SMT-Friendly Formalization of the Solidity Memory Model

Solidity is the dominant programming language for Ethereum smart contracts. This paper presents a high-level formalization of the Solidity language with a focus on the memory model. The presented formalization covers all features of the language related to managing state and memory. In addition, the formalization we provide is effective: all but few features can be encoded in the quantifier-free fragment of standard SMT theories. This enables precise and efficient reasoning about the state of smart contracts written in Solidity. The formalization is implemented in the solc-verify verifier and we provide an extensive set of tests that covers the breadth of the required semantics. We also provide an evaluation on the test set that validates the semantics and shows the novelty of the approach compared to other Solidity-level contract analysis tools.Comment: Authors' manuscript. Published in P. M\"uller (Ed.): ESOP 2020, LNCS 12075, 2020. The final publication is available at Springer via https://doi.org/10.1007/978-3-030-44914-8_

The influence of local anesthetic on pain after laparoscopic cholecystectomy

UVOD. Bilijarna kalkuloza je najčešće oboljenje hepatobilijarnog sistema, a holecistektomija predstavlja jedan od najčešće izvođenih operativnih zahvata. Laparoskopska holecistektomija je danas zlatni standard lečenja holelitijaze. Laparoskopska holecistektomija je pokazala poboljšanje u klinički značajnim ishodima kao što su skraćenje operativnog vremena, kraća hospitalizacija, smanjenje jačine i trajanja postoperativnog bola i brži povratak dnevnim i radnim aktivnostima. Postoperativna bol i vreme potpunog oporavka ostaju dva glavna problema posle nekomplikovane laparoskopske holecistektomije koje bi trebalo poboljšati. Bol koji je povezan sa laparoskopskom holecistektomijom je kompleksan i multifaktorijalan. On nastaje oštećenjem tkiva, disekcijom i uklanjanjem žučne kesice iz svoje lože, stimulacijom periportalnih nerava, iritacijom dijafragme, mehaničkim i hemijskim interakcijama gasa i pneumoperitoneuma, incizijama portova. Istraživanja su označila parijetalni i visceralni bol kao dva glavna mehanizma nastanka bola kod laparoskopske holecistektomije. Bol se ne može meriti nego proceniti jer je subjektivni osećaj. Pokazalo se potrebnim da se na čvršćim naučnim osnovama da odgovor na pitanje da li je moguće blokirati parijetalni i visceralni bol posle laparoskopske holecistektomije u akutnoj fazi. CILJEVI. Cilj studije je da uporedi standardnu analgeziju (ne-opioidnu) (grupa O) sa davanjem parijetalne blokade (grupa P), ili davanjem visceralne blokade (grupa V), ili sa obe date blokade (grupa P+V). Primarni ishodi studije su bolesnikov procenjeni bol pre operacije i posle operacije na 1, 2, 4, 6, 12, 24, 48 sati i 7. dana. Sekundarni ishodi studije su bolesnikova procenjena mučnina na 1,2,4,6,12 sati i bolesnikova procenjena mobilnost 1. 2. i 7. dan. HIPOTEZA. Blokada postoperativnog visceralnog bola i blokada postoperativnog parijetalnog bola posle laparoskopske holecistektomije putem intraperitonealne lokalne infiltracije anestetikom i putem lokalne infiltracije anestetikom pristupnih laparoskopskih portova može značajno smanjiti rani postoperativni bol. MATERIJAL I METODE. Ova prospektivna, randomizirana jednostruko slepa studija je započela septembra 2014. godine i trajala je do januara 2016. godine. Istraživanje je sprovedeno na Klinici za abdominalnu, endokrinu i transplantacionu hirurgiju i Urgentnom centru Kliničkog centra Vojvodine u Novom Sadu kod bolesnika operisanih metodom laparoskopske holecistektomije. Rad je podeljen u nekoliko celina. 1. Procena veličine uzorka; 2. Procena podobnosti za studiju; 3. Anketiranje i uključivanje u studiju; 4. Razvrstavanje u grupe i operativni rad; 5. Period postoperativnog praćenja; 6. Statistička obrada i pisanje rada. 1. Procena veličine uzorka. Studija je realizovana podelom bolesnika u 4 grupe. Neophodni broj bolesnika je izračunat uzimajući podatke iz pilot istraživanja slične studije iz 2012. godine. Veličina uzorka je računata za primarni ishod studije  (bolesnikov procenjen bol sa NAS) na pretpostavci da treba biti 20% smanjenja bola u prvom postoperativnom satu, uz verovatnoću Tip 1 greške α=0.05 i Tipa 2 greške β=0.10 da postigne adekvatnu statističku snagu oko 80% i da otkrije 20% razlike u srednjoj vrednosti procenjenog bola jedan sat nakon laparoskopske  holecistektomije. Procenjeni broj ispitanika po grupama prema zadatim kriterijumima je bio (P+V=65; P=68; V=68; O=65). Studija je započela uključivanjem prvog bolesnika u studiju a završena ispunjenim periodom praćenja sve dok poslednji bolesnik nije doneo upitnike o bolu, mučnini i kretanju. 2. Procena podobnosti za studiju. U periodu studije ukupan broj holecistektomiranih bolesnika je bio 1024 (440 klasično i 584 laparoskopski). Samo pogodni bolesnici su anketirani (584) i pročitali su informacioni list o istraživanju. Uključivanje ili procena podobnosti bolesnika za studiju sprovedena je na osnovu uključnih i isključnih kriterijuma. U studiju nije uključeno ukupno 226 bolesnika. Od tog broja 82 bolesnika je odbilo učestvovati u studiji a 144 bolesnika nije ispunilo uključne postavljene kriterijume. Svojim potpisom potvrdilo je učešće u studiji 358 bolesnika. 3. Anketiranje i uključivanje u studiju. Nakon prijema bolesnika u bolnicu ispitivači su uzimali anamnezu i bolesnicima je ponuđen informacioni list i informisani pristanak. Nakon čitanja informacije, potpisivanja informisanog pristanka i zadovoljavanja  uključnih i isključnih kriterijuma 358 bolesnika je uključeno u studiju. Obavljena je preoperativna priprema i ispitivači su popunili deo podataka u individualnom listu. 4. Razvrstavanje u grupe i operativni rad. Neposredno preoperativno od strane nezavisne osobe neuključene u studiju napravljena je randomizacija izabranih (n=358) u studijske grupe tablicama slučajnog izbora, tako da bolesnici nisu znali kojoj grupi pripadaju, dok su operater i osoblje to znali na početku operacije (jednostruko slepa studija). Nakon randomizacije i operacije bolesnici pripadaju jednoj od sledeće 4 grupe: Kontrolna grupa O=89, u kojoj su bolesnici sa urađenom laparoskopskom  holecistektomijom bez visceralne blokade anestetikom i bez parijetalne blokade anestetikom. Eksperimentalna grupa P=88, u kojoj su bolesnici sa urađenom laparoskopskom holecistektomijom bez visceralne blokade anestetikom i sa parijetalnom blokadom anestetikom. Eksperimentalna grupa V=92, u kojoj su bolesnici sa urađenom laparoskopskom holecistektomijom sa visceralnom blokadom anestetikom i bez parijetalne blokade anestetikom. Eksperimentalna grupa P+V=89, u kojoj će biti bolesnici sa urađenom laparoskopskom holecistektomijom sa visceralnom blokadom anestetikom i sa parijetalnom blokadom anestetikom. Primenjivan je uobičajni, standardni protokol anestezije za laparoskopske operacije kod svih ispitanika. Svim bolesnicima plasirana je orogastrična sonda koja se nakon operacije odstranjivala. Kod  bolesnika kod kojih je primenjivan lokalni anestetik neposredno pre početka operacije pravio se rastvor lokalnog anestetika (Marcaine® 0,25%). Bolesnici su otpušteni sa bolničkog lečenja prvog postoperativnog dana, pod uslovom da nisu imali komplikacija. 5. Postoperativno praćenje i ispunjavanje upitnika. Po dolasku na odeljenje  bolesnicima je odmah uključivana ista analgezija. Tokom ispunjavanja informisanog pristanka, bolesnici su dobili upitnik na kojoj će sami procenjivati nivo bola, mučnine i kretanja tokom ležanja u bolnici i vremena praćenja od 7 dana kući. Bolesnici su dolazili na unapred zakazane postoperativne kontrole 7 do 10 dana posle operacije i donosili ispunjene upitnike. Otpušteno je i za praćenje ostalo n=302 laparoskopski operisanih bolesnika a isključeno iz studije n=20 bolesnika. 6. Statistička obrada i pisanje rada. Ukupno je analizirano 274 listića operisanih bolesnika: u Grupi P+V =67; u Grupi P =70; u Grupi V =70 i u Grupi O =67. Od osnovnih deskriptivnih statističkih parametara za kvalitativnu i kvantitativnu procenu dobijenih rezultata su korišćeni apsolutni brojevi, relativni brojevi, mediana, mod, aritmetička sredina i standardna devijacija (SD). Obrada podataka se vršila  osnovnim i naprednim statističkim metodama i programima. Rezultati su prikazani tabelarno i grafički. REZULTATI. Demografski podaci. Ukupno je bilo 188 žena i 86 muškaraca, u odnosu 2,2 : 1. Prosečna starost cele grupe je bila 52,1 ± 15,72 godine. Ukupno je bilo 179 zaposlenih i 95 nezaposlenih. Ukupno je bilo 45 ispitanika sa osnovnim obrazovanjem, 153 ispitanika sa srednjim obrazovanjem i 76 ispitanika sa visokim obrazovanjem. Ukupno je bilo 186 nepušača i 88 pušača. Prosečna vrednost BMI cele grupe je bila 27,24 ± 4,21 kg/m2. Prosečna vrednost ASA u celoj grupi je bila 2,03 (mediana=2, mod=2). Ne postoji statistički značajna razlika između posmatranih grupa u odnosu na posmatrane parametre. Laboratorijski podaci. Postoji statistički značajna razlika u vrednosti leukocita između posmatranih grupa (p=0,039), u vrednosti uree između posmatranih grupa (p=0,040). Ne postoji statistički značajna razlika u vrednosti eritrocita, trombocita, hemoglobina, ŠUK-a, kreatinina i bilirubina posmatranih grupa. Operativni i postoperativni podaci. Ne postoji statistički značajna razlika u količini upotrebljenog Fentanila između posmatranih grupa. Postoji statistički značajna razlika u dužini trajanja operacije između posmatranih grupa (p=0,003), u trajanju postavljenog abdominalnog drena između posmatranih grupa (p=0,024), u trajanju hospitalizacije između posmatranih grupa (p=0,027), u broju dana do povratka uobičajenim aktivnostima između posmatranih grupa (p=0,000), u broju uzetih tableta između posmatranih grupa (p=0,000). Prosečna ocena zadovoljstva bolesnika posle operacije u celoj grupi je bila 8,80 (mediana=9; mod=10). Najbolju ocenu zadovoljstva bolesnika posle operacije je imala grupa P+V. Procena bola, mučnine i kretanja. Postoji statistički značajna razlika između posmatranih grupa u proceni jačine bola pre operacije (p=0,003). Postoji statistički značajna razlika između posmatranih grupa u proceni jačine bola 1h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 2h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 4h posle operacije (najbolju procenu bola je imala grupa P); u proceni jačine bola 6h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 12h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 24h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 48h posle operacije (najbolju procenu bola je imala grupa P) i u proceni jačine bola 7 dana posle operacije (najbolju procenu bola je imala grupa P). Procenjena bol se pojačava otprilike 2,5 sata posle operacije sa vrhom 3 sata posle operacije, a smanjuje se na istu vrednost kao 2. sata posle operacije, otprilike 5. sata posle operacije. U vremenskim intervalima 1, 2. i 7. postoperativni dan postoji značajno poboljšanje u postoperativnoj mobilnosti bolesnika. U vremenskim intervalima 1, 2, 4, 6 i 12 sati postoji značajno poboljšanje u procenjenoj vrednosti mučnine bolesnika. Korelacije. Statistički značajna pozitivna korelacija ocene bola posle 1. sata, posle 2. sata, posle 6. sata, posle 12. sata je utvrđena sa brojem uzetih tableta (p=0,000), kao i procene mučnine (p=0,000). Statistički značajna pozitivna korelacija procene bola posle 4. sata je utvrđena sa brojem uzetih tableta (p=0,006), kao i aktivnosti (p=0,014). Statistički značajna korelacija procene bola posle 24. sata je utvrđena sa brojem uzetih tableta (p=0,000; pozitivna) i trajanjem operacije (p=0,028; negativna). Statistički značajna pozitivna korelacija procene bola posle 48. sata i posle 7 dana je utvrđena sa brojem uzetih tableta (p=0,000). ZAKLJUČCI: Primena lokalnog anestetika datog na bilo koji način značajno smanjuje bol posle laparoskopske holecistektomije. Primena lokalnog anestetika datog i  portalno i visceralno (P+V) značajno smanjuje bol u odnosu na samo portalnu (P) ili visceralnu (V) primenu u vremenskim intervalima 2, 6, 12 sat posle laparoskopske holecistektomije. Portalna (P) primena sa ili bez visceralne (V) primene lokalnog anestetika značajno smanjuje bol u vremenskim intervalima 1, 4, 24, 48 sati i 7 dana posle laparoskopske holecistektomije. Najbolje kretanje je bilo u grupi P+V posle laparoskopske holecistektomije. Najbolje smanjenje procenjene mučnine je bilo u grupi P posle laparoskopske holecistektomije. Najraniji povratak uobičajenim aktivnostima zabeležen je u grupi P+V. Najbolja ocena zadovoljstva bolesnika hirurškim lečenjem bila je u grupi P+V. Postoperativna bol ima najznačajniju pozitivnu korelaciju sa procenjenom mučninom i brojem tableta uzetih od momenta otpusta do prve kontrole bolesnika.INTRODUCTION: Biliary calculosis is the most frequent disease of the hepatobiliary system, and cholecystectomy is one of the most frequently performed surgical procedures. Today laparoscopic cholecystectomy represents the golden standard in treating cholelithiasis. Laparoscopic cholecystectomy showed improvement in the clinically significant outcomes, such as: reducing the duration of the surgery, shorter hospital stay, reducing the intensity and duration of postoperative pain and faster return to normal daily and working activities. Postoperative pain and the time of full recovery remain the two major problems after a non-complicated laparoscopic cholecystectomy and they should be improved. The pain related to laparoscopic cholecystectomy is complex and multi-factorial in origin. The pain occurs due to damaged tissues, dissection and removal of gallbladder from its cavity, stimulation of periportal nerves, irritation of the diaphragm, mechanical and chemical interaction of gases and pneumoperitoneum and port incisions. Researches have denoted parietal and visceral pains as two major mechanisms in occurrence of pain in laparoscopic cholecystectomy. Pain cannot be measured, but estimated, as it is a subjective feeling. It was considered necessary to find the answer, based on solid scientific evidence, if it was possible to block parietal and visceral pain after laparoscopic cholecystectomy in its acute phase. OBJECTIVES: The aim of this study is to compare standard, non-opioid, analgesia (group O) with applying parietal blockade (group P), or visceral blockade (group V), or compare with both applied blockades (group P+V). The primary outcomes of the study are the patient´s estimated pain before surgery and 1, 2, 4, 6, 12, 24, 48 hours and 7th day after the surgery. The secondary outcomes of this study are the patient´s estimated nausea level during 1, 2, 4, 6, 12 hours, along with the patient´s estimated mobility 1st, 2nd and 7th day, postoperatively. HYPOTHESIS. Blockade of postoperative visceral pain and blockade of postoperative parietal pain following laparoscopic cholecystectomy, applying intraperitoneal local infiltration with anesthetic and also by local infiltration with anesthetic through accessible laparoscopic ports, can significantly reduce early postoperative pain. MATERIAL AND METHODS: This prospectively randomized single-blinded study started in September 2014 and lasted up to January 2016. The research was carried out at the Clinic for Abdominal, Endocrine and Transplantation Surgery and Emergency Center, Clinical Center of Vojvodina in Novi Sad and it involved patients who underwent laparoscopic cholecystectomy. This study has been divided into several units. 1. Assessment of sample size; 2. Assessment of eligibility for the study; 3. Survey and inclusion in the study; 4. Group formation and operational work; 5. Period of postoperative follow-up; 6. Statistical processing and writing the paper.1. Assessment of sample size. The study was realized by dividing the patients into 4 groups. The number of patients necessary was determined based on the data taken as pilot study from a similar study from 2012. Sample size was calculated for the primary outcome of the study (patient´s estimated pain with NAS) based on the assumption that a pain reduction of 20% should occur during the first postoperative hour, with the probability of Type 1 error α=0.05 and Type 2 error β=0.10 to reach the adequate statistical power of about 80%, and to reveal 20% difference in the average value of the estimated pain one hour after the laparoscopic cholecystectomy. The assessed number of respondents in groups according to the set criteria was (P+V =65;P =68;V =68; O =65). The study started when the first patient was included and it ended with the complete follow-up period when the last patient handed in the survey about pain, nausea and mobility. 2. Assessment of eligibility for the study. During the study the number of patients undergoing surgery applying the method of cholecystectomy was 1024 (440 classical and 584 laparoscopic). Only the suitable patients were surveyed (584) and given to read the information leaflet about the study. Inclusion and assessment of patients´ eligibility was performed on the basis of inclusion and exclusion criteria. A total of 226 patients was not included in the study. Out of that number 82 patients refused to participate in the study and 144 did not fulfill the inclusive criteria set. By signing 358 patients confirmed their participation in the study. 3. Survey and inclusion in the study. After admitting the patients to hospital the surveyors took their anamnesis and the patients were offered an information leaflet and informed consent. Following the reading of the information leaflet, signing the informed consent and satisfying the criteria for inclusion and exclusion, 358 patients were included in the study. Preoperative preparations were performed and the surveyors filled in some of the data on the individual list. 4. Group formation and operational work. Prior to the surgery an independent person not included in the study carried out the randomisation of the patients chosen (n=358) into study groups by random selection tables. The patients did not know which group they belonged to, while it became known to the surgeon and the operation stuff at the beginning of the surgery (singleblinded study). After randomization and surgery the patients belonged to one of the following groups: Control group O=89 of patients with performed laparoscopic cholecystectomy without visceral blockade by anesthetic and without parietal blockade by anesthetic. Experimental group P=88 of patients with performed laparoscopic cholecystectomy without visceral blockade by anesthetic but with parietal blockade by anesthetic. Experimental group V=92 of patients with performed laparoscopic cholecystectomy with visceral blockade by anesthetic but without parietal blockade by anesthetic. Experimental group P+V=89 of patients with performed laparoscopic cholecystectomy with visceral blockade by anesthetic and with parietal blockade by anesthetic. The standard protocol of anesthesia for laparoscopic cholecystectomy was applied to all patients. An orogastric tube used during the surgery, was removed after it. In patients with applied local anesthetic immediately before surgery a solution of local anesthetic was made (Marcaine® 0,25%). The patients were discharged from hospital the first postoperative day, provided that no complications occurred. 5. Postoperative follow-up and completing the questionnaire. When admitted to the ward the patients were given the same kind of analgesia. While completing the informed consent the patients were given a questionnaire for estimating their pain level, nausea and mobility during their stay in hospital and during the 7-day follow-up period at home. The patients were required to come for 7 and 10-day postoperative check-ups by appointment and then they handed in the questionnaires. n=302 patients with performed laparoscopic cholecystectomy were released and designated for follow-up, and n=20 patients were excluded from the study. 6. Statistical processing and writing the paper. In total 274 operated patients´ slips were analysed, by groups as follows: in Group P+V =67; in Group P =70; in Group V =70 and in Group O =67. From the basic descriptive statistical parametres for qualitative and quantitative assessment of results obtained, absolute numbers, relative numbers, the median, mode, arithmetic mean and standard deviation (SD) were used. Data processing was carried out using basic and advanced statistical methods and programmes. The results are presented in tabular and graphical manner. RESULTS. Demographic data. In total there were 188 women and 86 men, in proportion 2,2 : 1. The average age of the whole group was 52,1 ± 15,72 years. In total there were 179 employed and 95 unemployed persons. In total there were 45 surveyed patients with primary education, 153 surveyed patients with secondary education and 76 surveyed patients with higher education. In total there were 186 nonsmokers and 88 smokers. The mean BMI value of the whole group was 27,24 ± 4,21 kg/m2. The mean value of ASA of the whole group was 2,03 (the median=2, mode=2). There is no significant difference among the groups observed considering the observed parametres. Laboratory data. There is a statistically significant difference in the value of leukocytes among the observed groups (p=0,039), and in the value of urea among the observed groups (p=0,040). There is no statistically significant difference in the value of the erythrocyte, platelets, hemoglobin, blood glucose, creatinine and bilirubin of the  observed groups. Operative and postoperative data. There is no statistically significant difference in the amount of Fentanyl® applied among the observed groups. There is statistically significant difference in the length of the surgery among the observed groups (p=0,003), in the duration of the positioning of abdominal drainage among the observed groups (p=0,024), in the duration of hospital stay among the observed groups (p=0,027), in the number of days until getting back to regular activities among the observed groups  (p=0,000), in the number of taken pills among the observed groups (p=0,000). The patients´ average satisfaction grade after surgery in the whole group was 8,80 (the median=9; mode=10). Group P+V had the best patient‘s satisfaction grade after the surgery. Assessment of pain, nausea and mobility. There is statistically significant difference in the estimation of pain intensity before surgery among the observed groups (p=0,003). There is statistically significant difference in the estimation of pain intensity 1 hour after surgery among the observed groups (P+V having the best estimated pain); in the estimation of pain intensity 2 hours after  surgery (P+V having the best estimated pain); in the estimation of pain intensity 4 hours after surgery (P having the best

Modelovanje i analiza uticaja metalnih medicinskih implantata na raspodelu elektromagnetskog polja mobilnih telefona u tkivima korisnika

The aim of this PhD thesis is to present the results determined in research on influence of certain metal medical implants in head and neck surgery on the distribution of penetrating electromagnetic field and the amount of absorbed energy within certain biological tissues due to exposure to RF radiation from mobile phones. Within the research, several 3D numerical models in high resolution, were created. A 3D numerical model of the human head has been developed which, in terms of dimensions, morphology and tissue composition, corresponds to the characteristics of an adult's head, sufficiently to enable obtaining reliable results by applying appropriate numerical procedures. In addition, based on available 3D images of surgical interventions, 3D numerical models of individual metal medical implants have been created. As a source of electromagnetic radiation, a modern smartphone with appropriate antennas for 3G and 4G mobile network have been used. Accordingly, calculations and analyzes were performed for the frequencies 1800 MHz and 2600 MHz, which correspond to the carrier frequencies of the mentioned mobile networks. The paper presents the results for the electric field distribution and the amount of absorbed electromagnetic energy of a mobile phone inside the user head model in the presence of the following metal medical implants: - Titanium plate for the reconstruction of a major skull defect; - Titanium dynamic mesh for the reconstruction of minor skull defects; - Titanium plate and screws used in jaw traumatology; - Dental implants and - Fixed denture. In order to determine the degree of influence of these metal medical implants on the electric field distribution and the amount of absorbed energy of the electromagnetic wave, within the biological tissues of the mobile phone users, a comparative analysis of the user head model with and without metal medical implants has been performed. During the analysis, the same mobile phone electromagnetic radiation exposure conditions were assumed for both models. A comprehensive analysis of the obtained results, related to the spatial distribution of electric field intensity and absorbed electromagnetic energy, concluded that the presence of metal medical implants affects the change in the value of electric field intensity and SAR, within biological tissues with installed implants

The study of the level of correlation between the cytokine concentration in urine and serum with pathohistological and clinical characteristics of prostate cancer

UVOD: Karcinom prostate (KaP) u populaciji muškaraca starijih od 50 godina dolazi na drugo mesto po učestalosti . Čest uzgredni patohistološki nalaz u tkivu prostate uklonjene zbog tumora predstavlja prisustvo heterogenog ćelijskog upalnog infiltrata. Citokini produkovani od tumorskih ćelija i infiltrišućih imunskih ćelija omogućavaju preživljavanje tumorskih ćelija i njihov dalji rast. Objavljeni rezultati nekoliko studija ukazuju na povezanost vrednosti citokina iz seruma, eksprimata prostate i urina sa kliničkim i histološkim karakteristikama tumora u bolesnika sa KaP. Pokazano je da su serumske vrednosti IL-4 pojedinačni prediktor progresije bolesti i da su serumske vrednosti IL-1β i IL-12 povećane u rano otkrivenim KaP. U grupi sa malim tumorskim volumenom dominirali su HGF i IL18BP, dok su vrednosti IL18BP korelirale su sa Gleason skorom, vrednosti IL-17, GITR i ICAM-1 sa stepenom infiltracije neutrofila, a vrednosti IL18BP, IL17, GITR i ICAM-1 korelirale su sa stepenom infiltracije limfocita. IL18BP je bio prisutan u visokoj koncentraciji u uzorcima eksprimata prostate kod bolesnika sa KaP. METOD: U studiju je uključeno 88 bolesnika sa KaP i 35 zdravih osoba za dve kontrolne grupe (20 bolesnika u grupi sa benignom hiperplazijom prostate i 15 onih koji nemaju tegobe vezane za urogenitalni trakt). Nezavisne varijable su određene kliničkim karakteristikama tumora patohistološkim karakteristikama tumora i TNM stadijumom bolesti. Zavisne varijable su određene koncentracijom citokina u serumu i urinu u ispitivanim grupama. REZULTATI: Vrednosti inflamatornih citokina odražavaju stepen inflamacije u tumorskom i peritumorskom tkivu. Vrednosti hemokina odražavaju stepen infiltracije tumorskog tkiva adekvatnim tipom imunskih ćelija, koncentracija imunosupresivnih citokina odgovara veličini tumora, dok vrednosti urinarnih citokina TH1 tipa odgovoaraju stepenu limfocitne infiltracije. ZAKLjUČAK I ZNAČAJ STUDIJE: Dobijeni rezultati pružaju nove informacije o biološkim osobinama karcinoma prostate, mogućnost procene lokalnog imunskog odgovora u bolesnika sa KaP na osnovu vrednosti urinarnih citokina, pružaju mogućnost procene stepena inflamacije u tumorskom tkivu, kao i mogućnost procene efekta terapijskih procedura na lokalni imunski odgovor.INTRODUCTION: Prostate cancer (CaP) comes second in terms of frequency in the population of men older than 50. The presence of a heterogeneous cellular inflammatory infiltrate is a common incidental pathohistological finding in prostate tissue removed due to tumors. Cytokines produced by tumor cells and infiltrating immune cells enable the survival of tumor cells and their further growth. The published results of several studies indicate an association between serum cytokine values, prostate and urine excreta and clinical and histological characteristics of tumors in patients with KaP. Serum IL-4 values have been shown to be a single predictor of disease progression and serum IL-1β and IL-12 values are increased in early detected KaP. The small tumor volume group was dominated by HGF and IL18BP, while IL18BP values correlated with the Gleason score, IL-17, GITR, and ICAM-1 values with neutrophil infiltration rates, and IL18BP, IL17, GITR, and ICAM-1 values correlated with lymphocyte infiltration. IL18BP was present in high concentrations in prostate express samples in patients with KaP. METHODOLOGY: The study included 88 patients with CaP and 35 healthy individuals for two control groups (20 patients in the group with benign prostatic hyperplasia and 15 who did not have urogenital tract problems). The independent variables were determined by the clinical characteristics of the tumor, the pathohistological characteristics of the tumor and the TNM stage of the disease. The dependent variables were determined by the concentration of cytokines in the serum and urine in the examined groups. RESULTS: Inflammatory cytokine values reflect the degree of inflammation in tumor and peritumoral tissue. Chemokine values reflect the degree of infiltration of tumor tissue with an adequate type of immune cells, the concentration of immunosuppressive cytokines corresponds to the size of the tumor, while the values of urinary cytokines TH1 type correspond to the degree of lymphocytic infiltration. CONCLUSION AND THE IMPORTANCE OF THE STUDY: The obtained results provide new information on the biological properties of prostate cancer, the possibility of assessing the local immune response in patients with CaP based on urinary cytokine values, the possibility of assessing the degree of inflammation in tumor tissue, and the possibility of assessing the effect of therapeutic procedures on local immune response

The influence of local anesthetic on pain after laparoscopic cholecystectomy

UVOD. Bilijarna kalkuloza je najčešće oboljenje hepatobilijarnog sistema, a holecistektomija predstavlja jedan od najčešće izvođenih operativnih zahvata. Laparoskopska holecistektomija je danas zlatni standard lečenja holelitijaze. Laparoskopska holecistektomija je pokazala poboljšanje u klinički značajnim ishodima kao što su skraćenje operativnog vremena, kraća hospitalizacija, smanjenje jačine i trajanja postoperativnog bola i brži povratak dnevnim i radnim aktivnostima. Postoperativna bol i vreme potpunog oporavka ostaju dva glavna problema posle nekomplikovane laparoskopske holecistektomije koje bi trebalo poboljšati. Bol koji je povezan sa laparoskopskom holecistektomijom je kompleksan i multifaktorijalan. On nastaje oštećenjem tkiva, disekcijom i uklanjanjem žučne kesice iz svoje lože, stimulacijom periportalnih nerava, iritacijom dijafragme, mehaničkim i hemijskim interakcijama gasa i pneumoperitoneuma, incizijama portova. Istraživanja su označila parijetalni i visceralni bol kao dva glavna mehanizma nastanka bola kod laparoskopske holecistektomije. Bol se ne može meriti nego proceniti jer je subjektivni osećaj. Pokazalo se potrebnim da se na čvršćim naučnim osnovama da odgovor na pitanje da li je moguće blokirati parijetalni i visceralni bol posle laparoskopske holecistektomije u akutnoj fazi. CILJEVI. Cilj studije je da uporedi standardnu analgeziju (ne-opioidnu) (grupa O) sa davanjem parijetalne blokade (grupa P), ili davanjem visceralne blokade (grupa V), ili sa obe date blokade (grupa P+V). Primarni ishodi studije su bolesnikov procenjeni bol pre operacije i posle operacije na 1, 2, 4, 6, 12, 24, 48 sati i 7. dana. Sekundarni ishodi studije su bolesnikova procenjena mučnina na 1,2,4,6,12 sati i bolesnikova procenjena mobilnost 1. 2. i 7. dan. HIPOTEZA. Blokada postoperativnog visceralnog bola i blokada postoperativnog parijetalnog bola posle laparoskopske holecistektomije putem intraperitonealne lokalne infiltracije anestetikom i putem lokalne infiltracije anestetikom pristupnih laparoskopskih portova može značajno smanjiti rani postoperativni bol. MATERIJAL I METODE. Ova prospektivna, randomizirana jednostruko slepa studija je započela septembra 2014. godine i trajala je do januara 2016. godine. Istraživanje je sprovedeno na Klinici za abdominalnu, endokrinu i transplantacionu hirurgiju i Urgentnom centru Kliničkog centra Vojvodine u Novom Sadu kod bolesnika operisanih metodom laparoskopske holecistektomije. Rad je podeljen u nekoliko celina. 1. Procena veličine uzorka; 2. Procena podobnosti za studiju; 3. Anketiranje i uključivanje u studiju; 4. Razvrstavanje u grupe i operativni rad; 5. Period postoperativnog praćenja; 6. Statistička obrada i pisanje rada. 1. Procena veličine uzorka. Studija je realizovana podelom bolesnika u 4 grupe. Neophodni broj bolesnika je izračunat uzimajući podatke iz pilot istraživanja slične studije iz 2012. godine. Veličina uzorka je računata za primarni ishod studije  (bolesnikov procenjen bol sa NAS) na pretpostavci da treba biti 20% smanjenja bola u prvom postoperativnom satu, uz verovatnoću Tip 1 greške α=0.05 i Tipa 2 greške β=0.10 da postigne adekvatnu statističku snagu oko 80% i da otkrije 20% razlike u srednjoj vrednosti procenjenog bola jedan sat nakon laparoskopske  holecistektomije. Procenjeni broj ispitanika po grupama prema zadatim kriterijumima je bio (P+V=65; P=68; V=68; O=65). Studija je započela uključivanjem prvog bolesnika u studiju a završena ispunjenim periodom praćenja sve dok poslednji bolesnik nije doneo upitnike o bolu, mučnini i kretanju. 2. Procena podobnosti za studiju. U periodu studije ukupan broj holecistektomiranih bolesnika je bio 1024 (440 klasično i 584 laparoskopski). Samo pogodni bolesnici su anketirani (584) i pročitali su informacioni list o istraživanju. Uključivanje ili procena podobnosti bolesnika za studiju sprovedena je na osnovu uključnih i isključnih kriterijuma. U studiju nije uključeno ukupno 226 bolesnika. Od tog broja 82 bolesnika je odbilo učestvovati u studiji a 144 bolesnika nije ispunilo uključne postavljene kriterijume. Svojim potpisom potvrdilo je učešće u studiji 358 bolesnika. 3. Anketiranje i uključivanje u studiju. Nakon prijema bolesnika u bolnicu ispitivači su uzimali anamnezu i bolesnicima je ponuđen informacioni list i informisani pristanak. Nakon čitanja informacije, potpisivanja informisanog pristanka i zadovoljavanja  uključnih i isključnih kriterijuma 358 bolesnika je uključeno u studiju. Obavljena je preoperativna priprema i ispitivači su popunili deo podataka u individualnom listu. 4. Razvrstavanje u grupe i operativni rad. Neposredno preoperativno od strane nezavisne osobe neuključene u studiju napravljena je randomizacija izabranih (n=358) u studijske grupe tablicama slučajnog izbora, tako da bolesnici nisu znali kojoj grupi pripadaju, dok su operater i osoblje to znali na početku operacije (jednostruko slepa studija). Nakon randomizacije i operacije bolesnici pripadaju jednoj od sledeće 4 grupe: Kontrolna grupa O=89, u kojoj su bolesnici sa urađenom laparoskopskom  holecistektomijom bez visceralne blokade anestetikom i bez parijetalne blokade anestetikom. Eksperimentalna grupa P=88, u kojoj su bolesnici sa urađenom laparoskopskom holecistektomijom bez visceralne blokade anestetikom i sa parijetalnom blokadom anestetikom. Eksperimentalna grupa V=92, u kojoj su bolesnici sa urađenom laparoskopskom holecistektomijom sa visceralnom blokadom anestetikom i bez parijetalne blokade anestetikom. Eksperimentalna grupa P+V=89, u kojoj će biti bolesnici sa urađenom laparoskopskom holecistektomijom sa visceralnom blokadom anestetikom i sa parijetalnom blokadom anestetikom. Primenjivan je uobičajni, standardni protokol anestezije za laparoskopske operacije kod svih ispitanika. Svim bolesnicima plasirana je orogastrična sonda koja se nakon operacije odstranjivala. Kod  bolesnika kod kojih je primenjivan lokalni anestetik neposredno pre početka operacije pravio se rastvor lokalnog anestetika (Marcaine® 0,25%). Bolesnici su otpušteni sa bolničkog lečenja prvog postoperativnog dana, pod uslovom da nisu imali komplikacija. 5. Postoperativno praćenje i ispunjavanje upitnika. Po dolasku na odeljenje  bolesnicima je odmah uključivana ista analgezija. Tokom ispunjavanja informisanog pristanka, bolesnici su dobili upitnik na kojoj će sami procenjivati nivo bola, mučnine i kretanja tokom ležanja u bolnici i vremena praćenja od 7 dana kući. Bolesnici su dolazili na unapred zakazane postoperativne kontrole 7 do 10 dana posle operacije i donosili ispunjene upitnike. Otpušteno je i za praćenje ostalo n=302 laparoskopski operisanih bolesnika a isključeno iz studije n=20 bolesnika. 6. Statistička obrada i pisanje rada. Ukupno je analizirano 274 listića operisanih bolesnika: u Grupi P+V =67; u Grupi P =70; u Grupi V =70 i u Grupi O =67. Od osnovnih deskriptivnih statističkih parametara za kvalitativnu i kvantitativnu procenu dobijenih rezultata su korišćeni apsolutni brojevi, relativni brojevi, mediana, mod, aritmetička sredina i standardna devijacija (SD). Obrada podataka se vršila  osnovnim i naprednim statističkim metodama i programima. Rezultati su prikazani tabelarno i grafički. REZULTATI. Demografski podaci. Ukupno je bilo 188 žena i 86 muškaraca, u odnosu 2,2 : 1. Prosečna starost cele grupe je bila 52,1 ± 15,72 godine. Ukupno je bilo 179 zaposlenih i 95 nezaposlenih. Ukupno je bilo 45 ispitanika sa osnovnim obrazovanjem, 153 ispitanika sa srednjim obrazovanjem i 76 ispitanika sa visokim obrazovanjem. Ukupno je bilo 186 nepušača i 88 pušača. Prosečna vrednost BMI cele grupe je bila 27,24 ± 4,21 kg/m2. Prosečna vrednost ASA u celoj grupi je bila 2,03 (mediana=2, mod=2). Ne postoji statistički značajna razlika između posmatranih grupa u odnosu na posmatrane parametre. Laboratorijski podaci. Postoji statistički značajna razlika u vrednosti leukocita između posmatranih grupa (p=0,039), u vrednosti uree između posmatranih grupa (p=0,040). Ne postoji statistički značajna razlika u vrednosti eritrocita, trombocita, hemoglobina, ŠUK-a, kreatinina i bilirubina posmatranih grupa. Operativni i postoperativni podaci. Ne postoji statistički značajna razlika u količini upotrebljenog Fentanila između posmatranih grupa. Postoji statistički značajna razlika u dužini trajanja operacije između posmatranih grupa (p=0,003), u trajanju postavljenog abdominalnog drena između posmatranih grupa (p=0,024), u trajanju hospitalizacije između posmatranih grupa (p=0,027), u broju dana do povratka uobičajenim aktivnostima između posmatranih grupa (p=0,000), u broju uzetih tableta između posmatranih grupa (p=0,000). Prosečna ocena zadovoljstva bolesnika posle operacije u celoj grupi je bila 8,80 (mediana=9; mod=10). Najbolju ocenu zadovoljstva bolesnika posle operacije je imala grupa P+V. Procena bola, mučnine i kretanja. Postoji statistički značajna razlika između posmatranih grupa u proceni jačine bola pre operacije (p=0,003). Postoji statistički značajna razlika između posmatranih grupa u proceni jačine bola 1h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 2h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 4h posle operacije (najbolju procenu bola je imala grupa P); u proceni jačine bola 6h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 12h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 24h posle operacije (najbolju procenu bola je imala grupa P+V); u proceni jačine bola 48h posle operacije (najbolju procenu bola je imala grupa P) i u proceni jačine bola 7 dana posle operacije (najbolju procenu bola je imala grupa P). Procenjena bol se pojačava otprilike 2,5 sata posle operacije sa vrhom 3 sata posle operacije, a smanjuje se na istu vrednost kao 2. sata posle operacije, otprilike 5. sata posle operacije. U vremenskim intervalima 1, 2. i 7. postoperativni dan postoji značajno poboljšanje u postoperativnoj mobilnosti bolesnika. U vremenskim intervalima 1, 2, 4, 6 i 12 sati postoji značajno poboljšanje u procenjenoj vrednosti mučnine bolesnika. Korelacije. Statistički značajna pozitivna korelacija ocene bola posle 1. sata, posle 2. sata, posle 6. sata, posle 12. sata je utvrđena sa brojem uzetih tableta (p=0,000), kao i procene mučnine (p=0,000). Statistički značajna pozitivna korelacija procene bola posle 4. sata je utvrđena sa brojem uzetih tableta (p=0,006), kao i aktivnosti (p=0,014). Statistički značajna korelacija procene bola posle 24. sata je utvrđena sa brojem uzetih tableta (p=0,000; pozitivna) i trajanjem operacije (p=0,028; negativna). Statistički značajna pozitivna korelacija procene bola posle 48. sata i posle 7 dana je utvrđena sa brojem uzetih tableta (p=0,000). ZAKLJUČCI: Primena lokalnog anestetika datog na bilo koji način značajno smanjuje bol posle laparoskopske holecistektomije. Primena lokalnog anestetika datog i  portalno i visceralno (P+V) značajno smanjuje bol u odnosu na samo portalnu (P) ili visceralnu (V) primenu u vremenskim intervalima 2, 6, 12 sat posle laparoskopske holecistektomije. Portalna (P) primena sa ili bez visceralne (V) primene lokalnog anestetika značajno smanjuje bol u vremenskim intervalima 1, 4, 24, 48 sati i 7 dana posle laparoskopske holecistektomije. Najbolje kretanje je bilo u grupi P+V posle laparoskopske holecistektomije. Najbolje smanjenje procenjene mučnine je bilo u grupi P posle laparoskopske holecistektomije. Najraniji povratak uobičajenim aktivnostima zabeležen je u grupi P+V. Najbolja ocena zadovoljstva bolesnika hirurškim lečenjem bila je u grupi P+V. Postoperativna bol ima najznačajniju pozitivnu korelaciju sa procenjenom mučninom i brojem tableta uzetih od momenta otpusta do prve kontrole bolesnika.INTRODUCTION: Biliary calculosis is the most frequent disease of the hepatobiliary system, and cholecystectomy is one of the most frequently performed surgical procedures. Today laparoscopic cholecystectomy represents the golden standard in treating cholelithiasis. Laparoscopic cholecystectomy showed improvement in the clinically significant outcomes, such as: reducing the duration of the surgery, shorter hospital stay, reducing the intensity and duration of postoperative pain and faster return to normal daily and working activities. Postoperative pain and the time of full recovery remain the two major problems after a non-complicated laparoscopic cholecystectomy and they should be improved. The pain related to laparoscopic cholecystectomy is complex and multi-factorial in origin. The pain occurs due to damaged tissues, dissection and removal of gallbladder from its cavity, stimulation of periportal nerves, irritation of the diaphragm, mechanical and chemical interaction of gases and pneumoperitoneum and port incisions. Researches have denoted parietal and visceral pains as two major mechanisms in occurrence of pain in laparoscopic cholecystectomy. Pain cannot be measured, but estimated, as it is a subjective feeling. It was considered necessary to find the answer, based on solid scientific evidence, if it was possible to block parietal and visceral pain after laparoscopic cholecystectomy in its acute phase. OBJECTIVES: The aim of this study is to compare standard, non-opioid, analgesia (group O) with applying parietal blockade (group P), or visceral blockade (group V), or compare with both applied blockades (group P+V). The primary outcomes of the study are the patient´s estimated pain before surgery and 1, 2, 4, 6, 12, 24, 48 hours and 7th day after the surgery. The secondary outcomes of this study are the patient´s estimated nausea level during 1, 2, 4, 6, 12 hours, along with the patient´s estimated mobility 1st, 2nd and 7th day, postoperatively. HYPOTHESIS. Blockade of postoperative visceral pain and blockade of postoperative parietal pain following laparoscopic cholecystectomy, applying intraperitoneal local infiltration with anesthetic and also by local infiltration with anesthetic through accessible laparoscopic ports, can significantly reduce early postoperative pain. MATERIAL AND METHODS: This prospectively randomized single-blinded study started in September 2014 and lasted up to January 2016. The research was carried out at the Clinic for Abdominal, Endocrine and Transplantation Surgery and Emergency Center, Clinical Center of Vojvodina in Novi Sad and it involved patients who underwent laparoscopic cholecystectomy. This study has been divided into several units. 1. Assessment of sample size; 2. Assessment of eligibility for the study; 3. Survey and inclusion in the study; 4. Group formation and operational work; 5. Period of postoperative follow-up; 6. Statistical processing and writing the paper.1. Assessment of sample size. The study was realized by dividing the patients into 4 groups. The number of patients necessary was determined based on the data taken as pilot study from a similar study from 2012. Sample size was calculated for the primary outcome of the study (patient´s estimated pain with NAS) based on the assumption that a pain reduction of 20% should occur during the first postoperative hour, with the probability of Type 1 error α=0.05 and Type 2 error β=0.10 to reach the adequate statistical power of about 80%, and to reveal 20% difference in the average value of the estimated pain one hour after the laparoscopic cholecystectomy. The assessed number of respondents in groups according to the set criteria was (P+V =65;P =68;V =68; O =65). The study started when the first patient was included and it ended with the complete follow-up period when the last patient handed in the survey about pain, nausea and mobility. 2. Assessment of eligibility for the study. During the study the number of patients undergoing surgery applying the method of cholecystectomy was 1024 (440 classical and 584 laparoscopic). Only the suitable patients were surveyed (584) and given to read the information leaflet about the study. Inclusion and assessment of patients´ eligibility was performed on the basis of inclusion and exclusion criteria. A total of 226 patients was not included in the study. Out of that number 82 patients refused to participate in the study and 144 did not fulfill the inclusive criteria set. By signing 358 patients confirmed their participation in the study. 3. Survey and inclusion in the study. After admitting the patients to hospital the surveyors took their anamnesis and the patients were offered an information leaflet and informed consent. Following the reading of the information leaflet, signing the informed consent and satisfying the criteria for inclusion and exclusion, 358 patients were included in the study. Preoperative preparations were performed and the surveyors filled in some of the data on the individual list. 4. Group formation and operational work. Prior to the surgery an independent person not included in the study carried out the randomisation of the patients chosen (n=358) into study groups by random selection tables. The patients did not know which group they belonged to, while it became known to the surgeon and the operation stuff at the beginning of the surgery (singleblinded study). After randomization and surgery the patients belonged to one of the following groups: Control group O=89 of patients with performed laparoscopic cholecystectomy without visceral blockade by anesthetic and without parietal blockade by anesthetic. Experimental group P=88 of patients with performed laparoscopic cholecystectomy without visceral blockade by anesthetic but with parietal blockade by anesthetic. Experimental group V=92 of patients with performed laparoscopic cholecystectomy with visceral blockade by anesthetic but without parietal blockade by anesthetic. Experimental group P+V=89 of patients with performed laparoscopic cholecystectomy with visceral blockade by anesthetic and with parietal blockade by anesthetic. The standard protocol of anesthesia for laparoscopic cholecystectomy was applied to all patients. An orogastric tube used during the surgery, was removed after it. In patients with applied local anesthetic immediately before surgery a solution of local anesthetic was made (Marcaine® 0,25%). The patients were discharged from hospital the first postoperative day, provided that no complications occurred. 5. Postoperative follow-up and completing the questionnaire. When admitted to the ward the patients were given the same kind of analgesia. While completing the informed consent the patients were given a questionnaire for estimating their pain level, nausea and mobility during their stay in hospital and during the 7-day follow-up period at home. The patients were required to come for 7 and 10-day postoperative check-ups by appointment and then they handed in the questionnaires. n=302 patients with performed laparoscopic cholecystectomy were released and designated for follow-up, and n=20 patients were excluded from the study. 6. Statistical processing and writing the paper. In total 274 operated patients´ slips were analysed, by groups as follows: in Group P+V =67; in Group P =70; in Group V =70 and in Group O =67. From the basic descriptive statistical parametres for qualitative and quantitative assessment of results obtained, absolute numbers, relative numbers, the median, mode, arithmetic mean and standard deviation (SD) were used. Data processing was carried out using basic and advanced statistical methods and programmes. The results are presented in tabular and graphical manner. RESULTS. Demographic data. In total there were 188 women and 86 men, in proportion 2,2 : 1. The average age of the whole group was 52,1 ± 15,72 years. In total there were 179 employed and 95 unemployed persons. In total there were 45 surveyed patients with primary education, 153 surveyed patients with secondary education and 76 surveyed patients with higher education. In total there were 186 nonsmokers and 88 smokers. The mean BMI value of the whole group was 27,24 ± 4,21 kg/m2. The mean value of ASA of the whole group was 2,03 (the median=2, mode=2). There is no significant difference among the groups observed considering the observed parametres. Laboratory data. There is a statistically significant difference in the value of leukocytes among the observed groups (p=0,039), and in the value of urea among the observed groups (p=0,040). There is no statistically significant difference in the value of the erythrocyte, platelets, hemoglobin, blood glucose, creatinine and bilirubin of the  observed groups. Operative and postoperative data. There is no statistically significant difference in the amount of Fentanyl® applied among the observed groups. There is statistically significant difference in the length of the surgery among the observed groups (p=0,003), in the duration of the positioning of abdominal drainage among the observed groups (p=0,024), in the duration of hospital stay among the observed groups (p=0,027), in the number of days until getting back to regular activities among the observed groups  (p=0,000), in the number of taken pills among the observed groups (p=0,000). The patients´ average satisfaction grade after surgery in the whole group was 8,80 (the median=9; mode=10). Group P+V had the best patient‘s satisfaction grade after the surgery. Assessment of pain, nausea and mobility. There is statistically significant difference in the estimation of pain intensity before surgery among the observed groups (p=0,003). 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