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A Multifaceted Intervention To Improve Guideline Adherence Among Prescribing Physicians At Surgical Wards
Clinical Therapeutics tariquidar on brain distribution of the ABCB1 substrate (R)-[11C]verapamil in elderly versus young subjects. Methods: We performed two consecutive (R)-[11C]verapamil PET scans, before and 3 hours after intravenous infusion of the ABCB1 inhibitor tariquidar at an intermediate dose of 3 mg/kg body weight, in five young (mean age: 26 ± 1 years) and five elderly (mean age: 68 ± 6 years) healthy male volunteers. PET imaging was accompanied by arterial blood sampling and data were analyzed by kinetic modelling to estimate the total distribution volume (VT) of (R)-[11C]verapamil in whole brain gray matter. Results: In baseline scans before ABCB1 inhibition there were no significant differences in (R)-[11C]verapamil VT between the elderly and the young group (VT elderly: 0.78 ± 0.15, young: 0.79 ± 0.10, p = 1.00, Mann Whitney test). In scans after ABCB1 inhibition, VT increases were significantly higher in the elderly group (1.40 ± 0.16-fold) than in the young group (1.02 ± 0.17-fold, p = 0.032). There were no significant differences in the area under the curve of unmetabolized (R)-[11C]verapamil in plasma between the elderly and young group, both for baseline scans and scans after ABCB1 inhibition. Moreover, tariquidar plasma concentrations at the time of the PET scan were not significantly different between the two groups. Conclusions: We found significantly higher increases in brain distribution of (R)-[11C]verapamil in response to ABCB1 inhibition in elderly versus young subjects, which suggests an elevated risk for ABCB1-mediated DDIs at the BBB of elderly subjects due to reduced ABCB1 transport activity.
Learning by Doing in the Student-Run Pharmacovigilance Programme T. Schutte1,2; J. Tichelaar1,2; M.O. Reumerman1,2; R. van Eekeren3,4; L. Rolfes3,4; E.P. van Puijenbroek3,4; M.C. Richir1,2; and M.A. van Agtmael1,2 1 VU University Medical Center, Amsterdam, The Netherlands; 2 RECIPE (Research & Expertise Center In Pharmacotherapy Education), Amsterdam, The Netherlands; 3The Netherlands Pharmacovigilance Centre Lareb (Lareb), ‘s Hertogenbosch, The Netherlands; and 4University of Groningen, Groningen, the Netherlands Background: Pharmacovigilance, the monitoring of drug safety after marketing approval, depends highly on the adequate reporting of adverse drug reactions (ADRs). To improve pharmacovigilance awareness and future ADR reporting among medical students, we developed and evaluated a student-run pharmacovigilance programme. Methods: In this project, teams of medical students (1st-5th year) assessed real ADR-reports as submitted to the national pharmacovigilance centre. After assessment of causality, including identification of a potential pharmacological explanation for the ADR, they wrote a personalized feedback letter to the reporter and a summary for the EMA and WHO pharmacovigilance databases. This student assessment was then verified and evaluated by Lareb staff, using an E-questionnaire. Student attitudes, intentions, skills, and knowledge of ADR reporting were evaluated with an E-questionnaire before and after participation. Results: From May 2014 to January 2015, 43 students assessed 100 different ADR reports selected by Lareb staff (n= 3). Student assessments were rated as useful (93%), scientifically substantiated (90%), accurate (92%), and complete (92%), and, on average, did not cost Lareb staff extra time. Medical students were positive about ADR reporting. Their awareness of ADR reporting increased significantly following participation and they would be more likely to report ADRs in the future. The students’ knowledge of pharmacovigilance and ADR reporting showed that they had a high overall level of pharmacological understanding.
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Conclusions: The student-run pharmacovigilance programme is a win–win venture. It offers students a valuable “pharmacovigilance experience”, creates awareness in future doctors, and has the potential to increase pharmacovigilance skills and knowledge.
A Multifaceted Intervention To Improve Guideline Adherence Among Prescribing Physicians At Surgical Wards J.M. Bos1; S. Natsch2; P.M.L.A. van den Bemt3; J.L.W. Pot4; J.E. Nagtegaal4; A. Wieringa5; G.J. van der Wilt2; P.A.G.M. De Smet2; and C. Kramers1,2⁎ 1 Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; 2 Radboud University Medical Center, Nijmegen, The Netherlands; 3Erasmus University Medical Centre, Rotterdam, The Netherlands; 4Meander Medical Centre, Amersfoort, The Netherlands; and 5Isala Hospital, Zwolle, The Netherlands Background: The P-REVIEW study, a prospective, multicentre, open intervention study, has shown that an approach of education of the prescriber combined with audit and feedback by the hospital pharmacist can lead to a reduction of drug-related complications among patients at surgical wards.1 In this study we also determined whether such approach improves adherence of prescribing physicians to key pharmacotherapeutic guidelines. Methods: 1435 admissions of 1378 patients who were admitted to surgical, urological or orthopaedic wards during the usual care period and 1195 admissions of 1090 patients during the intervention period were included. An educational program covering pain management, antithrombotics, fluid and electrolyte management, prescribing in the case of renal insufficiency, application of radiographic contrast agents and surgical antibiotic prophylaxis was presented to all prescribers on the participating wards. National and local hospital guidelines were part of this program. Hospital pharmacists performed medication safety consultations, combining medication review of high-risk patients and visits to ward physicians. Primary outcome of the study was the proportion of patients in which the physician did not adhere to one or more of the included guidelines (overall non-adherence). Results: Overall non-adherence decreased significantly during the intervention period (21.8% (193/886)) compared to the usual care period (30.5% (332/1089)). The adjusted odds ratio (OR) was 0.61 (95% CI 0.49-0.76). Figure. Forest plot of nonadherence of prescribers to pharmacotherapeutic measures based on prevailing guidelines.
Conclusions: The P-REVIEW study shows that education and support of the prescribing physician with respect to high-risk patients in surgical departments can improve guideline adherence among prescribing physicians at surgical wards.
Reference 1. Bos JM, van den Bemt PM, Kievit W, Pot JL, Nagtegaal JE, Wieringa A, Van der Westerlaken MML, Van der Wilt GJ, De Smet PAGM, Kramers C. A multifaceted intervention to reduce drug-related complications in surgical patients. Br J Clin Pharmacol. 2016. http:// dx.doi.org/10.1111/bcp.13114
Volume 39 Number 8S
Oral Communications Hepatic Disposition Of [11C] Erlotinib at Micro- and Therapeutic Doses Assessed with Pet Imaging M. Bauer1; A. Matsuda1; B. Wulkersdorfer1; C. Philippe1; L. Nics1; E.M. Klebermass1; J. Stanek2; W. Wadsak1,2; M. Hacker1; M. Zeitlinger1; and O. Langer1,3 1 Medical University of Vienna, Vienna, Austria; 2Centre for Biomarker Research in Medicine-CBmed GmbH, Graz, Austria; and 3AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria Background: The tyrosine kinase inhibitor erlotinib displays large inter-individual variability in plasma PK. Erlotinib undergoes hepatobiliary clearance and is a substrate and/or inhibitor of different hepatic ABC and SLC transporters (P-gp, BCRP, OATPs). In this PET study we assessed hepatic disposition of 11C-erlotinib both at micro- and therapeutic doses to investigate the involvement of carriermediated processes in the hepatic clearance of erlotinib. Methods: Six healthy volunteers (mean age: 27 ± 6 years) underwent two consecutive abdominal [11C]erlotinib PET scans and arterial blood sampling. The first scan was performed after administration of a microdose of 11C-erlotinib (< 20 µg). In the second scan a microdose of 11C-erlotinib was administered at 3 hours after oral treatment with a therapeutic erlotinib dose (300 mg). Radiolabelled metabolites of 11C-erlotinib in plasma were assessed with a solid-phase extraction protocol. PET and blood data were analysed with compartment modelling. Results: During the PET scans only a low amount (< 5%) of radiolabelled metabolites of [11C]erlotinib was detected in plasma both for the micro- and therapeutic dose scans. As compared with the microdose scan, AUC values of concentration-time curves of 11C-erlotinib in plasma were significantly increased in the therapeutic dose scan by 99 ± 27%, whereas AUC values in the liver and liver-to-plasma AUC ratios were decreased by 55 ± 5% and 77 ± 5%, respectively. For the therapeutic dose a significant decrease (-39 ± 18%) in the influx rate constant of 11C-erlotinib from blood into hepatocytes was found, whereas the efflux rate constant from hepatocytes into gall bladder and bile duct remained unchanged. Conclusions: Our data show that liver uptake of a microdose of [11C]erlotinib occurred via a carrier-mediated process, which became inhibited at therapeutic erlotinib doses. Active uptake transport of erlotinib into the liver may account for variability in plasma PK and potentially play a role in transporter-mediated drug interactions.
Posaconazole Tablets Versus Posaconazole Oral Suspension in Lung Transplant Patients: Which Consequences on Immunosuppressive Therapy? E. Gautier-Veyret1,2,3; S. Chanoine1,3; H. Pluchart1; J. Tonini3; X. Fonrose3; J. Claustre1,3; P. Bedouch1,3; and F. Stanke-Labesque1,2,3 1 Univ. Grenoble Alpes, HP2, F-38041 Grenoble, France; 2 INSERM U1042, 38041 Grenoble, France; and 3Centre Hospitalier Universitaire des Alpes, 38043, Grenoble, France Background: Posaconazole (PCZ) is an antifungal agent widely used for prophylaxis of invasive fungal infections in lung transplantation. The new formulation of PZC delayed-release tablets (PCZtab) improves PZC bioavailability and plasma trough concentrations (Cmin) compared to oral suspension formulation (PCZ-susp). Since PZC is a well-known enzymatic inhibitor, we hypothesized that higher PZC exposure attributable to this new formulation could induce a greater drug-drug interaction with immunosuppressive therapies, especially with tacrolimus (TAC).
August 2017
Methods: Lung transplant patients receiving TAC and either PCZtab or both galenic forms between June 2015 and March 2016 were included. PCZ and TAC exposure were respectively assessed by the measurement of plasma or blood Cmin. Results: Eighteen patients (median age [Q1;Q3]= 48.5[34.7;57.4] years; 50% women) were included, among whom 8 received PCZtab only while others received both PCZ galenic forms. In patients (n= 10) who received both PCZ galenic forms, PCZ Cmin were higher for PCZ-tab compared to PCZ-susp (susp: 0.88±0.18 mg/L, n= 48 vs. tab: 1.9±0.44mg/L, n= 62; p< 0.0001). PCZ therapy initiation led to a significant increase in TAC Cmin adjusted on dose (D) (0.002±0.001L-1 before initiation vs. 0.008±0.007L-1 after initiation, p= 0.02). TAC Cmin/D was significantly higher during PCZ-tab treatment compared to PCZ-susp (0.004±0.004L-1 vs. 0.009±0.006L-1, p< 0.0001). A weak correlation was observed between PCZ Cmin/D and TAC Cmin/D for both PCZ galenic forms (PCZ-tab: r= 0.37, p= 0.0001 and PCZ-susp: r= 0.33, p= 0.02). Conclusions: Increased PCZ-Cmin obtained during PCZ-tab treatment was associated with an increased TAC exposure, which could be explained by the higher bioavailability of PCZ with the PCZ-tab formulation and a subsequent enhanced enzymatic inhibition of TAC metabolism.
Public Knowledge, Beliefs, and Behavior Regarding the Use of Antibiotics in Serbia O. Horvat; T. Halgato; A. Tomas; M. Paut-Kusturica; Z. Tomić ; and A. Sabo University of Novi Sad, Medical Faculty, Novi Sad, Serbia Background: A substantial evidence has shown that the general community plays a role in the increase and spread of antibiotic resistance. Thus, the objective of this study was to determine the public knowledge, beliefs, and behavior regarding the use of antibiotics in Serbia. Methods: The survey was conducted on a random sample of 325 adult subjects who consulted general practitioners (GP) at health centers. A self-administered questionnaire included questions on demographic characteristics, knowledge about antibiotics, beliefs and behaviours toward antibiotic use. The study was approved by the Ethical Committees of the Medical Faculty in Novi Sad and the Health Center Bačka Topola.Participants have signed an informed consent. Results: A total of 253 adults participated. The average age was 50.56 ± 17.05 years, and 64.82% of the respondents were women. The mean antibiotic knowledge score was 8.77±2.27. Respondents with with higher education, employed, with a family member working in the heath care sector were significantly more knowledgeable of antibiotics (p< 0.001). Overall, 47.83% of respondents believed that antibiotics could be used to treat common cold. 86.56% believed that frequent and inappropriate antibiotic use was dangerous Among the respondents, 31.62% stated that they used antibiotics without previous physicians’ consultation (self-medication). Although 85% of respondents claimed that antibiotic treatment should be taken as long as their GP prescribed (knowledge), only 61% followed this advice during the last infection (behaviour). Conclusions: Respondents had a relatively adequate knowledge about antibiotics (scoring 8.77 out of maximum 13). However, in further rationalization of the use of antibiotics, effective public education initiative should provide practical and appropriative means to change their behavior. Acknowledgments: This work was supported by the Ministry of Science and Technological Development, Serbia (project No. 41012) and by the Provincial Secretariat for Higher Education and Scientific Research of Vojvodina (project No.: 142-451-3680/2016-02).
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Learning by Doing in the Student-Run Pharmacovigilance Programme T. Schutte1,2; J. Tichelaar1,2; M.O. Reumerman1,2; R. van Eekeren3,4; L. Rolfes3,4; E.P. van Puijenbroek3,4; M.C. Richir1,2; and M.A. van Agtmael1,2 1 VU University Medical Center, Amsterdam, The Netherlands; 2 RECIPE (Research & Expertise Center In Pharmacotherapy Education), Amsterdam, The Netherlands; 3The Netherlands Pharmacovigilance Centre Lareb (Lareb), ‘s Hertogenbosch, The Netherlands; and 4University of Groningen, Groningen, the Netherlands Background: Pharmacovigilance, the monitoring of drug safety after marketing approval, depends highly on the adequate reporting of adverse drug reactions (ADRs). To improve pharmacovigilance awareness and future ADR reporting among medical students, we developed and evaluated a student-run pharmacovigilance programme. Methods: In this project, teams of medical students (1st-5th year) assessed real ADR-reports as submitted to the national pharmacovigilance centre. After assessment of causality, including identification of a potential pharmacological explanation for the ADR, they wrote a personalized feedback letter to the reporter and a summary for the EMA and WHO pharmacovigilance databases. This student assessment was then verified and evaluated by Lareb staff, using an E-questionnaire. Student attitudes, intentions, skills, and knowledge of ADR reporting were evaluated with an E-questionnaire before and after participation. Results: From May 2014 to January 2015, 43 students assessed 100 different ADR reports selected by Lareb staff (n= 3). Student assessments were rated as useful (93%), scientifically substantiated (90%), accurate (92%), and complete (92%), and, on average, did not cost Lareb staff extra time. Medical students were positive about ADR reporting. Their awareness of ADR reporting increased significantly following participation and they would be more likely to report ADRs in the future. The students’ knowledge of pharmacovigilance and ADR reporting showed that they had a high overall level of pharmacological understanding.
e2
Conclusions: The student-run pharmacovigilance programme is a win–win venture. It offers students a valuable “pharmacovigilance experience”, creates awareness in future doctors, and has the potential to increase pharmacovigilance skills and knowledge.
A Multifaceted Intervention To Improve Guideline Adherence Among Prescribing Physicians At Surgical Wards J.M. Bos1; S. Natsch2; P.M.L.A. van den Bemt3; J.L.W. Pot4; J.E. Nagtegaal4; A. Wieringa5; G.J. van der Wilt2; P.A.G.M. De Smet2; and C. Kramers1,2⁎ 1 Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; 2 Radboud University Medical Center, Nijmegen, The Netherlands; 3Erasmus University Medical Centre, Rotterdam, The Netherlands; 4Meander Medical Centre, Amersfoort, The Netherlands; and 5Isala Hospital, Zwolle, The Netherlands Background: The P-REVIEW study, a prospective, multicentre, open intervention study, has shown that an approach of education of the prescriber combined with audit and feedback by the hospital pharmacist can lead to a reduction of drug-related complications among patients at surgical wards.1 In this study we also determined whether such approach improves adherence of prescribing physicians to key pharmacotherapeutic guidelines. Methods: 1435 admissions of 1378 patients who were admitted to surgical, urological or orthopaedic wards during the usual care period and 1195 admissions of 1090 patients during the intervention period were included. An educational program covering pain management, antithrombotics, fluid and electrolyte management, prescribing in the case of renal insufficiency, application of radiographic contrast agents and surgical antibiotic prophylaxis was presented to all prescribers on the participating wards. National and local hospital guidelines were part of this program. Hospital pharmacists performed medication safety consultations, combining medication review of high-risk patients and visits to ward physicians. Primary outcome of the study was the proportion of patients in which the physician did not adhere to one or more of the included guidelines (overall non-adherence). Results: Overall non-adherence decreased significantly during the intervention period (21.8% (193/886)) compared to the usual care period (30.5% (332/1089)). The adjusted odds ratio (OR) was 0.61 (95% CI 0.49-0.76). Figure. Forest plot of nonadherence of prescribers to pharmacotherapeutic measures based on prevailing guidelines.
Conclusions: The P-REVIEW study shows that education and support of the prescribing physician with respect to high-risk patients in surgical departments can improve guideline adherence among prescribing physicians at surgical wards.
Reference 1. Bos JM, van den Bemt PM, Kievit W, Pot JL, Nagtegaal JE, Wieringa A, Van der Westerlaken MML, Van der Wilt GJ, De Smet PAGM, Kramers C. A multifaceted intervention to reduce drug-related complications in surgical patients. Br J Clin Pharmacol. 2016. http:// dx.doi.org/10.1111/bcp.13114
Volume 39 Number 8S
Oral Communications Hepatic Disposition Of [11C] Erlotinib at Micro- and Therapeutic Doses Assessed with Pet Imaging M. Bauer1; A. Matsuda1; B. Wulkersdorfer1; C. Philippe1; L. Nics1; E.M. Klebermass1; J. Stanek2; W. Wadsak1,2; M. Hacker1; M. Zeitlinger1; and O. Langer1,3 1 Medical University of Vienna, Vienna, Austria; 2Centre for Biomarker Research in Medicine-CBmed GmbH, Graz, Austria; and 3AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria Background: The tyrosine kinase inhibitor erlotinib displays large inter-individual variability in plasma PK. Erlotinib undergoes hepatobiliary clearance and is a substrate and/or inhibitor of different hepatic ABC and SLC transporters (P-gp, BCRP, OATPs). In this PET study we assessed hepatic disposition of 11C-erlotinib both at micro- and therapeutic doses to investigate the involvement of carriermediated processes in the hepatic clearance of erlotinib. Methods: Six healthy volunteers (mean age: 27 ± 6 years) underwent two consecutive abdominal [11C]erlotinib PET scans and arterial blood sampling. The first scan was performed after administration of a microdose of 11C-erlotinib (< 20 µg). In the second scan a microdose of 11C-erlotinib was administered at 3 hours after oral treatment with a therapeutic erlotinib dose (300 mg). Radiolabelled metabolites of 11C-erlotinib in plasma were assessed with a solid-phase extraction protocol. PET and blood data were analysed with compartment modelling. Results: During the PET scans only a low amount (< 5%) of radiolabelled metabolites of [11C]erlotinib was detected in plasma both for the micro- and therapeutic dose scans. As compared with the microdose scan, AUC values of concentration-time curves of 11C-erlotinib in plasma were significantly increased in the therapeutic dose scan by 99 ± 27%, whereas AUC values in the liver and liver-to-plasma AUC ratios were decreased by 55 ± 5% and 77 ± 5%, respectively. For the therapeutic dose a significant decrease (-39 ± 18%) in the influx rate constant of 11C-erlotinib from blood into hepatocytes was found, whereas the efflux rate constant from hepatocytes into gall bladder and bile duct remained unchanged. Conclusions: Our data show that liver uptake of a microdose of [11C]erlotinib occurred via a carrier-mediated process, which became inhibited at therapeutic erlotinib doses. Active uptake transport of erlotinib into the liver may account for variability in plasma PK and potentially play a role in transporter-mediated drug interactions.
Posaconazole Tablets Versus Posaconazole Oral Suspension in Lung Transplant Patients: Which Consequences on Immunosuppressive Therapy? E. Gautier-Veyret1,2,3; S. Chanoine1,3; H. Pluchart1; J. Tonini3; X. Fonrose3; J. Claustre1,3; P. Bedouch1,3; and F. Stanke-Labesque1,2,3 1 Univ. Grenoble Alpes, HP2, F-38041 Grenoble, France; 2 INSERM U1042, 38041 Grenoble, France; and 3Centre Hospitalier Universitaire des Alpes, 38043, Grenoble, France Background: Posaconazole (PCZ) is an antifungal agent widely used for prophylaxis of invasive fungal infections in lung transplantation. The new formulation of PZC delayed-release tablets (PCZtab) improves PZC bioavailability and plasma trough concentrations (Cmin) compared to oral suspension formulation (PCZ-susp). Since PZC is a well-known enzymatic inhibitor, we hypothesized that higher PZC exposure attributable to this new formulation could induce a greater drug-drug interaction with immunosuppressive therapies, especially with tacrolimus (TAC).
August 2017
Methods: Lung transplant patients receiving TAC and either PCZtab or both galenic forms between June 2015 and March 2016 were included. PCZ and TAC exposure were respectively assessed by the measurement of plasma or blood Cmin. Results: Eighteen patients (median age [Q1;Q3]= 48.5[34.7;57.4] years; 50% women) were included, among whom 8 received PCZtab only while others received both PCZ galenic forms. In patients (n= 10) who received both PCZ galenic forms, PCZ Cmin were higher for PCZ-tab compared to PCZ-susp (susp: 0.88±0.18 mg/L, n= 48 vs. tab: 1.9±0.44mg/L, n= 62; p< 0.0001). PCZ therapy initiation led to a significant increase in TAC Cmin adjusted on dose (D) (0.002±0.001L-1 before initiation vs. 0.008±0.007L-1 after initiation, p= 0.02). TAC Cmin/D was significantly higher during PCZ-tab treatment compared to PCZ-susp (0.004±0.004L-1 vs. 0.009±0.006L-1, p< 0.0001). A weak correlation was observed between PCZ Cmin/D and TAC Cmin/D for both PCZ galenic forms (PCZ-tab: r= 0.37, p= 0.0001 and PCZ-susp: r= 0.33, p= 0.02). Conclusions: Increased PCZ-Cmin obtained during PCZ-tab treatment was associated with an increased TAC exposure, which could be explained by the higher bioavailability of PCZ with the PCZ-tab formulation and a subsequent enhanced enzymatic inhibition of TAC metabolism.
Public Knowledge, Beliefs, and Behavior Regarding the Use of Antibiotics in Serbia O. Horvat; T. Halgato; A. Tomas; M. Paut-Kusturica; Z. Tomić ; and A. Sabo University of Novi Sad, Medical Faculty, Novi Sad, Serbia Background: A substantial evidence has shown that the general community plays a role in the increase and spread of antibiotic resistance. Thus, the objective of this study was to determine the public knowledge, beliefs, and behavior regarding the use of antibiotics in Serbia. Methods: The survey was conducted on a random sample of 325 adult subjects who consulted general practitioners (GP) at health centers. A self-administered questionnaire included questions on demographic characteristics, knowledge about antibiotics, beliefs and behaviours toward antibiotic use. The study was approved by the Ethical Committees of the Medical Faculty in Novi Sad and the Health Center Bačka Topola.Participants have signed an informed consent. Results: A total of 253 adults participated. The average age was 50.56 ± 17.05 years, and 64.82% of the respondents were women. The mean antibiotic knowledge score was 8.77±2.27. Respondents with with higher education, employed, with a family member working in the heath care sector were significantly more knowledgeable of antibiotics (p< 0.001). Overall, 47.83% of respondents believed that antibiotics could be used to treat common cold. 86.56% believed that frequent and inappropriate antibiotic use was dangerous Among the respondents, 31.62% stated that they used antibiotics without previous physicians’ consultation (self-medication). Although 85% of respondents claimed that antibiotic treatment should be taken as long as their GP prescribed (knowledge), only 61% followed this advice during the last infection (behaviour). Conclusions: Respondents had a relatively adequate knowledge about antibiotics (scoring 8.77 out of maximum 13). However, in further rationalization of the use of antibiotics, effective public education initiative should provide practical and appropriative means to change their behavior. Acknowledgments: This work was supported by the Ministry of Science and Technological Development, Serbia (project No. 41012) and by the Provincial Secretariat for Higher Education and Scientific Research of Vojvodina (project No.: 142-451-3680/2016-02).
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