Impact of Differences in Economic Development and Socioeconomic Stability on Benzodiazepine Exposure between the Three Balkans Countries.

INTRODUCTION: Anxiety disorders are among the most common mental disorders. Benzodiazepines belong to the group of anxiolytic sedatives and the most prescribed drugs in the world. The aim in ours study was to evaluate the differences in the exposure of the population to benzodiazepines (in period from 2014-2018) between Serbia, Slovenia and Croatia, the three countries of the Southwestern Balkans with varying degrees of socioeconomic development. STUDY DESIGN: A academic investigator initiated, pharmacoepidemiological difference-in-difference time series analysis of population exposure to benzodiazepines between the three, geographically close Balkans countries (Slovenia, Serbia, Croatia) with varying degrees of socioeconomic development has been carried out. Study was conducted as academic investigator initiated, in a retrospective manner on monthly basis international data set from January 2014 to December 2018. RESULTS: At the annual level, during the study period from January 2014 to December 2018, compared to Slovenia, Serbia and Croatia had higher DIDs, from 5 fold (Croatia) to 6 fold (Serbia), for all benzodiazepines in total. By analyzing the differences-in-difference, we have shown that influence of both time (month) and country on DIDs is significant as well as their mutual interaction (the country x month) for all benzodiazepines in total. CONCLUSION: Serbia and Croatia must implement explicit measures of reducing benzodiazepine prescription in health primary care based on evidence-based recommendations in the indications where general medicine practitioners/family doctors most commonly prescribe these medicines. Without providing a realistic supplement/alternative to benzodiazepines such as increasing the availability of psychotherapy and improving the structure of psychiatric professionals in healthcare settings, implicit measures are not recommended for reducing prescription, implementing accountability measures for prolonged prescription of benzodiazepines, and in particular for "masked" somatic diseases. All this comes to the fore by raising economic development and socioeconomic stability.

Can didactic continuing education improve clinical decision making and reduce cost of quality? Evidence from a case study.

INTRODUCTION: Administration of human serum albumin (HSA) solutions for the resuscitation of critically ill patients remains controversial. The objective of this study was to assess the effect of continuing medical education (CME) on health care professionals' clinical decision making with regard to HSA administration and the costs of quality (COQ). A quasi-experimental study of time series association of CME intervention with COQ and use of HSA solution was conducted at the Surgery Department of the Hospital Valjevo, Serbia. The CME contained evidence-based criteria for HSA solution administration in surgical patients. The preintervention period was defined as January 2009 to May 2011. CME was provided in June 2011, with the postintervention period June 2011 to May 2012. METHODS: Total mortality rate, the rate of nonsurgical mortality, the rate of surgical mortality, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and number of hospital days per hospitalized patient were collected for each month as quality indicators. Statistical analysis was performed by multivariate autoregressive integrated moving average (MARIMA) modeling. The specification of the COQ was performed according to a traditional COQ model. RESULTS: The CME intervention resulted in an average monthly reduction of the hospital days per hospitalized patient, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and COQ for $593,890.77 per year. DISCUSSION: Didactic CME presenting evidence-based criteria for HSA administration was associated with improvements in clinical decisions and COQ. In addition, this study demonstrates that models combining MARIMA and traditional COQ models can be useful in the evaluation of CME interventions aimed at reducing COQ.

[Reductions in anesthesia direct costs is not the right way for racionalization of anesthesia costs].

INTRODUCTION: Anesthesia management is characterized by salary limiting and pressure for decreasing anesthetics and other drug budget. The aim of this paper is to determine the possibility of reducing the direct costs in anesthesia. MATERIALS AND METHODS: This paper is a part ofa five-year (2005-2009), academic, pharmaco-economic retrospective- prospective study (phase IV). The study was done according to European Union Directive for Clinical Research. We retrospectively calculated and analyzed all anesthesia direct costs (personnel costs, anesthetics and other drug costs, materials, laboratory analyses, and machines) at the Institute For Ane- sthesia and Reanimation, Clinical Center of Serbia in relation to the costs refunded by National Health Insurance in all patients who underwent anesthesia in 2006. RESULTS: Out of 70 195 anesthesia services rendered to 32 267 patients in one-year period, 47% were general anesthesia, 23% were local anesthesia, and 30% were anesthetic procedures. Our results of highly significant association between personnel costs (r = 0.980, p = 0.000) and consumption of anesthetics and drugs (r = 0.885, p = 0.000) with the direct costs do not provide an opportunity for further cost reduction due to disassociation of direct costs and the "unit price" of National Health Insurance issued in terms of the restricted maximum budget for health. CONCLUSION: There is no space for direct cost reduction in anesthesia.

Serotonergic organization of the central nervous system.

The last 50 years of researches of biochemism and the CNS functionality are intensively engaged in studying the role of monoamine neurotramsmitter serotonin (5-hydroxytryptamin) (5-HT). The serotonergic receptors function depends on spot where the receptor function, the dynamic relationship with other transmitters and stimulation that can activate or inhibit specific neurons. The results of research in biochemistry, neurophysiology and neuroradiology have provided insight into the complexity of the operation of key structures such as the amygdala, prefrontal cortex and hippocampus, whose role varies depending on the received external impulses and the impulses that are sent to relevant areas. This implies that the transmitters and especially 5-HT, have much wider effects that are determined not to structures but by the impulse dynamics. It also means that psychopharmaceutical drugs whose therapeutic effect is based on the change of the concentration of serotonin in the synapse and the postsynaptic receptors depending on where they operate, have an effect on affective or cognitive symptoms. Serotonergic antidepressants by changing the concentration of serotonin change primarily affective manifestations but also they have significant influence on all the spectrum of serotonergic disorders not only emotional, but also the cognitive level, which is also a confirmation that the therapeutic effects do not depend only on the simple change of serotonin concentration but also of the level where these changes occur in dynamic comparison of key transmitters. Atypical antipsychotics which have low affinity for dopaminergic and high affinity for serotonergic receptors are seen through the dynamic relationship of serotonin, dopamine and noradrenalin in nigrostriatal, mezocortical, mezolimbic and tuberoinfudibular pathways.

[Awareness detection in anaesthesia during otorhino-maxillofacial surgery using bispectral index-monitoring technology].

INTRODUCTION: Awareness is characterized by intraoperative presence of consciousness and recollecting of the events occurring during general anaesthesia. The study was aimed at detecting awareness during general anaesthesia in otorhino-maxillofacial procedure. METHODS: The study is a part of a prospective, phase IV academic study carried out at the Department for Otorhinolaringology, Clinical Centre of Serbia, and Maxillofacial Surgery. The study was approved by the Ethics Committee of the Clinical Centre of Serbia and performed in accordance with European Union Clinical Trials Directive. The evaluation included 40 patients (T-propofol and E-sevofluran group) subjected to different surgical procedures (American Society ofAnesthesiologists I-III). Depth of anaesthesia was monitored during surgical procedures according to the hemodynamic parameters (blood pressure, pulse, oxygen saturation, electrocardiography, capnometry). Bispectral index monitoring was applied; however, the insight into the obtained bispectral index values was possible only after the completion of the surgery when the comparison with hemodynamic values was performed. Modified Brice interview was postoperatively applied to the patients in whom awareness was suspected. RESULTS: Based on the hemodynamic parameter values obtained in 40 anesthetized patients, no cases of awareness were expected. After the completion of the surgical procedures, the recorded graphic and numeric bispectral index values obtained in the course of anaesthesia were analyzed. Higher bispectral index values (BIS > 60) were recorded in 1 T-group patient. CONCLUSION: It is possible to miss an awareness episode without using bispectral index technology monitoring during general anaesthesia in otorhinolaryngology and maxillofacial surgery. Bispectral index monitoring should be the clinical standard in general anaesthesia.

[Anesthetic dose correction in hospital pharmacology using bispectral index monitoring technology].

INTRODUCTION: Modern hospital pharmacology insists on assessing each patient's individual characteristics because of their influence on drug pharmacokinetics and pharmacodynamic effect. The study was aimed at evaluating anesthetic doses in patients with benign larynx tumors treated by general endotracheal anesthesia during endoscopic surgery procedures. MATERIAL AND METHODS: The study is a part of a prospective, phase IV, academic study carried out at the Clinical Center of Serbia. The evaluation included 30 patients, who were divided into two groups: Group A - 10 patients, anesthetized with standard recommended anesthetic doses. The insight into the obtained bispectral index values was possible only after completion of the surgery. Group B consisted of 20 patients, anesthetized with anesthetic doses corrected according to bispectral index monitoring values. RESULTS: The average duration of waking up in group A and B was 120.0 +/- 10.0 sec and B 70.0 +/- 9.0 sec, respectively, (p<0.01). When compared with group A the corrected induction anesthetic doses, corrected maintenance doses and anesthetic total consumption were lower in group B by 25% (p<0.01), 15% (p<0.01) and 25% (p<0.01), respectively. CONCLUSION: It is possible to overdose anesthetic drug during surgery without using bispectral index technology monitoring during general anesthesia in otorhinolaryngology maxillofacial surgery. Bispectral index monitoring should be the clinical standard in general anesthesia.

[Costs of anesthetics and other drugs in anesthesia].

INTRODUCTION: Drugs are real and transparent costs of treatment, which are subject to constant monitoring and changes. The study was aimed at measuring and analyzing consumption of anesthetics and other drugs in anesthesia in the Clinical Centre of Serbia. MATERIAL AND METHODS: This paper is part of a five-year (2005-2009), academic, pharmacoeconomic retrospective-prospective study (the 4th phase). We calculated the costs of anesthetics and other drugs in all anesthetized patients at the Institute of Anesthesia and Reanimation, Clinical Center of Serbia in 2006. The data, obtained from the Clinical Centre of Serbia Database, were analyzed by descriptive statistical methods using computer program Microsoft Office Excel 2003 and the Statistical Package for the Social Sciences (SPSS) for Windows. RESULTS: The amount of money spent for the application of 33,187 general and 16,394 local anesthesia and 20,614 anesthesiology procedures was 83,322,046.36 RSD (Euros 1,054,705.4), which was 5.93% of the funds allocated for all drugs used at the Clinical Center of Serbia. Of the total fund for drugs, 57.8% was spent for anesthetics (local anesthetics 1.20%) and muscle relaxants, whereas 42.2% was spent for other drugs in anesthesia. The highest amount was spent at the Emergency Center (35.8%), then at the Cardio-surgery (11.9%) and the Neurosurgery (10.9%) because of the large number and length of surgical interventions. CONCLUSION: There is no space for rationalizing the costs of anesthetics and other drugs in anesthesia.

Prevalidation of salivary biomarkers for oral cancer detection.

BACKGROUND: Oral cancer is the sixth most common cancer with a 5-year survival rate of approximately 60%. Presently, there are no scientifically credible early detection techniques beyond conventional clinical oral examination. The goal of this study is to validate whether the seven mRNAs and three proteins previously reported as biomarkers are capable of discriminating patients with oral squamous cell carcinomas (OSCC) from healthy subjects in independent cohorts and by a National Cancer Institute (NCI)-Early Detection Research Network (EDRN)-Biomarker Reference Laboratory (BRL). METHODS: Three hundred and ninety-five subjects from five independent cohorts based on case controlled design were investigated by two independent laboratories, University of California, Los Angeles (Los Angeles, CA) discovery laboratory and NCI-EDRN-BRL. RESULTS: Expression of all seven mRNA and three protein markers was increased in OSCC versus controls in all five cohorts. With respect to individual marker performance across the five cohorts, the increase in interleukin (IL)-8 and subcutaneous adipose tissue (SAT) was statistically significant and they remained top performers across different cohorts in terms of sensitivity and specificity. A previously identified multiple marker model showed an area under the receiver operating characteristic (ROC) curve for prediction of OSCC status ranging from 0.74 to 0.86 across the cohorts. CONCLUSIONS: The validation of these biomarkers showed their feasibility in the discrimination of OSCCs from healthy controls. Established assay technologies are robust enough to perform independently. Individual cutoff values for each of these markers and for the combined predictive model need to be further defined in large clinical studies. IMPACT: Salivary proteomic and transcriptomic biomarkers can discriminate oral cancer from control subjects.

[Operating cost analysis of anaesthesia: activity based costing (ABC analysis)].

INTRODUCTION: Cost of anaesthesiology represent defined measures to determine a precise profile of expenditure estimation of surgical treatment, which is important regarding planning of healthcare activities, prices and budget. OBJECTIVE: In order to determine the actual value of anaestesiological services, we started with the analysis of activity based costing (ABC) analysis. METHODS: Retrospectively, in 2005 and 2006, we estimated the direct costs of anestesiological services (salaries, drugs, supplying materials and other: analyses and equipment.) of the Institute of Anaesthesia and Resuscitation of the Clinical Centre of Serbia. The group included all anesthetized patients of both sexes and all ages. We compared direct costs with direct expenditure, "each cost object (service or unit)" of the Republican Healthcare Insurance. The Summary data of the Departments of Anaesthesia documented in the database of the Clinical Centre of Serbia. Numerical data were utilized and the numerical data were estimated and analyzed by computer programs Microsoft Office Excel 2003 and SPSS for Windows. We compared using the linear model of direct costs and unit costs of anaesthesiological services from the Costs List of the Republican Healthcare Insurance. RESULTS: Direct costs showed 40% of costs were spent on salaries, (32% on drugs and supplies, and 28% on other costs, such as analyses and equipment. The correlation of the direct costs of anaestesiological services showed a linear correlation with the unit costs of the Republican Healthcare Insurance. CONCLUSION: During surgery, costs of anaesthesia would increase by 10% the surgical treatment cost of patients. Regarding the actual costs of drugs and supplies, we do not see any possibility of costs reduction. Fixed elements of direct costs provide the possibility of rationalization of resources in anaesthesia.

Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population.

Early detection of oral squamous cell cancer (OSCC) is the key to improve the low 5-year survival rate. Using proteomic and genomic technologies we have previously discovered and validated salivary OSCC markers in American patients. The question arises whether these biomarkers are discriminatory in cohorts of different ethnic background. Six transcriptome (DUSP1, IL8, IL1B, OAZ1, SAT1, and S100P) and three proteome (IL1B, IL8, and M2BP) biomarkers were tested on 18 early and 17 late stage OSCC patients and 51 healthy controls with quantitative PCR and ELISA. Four transcriptome (IL8, IL1B, SAT1, and S100P) and all proteome biomarkers were significantly elevated (p<0.05) in OSCC patients. The combination of markers yielded an AUC of 0.86, 0.85 and 0.88 for OSCC total, T1-T2, and T3-T4, respectively. The sensitivity/specificity for OSCC total was 0.89/0.78, for T1-T2 0.67/0.96, and for T3-T4 0.82/0.84. In conclusion, seven of the nine salivary biomarkers (three proteins and four mRNAs) were validated and performed strongest in late stage cancer. Patient-based salivary diagnostics is a highly promising approach for OSCC detection. This study shows that previously discovered and validated salivary OSCC biomarkers are discriminatory and reproducible in a different ethnic cohort. These findings support the feasibility to implement multi-center, multi-ethnicity clinical trials towards the pivotal validation of salivary biomarkers for OSCC detection.

[Radiotherapeutical chromosomal aberrations in laryngeal cancer patients]. / Radioterapijska ostecenja hromozoma kod karcinoma larinksa.

INTRODUCTION: The authors present the results of cytogenetic analysis of 21 patients with laryngeal carcinomas diagnosed and treated in the period 1995-2000 at the Institute of Otorhinolaryngology and Maxillofacial Surgery, Clinical Center of Serbia and Clinical Center of Novi Sad. MATERIAL AND METHODS: The patients were specially monitored and the material was analyzed at the Institute of Human Genetics of the School of Medicine in Belgrade as well as in the Laboratory for Radiological Protection of the Institute of Occupational and Radiological Health "Dr Dragomir Karajovic" in Belgrade. RESULTS: The incidence of chromosomal aberrations and incidence of exchange of material between sister chromatids were observed in the preparation of the metaphasic lymphocyte chromosomes of the peripheral blood obtained in the culture. Structural aberrations were found on the chromosomes in the form of breakups, rings, translocations and dicentrics as early as after a single exposure of patients to tumor radiation dose of 2 Gy in the field sized 5x7. Out of the total number of 35 cultivated blood samples obtained from 13 patients, 21 were successfully cultivated and they were proved to contain chromosomal aberrations. Some of the peripheral blood samples failed to show cell growth in vitro due to the lethal cell damages in vivo. DISCUSSION: We have concluded that the number of structural aberrations cannot be used as a biological measure of the absorbed ionizing radiation dose. The presence of aberrations per se is indicative of the mutagenic effect of the ionizing radiation, which was also confirmed in our series on the original model by cultivation of the peripheral blood lymphocytes in the culture of the cells of the volunteer donors upon in vitro radiation. Using the method of bromdeoxyuridylreductase, the increased incidence of SCE as a mutagenic effect was registered. CONCLUSION: It has been concluded that the increase of absorbed radiation dose in vitro leads to prolonged duration of cell cycle in the same conditions, which proves cytostatic effect of radiation. Further fundamental studies are required for clinical implementation of the findings.

Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection.

PURPOSE: We have previously shown that a transcriptome is found in saliva and subpanels of these mRNAs can be used as oral cancer biomarkers. In this study, we measured the presence of microRNAs (miRNA) in saliva and determined their potential as an additional set of oral cancer biomarkers. EXPERIMENTAL DESIGN: A total of 314 miRNAs were measured using reverse transcriptase-preamplification-quantitative PCR in 12 healthy controls. Degradation pattern of endogenous and exogenous saliva miRNAs were measured at room temperature over time. Selected miRNAs were validated in saliva of 50 oral squamous cell carcinoma patients and 50 healthy matched control subjects. RESULTS: We detected approximately 50 miRNAs in both the whole and supernatant saliva. Endogenous saliva miRNA degraded much slower compared with exogenous miRNA. Two miRNAs, miR-125a and miR-200a, were present in significantly lower levels (P < 0.05) in the saliva of oral squamous cell carcinoma patients than in control subjects. CONCLUSIONS: Both whole and supernatant saliva of healthy controls contained dozens of miRNAs, and similar to saliva mRNAs, these miRNAs are stable. Saliva miRNAs can be used for oral cancer detection.

Head-neck cancer drug therapy--could it be improved?

Head-neck cancer is an area requiring more attention to a highly demanding therapy which has not been fully developed yet. Despite advances in diagnosis and treatment, including improvements of surgical techniques, radio- and chemotherapy and prevention strategies, the survival rates of patients with recurrent head-neck cancer are low. New drugs, including those targeting the epidermal growth factor receptor, p53 gene, RAS protein post-translation modification, the proteosome, vascular endothelial growth factor, cyclooxigenase-2 and other molecular pathways, are promising agents for management of head-neck cancer. Their potential is being tested in various settings, including chemoprevention, recurrent and metastatic disease and combination with radiotherapy and/or cytotoxic agents. Cytotoxic drugs could produce better effects if administered locally--laser thermal cisplatin application. The metronomic low-dose chemotherapy will prove effective. The anticoagulant therapy undoubtedly has its place. The potential lies in sound ongoing academic clinical trial--biomarkers leading to maximally promising pharmacogenomic based therapy. Better comprehension of tumor biology and mechanisms of resistance is necessary as well as the institution of reliable assays for clinical use.

Carvedilol increases copper-zinc superoxide dismutase activity in patients with acute myocardial infarction.

Balanced and coordinated antioxidant defence enzyme activities are of utmost importance for correct physiological function and for shielding against unwelcome pathological conditions. We determined the activities of copper-zinc superoxide dismutase (CuZnSOD), catalase, glutathione peroxidase and glutathione reductase in erythrocytes isolated from patients receiving different therapy (streptokinase alone or in combination with metoprolol or with carvedilol) for up to 168 hr after starting treatment for acute myocardial infarction. We observed increased CuZnSOD activity in erythrocytes isolated from patients treated with streptokinase-carvedilol (after 6, 24 and 168 hr) and in erythrocytes isolated from patients treated with streptokinase-metoprolol (after 24 hr). In addition, positive correlation between CuZnSOD and catalase activities was found in erythrocytes isolated from patients that received streptokinase-carvedilol after 168 hr. As metoprolol does not react directly with hydrogen peroxide, it would appear that combined streptokinase-metoprolol therapy exerted its effects primarily via by beta-blockade whereas combined streptokinase-carvedilol therapy appeared to function via both beta-blockade and direct antioxidant mechanisms.

[Effects of nitrous oxide on middle ear pressure].

INTRODUCTION: Recent literature data suggest that permanent or reversible hearing loss may occur after general anesthesia. The etiology varies, while hearing loss following middle ear surgery is attributed to exposure to nitrous oxide (N,0). The objective of our study was to measure, using tympanometry, the middle air pressure change caused by nitrous oxide during general anesthesia and to establish its emetogenic effects during the postoperative period. MATERIAL AND METHODS: This academic (non-commercial) prospective study included two groups of patients (a total of 58), with ASA status I, II and III. The study group (n 30) consisted of patients undergoing unilateral ear surgery. In this group, the intratympanic pressure was measured in the unoperated (healthy) ear before and during the surgery. The control group (n 28) patients underwent nose, throat or neck surgical interventions. This group underwent measurement of bilateral intratympanic pressure in healthy ears, before and during the surgery. Both groups were operated under general balanced anesthesia. Pain, nausea and antiemetics were monitored during the first 24 postoperative hours. Statistical analysis was performed using the Mann-Whitney-Wilcoxon test. RESULTS: This perioperative study confirmed the following: highly significant (p < 0.001) increase in intratympanic pressure in nonoperated ears in the study group and significant (p < 0.05) in controls. However, there was no statistical significance (p > 0.05) between groups. Pain was more freguent in controls, and nausea in the study group, but without significant difference (p > 0.05). CONCLUSIONS: Postoperative audiometry findings showed no conductive or sensorineural hearing loss after interventions. Nitrous oxide can be used in general balanced anesthesia with discontinuation 15 to 45 minutes before insertion of the tvmpanic membrane and completion of middle ear surgery.

Antibiotic consumption monitoring at the Institute of Otorhinolaryngology and Maxillofacial Surgery--Clinical Center of Serbia in 2001-2003.

BACKGROUND: At the Clinical Center of Serbia (CCS), which includes 21 Institutes and 6 Centers, approximately 10% of the total annual budgetary funds is spent on the drugs. During the studied period, it was estimated that 0.5% of the above amount has been spent at the Institute for Otorhinolaryngology and Maxillofacial surgery (Institute for ORL and MFS), Clinical Center of Serbia. The aim of this study was to find out if these antibiotics had been used rationally by the monitoring of antibiotics in relation to the number of inpatients, and by the 5 most frequent diagnoses. METHODS: The authors monitored the three-year consumption of antibiotics for inhospital treated patients during the period 2001-2003. Data were obtained from the itemized quarterly report on the consumption by the Central Pharmacy of the CCS. RESULTS: The results were statistically analyzed and presented in percentages and Defined Daily Dosages (DDD) for each group of the antibiotics. The results were analyzed in accordance with the World Health Organization Recommendations and the Guidelines. CONCLUSION: The authors concluded that antibiotics were adequately used at the Institute for ORL and MFS-CCS. The most commonly used antibiotics for gram-positive infections were those from the penicillin and cephalosporin groups. According to the international trends and recommendations, the selected therapy was rational and the antibiotics consumption was cut down during the observed three-year period. It was a true confirmation that the recommendations for the rational antibiotics consumption had been fruitful (produced good results).