of phenolic acid must have at least two hydroxyl groups. Replacement of hydroxyl groups to methoxy group leads to a reduction of antiviral properties. Gallic acid demonstrated high antiviral activity against influenza viruses, including Rimantadine and Oseltamivir resistant strains, and could be used as a potential candidate for the development of antiviral drug against influenza virus.

Keywords: antiviral activity, influenza virus, drug resistance, phenolic acids

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Authors: Kwaku Damoah

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This study presents a comprehensive data-driven analysis to understand the evolution of adverse events (AEs) in pharmacovigilance. Utilizing data from the FDA Adverse Event Reporting System (FAERS), we employed three analytical methods: rank-based, frequency-based, and percentage change analyses. These methods assessed temporal trends and patterns in AE reporting, focusing on various drug-active ingredients and patient demographics. Our findings reveal significant trends in AE occurrences, with both increasing and decreasing patterns from 2000 to 2023. This research highlights the importance of continuous monitoring and advanced analysis in pharmacovigilance, offering valuable insights for healthcare professionals and policymakers to enhance drug safety.

Keywords: event analysis, FDA adverse event reporting system, pharmacovigilance, temporal trend analysis

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Authors: Majid Abdolrazzagh-Nezhad, Salwani Abdullah

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The job-shop scheduling problem (JSSP) is an important decision facing those involved in the fields of industry, economics and management. This problem is a class of combinational optimization problem known as the NP-hard problem. JSSPs deal with a set of machines and a set of jobs with various predetermined routes through the machines, where the objective is to assemble a schedule of jobs that minimizes certain criteria such as makespan, maximum lateness, and total weighted tardiness. Over the past several decades, interest in meta-heuristic approaches to address JSSPs has increased due to the ability of these approaches to generate solutions which are better than those generated from heuristics alone. This article provides the classification, constraints and objective functions imposed on JSSPs that are available in the literature.

Keywords: job-shop scheduling, classification, constraints, objective functions

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Authors: Donna L. Roberts

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2019 marked 23 years since Purdue Pharma launched its flagship drug, OxyContin, that unleashed an unprecedented epidemic touching both celebrities and common citizens, metropolitan, suburbia and rural areas and all levels of socioeconomic status. From rural Appalachia to East LA individuals, families and communities have been devastated by a trajectory of addiction that often began with the legitimate prescription of a pain killer for anything from a tooth extraction to a sports injury to recovery from surgery or chronic arthritis. Far from being a serendipitous progression of events, the proliferation of this new breed of 'miracle drug' was instead a carefully crafted marketing program aimed at both the medical community and common citizens. This research represents and in-depth investigation of the evolution of the marketing, distribution and promotion of prescription opioids by pharmaceutical companies and its relationship to the propagation of the opioid crisis. Specifically, key components of Purdue Pharma’s aggressive marketing campaign, including its bonus system and sales incentives, were analyzed in the context of the sociopolitical environment that essential created the proverbial 'perfect storm' for the changing manner in which pain is treated in the U.S. The analyses of these series of events clearly indicate their role in first, the increase in prescription of opioids for non-terminal pain relief and subsequently, the incidence of related addiction, overdose, and death. Through this examination of the conditions that facilitated and maintained this drug crisis, perhaps we can begin to chart a course toward its resolution.

Keywords: addiction, opioid, opioid crisis, Purdue Pharma

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Authors: Seyedmirsajad Mokhtarimousavi, Danial Talebi, Hamidreza Asgari

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Gate Assignment Problem (GAP) is one of the most substantial issues in airport operation. In principle, GAP intends to maintain the maximum capacity of the airport through the best possible allocation of the resources (gates) in order to reach the optimum outcome. The problem involves a wide range of dependent and independent resources and their limitations, which add to the complexity of GAP from both theoretical and practical perspective. In this study, GAP was mathematically formulated as a three-objective problem. The preliminary goal of multi-objective formulation was to address a higher number of objectives that can be simultaneously optimized and therefore increase the practical efficiency of the final solution. The problem is solved by applying the second version of Non-dominated Sorting Genetic Algorithm (NSGA-II). Results showed that the proposed mathematical model could address most of major criteria in the decision-making process in airport management in terms of minimizing both airport/airline cost and passenger walking distance time. Moreover, the proposed approach could properly find acceptable possible answers.

Keywords: airport management, gate assignment problem, mathematical modeling, genetic algorithm, NSGA-II

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Authors: Lugean K. Alomari, Rahaf K. Sharif, Basil K. Alomari, Hind M. Aljabri, Faisal F. Aljahdali, Amal A. Alomari, Saeed A. Alghamdi

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Background: The thermal pulsation system is a therapy that uses heat and massage to treat dry eye disease; thus, some trials have been published to compare it with the conventional treatment. The aim of this study is to conduct a systematic review and meta-analysis comparing the efficacy of thermal pulsation systems with conventional treatment in patients undergoing cataract surgery. Methods: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for eligible trials. We included three randomized controlled trials (RCTs) that compared the thermal pulsation system with the conventional treatment in patients undergoing cataract surgery. A table of characteristics was plotted, and the Quality of the studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). Forest plots were plotted using the Random-effect Inverse Variance method. χ2 test and the Higgins-I-squared (I2) model were used to assess heterogeneity. A total of 201 cataract surgery patients were included, with 105 undergoing preoperative pulsation therapy and 96 receiving conventional treatment. Demographic analysis revealed comparable distributions across groups. Results: All the studies in our analysis are of good quality with a low risk of bias. A total of 201 patients were included in the analysis, out of which 105 underwent pulsation therapy, and 95 were in the control group. Tear Break-up Time (TBUT) analysis revealed no significant baseline differences, except pulsation therapy being better at 1 month. (SMD 0.42 [95%CI 0.14 - 0.70] p=0.004). This positive trend continued at three months (SMD 0.52 [95% CI (0.20 – 0.84)] p=0.002). Corneal fluorescein staining scores and Meibomian gland-yielding secretion scores showed no significant differences at baseline. However, at one month, pulsation therapy significantly improved Meibomian gland function (SMD -0.86 [95% CI (-1.20 - -0.53)] p<0.00001), indicating a reduced risk of dry eye syndrome. Conclusion: Preoperative pulsation therapy appears to enhance post-cataract surgery outcomes, particularly in terms of tear film stability and Meibomian gland secretory function. The sustained positive effects observed at one and three months post-surgery suggest the potential for long-term benefits.

Keywords: lipiflow, cataract, thermal pulsation, dry eye

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Authors: Muhammet Baldan, Emel Timuçin

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Generally, absorption and bioavailability increase if solubility increases; therefore, it is crucial to predict them in drug discovery applications. Molecular descriptors and Molecular properties are traditionally used for the prediction of water solubility. There are various key descriptors that are used for this purpose, namely Drogan Descriptors, Morgan Descriptors, Maccs keys, etc., and each has different prediction capabilities with differentiating successes between different data sets. Another source for the prediction of solubility is structural features; they are commonly used for the prediction of solubility. However, there are little to no studies that combine three or more properties or descriptors for prediction to produce a more powerful prediction model. Unlike available models, we used a combination of those features in a random forest machine learning model for improved solubility prediction to better predict and, therefore, contribute to drug discovery systems.

Keywords: solubility, random forest, molecular descriptors, maccs keys

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Authors: Shirajul Islam Khan, Muhammad Ashraful Alam Bhuiyan, Syeda Tania Begum

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Introduction: Acne vulgaris is one of the most common dermatologic conditions and affects the vast majority of people at some point during their lifetime, so effective treatment is of major importance. The failure of usual treatment modalities, teratogenic effects with some severe side effects, and resistance to P.Acne by Retinoides have been focusing on new therapeutic options for the treatment of acne. More recently, pulsed dye laser therapy has been reported to reduce acne lesion counts. The negligible morbidity of these treatment modalities and some other benefits of subsequent acne scar management lead this therapy more attractive. Objective: The objective of this study is to assess the efficacy and safety of pulsed dye laser therapy in the treatment of inflammatory acne vulgaris. Materials and Methods: A prospective clinical trial was done in the Department of Dermatology and Venereology, Combined Military Hospital (CMH), Dhaka, to find out the role of pulse dye laser in the treatment of inflammatory acne vulgaris. The study was carried out with 60 patients with mild to moderate acne vulgaris, and those were treated with pulsed dye laser therapy at baseline and after 4, 8, and 12 weeks. Results: Among 60 patients with inflammatory acne, 42(70%) were in the age group of less than 20 years, and 36(60%) were female. Regarding the number of inflammatory lesions, the baseline mean number (± SD) was 12.77 ± 4.01; after 4 weeks of treatment of inflammatory acne by pulsed dye laser was 7.80 ± 4.11; after 8 weeks of treatment, 6.10 ± 4.03 and after 12 weeks of treatment was 4.17 ± 4.02. After 4 weeks of treatment by pulse dye laser, the level of improvement was excellent at 3.3%, good at 10%, fair at 60%, and poor at 26.7%; after 8 weeks of treatment, excellent was 13.3%, good was 46.7%, the fair was 30% and poor 10% and after 12 weeks of treatment, excellent was 56.7%, good 13.3%, fair 23.3% and poor 6.7%. Regarding safety level, out of 60 patients of inflammatory acne vulgaris treated by pulsed dye laser, about 52(86.7%) patients did not observe any side effects. Conclusions: On the basis of the study results, it can be concluded that pulsed-dye laser is highly effective and well tolerated by patients in the treatment of inflammatory acne.

Keywords: pulsed-dye laser, inflammatory acne, acne vulgaris, retinoids

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Authors: Xiaobao Han, Huacong Li, Jia Li

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For dynamic decoupling of linear parameter varying system, a robust dominance pre-compensator design method is given. The parameterized pre-compensator design problem is converted into optimal problem constrained with parameterized linear matrix inequalities (PLMI); To solve this problem, firstly, this optimization problem is equivalently transformed into a new form with elimination of coupling relationship between parameterized Lyapunov function (PLF) and pre-compensator. Then the problem was reduced to a normal convex optimization problem with normal linear matrix inequalities (LMI) constraints on a newly constructed convex polyhedron. Moreover, a parameter scheduling pre-compensator was achieved, which satisfies robust performance and decoupling performances. Finally, the feasibility and validity of the robust diagonal dominance pre-compensator design method are verified by the numerical simulation of a turbofan engine PLPV model.

Keywords: linear parameter varying (LPV), parameterized Lyapunov function (PLF), linear matrix inequalities (LMI), diagonal dominance pre-compensator

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Authors: Joselito Medina Marin, Norberto Hernández Romero, Juan Carlos Seck Tuoh Mora, Erick S. Martinez Gomez

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The Flow Shop Scheduling Problem (FSSP) is a typical problem that is faced by production planning managers in Flexible Manufacturing Systems (FMS). This problem consists in finding the optimal scheduling to carry out a set of jobs, which are processed in a set of machines or shared resources. Moreover, all the jobs are processed in the same machine sequence. As in all the scheduling problems, the makespan can be obtained by drawing the Gantt chart according to the operations order, among other alternatives. On this way, an FMS presenting the FSSP can be modeled by Petri nets (PNs), which are a powerful tool that has been used to model and analyze discrete event systems. Then, the makespan can be obtained by simulating the PN through the token game animation and incidence matrix. In this work, we present an adaptive PN to obtain the makespan of FSSP by applying PN analytical tools.

Keywords: flow-shop scheduling problem, makespan, Petri nets, state equation

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Authors: V. Bezverbny

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The actuality of the project deals with stable growing of deviant behavior’ statistics among Moscow citizens. During the recent years the socioeconomic health, wealth and life expectation of Moscow residents is regularly growing up, but the limits of crime and drug addiction have grown up seriously. Another serious Moscow problem has been economical stratification of population. The cost of identical residential areas differs at 2.5 times. The project is aimed at complex research and the development of methodology for main factors and reasons evaluation of deviant behavior growing in Moscow. The main project objective is finding out the links between the urban environment quality and dynamics of citizens’ deviant behavior in regional and municipal aspect using the statistical research methods and GIS modeling. The conducted research allowed: 1) to evaluate the dynamics of deviant behavior in Moscow different administrative districts; 2) to describe the reasons of crime increasing, drugs addiction, alcoholism, suicides tendencies among the city population; 3) to develop the city districts classification based on the level of the crime rate; 4) to create the statistical database containing the main indicators of Moscow population deviant behavior in 2010-2015 including information regarding crime level, alcoholism, drug addiction, suicides; 5) to present statistical indicators that characterize the dynamics of Moscow population deviant behavior in condition of expanding the city territory; 6) to analyze the main sociological theories and factors of deviant behavior for concretization the deviation types; 7) to consider the main theoretical statements of the city sociology devoted to the reasons for deviant behavior in megalopolis conditions. To explore the level of deviant behavior’ factors differentiation, the questionnaire was worked out, and sociological survey involved more than 1000 people from different districts of the city was conducted. Sociological survey allowed to study the socio-economical and psychological factors of deviant behavior. It also included the Moscow residents’ open-ended answers regarding the most actual problems in their districts and reasons of wish to leave their place. The results of sociological survey lead to the conclusion that the main factors of deviant behavior in Moscow are high level of social inequality, large number of illegal migrants and bums, nearness of large transport hubs and stations on the territory, ineffective work of police, alcohol availability and drug accessibility, low level of psychological comfort for Moscow citizens, large number of building projects.

Keywords: deviant behavior, megapolis, Moscow, urban environment, social stratification

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Authors: Yang-Kuei Lin, Yun-Xi Zhang

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This research focuses on the bicriteria correlated parallel machine scheduling problem. The two objective functions considered in this problem are to minimize maximum lateness and total weighted completion time. We first present a mixed integer programming (MIP) model that can find the entire efficient frontier for the studied problem. Next, we have proposed a bicriteria heuristic that can find non-dominated solutions for the studied problem. The performance of the proposed bicriteria heuristic is compared with the efficient frontier generated by solving the MIP model. Computational results indicate that the proposed bicriteria heuristic can solve the problem efficiently and find a set of diverse solutions that are uniformly distributed along the efficient frontier.

Keywords: bicriteria, correlated parallel machines, heuristic, scheduling

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Authors: Ching-Yi Yiu, Hui-Chen Hsu

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Objectives: Head and neck cancer (HNC) is a big global health problem in the world. Despite the development of diagnosis and treatment, the overall survival of HNC is still low. The well recognition of the interaction of the host immune system and cancer cells has led to realizing the processes of tumor initiation, progression and metastasis. Many systemic inflammatory responses have been shown to play a crucial role in cancer progression. The pre and post-treatment nutritional and immunological status of HNC patients is a reliable prognostic indicator of tumor outcomes and survivors. Methods: Between July 2020 to June 2022, We have enrolled 60 HNC patients, including 59 males and 1 female, in Chi Mei Medical Center, Liouying, Taiwan. The age distribution was from 37 to 81 years old (y/o), with a mean age of 57.6 y/o. We evaluated the pre-and post-treatment nutritional and immunological status of these HNC patients with body weight, body weight loss, body mass index (BMI), whole blood count including hemoglobin (Hb), lymphocyte, neutrophil and platelet counts, biochemistry including prealbumin, albumin, c-reactive protein (CRP), with the time period of before treatment, post-treatment 3 and 6 months. We calculated the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to assess how these biomarkers influence the outcomes of HNC patients. Results: We have carcinoma of the hypopharynx in 21 cases with 35％, carcinoma of the larynx in 9 cases, carcinoma of the tonsil and tongue every 6 cases, carcinoma soft palate and tongue base every 5 cases, carcinoma of buccal mucosa, retromolar trigone and mouth floor every 2 cases, carcinoma of the hard palate and low lip each 1 case. There were stage I 15 cases, stage II 13 cases, stage III 6 cases, stage IVA 10 cases, and stage IVB 16 cases. All patients have received surgery, chemoradiation therapy or combined therapy. We have wound infection in 6 cases, 2 cases of pharyngocutaneous fistula, flap necrosis in 2 cases, and mortality in 6 cases. In the wound infection group, the average BMI is 20.4 kg/m2; the average Hb is 12.9 g/dL, the average albumin is 3.5 g/dL, the average NLR is 6.78, and the average PLR is 243.5. In the PC fistula and flap necrosis group, the average BMI is 21.65 kg/m2; the average Hb is 11.7 g/dL, the average albumin is 3.15 g/dL, average NLR is 13.28, average PLR is 418.84. In the mortality group, the average BMI is 22.3 kg/m2; the average Hb is 13.58 g/dL, the average albumin is 3.77 g/dL, the average NLR is 6.06, and the average PLR is 275.5. Conclusion: HNC is a big challenging public health problem worldwide, especially in the high prevalence of betel nut consumption area Taiwan. Besides the definite risk factors of smoking, drinking and betel nut related, the other biomarkers may play significant prognosticators in the HNC outcomes. We concluded that the average BMI is less than 22 kg/m2, the average Hb is low than 12.0 g/dL, the average albumin is low than 3.3 g/dL, the average NLR is low than 3, and the average PLR is more than 170, the surgical complications and mortality will be increased, and the prognosis is poor in HNC patients.

Keywords: nutritional, immunological, neutrophil-to-lymphocyte ratio, paltelet-to-lymphocyte ratio.

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Authors: Rajeev, N. K. Raigar

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In this study, one dimensional phase change problem (a Stefan problem) is considered and a numerical solution of this problem is discussed. First, we use similarity transformation to convert the governing equations into ordinary differential equations with its boundary conditions. The solutions of ordinary differential equation with the associated boundary conditions and interface condition (Stefan condition) are obtained by using a numerical approach based on operational matrix of differentiation of shifted second kind Chebyshev wavelets. The obtained results are compared with existing exact solution which is sufficiently accurate.

Keywords: operational matrix of differentiation, similarity transformation, shifted second kind chebyshev wavelets, stefan problem

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Authors: A. Zuchowska, A. Buta, M. Mazurkiewicz-Pawlicka, A. Malolepszy, L. Stobinski, Z. Brzozka

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In recent years, graphene-based materials are finding more and more applications in biological science. As a thin, tough, transparent and chemically resistant materials, they appear to be a very good material for the production of implants and biosensors. Interest in graphene derivatives also resulted at the beginning of research about the possibility of their application in cancer therapy. Currently, the analysis of their potential use in photothermal therapy and as a drug carrier is mostly performed. Moreover, the direct anticancer properties of graphene-based materials are also tested. Nowadays, cytotoxic studies are conducted on in vitro cell culture in standard culture vessels (macroscale). However, in this type of cell culture, the cells grow on the synthetic surface in static conditions. For this reason, cell culture in macroscale does not reflect in vivo environment. The microfluidic systems, called Lab-on-a-chip, are proposed as a solution for improvement of cytotoxicity analysis of new compounds. Here, we present the evaluation of cytotoxic properties of graphene oxide (GO) on breast, liver and colon cancer cell line in a microfluidic system in two spatial models (2D and 3D). Before cell introduction, the microchambers surface was modified by the fibronectin (2D, monolayer) and poly(vinyl alcohol) (3D, spheroids) covering. After spheroid creation (3D) and cell attachment (2D, monolayer) the selected concentration of GO was introduced into microsystems. Then monolayer and spheroids viability/proliferation using alamarBlue® assay and standard microplate reader was checked for three days. Moreover, in every day of the culture, the morphological changes of cells were determined using microscopic analysis. Additionally, on the last day of the culture differential staining using Calcein AM and Propidium iodide were performed. We were able to note that the GO has an influence on all tested cell line viability in both monolayer and spheroid arrangement. We showed that GO caused higher viability/proliferation decrease for spheroids than a monolayer (this was observed for all tested cell lines). Higher cytotoxicity of GO on spheroid culture can be caused by different geometry of the microchambers for 2D and 3D cell cultures. Probably, GO was removed from the flat microchambers for 2D culture. Those results were also confirmed by differential staining. Comparing our results with the studies conducted in the macroscale, we also proved that the cytotoxic properties of GO are changed depending on the cell culture conditions (static/ flow).

Keywords: cytotoxicity, graphene oxide, monolayer, spheroid

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Authors: Ji Hye Im, Nguyen T. T. Phuong, Keon Wook Kang

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Estrogens are important for the development and growth of estrogen receptor (ER)-positive breast cancer, for which anti-estrogen therapy is one of the most effective treatments. However, its efficacy can be limited by either de novo or acquired resistance. Aromatase is a key enzyme for the biosynthesis of estrogens, and inhibition of this enzyme leads to profound hypoestrogenism. Here, we found that the basal expression and activity of aromatase were significantly increased in tamoxifen (TAM)-resistant human breast cancer (TAMR-MCF-7) cells compared to control MCF-7 cells. We further revealed that aromatase immunoreactivity in tumor tissues was increased in recurrence group after TAM therapy compared to non-recurrence group after TAM therapy. Phosphorylation of Akt, extracellular signal-regulated kinase (ERK), and p38 kinase were all increased in TAMR-MCF-7 cells. Inhibition of phosphoinositide 3-kinase (PI3K) suppressed the transactivation of the aromatase gene and its enzyme activity. Furthermore, we have also shown that PI3K/Akt-dependent cAMP-response element binding protein (CREB) activation was required for the enhanced expression of aromatase in TAMR-MCF-7 cells. Our findings suggest that aromatase expression is up-regulated in TAM-resistant breast cancer via PI3K/Akt-dependent CREB activation.

Keywords: TAMR-MCF-7, CREB, estrogen receptor, aromatase

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Authors: Brian E. Usibe

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This paper addresses the problem of a linear crack located in the middle of a homogeneous elastic media under normal tension-compression harmonic loading. The problem of deformation of the fractured media is solved using the direct finite element numerical procedure, including the analysis of the dynamic field variables of the problem. A finite element algorithm that satisfies the unilateral Signorini contact constraint is also presented for the solution of the contact interaction of the crack faces and how this accounts for the qualitative and quantitative changes in the solution when determining the dynamic fracture parameter.

Keywords: harmonic loading, linear crack, fracture parameter, wave number, FEA, contact interaction

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Authors: Syed Beenish Rufai, Sarman Singh

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Background: Performance of Genotype MTBDRsl (Hain Life science GmbH Germany) for detection of mutations associated with second-line drug resistance is well known. However, less evidence regarding the association of mutations and genetic background of strains is known which, in the future, is essential for clinical management of anti-tuberculosis drugs in those settings where the probability of particular genotype is predominant. Material and Methods: During this retrospective study, a total of 259 MDR-TB isolates obtained from pulmonary TB patients were tested for second-line drug susceptibility testing (DST) using Genotype MTBDRsl VER 1.0 and compared with BACTEC MGIT-960 as a reference standard. All isolates were further characterized using spoligotyping. The spoligo patterns obtained were compared and analyzed using SITVIT_WEB. Results: Of total 259 MDR-TB isolates which were screened for second-line DST by Genotype MTBDRsl, mutations were found to be associated with gyrA, rrs and emb genes in 82 (31.6%), 2 (0.8%) and 90 (34.7%) isolates respectively. 16 (6.1%) isolates detected mutations associated with both FQ as well as to AG/CP drugs (XDR-TB). No mutations were detected in 159 (61.4%) isolates for corresponding gyrA and rrs genes. Genotype MTBDRsl showed a concordance of 96.4% for detection of sensitive isolates in comparison with second-line DST by BACTEC MGIT-960 and 94.1%, 93.5%, 60.5% and 50% for detection of XDR-TB, FQ, EMB, and AMK/CAP respectively. D94G was the most prevalent mutation found among (38 (46.4%)) OFXR isolates (37 FQ mono-resistant and 1 XDR-TB) followed by A90V (23 (28.1%)) (17 FQ mono-resistant and 6 XDR-TB). Among AG/CP resistant isolates A1401G was the most frequent mutation observed among (11 (61.1%)) isolates (2 AG/CP mono-resistant isolates and 9 XDR-TB isolates) followed by WT+A1401G (6 (33.3%)) and G1484T (1 (5.5%)) respectively. On spoligotyping analysis, Beijing strain (46%) was found to be the most predominant strain among pre-XDR and XDR TB isolates followed by CAS (30%), X (6%), Unique (5%), EAI and T each of 4%, Manu (3%) and Ural (2%) respectively. Beijing strain was found to be strongly associated with D94G (47.3%) and A90V mutations by (47.3%) and 34.8% followed by CAS strain by (31.6%) and 30.4% respectively. However, among AG/CP resistant isolates, only Beijing strain was found to be strongly associated with A1401G and WT+A1401G mutations by 54.5% and 50% respectively. Conclusion: Beijing strain was found to be strongly associated with the most prevalent mutations among pre-XDR and XDR TB isolates. Acknowledgments: Study was supported with Grant by All India Institute of Medical Sciences, New Delhi reference No. P-2012/12452.

Keywords: tuberculosis, line probe assay, XDR TB, drug susceptibility

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Authors: Ramesh Subramani, Mathivanan Narayanasamy, William Aalbersberg

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It is well accepted by last 35 years of research and on-going programmes that marine environment harbours abundant and unique biodiversity, which is currently playing as an important source in bioprospecting. It has become apparent that marine microorganisms are lead in the biodiscovery. Among marine organisms, actinobacteria are a target phylum for discovering novel antibiotics against increasing the multi-drug resistant human pathogens because of these taxa representing for novel genera and species. Marine actinomycetes are a proven source of new antibiotic leads and novel enzymes with important industrial applications. A total of 183 streptomycete and 25 non-streptomycete strains were isolated from different marine samples collected from north-eastern part of the Indian Ocean. Among them, 111 isolates displayed antibacterial activity against human pathogens and 151 exhibited antifungal activity against phytopathogens. Importantly, most of them produced various extracellular enzymes and 58 of them produced exopolysaccharides. Totally eight small bioactive compounds and a thermostable alkaline protease have been purified from a selected strain, Streptomyces fungicidicus. Besides, our on-going studies on non-streptomycete strains (rare actinomycetes) are most likely promising resource for new and unique compounds against current emerging drug-resistant pathogens. We have just recognised the chemical diversity in marine microorganisms. Therefore it is worthwhile to continue the exploration of marine microorganisms for new drug leads, novel enzymes and other bioprospecting research.

Keywords: bioactive compounds, industrial enzymes, marine actinobacteria, microbial metabolites, marine natural products

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Authors: Sunyoung Bu, Wonkyu Chung, Philsu Kim

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In this paper, we introduce a method for improving the embedded Runge-Kutta-Fehlberg 4(5) method. At each integration step, the proposed method is comprised of two equations for the solution and the error, respectively. This solution and error are obtained by solving an initial value problem whose solution has the information of the error at each integration step. The constructed algorithm controls both the error and the time step size simultaneously and possesses a good performance in the computational cost compared to the original method. For the assessment of the effectiveness, EULR problem is numerically solved.

Keywords: embedded Runge-Kutta-Fehlberg method, initial value problem, EULR problem, integration step

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Authors: Ahmed A. Abd El Rahim, Andrew Anis Fakhrey Mosaad

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Background: An important psychological issue that has an impact on both mental and physical function is anxiety disorders. The general consensus is that aerobic exercise and physical activity are good for lowering anxiety and mood. Purpose: This study's goal was to look into how patients with anxiety disorders responded to aerobic exercise. Subjects: Anxiety disorders were identified in 30 individuals from the psychiatric hospital at Sohag University who were chosen based on inclusive criteria and had ages ranging from 25 to 45. Methods: Patients were split into two equal groups at random: For four weeks, three sessions per week, fifteen patients in group A (the study group), seven men and eight women, underwent medication therapy and aerobic exercise. Age (28.4 ± 2.11 years), weight (72.5 ± 10.06 kg), height (164.8 ± 9.64 cm), and BMI (26.65 ± 2.68 kg/m2) were all mean SD values. And in Group B (Control Group), only medication therapy was administered to 15 patients (9 males and 6 females). Age (29.6 ± 3.68), weight (75 ± 7.07 kg), height (166.9 ± 6.75) cm, and BMI (26.87 ± 1.11) kg/m2 were the mean SD values. Before and after the treatment, the Hamilton Anxiety Scale was used to gauge the patient's degree of anxiety. Results: Within the two groups, there were significant differences both before and after the treatment. Following therapy, there was a significant difference between the two groups; the study group displayed better improvement on the Hamilton Anxiety Scale. Conclusion: Patients with anxiety problems can benefit from aerobic activities and antianxiety drugs as effective treatments for lowering anxiety levels.

Keywords: aerobic exercises, anxiety disorders, antianxiety medications, Hamilton anxiety scale

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Authors: Richa Mardianingrum, Srie R. N. Endah

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In this research, we have designed four isoniazid derivatives i.e., isonicotinohydrazide (1-isonicotinoyl semicarbazide, 1-thiosemi isonicotinoyl carbazide, N '-(1,3-dimethyl-1 h-pyrazole-5-carbonyl) isonicotino hydrazide, and N '-(1,2,3- 4-thiadiazole-carbonyl) isonicotinohydrazide. The docking and molecular dynamic have performed to them in order to study its interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (InhA). Based on this research, all of the compounds were predicted to have a stable interaction with Mycobacterium tuberculosis Enoyl-Acyl Carrier Protein Reductase (INHA) receptor, so they could be used as an anti-tuberculosis drug candidate.

Keywords: anti-tuberculosis, docking, Inhibin alpha subunit, InhA, inhibition, synthesis, isonicotinohydrazide

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Authors: Sutapa Som Chaudhury, Chitrangada Das Mukhopadhyay

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Alzheimer’s disease is a well-known form of dementia since its discovery in 1906. Current Food and Drug Administration approved medications e.g. cholinesterase inhibitors, memantine offer modest symptomatic relief but do not play any role in disease modification or recovery. In last three decades many small molecules, chaperons, synthetic peptides, partial β-secretase enzyme blocker have been tested for the development of a drug against Alzheimer though did not pass the 3rd clinical phase trials. Here in this study, we designed a PEGylated, aminogenic, tripeptidic polymer with two different molecular weights based on the aggregation prone amino acid sequence 17-20 in amyloid beta (Aβ) 1-42. Being conjugated with poly-ethylene glycol (PEG) which self-assembles into hydrophilic nanoparticles, these PEGylated tripeptides constitute a very good drug delivery system crossing the blood brain barrier while the peptide remains protected from proteolytic degradation and non-specific protein interactions. Moreover, being completely aminogenic they would not raise any side effects. These peptide inhibitors were evaluated for their effectiveness against Aβ42 fibrillation at an early stage of oligomer to fibril formation as well as preformed fibril clearance via Thioflavin T (ThT) assay, dynamic light scattering analyses, atomic force microscopy and scanning electron microscopy. The inhibitors were proved to be safe at a higher concentration of 20µM by the reduction assay of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Moreover, SHSY5Y neuroblastoma cells have shown a greater survivability when treated with the inhibitors following Aβ42 fibril and oligomer treatment as compared with the control Aβ42 fibril and/or oligomer treated neuroblastoma cells. These make the peptidic inhibitors a promising compound in the aspect of the discovery of alternative medication for Alzheimer’s disease.

Keywords: Alzheimer’s disease, alternative medication, amyloid beta, PEGylated peptide

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Authors: Sara Assi, Berthe Hayar, Claudio Pisano, Nadine Darwiche, Walid Saad

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Nanomedicine, the application of nanotechnology to medicine, is an emerging discipline that has gained significant attention in recent years. Current breakthroughs in nanomedicine have paved the way to develop effective drug delivery systems that can be used to target cancer. The use of nanotechnology provides effective drug delivery, enhanced stability, bioavailability, and permeability, thereby minimizing drug dosage and toxicity. As such, the use of nanoparticle (NP) formulations in drug delivery has been applied in various cancer models and have shown to improve the ability of drugs to reach specific targeted sites in a controlled manner. Cancer is one of the major causes of death worldwide; in particular, colorectal cancer (CRC) is the third most common type of cancer diagnosed amongst men and women and the second leading cause of cancer related deaths, highlighting the need for novel therapies. Retinoids, consisting of natural and synthetic derivatives, are a class of chemical compounds that have shown promise in preclinical and clinical cancer settings. However, retinoids are limited by their toxicity and resistance to treatment. To overcome this resistance, various synthetic retinoids have been developed, including the adamantyl retinoid ST1926, which is a potent anti-cancer agent. However, due to its limited bioavailability, the development of ST1926 has been restricted in phase I clinical trials. We have previously investigated the preclinical efficacy of ST1926 in CRC models. ST1926 displayed potent inhibitory and apoptotic effects in CRC cell lines by inducing early DNA damage and apoptosis. ST1926 significantly reduced the tumor doubling time and tumor burden in a xenograft CRC model. Therefore, we developed ST1926-NPs and assessed their efficacy in CRC models. ST1926-NPs were produced using Flash NanoPrecipitation with the amphiphilic diblock copolymer polystyrene-b-ethylene oxide and cholesterol as a co-stabilizer. ST1926 was formulated into NPs with a drug to polymer mass ratio of 1:2, providing a stable formulation for one week. The contin ST1926-NP diameter was 100 nm, with a polydispersity index of 0.245. Using the MTT cell viability assay, ST1926-NP exhibited potent anti-growth activities as naked ST1926 in HCT116 cells, at pharmacologically achievable concentrations. Future studies will be performed to study the anti-tumor activities and mechanism of action of ST1926-NPs in a xenograft mouse model and to detect the compound and its glucuroconjugated form in the plasma of mice. Ultimately, our studies will support the use of ST1926-NP formulations in enhancing the stability and bioavailability of ST1926 in CRC.

Keywords: nanoparticles, drug delivery, colorectal cancer, retinoids

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Authors: N. M. Sani, E. D. Jatau, O. S. Olonitola, M. Y. Gwarzo, P. Moodley, N. S. Mujahid

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Haemoglobin (HB) indicates anaemia level and by extension may reflect the nutritional level and perhaps the immunity of an individual. Some antiretroviral drugs like zidovudine are known to cause anaemia in People living with HIV/AIDS (PLWHA). A cross-sectional study using demographic data and blood specimen from 218 female commercial sex workers attending antiretroviral therapy (ART) clinics was conducted between December 2009 and July 2011 to assess the effect of zidovudine on haematologic and RNA viral load of female sex workers receiving antiretroviral treatment in north-western Nigeria. Anaemia is a common and serious complication of both HIV infection and its treatment. In the setting of HIV infection, anaemia has been associated with decreased quality of life, functional status, and survival. Antiretroviral therapy, particularly the highly active antiretroviral therapy (HAART), has been associated with a decrease in the incidence and severity of anaemia in HIV-infected patients who have received a HAART regimen for at least 1 year. In this study, result has shown that out of 218 patients, 26 with haemoglobin count between 5.1–10 g/dl were observed to have the highest viral load count of 300,000–350,000 copies/ml. It was also observed that most patients (190) with HB of 10.1–15.0 g/dl had viral load count of 200,000–250,000 copies/ml. An inverse relationship therefore exists, i.e. the lower the haemoglobin level, the higher the viral load count, even though the test statistics did not show any significance between the two (P=0.206). This shows that multivariate logistic regression analysis demonstrated that anaemia was associated with a CD4+ cell count below 50/µL in female sex workers with a viral load above 100,000 copies/mL who use zidovudine. Severe anaemia was less prevalent in this study population than in historical comparators; however, mild to moderate anaemia rates remain high. The study, therefore, recommends that hematological and virologic parameters be monitored closely in patients receiving first line ART regimen.

Keywords: anaemia, female sex worker, haemoglobin, Zidovudine

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Authors: K. -H. Yang

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Supplier selection problem is one of the important issues of supply chain problems. Two categories of methodologies include qualitative and quantitative approaches which can be applied to supplier selection problems. However, due to the complexities of the problem and lacking of reliable and quantitative data, qualitative approaches are more than quantitative approaches. This study considers operational cost and supplier’s reliability factor and solves the problem by using a quantitative approach. A mixed integer programming model is the primary analytic tool. Analyses of different scenarios with variable cost and reliability structures show that the effectiveness of this approach to the supplier selection problem.

Keywords: mixed integer programming, quantitative approach, supplier’s reliability, supplier selection

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Authors: Olteanu Constanta, Olteanu Lucian

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Researchers note that algebraic reasoning and sense making is essential for building conceptual knowledge in school mathematics. Consequently, pre-service teachers’ own reasoning and sense making are useful in fostering and developing students’ algebraic reasoning and sense making. This article explores the forms of reasoning and sense making that pre-service mathematics teachers exhibit and use in the process of analysing problem-posing tasks with a focus on first-degree equations. Our research question concerns the characteristics of the problem-posing tasks used for reasoning and sense making of first-degree equations as well as the characteristics of pre-service teachers’ reasoning and sense making in problem-posing tasks. The analyses are grounded in a post-structuralist philosophical perspective and variation theory. Sixty-six pre-service primary teachers participated in the study. The results show that the characteristics of reasoning in problem-posing tasks and of pre-service teachers are selecting, exploring, reconfiguring, encoding, abstracting and connecting. The characteristics of sense making in problem-posing tasks and of pre-service teachers are recognition, relationships, profiling, comparing, laddering and verifying. Beside this, the connection between reasoning and sense making is rich in line of flight in problem-posing tasks, while the connection is rich in line of rupture for pre-service teachers.

Keywords: first-degree equations, problem posing, reasoning, rhizomatic assemblage, sense-making, variation theory

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