bluuebunny/crossref_metadata_2025 huggingface dataset:
HEAT SHOCK PROTEIN HSP70: PREREQUISITES FOR USE AS A MEDICINAL PRODUCT
Authors: Pokrovsky V. M. , Patrakhanov E. A. , Antsiferov O. V. , Kolesnik I. M. , Belashova A. V. , Soldatova V. A. , Pokopeiko O. N. , Karagodina A. Yu. , Arkhipov I. A. , Voronina D. G. , Sushkova D. N.
Published: October 2021

Heat shock protein Hsp70 is one of the main cytoprotection components under the action of various external stimuli. The analysis of the literature data shows that nowadays, the researches’ overwhelming evidence has proven the role of Hsp70 as a biological target for the drug development; however, the ideas about its use as a drug are often multidirectional.

The aim of the article is to analyze and generalize the literature data on the features of the physiological functions of heat shock protein Hsp 70, and indicate the possibilities of its use for the pharmacological correction of various pathological conditions.

Materials and methods. In the process of selecting material for writing this review article, such databases as Google Patents, Science Research Portal, Google Scholar, ScienceDirect, CiteSeer, Publications, ResearchIndex, Ingenta, PubMed, KEGG, etc. were used The following words and word combinations were selected as markers for identifying the literature: Hsp70, Hsp70 stroke, Hsp70 neuroprotection, Hsp70 cytoprotection, recombinant drugs.

Results. In this review, the pharmacology of one of the key members of this family, Hsp70, was focused on. The literary analysis confirms that this molecule is an endogenous regulator of many physiological processes and demonstrates tissue protective effects in modeling ischemic, neurodegenerative and inflammatory processes. The use of recombinant exogenous Hsp70 mimics the endogenous function of the protein, indicating the absence of a number of typical limitations characteristic of pharmacotherapy with high molecular weight compounds, such as immunogenicity, a rapid degradation by proteases, or a low penetration of histohematogenous barriers.

Conclusion. Thus, Hsp70 may become a promising agent for clinical trials as a drug for the treatment of patients with neurological, immunological, and cardiovascular profiles.
TYPE 2 DIABETES MELLITUS’S DECOMPENSATED FORM: ON THE PROBLEM OF EFFECTIVE PHARMACOTHERAPY IN REAL CLINICAL PRACTICE
Authors: Safronenko A. V. , Gantsgorn E. V. , Sanina E. A. , Khachumova M. A. , Panenko S. O. , Kuznetsov I. I. , Kivva A. A. , Polyakova V. I.
Published: October 2021

The aim of this retrospective study was to analyze the pharmacotherapy regimens of the decompensated form of type 2 diabetes mellitus (DM2) and to evaluate its effectiveness, its compliance with clinical recommendations.

Materials and methods: A retrospective analysis of 54 medical cards of patients with decompensated DM2 was conducted. The 1st group (n=24; 44%) included the patients who had a decrease in glycated hemoglobin (HbA1c) by 50% or more in 3 months after hypoglycemic therapy; and the 2nd group (n=30; 56%) – the patients whose HbA1c level decreased by less than 50%.

Results. A HbA1c level was 10.4% in the 1st group and 13.2% in the 2nd group (р<0.001). However, the target levels of venous blood plasma glucose and HbA1c were not achieved in any of the patient groups. The total number of the drugs prescribed to the patients ranged from 4 (in 25% (n=6) and 10% (n=3) cases in the 1st and the 2nd groups, respectively) to 8 (in 12.5% (n=3) and 20% (n=6) cases in the 1st and the 2nd, groups, respectively). However, in a number of cases some violations of clinical recommendations were recorded: the prescription to the obese patients of insulin drugs, the administration of sulfonylureas derivatives to patients with a history of cardiovascular diseases of the atherosclerotic origin, but modern hypoglycemic drugs with proven benefits in reducing cardiovascular risks were rarely prescribed.

Conclusion. The tactics of pharmacotherapy in the patients with a decompensated form of DM2 does not fully comply with the approved clinical guidelines, which requires the effectiveness of treatment optimization of this medically and socially significant pathology.
COST-MINIMIZATION ANALYSIS OF USING SHORT AND LONG-ACTING ERYTHROPOESIS-STIMULATING AGENTS FOR CORRECTION OF NEPHROGENIC ANEMIA AGAINST THE BACKGROUND OF SUBSTITUTION THERAPY
Authors: Krysanov I. S. , Ermakova E. Yu. , Vaskova L. B. , Tiapkina M. V.
Published: October 2021

Clinical trials conducted in various countries indicate that the use of epoetin alfa in patients with nephrogenic anemia in chronic kidney disease can increase the effectiveness of treatment, reduce the incidence of cardiovascular and infectious complications, and reduce mortality in patients with chronic kidney disease.

The aim of the article was to conduct a comparative clinical and economic assessment of the treatment costs of nephrogenic anemia in adult dialysis patients with recombinant human erythropoietins: epoetin alfa, darbepoetin and long-acting methoxy polyethylene glycol – epoetin beta.

Materials and methods. The study took into account direct medical costs of nephrogenic anemia pharmacotherapy on the basis of 1 year maintenance therapy according to the following scheme: epoetin alfa – 3 times per week, darbepoetin alfa – once per week, methoxy polyethylene glycol – epoetin beta – once per 2 or 4 weeks. A “costs minimization” analysis was performed for equivalent maintenance epoetins doses for intravenous and subcutaneous administrations. Epoetin alpha equivalents were calculated for an average patient weighing 75 kg by converting a weekly dose of short-acting epoetin (7500 IU) into equivalent doses using dose conversion factors.

Results. In the hypothetical cohort of patients under study, epoetin alfa, darbepoetin alfa, and methoxy polyethylene glycol – epoetin beta not differ in effectiveness in achieving target Hb values and in safety. With the equal effectiveness of the investigated drugs, in the studied patients, intravenous epoetin alfa can be less expensive drug therapy relative to the equivalent doses obtained by the calculation: darbepoetin by 14–24% and methoxy polyethylene glycol – epoetin beta by 4–30%. The change-over of patients to the subcutaneous administration makes it possible to decline a weekly dose of epoetin alfa by 20–30% by reducing the frequency of taking the drug to twice a week, and to reduce the cost of drug therapy by a third.

Conclusion. Intravenous and subcutaneous administrations of epoetin alfa 2500 IU may be a more economical drug therapy in comparison with the equivalent doses of darbepoetin and methoxy polyethylene glycol – epoetin beta.
ANTIHISTAMINES: RESEARCH AND ANALYSIS OF THE REGIONAL RETAIL MARKET
Authors: Prokopenko V. V. , Kabakova T. I. , Chernikov M. V. , Goryachev A. B. , Mikhailova S. A. , Knysh O. I.
Published: October 2021

the aim. Focused on optimizing the assortment portfolio of pharmacy organizations and improving the process of drug supply to end-consumers, the aim of the study was to analyze the regional pharmaceutical market for antihistamines.

Materials and methods. In the study, the following methods were used: a content analysis of regulatory documents; a documentary observation method of the volume of antihistamines sales; a sociological survey method. The objects of the study were accounting registers in 32 pharmacy organizations for 2020, as well as the sociological survey results of 174 respondents – consumers of antihistamines.

Results. The classification analysis of 38 international non-proprietary trade names of antihistamines, represented by 187 names of drugs, revealed the prevalence of the first-generation drugs (63%). On the Russian pharmaceutical market, there were also 55% of foreign production drugs. At the regional level, there are 66 types of drugs in circulation, 50% of which are second-generation ones. The cost analysis showed rather a wide rage of the pricing proposal and the economic availability of antihistamines for patients. The sociological survey revealed the fact that 46% of the consumers were ready to pay for the necessary drugs in the price range “over 100 and up to 500 rubles” (over $ 1.38 and up to $ 6.88) for one conventional package. A medical-demographic profile of the antihistamines consumer at the regional level has been made up, and guidelines for pharmaceutical specialists on managing the assortment portfolio of pharmaceutical organizations have been developed.

Conclusion. As a result of the study, the following facts have been established: the seasonal peaks in the antihistamines consumption; a gradual renewal of the pharmacies assortment portfolio due to the increased consumption of the second and third generation antihistamines. The medical and demographic profile of the consumer should be taken into consideration when planning a drug provision for the patients with allergic pathologies, and it is connected with the growth in pharmacies profits due to the sale of drugs in the range from 100 to 500 rubles (from $ 1.38 to $ 6.88). The methodical recommendations have been brought to the attention of the management of regional pharmacy organizations.
ACTUAL PROBLEMS OF PROFESSIONAL AND PERSONAL DEVELOPMENT QUALIFIED PERSONS RESPONSIBLE FOR QUALITY OF MEDICINAL PRODUCTS FOR HUMAN USE
Authors: Aladysheva Zh. I. , Pyatigorskaya N. V. , Belyaev V. V. , Nikolenko N. S. , Nesterkina E. I. , Loseva S. A.
Published: October 2021

The aim of the study is to investigate topical problems of the professional and personal development of qualified persons responsible for quality of medicinal products for human use.

Materials and methods. In the period from April 6 to May 10, 2020, an online survey of leading employees in the field of quality assurance of Russian manufacturers was conducted. 176 people took part in the survey; the return of questionnaires was about 17.9%.

Results. From the standpoint of D. Super’s theory of professional development, the largest number of respondents was at the maintenance stage, holding their achieved positions (53.2%). All respondents, regardless of age, were motivated for professional development. Most often qualified persons had chemical engineering (27.3%) and pharmaceutical education (22.2%). Most of them had a working experience in 1–2 divisions of the enterprise, and combined the functions of qualified persons with managerial positions (74.5% and 71.9%, respectively). The majority of the qualified persons (86.4%) indicated the sufficiency of the available knowledge and the lack of knowledge on certain issues. Knowledge and skills in the quality risk management, specific GMP issues and statistical methods (59.0%, 49.2 and 44.2%, respectively); communication and interpersonal skills and, in particular, stress management, emotion management and the art of negotiation (49.4%, 41.3% and 40.9%, respectively), were most popular. About 36% of respondents notified the need for the digital economy competencies, while only 5.1% notified the presence of an electronic batch production record at the enterprise. Finally, only half of the respondents (50.5%) had a formal training plan for qualified persons.

Conclusion. This pilot study revealed the need for the revision of the Exemplary Additional Professional Training Program for Qualified Persons and the professional standard, the urgent need for the regulatory body to develop a scheme and principles for the continuous professional development of qualified persons, and showed the direction of further research in this area.
preservação dos documentos históricos em ambientes digitais
Authors: Moura Eda Maria Bastos de , Campos Linair Maria
Published: October 2021

O artigo tem por objetivo abordar a importância da preservação dos documentos históricos de natureza digital. Para isso, conceitua documento, documento digital e explicita a importância dos documentos históricos situando a preocupação com os processos de digitalização em ambiente digital, por conta da obsolescência tecnológica. Metodologia: É feita mediante revisão bibliográfica, sua natureza é qualitativa e o procedimento técnico feito por meio de levantamento bibliográfico. Resultado: Traz uma comparação de destruições de acervos convencionais como no caso de destruição de documentos históricos do Museu Nacional com as possíveis perdas dos documentos em ambiente digital. Conclusões: Aponta as ausências de políticas públicas que permitam a preservação dos documentos digitais em longo prazo.
Chronic endometritis: prevention and treatment options
Authors:   N.I.Pirogov Russian National Research Medical University, Moscow, Russian Federation, Dobrokhotova Yu.E. , Borovkova E.I. ,   N.I.Pirogov Russian National Research Medical University, Moscow, Russian Federation, Nugumanova O.R. ,   City Clinical Hospital No 40, Moscow, Russian Federation
Published: October 2021

This article is a review of publications devoted to the treatment of chronic endometritis and methods of its prevention. Methods of empiric therapy, standards of antibacterial therapy, and modern guidelines for treatment under development (colonystimulating factor, immunotherapy, amplipulse therapy) are presented. Key words: infertility, miscarriage, colony-stimulating factor, chronic endometritis, cytokine therapy
Pharmacoeconomic evaluation of various treatment options for respiratory distress syndrome in newborns
Authors:   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Serpik V.G. , Yagudina R.I. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Ionov O.V. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation,   Academician V.I.Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russian Federation, Kulikov A.Yu. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Protsenko M.V. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
Published: October 2021

The treatment strategy for neonatal respiratory distress syndrome (NRDS) includes several options such as early prescription of surfactants, prescription “on demand” using different methods of their administration. A pharmacoeconomic evaluation of various NRDS treatment options was performed using a budget impact analysis according to an appropriate pharmacoeconomic model. The pharmacoeconomic model was based on the results of clinical trials in terms of the risks factors for the most significant complications of NRDS. The model also considered all relevant costs for the national health care system associated with prescribing surfactant therapy. Conclusion. A pharmacoeconomic evaluation of NRDS treatment using the example of two hypothetical cohorts of patients at gestational age of 29 and 32 weeks showed that early surfactant prescription (using Poractant alfa as an example) by Less Invasive Surfactant Administration (LISA) procedure in patients with FiO2 ≥0.3 is strongly preferable in comparison with Continuous Positive Airway Pressure (CPAP) therapy, reducing the mortality rate (by 0.69%), the incidence of life-threatening complications (bronchopulmonary dysplasia, severe intraventricular hemorrhage, and air leak syndrome), as well as providing cost savings to the healthcare system. Key words: poractant alfa, early administration, neonatal respiratory distress syndrome, surfactant
Management of pregnant women with congenital cytomegalovirus and parvovirus infection
Authors:   Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological Agency, Saint Petersburg, Russian Federation, Grineva A.A. , Vasiliev V.V. ,   Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological Agency, Saint Petersburg, Russian Federation,   I.I.Mechnikov North-Western State Medical University, Saint Petersburg, Russian Federation, Rogozina N.V. ,   Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological Agency, Saint Petersburg, Russian Federation,   Saint-Petersburg State Pediatric Medical University, Saint Petersburg, Russian Federation
Published: October 2021

The development of management tactics for pregnant women with congenital infections is the most important medical and social task, since it determines the prognosis and outcome of the disease for the mother and her children. The lack of standardized approaches to the diagnosis and treatment of congenital infectious diseases, as well as the insufficient level of interaction between obstetric and gynecological and infectious diseases services necessitate a comprehensive multidisciplinary approach to the early diagnosis and treatment of congenital infectious diseases in the antenatal period. The article presents our own cases of management of pregnant women with congenital cytomegalovirus and parvovirus B19 infections. Key words: pregnancy, diagnosis, infections, treatment, parvovirus B19, cytomegalovirus
Promontofixation using titanium implant in patients with polyvalent allergy and combined gynecologic pathology
Authors:   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Ishchenko A.I. , Ishchenko A.A. ,   National Medical Research Center “Treatment and Rehabilitation Center”, Moscow, Russian Federation, Khokhlova I.D. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Dzhibladze T.A. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Gorbenko O.Yu. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Asambaeva A. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
Published: October 2021

Clinical observation of two patients with polyvalent allergy, uterine leiomyoma, and stage II apical prolapse who underwent a combined surgical intervention of subtotal/total hysterectomy followed by cervical stump/vaginal stump promontofixation using titanium mesh implants. Dynamic follow-up for 3–12 months after surgery showed the absence of pelvic organ prolapse during gynecologic examination, Valsalva maneuver, and transperineal ultrasound. A questionnaire survey of the patients revealed satisfaction with the results of surgery and improvement of the quality of life. Conclusion. The study demonstrated the efficacy and safety of combined laparoscopic surgery for uterine leiomyoma and stage II apical prolapse in premenopausal patients with polyvalent allergy. The surgery contributed to the normalization of anatomical relations in the small pelvis and relieving the apical prolapse symptoms. The use of titanium mesh implants minimized the risk of allergic reactions and mesh-associated complications, which resulted in satisfaction with the results of surgery and improvement in the quality of life of the patients. Key words: pelvic organ prolapse, apical prolapse, hysterectomy, titanium mesh implants
Surgical treatment of patients with deep infiltrating endometriosis of the rectovaginal septum
Authors:   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Galliamov E.A. , Aminova L.N. ,   Medsi Group of Companies, Moscow, Russian Federation, Alimov V.A. ,   Medsi Group of Companies, Moscow, Russian Federation, Kozub A.G. ,   Medsi Group of Companies, Moscow, Russian Federation, Alimova O.S. ,   Central Clinical Hospital of the Presidential Administration of the Russian Federation, Moscow, Russian Federation, Golubenko E.O. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation, Garina A.O. ,   I.M.Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
Published: October 2021

Objective. To optimize the tactics of surgical treatment of deep infiltrating endometriosis of the rectovaginal septum, including with bowel involvement. Patients and methods. The study included 122 patients diagnosed with deep infiltrating endometriosis of the rectovaginal septum, who underwent surgical interventions of different volumes using laparoscopy. The patients were divided into a main group and a comparison group. The main group consisted of 92 patients with deep infiltrating endometriosis of the rectovaginal septum who underwent surgical treatment using the original technique of systematic approach; the comparison group consisted of 30 patients who were operated using the generally accepted technique. Results. There was a statistically significant decrease in the operation duration, intraoperative blood loss, as well as more effective relief of dysmenorrhea and chronic pelvic pain syndrome, less complications and relapses in the main group compared to the comparison group. In addition, it was found that the combination of three symptoms such as dysmenorrhea, dyspareunia and chronic pelvic pain increase the likelihood of deep infiltrating endometriosis up to 93%. Conclusion. Based on the results obtained, the proposed method of surgical treatment of deep infiltrating endometriosis is more efficient and safer in comparison with the generally accepted technique, which can be considered as a valid reason for its wide introduction into clinical practice. Key words: deep infiltrating endometriosis, bowel endometriosis, surgical treatment of endometriosis, treatment algorithm
Adaptive homeostasis in pregnant women with moderate preeclampsia
Authors:   Rostov State Medical University, Rostov-on-Don, Russian Federation, Tumanyan S.S. , Tumanyan S.V. ,   Rostov State Medical University, Rostov-on-Don, Russian Federation, Udovenko E.A. ,   Rostov State Medical University, Rostov-on-Don, Russian Federation
Published: October 2021

Objective. To study the features of adaptive homeostasis in women with normal pregnancy and moderate preeclampsia (MPE). Patients and methods. Sixty-eight pregnant women were under study. General non-specific adaptive responses and adaptive cardiovascular responses were examined in 30 women with normal pregnancy and in 38 women with MPE. Results. Both general and organ adaptive responses were found to have a close correlation with the course of labor, the immediate postpartum period, and perinatal outcomes. Identification of general non-specific adaptive responses in the group of patients with MPE indicated the development of moderate stress response in 37%. Anti-stress responses accounted for 67%, mostly due to the training response. Conclusion. The analysis of comprehensive indicators of systemic and organ adaptation in pregnant women with MPE revealed the maladaptation of their regulatory mechanisms and signs of exhaustion of adaptation and energy reserves. The detected changes in systemic and organ adaptation have a negative effect on pregnancy and perinatal outcomes. Key words: moderate preeclampsia, adaptation, course of labor, prenatal outcomes
THE IMPACT OF COVID-19 ON THE IMPROVEMENT OF TEACHING SKILLS ON PROBLEM-BASED LEARNING (PBL)
Authors: Zascerinska Jelena , Aļeksejeva Ludmila , Zascerinskis Mihails , Gukovica Olga , Aleksejeva Anastasija
Published: October 2021

Teaching problem solving skills is essential for the continuous training of university teachers. However, the COVID-19 pandemic has had a dramatic effect on the improvement of teachers’ skills in problem-based teaching. The aim of the paper is to explore the impact of the COVID-19 pandemic on the enhancement of university teachers’ skills in problem-based teaching underpinning the implementation of the empirical analysis carried out within an international project. The research is based on the methodology of the system of the external and internal perspectives. The exploratory research was employed in the empirical study. The survey was conducted in July-August 2020. The sample contained 18 respondents (3 females and 15 males). The age of the respondents ranged from 30 to 70 years old. The data were processed by making use of the content analysis. The content analysis of the data from the survey consists of the content structuring and summarizing. The COVID-19 pandemic has had a significant impact on the external perspective of the enhancement of university teachers’ skills on problem-based teaching within the international project as the project participants consider the COVID-19 pandemic as a challenge. Another finding is that the negative impact of the COVID-19 pandemic on the enhancement of university teachers’ skills in problem-based teaching within the international project prevails. The theoretical finding is the newly defined structural elements of problem solving, namely challenge, opportunities, gains and possibilities, analysed within the methodology of the development of the system of the external and internal perspectives. The empirical study shows that the COVID-19 pandemic has negatively impacted the enhancement of university teachers’ skills in problem-based teaching within this international project.
Influence of Temperature on Quantification of Mesocracks: Implications for Physical Properties of Fine-Grained Granite
Authors: Chun Zhu , Yun Lin , Gan Feng
Published: October 2021

Thermally induced changes in mesocrack and the physical properties of fine-grained granite may influence their stability, transport characteristics, and performance related to various deep subsurface energy projects. In this study, granite was heat-treated at different temperatures (20°C, 100°C, 200°C, 300°C, 400°C, 500°C, and 600°C). The propagation and evolution of different types of cracks and the physical properties of the granite were quantitatively investigated, using optical observations of petrographic thin sections, P-wave velocity measurements, and permeability tests. The results show that as the temperature increased, the number and length of cracks increased, and the cracks were randomly distributed in all directions. This led to an increase in rock damage (λn) and an increase in permeability (K). In particular, when the temperature was ≥400°C, the damage rate significantly increased, and the number and length of intragranular cracks significantly exceeded the number and length of intergranular cracks. This led to changes in the permeation path, causing it to mainly travel through the interior of mineral particles. Using the inverse of P-wave velocity (VP), the dimensionless crack density (ρ) of granite was found to increase as the temperature increased, and this result was similar to the change of optical crack density (Pl). These analyses laid a reference for understanding the correlation between microcrack characteristics and macrophysical properties of granite.
Reservoir Simulation of CO2 Sequestration in Shale Reservoir
Authors: He Qin , Reid Teresa , Zheng Guofang
Published: October 2021

Increased production in natural gas from shale reservoirs has sparked concern that greenhouse gas emissions have also been on the rise. As a result, large- and small-scale operators and service companies are enthusiastically supporting a push toward "net carbon zero emissions". Carbon capture utilization and storage (CCUS) is playing an impactful role in companies’ goals to reach net zero. CO2 sequestration is the process of capturing and storing CO2 emissions from industrial and energy-related sources. Most CO2 sequestration are recommended to locate in saline aquifer, coalbed zone and depleted reservoirs, while CO2 sequestration in shale reservoir could become another good option to minimize the environmental footprint and enhance the gas production. Similar as CO2 sequestration into coalbed methane reservoir, the fluid flow mechanism in shale also includes desorption, diffusion and Darcy's law.

In this paper, the effects of CO2 sequestration on shale reservoirs will be discussed from a technical and economical viewpoint. A reservoir simulation was used to evaluate the quantity of CO2 that can be stored in shale, the effects of CO2 mitigation when injected into shale, and any significant opportunities for CO2 enhanced shale gas recovery. Lastly, an economic analysis was performed to evaluate the economic efficiency of such projects in shales.
Application Investigation of Light Proppant in Hydraulic Fracturing of Marcellus Shale
Authors: Alhemdi Aymen , Gu Ming
Published: October 2021

Slickwater-sand fracturing design is widely employed in Marcellus shale. The slickwater- sand creates long skinny fractures and maximizes the stimulated reservoir volume (SRV). However, due to the fast settling of sand in the water, lots of upper and deeper areas are not sufficiently propped. Reducing sand size can lead to insufficient fracture conductivity. This study proposes to use three candidate ultra-lightweight proppants ULWPs to enhance the fractured well performance in unconventional reservoirs.

In step 1, the current sand pumping design is input into an in-house P3D fracture propagation simulator to estimate the fracture geometry and proppant concentrations. Next, the distribution of proppant concentration converts to conductivity and then to fracture permeability. In the third step, the fracture permeability from the second step is input into a reservoir simulator to predict the cumulative production for history matching and calibration. In step 4, the three ULWPs are used to replace the sand in the frac simulator to get new frac geometry and conductivity distribution and then import them in reservoir model for production evaluation. Before this study, the three ULWPs have already been tested in the lab to obtain their long-term conductivities under in-situ stress conditions. The conductivity distribution and production performance are analyzed and investigated.

The induced fracture size and location of the produced layer for the current target well play a fundamental effect on ultra-light proppant productivity. The average conductivity of ULWPs with mesh 40/70 is larger and symmetric along the fracture except for a few places. However, ULWPs with mesh 100 generates low average conductivity and create a peak conductivity in limited areas. The ULW-3 tends to have less cumulative production compared with the other ULWPs. For this Marcellus Shale study, the advantages of ultra-lightweight proppant are restricted and reduced because the upward fracture height growth is enormous. And with the presence of the hydrocarbon layer is at the bottom of the fracture, making a large proportion of ULWPs occupies areas that are not productive places.

The current study provides a guidance for operators in Marcellus Shale to determine (1) If the ULWP can benefit the current shale well treated by sand, (2) what type of ULWP should be used, and (3) given a certain type of ULWP, what is the optimum pumping schedule and staging/perforating design to maximize the well productivity. The similar workflow can be expanded to evaluate the economic potential of different ULWPs in any other unconventional field.
Application of Artificial Intelligence To Predict Time-Dependent Mud-Weight Windows in Real Time
Authors: Phan Dung T. , Liu Chao , AlTammar Murtadha J. , Han Yanhui , Abousleiman Younane N.
Published: October 2021

Selection of a safe mud weight is crucial in drilling operations to reduce costly wellbore-instability problems. Advanced physics models and their analytical solutions for mud-weight-window computation are available but still demanding in terms of central-processing-unit (CPU) time. This paper presents an artificial-intelligence (AI) solution for predicting time-dependent safe mud-weight windows and very refined polar charts in real time. The AI agents are trained and tested on data generated from a time-dependent coupled analytical solution (poroelastic) because numerical solutions are prohibitively slow. Different AI techniques, including linear regression, decision tree, random forest, extra trees, adaptive neuro fuzzy inference system (ANFIS), and neural networks are evaluated to select the most suitable one. The results show that neural networks have the best performances and are capable of predicting time-dependent mud-weight windows and polar charts as accurately as the analytical solution, with 1/1,000 of the computer time needed, making them very applicable to real-time drilling operations. The trained neural networks achieve a mean squared error (MSE) of 0.0352 and a coefficient of determination (R2) of 0.9984 for collapse mud weights, and an MSE of 0.0072 and an R2 of 0.9998 for fracturing mud weights on test data sets. The neural networks are statistically guaranteed to predict mud weights that are within 5% and 10% of the analytical solutions with probability up to 0.986 and 0.997, respectively, for collapse mud weights, and up to 0.9992 and 0.9998, respectively, for fracturing mud weights. Their time performances are significantly faster and less demanding in computing capacity than the analytical solution, consistently showing three-orders-of-magnitude speedups in computational speed tests. The AI solution is integrated into a deployed wellbore-stability analyzer, which is used to demonstrate the AI’s performances and advantages through three case studies.
Proppant Transport Using High-Viscosity Friction Reducer Fracture Fluids at High-Temperature Environment
Authors: Biheri Ghith , Imqam Abdulmohsin
Published: October 2021

The stimulation of unconventional reservoirs to improve oil productivity in tight formations of shale basins is a key objective in hydraulic fracturing treatments. Such stimulation can be made by reliable fracture fluids that have a high viscosity and elasticity to suspend the proppant in the fracture networks. Recently, due to several operational and economic reasons, the oil industry began using high-viscosity friction reducers (HVFRs) as direct replacements for linear and crosslinked gels. However, some issues can limit the capability of HVFRs to provide effective sand transport, including the high fluid temperature during fracture treatment inside the formations. This may lead to unstable fracture fluids caused by a decrease in the interconnective strength between the fluid chains, which results in reduced viscosity and elasticity. This study comprehensively investigated HVFRs in comparison with guar at various temperatures. An HVFR at 4 gallons per thousand gallons of water (gpt) and guar at 25 pounds per thousand gallons of water (ppt) were selected based on fluid rheology tests and hydraulic fracture execution field results. The rheological measurements of both fracture fluids were conducted at different temperature values (i.e., 25, 50, 75, and 100°C). Static and dynamic proppant settling tests were also conducted at the same temperatures. The results showed that the HVFR provided better proppant transport capability than the guar. The HVFR had better thermal stability than guar, but its viscosity and elasticity decreased significantly when the temperature exceeded 75°C. An HVFR can carry and hold the proppant more deeply inside the fracture than liner gel, but that ability decreases as the temperature increases. Therefore, using conditions that mimic field conditions to measure the fracture fluid rheology, proppant static settling velocity, and proppant dune development under a high temperature is crucial for enhancing the fracture treatment results.
Associated factors with poor treatment response to initial glucocorticoid therapy in patients with adult-onset Still’s disease
Authors: Kondo Fumiaki , Sugihara Takahiko , Umezawa Natsuka , Hasegawa Hisanori , Hosoya Tadashi , Kimura Naoki , Mori Masaaki , Yasuda Shinsuke
Published: October 2021

Background

High-dose glucocorticoids (GC) are first-line treatment for adult onset Still’s disease (AOSD), however some of the patients remain refractory to initial GC therapy, or rapidly relapse. The aim of this study was to identify prognostic factors for poor treatment response to initial GC therapy for AOSD.
Methods

Data on newly-diagnosed AOSD patients were extracted from our database (n=71, mean age 51.6 years). The primary outcome was a poor treatment outcome at 4 weeks, which was defined as failure to achieve remission or relapse after achieving remission within 4 weeks, followed by administration of two or more rounds of GC pulse therapy or of any other immunosuppressive drugs.
Results

The initial mean dose ± standard deviation of prednisolone was 0.82 ± 0.23 mg/kg/day, and 34 (47.3%) patients received GC pulse therapy at week 0. Twenty-nine of 71 patients exhibited a poor treatment outcome at 4 weeks (40.8%). The second round of GC pulse therapy or immunosuppressive drugs was added in 17 or 24 of the 29 patients, respectively. These patients had higher baseline white blood cell (WBC) counts, serum ferritin levels, systemic feature score based on clinical symptoms (modified systemic feature score, mSFS), more hemophagocytic syndrome (HPS) over the 4 weeks, and the higher severity score based on modified Pouchot score or severity index of the Japanese Ministry of Health, Labour and Welfare, than the remaining 42 patients. Multivariable logistic regression model identified baseline WBC count as a prognostic factor for poor outcome (odds ratio per 1,000/µl increment: 1.12, 95% CI 1.04-1.29), while thrombocytopenia, hyperferritinemia, and mSFS at baseline did not achieve statistical significance. Receiver-Operating Characteristic curve analysis showed that the optimal cut-off for WBC count was 13,050/µl. The Kaplan-Meier method showed the cumulative rate of poor treatment outcome to be 60.0% in patients with WBC ≥13,050/µl and 23.5% in those with WBC <13,050/µl.
Conclusions

A higher WBC count but not thrombocytopenia, hyperferritinemia, and mSFS at baseline was a significant prognostic factor for poor treatment outcome at week 4 in this retrospective cohort of AOSD patients. Our findings provide important information for determining the initial treatment strategy of newly-diagnosed AOSD.
Phenotypic Change of Mesenchymal Stem Cells Into Smooth Muscle Cells Regulated By Dynamic Cell-Surface Interactions On Patterned Arrays of Ultrathin Graphene Oxide Substrates
Authors: Park Rowoon , Yoon Jung Won , Lee Jin-Ho , Hong Suck Won , Kim Jae Ho
Published: October 2021

The topographical interface of the extracellular environment has been appreciated as a principal biophysical regulator for modulating cell functions, such as adhesion, migration, proliferation, and differentiation. Despite the existed approaches that use two-dimensional nanomaterials to provide beneficial effects, opportunities evaluating their impact on stem cells remain open to elicit unprecedented cellular responses. Herein, we report an ultrathin cell-culture platform with potential-responsive nanoscale biointerfaces for monitoring mesenchymal stem cells (MSCs). We designed an intriguing nanostructured array through self-assembly of graphene oxide sheets and subsequent lithographical patterning method to produce chemophysically defined regions. MSCs cultured on anisotropic micro/nanoscale patterned substrate were spontaneously organized in a highly ordered configuration mainly due to the cell-repellent interactions. Moreover, the spatially aligned MSCs were spontaneously differentiated into smooth muscle cells upon the specific crosstalk between cells. This work provides a robust strategy for directing stem cells and differentiation, which can be utilized as a potential cell culture platform to understand cell-substrate or cell-cell interactions, further developing tissue repair and stem cell-based therapies.
Optimization of Illumina® Nextera® XT Library Preparation for Analysis of Complete Mitochondrial Genomes from Human Reference Samples
Authors: Sukser Viktorija , Račić Ivana , Rožić Sara , Barbarić Lucija , Korolija Marina
Published: October 2021

Background: Optimized and efficient library preparation workflow is one of the most important prerequisites for obtaining high quality and quantity of results in massively parallel sequencing (MPS). Our aim was to assess and optimize different steps of Illumina® Nextera® XT assay for analysis of whole mitochondrial genomes.Methods and Results: Among the three long-range high-fidelity DNA polymerases tested here, PrimeSTAR® GXL performed best in aspects of specificity and yield for mitochondrial DNA (mtDNA) enrichment. Furthermore, library quantification combined with individual library-by-library dilution outperformed bead-based normalization in terms of more equal distribution of reads per library, reduced hands-on time and simplified workflow. Increasing the number of amplification cycles in the index-adapters-adding PCR step had no adverse effect on the level of sequencing noise, which remained low both in negative controls and in samples.Conclusions: Optimizations described herein provide beneficial insights for laboratories aiming at implementation and/or advancement of similar MPS workflows (e.g. small genomes, PCR amplicons and plasmids).
The Breast Cancer Immune Microenvironment is Modified by Neoadjuvant Chemotherapy
Authors: Urueña Claudia , Lasso Paola , Bernal-Estevez David , Rubio Diego , Salazar Ana Janeth , Olaya Mercedes , Barreto Alfonso , Tawil Mauricio , Torregrosa Lilian , Fiorentino Susana
Published: October 2021

Neoadjuvant chemotherapy (NAT) in breast cancer (BC) has been used to reduce tumor burden prior to surgery. However, the impact on prognosis depends on the establishment of Pathological Complete Response (pCR), which is influenced by tumor-infiltrating lymphocyte levels and the activation of the antitumor immune response. Nonetheless, NAT can affect immune infiltration and the quality of the response. Here, we showed that NAT induces dynamic changes in the tumor microenvironment (TME). After NAT, an increase of regulatory T cells and a decrease of CD8 + T cells was found in tumor, correlated with the presence of metastatic cells in lymph nodes. In addition, an increase of polymorphonuclear myeloid-derived suppressor like cells was found in luminal patients post-NAT. pCR patients showed a balance between the immune populations, while non-pCR patients presented an inverse relationship in the frequency of CD68 + versus CD3 + , CD8 + , and CD20 + cells. Moreover, activated T cells were found in peripheral blood, as well as an increase in T cell clonality with a lower diversity post-NAT. Overall, these results shown that NAT induces an activation of immune response, however, a balance in the TME seems to be related to a better antigenic presentation and therefore a better response to treatment.
Microarray Analysis of Breast Cancer Gene Expression Profiling in Response to 2-Deoxyglucose, Metformin, and Glucose Starvation
Authors: Aoun Rita , Hadi Christopher El , Tahtouh Roula , Habre Rita El , Hilal George
Published: October 2021

Background: Breast cancer (BC) is the most frequently diagnosed cancer in women. Altering glucose metabolism and its effects on cancer progression and treatment resistance is an emerging interest in BC research. For instance, combining chemotherapy with glucose-lowering drugs (2-deoxyglucose (2-DG), metformin) or glucose starvation (GS) has shown better outcomes than with chemotherapy alone. However, the genes and molecular mechanisms that govern the action of these glucose deprivation conditions have not been fully elucidated. Here, we compared the effect of glucose deprivation (2-DG, metformin, GS) on MDA-MB-231 and MCF-7 BC cell lines using microarray analysis to establish a database of differentially expressed genes and enrichment pathways, in order to investigate the beneficial effect of glucose-lowering treatments on the vulnerability of BC cells.Methods: MDA-MB-231 and MCF-7 cells were treated with 20 mM metformin or 4 mM 2-DG for 48 hours. GS was performed by gradually decreasing the concentration of glucose in the culture medium to 0 g/L with fetal bovine serum over 1 week. Expression profiling was carried out using Affymetrix Human Clariom S microarrays. Differentially expressed genes were obtained from the Transcriptome Analysis Console and enriched using DAVID and R packages.Results: Our results showed that MDA-MB-231 cells were more responsive to glucose deprivation than MCF-7 cells. Endoplasmic reticulum stress response and cell cycle inhibition were detected after all three glucose deprivations in MDA-MB-231 cells and only under the metformin and GS conditions in MCF-7 cells. Induction of apoptosis and inhibition of DNA replication were observed with all three treatments in MDA-MB-231 cells and metformin-treated MCF-7 cells. Upregulation of cellular response to reactive oxygen species and inhibition of DNA repair mechanisms resulted after metformin and GS administration in MDA-MB-231 cell lines and metformin-treated MCF-7 cells. Autophagy was induced after 2-DG treatment in MDA-MB-231 cells and after metformin in MCF-7 cells. Finally, enhanced cell-cell adhesion and inhibition of DNA methylation and cholesterol biosynthesis were observed with GS only in MDA-MB-231 cells. Conclusion: GS had the greatest effect on breast cancer cells compared to 2-DG and metformin. Our results suggest that the combination of metformin and GS should weaken both cell lines and makes them more vulnerable to conventional chemotherapy.
Six-month decline of serum anti-spike S1 subunit IgA in SARS-CoV-2 in seronegative healthcare workers after mRNA-based COVID-19 vaccination
Authors: Salvagno Gian Luca , Henry Brandon M. , Pighi Laura , De Nitto Simone , Lippi Giuseppe
Published: October 2021

Background: Since serum anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) IgA antibodies correlate with secretory anti-SARS-CoV-2 IgA and contribute to virus neutralization, we planned an observational study to measure serum anti-SARS-CoV-2 IgAs kinetics throughout a 6-month period in coronavirus disease 2019 (COVID-19) vaccine recipients.Methods: The study sample consisted of 97 baseline SARS-CoV-2 seronegative healthcare workers (median age 42 years and IQR 31-52 years; 52 females), who underwent vaccination with Pfizer/BioNTech Comirnaty mRNA-based vaccine (two 30 µg doses, 21 days apart). Serum samples were collected at baseline, before the second vaccine dose (i.e., day 21), and then 51, 111 and 201 days after enrolment (i.e., 1, 3 and 6 months after the second vaccine dose). Serum anti-SARS-CoV-2 spike S1 subunit IgA were measured with Anti-SARS-CoV-2 ELISA IgA (Euroimmun, Lübeck, Germany).Results: Anti-SARS-CoV-2 spike S1 subunit IgA displayed a peak at 1 month after the second vaccine dose, but then progressively waned afterwards. The 6-month serum anti-spike S1 subunit IgA concentration was 71% lower than the peak concentration. The rate of subjects with positive IgA values was 0% at baseline, 80.4% at day 21, 97.9% at day 51, but then declined to 73.2% and 53.6% at 3 and 6 months after the second vaccine dose. Serum anti-spike S1 subunit IgAs measured at 111 and 201 days was significantly lower than at the 51-day peak (both p<0.001). Significant inverse correlation was found between anti-SARS-CoV-2 IgA antibodies decline at 6 months/ and recipients’ age (r=-0.24; p=0.019).Conclusion: These findings may provide possible explanation to decreased efficacy of COVID-19 vaccines in preventing SARS-CoV-2 infection 6 months after vaccination.