Dissertations / Theses on the topic 'Drum language'

This research project is a documentation of a developmental journey centered on the incorporation of rhythmic elements from South Indian Carnatic music into an existing musical practice. The research provides an insight into the creative process of learning, adaptation and recontextualization of new musical elements into an existing musical practice that may provide a model and transferable methodology for musicians endeavouring to undertake similar research journeys of musical development. The Adaptation of Indian Carnatic Rhythmic Structures and Improvisation Methods into Drum Set Language and Performance explores the transformation process that occurs as a result of incorporating Carnatic rhythmic elements into the author’s drum set playing style. Through learning Carnatic rhythms, adapting the rhythms to the drum set and then applying the rhythms to musical situations, the research aims to observe the influence of this process on the author’s drum set playing within a performance context. The research focuses on examining the drum set playing on two different recordings. The recordings are presented as the creative works of the research, emphasizing audio-as-research which places listening as the central method of transmission. The creative works can be considered the primary vehicles through which the investigation of the performance practice occurs, with the exegesis serving to place the recordings within a written research context. The exegesis also provides the necessary background and contextual framework for the creative works.
Thesis (Professional Doctorate)
Doctor of Musical Arts (DMA)
Queensland Conservatorium of Music
Arts, Education and Law
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Pharamacovigilance relates to activities involving drug safety monitoring in the post-marketing phase of the drug development life-cycle. Despite rigorous trials and experiments that drugs undergo before they are available in the market, they can still cause previously unobserved side-effects (also known as adverse events) due to drug–drug interaction, genetic, physiological or demographic reasons. The Uppsala Monitoring Centre (UMC) is the custodian of the global reporting system, VigiBase, for adverse drug reactions in collaboration with the World Health Organization (WHO). VigiBase houses over 20 million case reports of suspected adverse drug reactions from all around the world. However, not all case reports that the UMC receives pertains to adverse reactions that are novel in the safety profile of the drugs. In fact, many of the reported reactions found in the database are known adverse events for the reported drugs. With more than 3 million potential associations between all possible drugs and all possible adverse events present in the database, identifying associations that are likely to represent previously unknown safety concerns requires powerful statistical methods and knowledge of the known safety profiles of the drugs. Therefore, there is a need for a knowledge base with mappings of drugs to their known adverse reactions. To-date, such a knowledge base does not exist. The purpose of this thesis is to develop a deep-learning model that learns to extract adverse reactions from product labels — regulatory documents providing the current state of knowledge of the safety profile of a given product — and map them to a standardized terminology with high precision. To achieve this, I propose a two-phase algorithm, with a first scanning phase aimed at finding regions of the text representing adverse reactions, and a second mapping phase aiming at normalizing the detected text fragments into Medical Dictionary for Regulatory Activities (MedDRA) terms, the terminology used at the UMC to represent adverse reactions. A previous dictionary-based algorithm developed at the UMC achieved a scanning F1 of 0.42 (0.31 precision, 0.66 recall) and mapping macro-averaged F1 of 0.43 (0.39 macro-averaged precision, 0.64 macro-averaged recall). State-of-the-art methods achieve F1 above 0.8 and above 0.7 for the scanning and mapping problems respectively. To develop algorithms for adverse reaction extraction, I use the 2019 ADE Evaluation Challenge data, a dataset made by the FDA with 100 product labels annotated for adverse events and their mappings to MedDRA. This thesis explores three architectures for the scanning problem: 1) a Bidirectional Long Short-Term Memory (BiLSTM) encoder followed by a softmax classifier, 2) a BiLSTM encoder with Conditional Random Field (CRF) classifier and finally, 3) a BiLSTM encoder with CRF classifier with Embeddings from Language Model (ELMo) embeddings. For the mapping problem, I explore Information Retrieval techniques using the search engines whoosh and Solr, as well as a Learning to Rank algorithm. The BiLSTM encoder with CRF gave the highest performance on finding the adverse events in the texts, with an F1 of 0.67 (0.75 precision, 0.61 recall), representing a 0.06 absolute increase in F1 over the simpler BiLSTM encoder with softmax. Using the ELMo embeddings was proven detrimental and lowered the F1 to 0.62. Error analysis revealed the adopted Inside, Beginning, Outside (IOB2) labelling scheme to be poorly adapted for denoting discontinuous and compound spans while introducing ambiguity in the training data. Based on the gold standard annotated mappings, I also evaluated the whoosh and Solr search engines, with and without Learning to Rank. The best performing search engine on this data was Solr, with a macro-averaged F1 of 0.49 compared to the macro-averaged F1 of 0.47 for the whoosh search engine. Adding a Learning to Rank algorithm on top of each engine did not improve mapping performance, as both macro-averaged F1 dropped by over 0.1 when using the re-ranking approach. Finally, the best performing scanning and mapping algorithms beat the aforementioned dictionary-based baseline F1 by 0.25 in the scanning phase and 0.06 in the mapping phase. A large source of error for the Solr search engine came from tokenisation issues, which had a detrimental impact on the performance of the entire pipeline. In conclusion, modern Natural Language Processing (NLP) techniques can significantly improve the performance of adverse event detection from free-formtext compared to dictionary-based approaches, especially in cases where context is important.
Farmakovigilans berör de aktiviteter som förbättrar förståelsen av biverkningar av läkemedel. Trots de stränga prövningar som behövs för läkemedelsutvecklingen finns ändå en del biverkningar som är okända p.g.a. genetik, fysiologiska eller demografiska faktorer. Uppsala Monitoring Centre (UMC), i samarbete med World Health Organization (WHO) är vårdnadshavare till den globala databasen av rapporter på medicinska biverkningar, VigiBase. VigiBase innehåller över 20 miljoner misstänkta rapporter från hela världen. Dock, en andel av dessa rapporter beskriver biverkningar som är redan kända. Egentligen finns det över 3 miljoner potentiella samband mellan alla läkemedel och biverkningar i databasen. Att hitta den riktiga och okända biverkningar behövs kraftfulla statistiska metoder samt kunskap om det kända säkerhetsprofil av läkemedlet. Det finns ett behöv för ett databas som kartlägger läkemedel med alla kända biverkningar men, inget sådant databas finns idag. Syftet med detta examensarbete är att utveckla en djup-lärandemodell som kan läsa av texter på läkemedels etiketter — tillsynsdokument som beskriver säkerhetsprofil av läkemedel — och kartlägga dem till ett standardiserat terminologi med hög precision. Problemet kan brytas in i två fas, den första scanning och den andra mapping. Scanning handlar om att kartlägga position av text-fragmentet i etiketter. Mapping handlar om att kartlägga de detekterade text-fragmentet till Medical Dictionary for Regulatory Activities (MedDRA), den terminologi som används i UMC för biverkningar. Tidigare försök, s.k. dictionary-based approach på UMC uppnådde scanning F1 i 0,42 (0,31 precision; 0,64 recall) och mapping macro-averaged F1 i 0,43 (0,39 macro-averaged precision; 0,64 macro-averaged recall). De bästa systemen (s.k. state-of-the-art) uppnådde scanning F1 över 0,8 och 0,7 för den scanning respektive mapping problemet. Jag använder den 2019 ADE Evaluation Challenge dataset att utveckla algoritmerna i projektet. Detta dataset innehåller 100 läkemedels etiketter annoterad med biverkningar och deras kartläggning i MedDRA. Denna avhandling utforskar tre arkitekturer till scanning problemet: 1) Bidirectional Long Short-Term Memory (BiLSTM) och softmax för klassificering, 2) BiLSTM med Conditional Random Field (CRF) klassificering och, till sist, 3) BiLSTM med CRF klassificering och Embeddings from Language Model (ELMo) embeddings. Med avseende till mapping problematiken utforskar jag metoder inom Information Retrieval genom användning av sökmotorerna whoosh och Solr. För att förbättra prestandan i mapping utforskar jag Learning to Rank metoder. BiLSTM med CRF presterade bäst inom scanning problematiken med F1 i 0,67 (0,75 precision; 0,61 recall) som är ett 0,06 absolut ökning över den BiLSTM encoder med softmax klassificering. Med ELMo försämrade F1 till 0,62. Analys av felet visade att Inside, Beginning, Outside (IOB2) märkning som jag har valt att använda passar inte till att beteckna diskontinuerliga och sammansatta spans, och tillför betydande osäkerhet i träningsdata. Med avseende till mapping problematiken har jag kollat på sökmotorn Solr och whoosh, med, och utan Learning to Rank. Solr visade sig som den bäst presterande sökmotorn med macro-averaged F1 i 0,49 jämfört med whoosh som visade macro-averaged F1 i 0,47. Learning to Rank algoritmerna försämrade F1 med över 0,1 för båda sökmotorer. Den bäst presterande scanning och mapping algoritmer slog den baseline systemets F1 med 0,25 i scanning faset, och 0,06 i mapping fasen. Ett stor källa av fel för den Solr sökmotorn har kommit från tokeniserings-fel, som hade en försämringseffekt i prestanda genom hela pipelinen. I slutsats, moderna Natural Language Processing (NLP) tekniker kan kraftigt öka prestanda inom detektering av biverkningar från etiketter och texter, jämfört med gamla dictionary metoder, särskilt när kontexten är viktigt.

Zbog visoke stope morbiditeta i mortaliteta od kardiovaskularnih bolesti, udeo lekova za terapiju kardiovaskularnih bolesti značajno učestvuje u ukupno utrošenoj količini lekova u svetu. Evidentan je porast potrošnje lekova za kardiovaskularne bolesti. Radi postizanja što je moguće višeg stepena racionalizacije terapije u većini zemalja stručna tela donose farmakoterapijske smernice kako bi se mogućnost pogrešnog lečenja svela na najmanju moguću meru. Na ovaj način lekaru-praktičaru pružena je sigurnost pravilnog izbora i najadekvatnijeg postupka u datim okolnostima. Ciljevi ovog istraživanja bili su: 1) izračunavanje ukupne vanbolničke potrošnje lekova za lečenje kardiovaskularnih bolesti na teritoriji Novog Sada i njeno poređenje sa propisivanjem u Republici Srbiji i u zemljama sa razvijenom farmakoterapijskom praksom; 2) analiza strukture propisanih lekova za lečenje kardiovaskularnih bolesti (grupa C prema ATC klasifikaciji) po grupama i njeno poređenje sa propisivanjem u Republici Srbiji i u zemljama sa razvijenom farmakoterapijskom praksom; 3) analiza strukture propisanih lekova po dijagnozama i provera usklađenosti sa farmakoterapijskim smernicama; 4) komparacija propisanih lekova sa morbiditetnom statistikom kardiovaskularnih bolesti; 5) analiza farmakoekonomskih aspekata propisivanja lekova za kardiovaskularne bolesti. Sprovedeno istraživanje spada u IV fazu kliničkih ispitivanja-farmakoepidemiološko, retrospektivno, opservaciono. Podaci su prikupljeni na osnovu izveštaja iz elektronske baze podataka za period od 6 meseci (01. 01. 2012 − 01. 07. 2012), na teritoriji grada Novog Sada. Na osnovu ovih podataka na teritoriji grada Novog Sada analizirana je upotreba lekova za kardiovaskularne bolesti na 100% uzorku stanovnika. Ispitivanje se sastojalo iz dva dela. Prvi deo obuhvata prikupljanje, obradu i analizu podataka o ukupno propisanoj količni lekova za kardiovaskularne bolesti na teritoriji grada Novog Sada. U drugom delu istraživanja korišćenjem podataka dobijenih iz državne „Apoteke Novi Sad“ detaljnije je analizirana upotreba lekova za lečenje kardiovaskularnih bolesti izdatih na recept. Upotreba lekova analizirana je: prema uzrastu i polu pacijenata, prema dijagnozama za koje su lekovi propisani i prema ceni. Sruktura upotrebe lekova po indikacijama za dijagnoze kod kojih je ukupna upotreba propisanih lekova bila veća od 1 DDD/1000stanovnika/dan upoređena je sa postojećim nacionalnim vodičima i sa upotrebom u zemljama sa razvijenom farmakoterapijskom praksom, odnosno sa međunarodnim vodičima. Ovi podaci upoređeni su sa morbiditetnom statistikom na teritoriji grada Novog Sada. Ukupno propisana količina lekova za kardiovaskularne bolesti u posmatranom periodu iznosila je 399,79 DDD/1000st/dan. Od te količine, preko polovine (201,11DDD/1000st/dan) propisivanih lekova za kardiovaskularne bolesti su lekovi koji deluju na sistem renin-angiotenzin, slede blokatori kalcijumskih kanala, zatim blokatori beta-adrenergičkih receptora, a na četvrtom mestu po ukupno propisanoj količini su lekovi za terapiju bolesti srca. Od najčešćih dijagnoza za koje su propisivani lekovi za kardiovaskularne bolesti, najzastupljenije su bile arterijska hipertenzija, a potom ishemijska bolest srca. Upotreba lekova za kardiovaskularne bolesti u vanbolničkoj sredini na teritoriji grada Novog Sada (399,79 DDD/1000st/dan) viša je u odnosu na zemlje u okruženju (Hrvatsku, Crnu Goru), a niža u odnosu na zemlje sa razvijenom farmakoterapijskom praksom. U odnosu na zemlje sa razvijenom farmakoterapijskom praksom postoje odstupanja u pogledu strukture propisivanja. Struktura propisivanja lekova za kardiovaskularne bolesti odstupa od važećih nacionalnih vodiča o racionalnoj upotrebi lekova za kardiovaskularne bolesti u Republici Srbiji. Istovremeno struktura propisanih lekova nije u skladu sa morbiditetnom statistikom kardiovaskularnih bolesti prema zvaničnim podacima. Među 10 najčešće propisanih lekova nalaze se i skupi lekovi, koji imaju adekvatne, a mnogo jeftinije paralele. Nedovoljno i neracionalno lečenje kardiovaskularnih bolesti verovatno su jedan od značajnih razloga za visoku smrtnost od kardiovaskularnih bolesti u Srbiji.
Due to high rates of morbidity and mortality from cardiovascular diseases, the share drugs for the treatment of cardiovascular diseases significantly contributes to a total utilization among drugs in the world. There is an evident increase in the consumption of drugs for cardiovascular diseases. In order to achieve as much as possible a higher level of rationalization of therapy in most countries the professional bodies making pharmacotherapeutic guidelines to the possibility of the wrong treatment was reduced to a minimum. In this way, the physician-practitioner provided the security proper selection and the most appropriate procedure in the circumstances. The objectives of this study were: 1) the calculation of the total outpatient consumption of drugs for the treatment of cardiovascular diseases on the territory of Novi Sad and its comparison with the prescribing in the Republic of Serbia and the countries with developed pharmacotherapeutical practice; 2) analysis of the structure of prescribed drugs for the treatment of cardiovascular diseases (group C according to the ATC classification) by the groups and its comparison with the prescribing in the Republic of Serbia and the countries with developed pharmacotherapeutical practice 3) analysis of the structure of prescribed drugs per diagnosis and verification of compliance with pharmacotherapeutic guidelines; 4) comparison of prescribed drugs with morbidity statistics cardiovascular diseases; 5) analysis of pharmacoeconomic aspects of prescribing drugs for cardiovascular diseases. A research conducted among the phase IV clinical trials-pharmacoepidemiological, retrospective observational. Data were collected on the basis of a report from the electronic database for the period of 6 months (01. 01. 2012 - 01. 07. 2012), on the territory of the city of Novi Sad. Based on these data on the territory of the city of Novi Sad analyzed the use of drugs for cardiovascular diseases at 100% sample of the population. The research consisted of two parts. The first part comprises the collection, processing and analysis of data on the total quantity of the prescribed cardiovascular drugs on the territory of the city of Novi Sad. In the second part of this research using data from the public "Pharmacy Novi Sad" is a more detailed analysis of the utilization of drugs for the treatment of cardiovascular diseases of prescription. The utilization of drugs is analyzed: according to the age and sex of patients, in diagnosis for which the drugs prescribed and to the cost. Structure of the use of drugs by indications for diagnosis in which the total utilization of prescribed drugs was greater than 1 DDD/1000inhabitants/day was compared with the existing national guidelines and use in countries with developed pharmacotherapeutical practice, and with international guidelines. These data were compared with morbidity statistics on the territory of the city of Novi Sad. Total amount of prescribed drugs for cardiovascular diseases in the examined period was 399.79 DDD/1000inh/day. Of this amount, more than half (201.11 DDD/1000inh/day) were drugs acting on the renin-angiotensin system, followed by calcium channel blockers, beta adrenergic receptor blockers, and fourth in total prescribed quantity drugs for treatment of heart diseases. Of the most common diagnosis for which drugs for cardiovascular diseases were prescribed, the most common were arterial hypertension, and then ischemic heart disease. The use of drugs for cardiovascular diseases in outpatient environment on the territory of the city of Novi Sad (399.79 DDD/1000inh/day) is higher compared to neighboring countries (Croatia, Montenegro), and lower than in countries with developed pharmacotherapeutical practice. Compared to countries with developed pharmacotherapeutical practice there are variations in terms of the structure of prescribing. Structure of prescribing of drugs for cardiovascular diseases deviates from the existing national guidelines on rational use of drugs for cardiovascular diseases in the Republic of Serbia. At the same time the structure of prescribed drugs is not in compliance with morbidity statistics cardiovascular diseases according to official data. Among the 10 most commonly prescribed drugs are costly drugs, that have adequate, and much cheaper parallels. Insufficient and irrational treatment of cardiovascular diseases are probably one of the major reasons for the high mortality from cardiovascular diseases in Serbia.

This thesis evaluates if and how drug name recognition can be used to find drug names in verbatims from reports on concomitant medication in clinical trial studies. In clinical trials, reports on concomitant medication are written if a trial participant takes other drugs than the studied drug. This information needs to be coded to a drug reference dictionary. Coded verbatims were used to create the data needed to train the drug name recognition models in this thesis. Labels for where in each verbatim the coded drugs name was, were created using a Levensthein distance. The drug name recognition models were trained and tested on verbatims with labels. Drug name recognition was performed using a logistic regression model and a bidirectional long short-term memory model. The bidirectional long short-term memory model performed the best result with an F1 score of 82.5% on classifying which words in the verbatims that were drug names. When the results were studied from case to case, they showed that the bidirectional long short-term memory classifications sometimes outperformed labels it was trained on in single word verbatims. The model was also tested on manually labelled golden standard data where it performed an F1-score of 46.4%. The results indicate that a bidirectional long short-term memory model can be implemented for drug name recognition, but that label reliability is an issue in this thesis.

Uvod: Antimikrobna rezistencija bakterija predstavlja globalni problem. Najvažniji faktor za njen nastanak je neadekvatna primena antibiotika, koja podrazumeva: Upotrebu antibiotika bez odgovarajuće dijagnoze, neadekvatan izbor leka, dužinuprimene i doziranje. Zbog specifičnosti populacije vitalno ugroženih bolesnika u jedinicama intenzivne terapije (JIT) i bolničkih infekcija uzrokovanih multirezistentnim bakterijama, primena antibiotika je na ovim odeljenjima učestala. Pokazana je povezanost između razvoja antimikrobne rezistencije i veličine potrošnje antibiotika u JIT. Cilj: Analiza primene antibiotika prema indikacijama na Klinici za anesteziju i intenzivnu terapiju, KC Vojvodine, zatim analiza stanja antimikrobne rezistencijenajčešćih uzročnika bolničkih infekcija i analiza korelacije između navedenih uzročnika bolničkih infekcija i empirijski primenjivane antibiotske terapije na Klinici za anesteziju i intenzivnu terapiju. Materijal i metode: Prospektivna, opservaciona studija, sprovedena u jednogodišnjem period, u JIT, Klinike za anesteziju i intenzivnu terapiju, uključila je 856 ispitanika, oba pola, starijih od 18 godina kod kojih je tokom hospitalizacije u JIT bio primenjen antibiotik. Ispitanici su, radi prikupljanja podataka, bili podeljeni u dve grupe u zavisnosti od toga da li su imali bolničku infekciju ili ne. Adekvatnost primene antibiotika je analizirana prema indikacijama (hirurška profilaksa, bolničke infekcije, vanbolničke infekcije i drugo), a u odnosu na izbor antibiotika, dužinu primene, režim doziranja, veličinu pojedinačne doze i način promene terapije (prema preporukama farmakoterapijskog vodiča The Sanford guide to antimicrobial therapy i antimikrobnoj osetljivosti bakterijskih uzročnika bolničkih infekcija u JIT. Za izračunavanje potrošnje antibiotika u JIT korišćena je ATC/DDD metodologija. Podaci o antimikrobnoj osetljivosti dobijeni su iz rezultata mikrobiološke obrade uzorkovanog materijala. Statistička analiza je izvršena pomoću statističkog paketa IBM SPSS 21 Statistics. Podaci su predstavljeni tabelarno i grafički, obrađeni su standardnim statističkim testovima, a statistička značajnost određivanja je bila na nivou p< 0,05. Ispitivanje povezanosti između potrošnje anibiotika i antimikrobne rezistencije urađeno je primenom Pirsonovog koeficijenta korelacije. Rezultati: Izbor antibiotika kod bolesnika u JIT nije bio adekvatan u 52,19% preskripcija. Izbor empirijski indikovanih antibiotika za lečenje bolničkih infekcija nije bio u skladu antimikrobnom osetljivošću izolovanog uzročnika u 78,44% preskripcija. Izbor antibiotika za hiruršku profilaksu nije bio adekvatan u 55,6% preskripcija. Antimikrobna rezistencija Acinetobacter spp.na karbapeneme, fluorohinolone i cefalosporine bila je preko 90%, na aminoglikozide preko 70%. Klebsiella pneumoniae bila je rezistentna na fluorohinolone i cefalosporine 80%, dok je na grupu karbapenema bila 18%. Pseudomonas aeruginosa je bio rezistentan na karbapeneme i aminoglikozide preko 50%, na antipseudomonasne cefalosporine preko 40%. Na kolistin nije zabeležena rezistencija ni jedne izolovane bakterijske vrste. Značajna pozitivna korelacija zabeležena je između potrošnje empirijski indikovanog meropenema i rezistencije Acinetobacter spp. Zaključak: U vise od 50% slučajeva primena antibiotika u JIT nije bila u skladu sa stanjem antimikrobne rezistencije bakterijskih uzročnika bolničkih infekcija i savremenim farmakoterapijskim protokolima. Antimikrobna rezistencija Acinetobacter spp, Klebsiellae pneumoniae и Pseudomonas aeruginosae je iznosila preko 20% na antibiotike preporučene savremenim farmakoterapijskim smernicama, osim u slučaju rezistencije Klebsiellaе pneumoniae na grupu karbapenema. Između pojave rezistencije Acinetobacter spp. i potrošnje empirijski indikovanog meropenema utvrđena je statistički značajna pozitivna povezanost, dok za druge dve navedene bakterijske vrste ova povezanost nije bila statistički značajna. Na osnovu podataka o najčešćim bakterijskim uzročnicima i njihovoj antimikrobnoj osetljivosti za empirijskuterapiju pneumonija mogao bi biti preporučen jedino kolistin, dok bi za lečenje urinarnih infekcija mogao biti preporučen imipenem ili meropenem. Potrebno je promeniti farmakoterapijski pristup u primeni antibiotika u JIT.
Uvod: Antimikrobna rezistencija bakterija predstavlja globalni problem. Najvažniji faktor za njen nastanak je neadekvatna primena antibiotika, koja podrazumeva: Upotrebu antibiotika bez odgovarajuće dijagnoze, neadekvatan izbor leka, dužinuprimene i doziranje. Zbog specifičnosti populacije vitalno ugroženih bolesnika u jedinicama intenzivne terapije (JIT) i bolničkih infekcija uzrokovanih multirezistentnim bakterijama, primena antibiotika je na ovim odeljenjima učestala. Pokazana je povezanost između razvoja antimikrobne rezistencije i veličine potrošnje antibiotika u JIT. Cilj: Analiza primene antibiotika prema indikacijama na Klinici za anesteziju i intenzivnu terapiju, KC Vojvodine, zatim analiza stanja antimikrobne rezistencijenajčešćih uzročnika bolničkih infekcija i analiza korelacije između navedenih uzročnika bolničkih infekcija i empirijski primenjivane antibiotske terapije na Klinici za anesteziju i intenzivnu terapiju. Materijal i metode: Prospektivna, opservaciona studija, sprovedena u jednogodišnjem period, u JIT, Klinike za anesteziju i intenzivnu terapiju, uključila je 856 ispitanika, oba pola, starijih od 18 godina kod kojih je tokom hospitalizacije u JIT bio primenjen antibiotik. Ispitanici su, radi prikupljanja podataka, bili podeljeni u dve grupe u zavisnosti od toga da li su imali bolničku infekciju ili ne. Adekvatnost primene antibiotika je analizirana prema indikacijama (hirurška profilaksa, bolničke infekcije, vanbolničke infekcije i drugo), a u odnosu na izbor antibiotika, dužinu primene, režim doziranja, veličinu pojedinačne doze i način promene terapije (prema preporukama farmakoterapijskog vodiča The Sanford guide to antimicrobial therapy i antimikrobnoj osetljivosti bakterijskih uzročnika bolničkih infekcija u JIT. Za izračunavanje potrošnje antibiotika u JIT korišćena je ATC/DDD metodologija. Podaci o antimikrobnoj osetljivosti dobijeni su iz rezultata mikrobiološke obrade uzorkovanog materijala. Statistička analiza je izvršena pomoću statističkog paketa IBM SPSS 21 Statistics. Podaci su predstavljeni tabelarno i grafički, obrađeni su standardnim statističkim testovima, a statistička značajnost određivanja je bila na nivou p< 0,05. Ispitivanje povezanosti između potrošnje anibiotika i antimikrobne rezistencije urađeno je primenom Pirsonovog koeficijenta korelacije. Rezultati: Izbor antibiotika kod bolesnika u JIT nije bio adekvatan u 52,19% preskripcija. Izbor empirijski indikovanih antibiotika za lečenje bolničkih infekcija nije bio u skladu antimikrobnom osetljivošću izolovanog uzročnika u 78,44% preskripcija. Izbor antibiotika za hiruršku profilaksu nije bio adekvatan u 55,6% preskripcija. Antimikrobna rezistencija Acinetobacter spp.na karbapeneme, fluorohinolone i cefalosporine bila je preko 90%, na aminoglikozide preko 70%. Klebsiella pneumoniae bila je rezistentna na fluorohinolone i cefalosporine 80%, dok je na grupu karbapenema bila 18%. Pseudomonas aeruginosa je bio rezistentan na karbapeneme i aminoglikozide preko 50%, na antipseudomonasne cefalosporine preko 40%. Na kolistin nije zabeležena rezistencija ni jedne izolovane bakterijske vrste. Značajna pozitivna korelacija zabeležena je između potrošnje empirijski indikovanog meropenema i rezistencije Acinetobacter spp. Zaključak: U vise od 50% slučajeva primena antibiotika u JIT nije bila u skladu sa stanjem antimikrobne rezistencije bakterijskih uzročnika bolničkih infekcija i savremenim farmakoterapijskim protokolima. Antimikrobna rezistencija Acinetobacter spp, Klebsiellae pneumoniae i Pseudomonas aeruginosae je iznosila preko 20% na antibiotike preporučene savremenim farmakoterapijskim smernicama, osim u slučaju rezistencije Klebsiellae pneumoniae na grupu karbapenema. Između pojave rezistencije Acinetobacter spp. i potrošnje empirijski indikovanog meropenema utvrđena je statistički značajna pozitivna povezanost, dok za druge dve navedene bakterijske vrste ova povezanost nije bila statistički značajna. Na osnovu podataka o najčešćim bakterijskim uzročnicima i njihovoj antimikrobnoj osetljivosti za empirijskuterapiju pneumonija mogao bi biti preporučen jedino kolistin, dok bi za lečenje urinarnih infekcija mogao biti preporučen imipenem ili meropenem. Potrebno je promeniti farmakoterapijski pristup u primeni antibiotika u JIT.
Introduction: Antimicrobial resistance is a global health problem.The most important factor in the development of antimicrobial resistance is inadequate use of antibiotics, which means: inadequate diagnosis of bacterial infection, inadequate antibiotic choice, dosage and duration of therapy. Specificities of critically ill patients and nosocomial infections caused by multidrug-resistant pathogens are important reasons for large antibiotic consumption in ICU settings. Many studies have confirmed a positive correlation between antibiotic use and antimicrobial resistance. Aims: The aims of this study were: to analyze the use of antibiotics at the ICU of the Clinic for anesthesia and intensive care at the Clinical Centre of Vojvodina, according to indications for antibiotic treatment; to analyze the pattern of antimicrobial resistance ofthe most common bacteria causing hospital acquired infections in our participants and to analyze the correlation between the consumption of empirically indicated antibiotics and antimicrobial resistance pattern. Methodology: Prospective observational study was conducted during a one-year period at the Clinic for anesthesia and intensive care, Clinical Centre of Vojvodina. The study included 856 participatns, aged over 18 years and of both genders. The participants were divided into two cohorts, depending on whether they showed symptoms of hospital-acquired infection or not. Adequacy of antibiotic use was analyzed with regard to indication for antibiotic treatment (surgical prophylaxis, treatment of hospital acquired infection, outpatient infection or other) and with regard to antibiotic choice, dosage and duration of treatment. An adequate antibiotic choice was compared to the resistance pattern of positive bacterial isolates as outlined by The Sanford guide to antimicrobial therapy). To calculate the consumption of antibiotics in ICU we used ATC/DDD methodology. Data on antibacterial sensitivity was obtained from the results of microbiological analysis of sample materials. IBM SPSS version 21 was used for statistical analysis, standard statistical tests were applied. The results were presented in tables and graphs. Statistically significant correlation was set at the value of p˂0.05. Pearson correlation coefficient was used to measure the strength between variables. Results: Antibiotic choice was inadequate in 52,19% of all antibiotic prescriptions for all indications. Antibiotic choice in surgical prophylaxis was inadequate in 55,59% of prescriptions for this indication. Inadequate choice of empirically indicated antibiotics (for treatment of hospital-acquired infections) according to antimicrobial resistance pattern occurred in 78,44% of all prescription for this indication. The three the most important bacterial causative agents of hospital acquired infections in ICU were: Acinetobacter spp, Klebsiella pneumonia and Pseudomonas aeruginosa. The resistance of Acinetobacter spp. to antibiotic groups was as follows: to carbapenems, fluoroquinolones and cephalosporins over 90% and to aminoglycosides over 70%. The antimicrobial resistance of Klebsiella pneumoniae was: to fluoroquinolones and cephalosporins over 80% and to carbapenems up to 20%. The resistance pattern of Pseudomonas aeruginosa was as follows: to carbapenems and aminoglykozides over 50%, and to antipseudomonal cephalosporins over 40%. Statistically significant correlation was found between the consumption of empirically prescribed meropenem and antimicrobial resistance of Acinetobacter spp. Conclusion:In more than 50% of antibiotic prescriptions at ICU, regardless of indication, the choice of prescribed antibiotics was inadequate. Antimicrobial resistance pattern of Acinetobacter spp, Klebsiella pneumoniae and Pseudomonas aeruginosa to antibiotics recomennded by contemporary guidelines for antimicrobial therapy was over 20%, except in the case of the resistance of Klebsiellae peneumoniae to carbapenems. Statistically significant correlation was found between the consumption of empirically prescribed meropenem and antimicrobial resistance of Acinetobacter spp. No statistically significant correlation was observed in the other two bacterial strains. Initial, empiric therapy for nosocomial pneumonia in our ICU, should be colistin, and for urinary tract infection imipenem or meropenem. It is important to change antibiotic prescribing praxis in ICU.

The purpose of the project is to develop and evaluate a writing unit that could be used to teach adult students in a drug court program. The project is based on theories behind narrative therapy, its use in the treatment of persons with addiction problems, and how the reframing of students' own life stories through writing can bring about change. By using writing prompts as both therapeutic and educational tools, the author hoped to improve the students' life-coping skills and their writing abilities. The unit consists of paragraph writing, essay writing, reflective writing that focused on past events, and using computers to compose and format texts. The author evaluated a preliminary draft of the unit by submitting it to four education professionals with a questionnaire. Data was also collected from the author's students by means of surveys, interviews, and writing samples. Feedback from the professionals and the students guided the revision of the unit. The questionnaire, survey, and interview questions used in the project and the preliminary and final revised drafts of the teaching unit are included.

Metotreksat kao antagonista folne kiseline ima široku upotrebu za lečenje brojnih maligniteta, primenjen u visokim dozama i u  kombinciji  sa leukovorinom. Iako  je  terapija  visokim  dozama  metotreksata drastično poboljšala  prognozu pacijenata sa malignitetom, teški neželjeni efekti terapije predstavljaju stalan klinički problem. Ciljevi istraživanja bili su određivanje serumske koncentracije metotreksata i izračunavanje farmakokinetičkih  parametara  metotreksata kod dece obolele od malignih  bolesti  koja su na terapiji visokim dozama metotreksata (2  g/m² i  5  g/m² ); ispitivanje postojanja uticaja primenjene doze metotreksata, demografskih i kliničkih karakteristika ispitanika  na koncentracije i farmakokinetičke parametare. Ispitivano je prisustvo i stepen kliničkih i laboratorijskih znakova toksičnosti metotreksata, kao i uticaj primenjene  doze  metotreksata  i demografskih karakteristika ispitanika  na pojavu i stepen toksičnosti . U okviru retrospektivno - prospektivne  studije  ukjučeno  je  četrdeset  i dva pedijatrijska  pacijenta  uzrasta od  0,75 do 17,75 godina (medijana 5,75  godina). Svi pacijenti  su lečeni  u  Službi  za  hematologiju i  onkologiju  Instituta  za  zdravstvenu zaštitu dece i omladine Vojvodine (Novi Sad, Srbija) u periodu od juna 2004. godine do juna 2012. godine. Trideset i osam ispitanika  je lečeno pod dijagnozom akutne limfoblastne leukemije  prema dva  uzastopna  protokola ALL IC - BFM 2002 i ALL IC - BFM 2009 Internacionalne  BFM studijske  grupe „I - BFM - SG“  (International Berlin -Frankfurt - Münster Study Group) za proučavanje i lečenje dečje non-B akutne limfoblastne leukemije. Četvoro je  imalo  dijagnozu non - Hodgkin limfoma  i bili su uključen i u  protokol NHL - BFM  95. Istraživanje je obuhvatilo 113 ciklusa terapije metotreksatom (1– 4 ciklusa po pacijentu) sa 386 izmerenih serumskih koncentracija metotreksata. Raspon primenjenih doza metotreksata kretao se od 800 do 10.000 mg. Koncentracije metotreksata su merene 24, 36 i 42 sata nakon započinjanja infuzije metotreksata, a po potrebi i u dužim vremenskim intervalima. Za izračunavanje farmakokinetičkih parametara korišćen je dvokompartmanskih farmakokinetički  model posle obustavljanja  intravenske  infuzije,  gde  postoje relacije  za  farmakokinetičke  tačke. Podaci o kliničkim i laboratorijskim znacima toksičnosti metotreksata prikupljani su iz medicinske dokumentacije, a za stepenovanje toksičnosti korišćen je skor sistem - Common Terminology Criteria for  Adverse  Events (CTCAE), Version 4.0, U.S. Department  of  health  and  human services, National Institute of Health, National Cancer Institute. U cilju utvrđivanju uticaja karakteristika ispitanika, primenjene doze i prisustva produžene eliminacije na posmatrane parametre, vršeno je poređenje tri grupe  pacijenata (doza 2 g/m² bez produžene eliminacije, 5 g/m² bez produžene liminacije i 5 g/m² sa produženom eliminacijom metotreksata). Za celokupnu grupu ispitanika,  medijane  koncentracije metotreksta  bile  su 25,82 μmol/l u 24. satu, 0,68 μmol/l u 36. satu i 0,24 μmol/l u 42. satu merenja. Najizraženija interindividualna varijabilnost u koncentracijama metotreksata bila je u 42. satu merenja, dok je  intraindividualna varijabilnost bila najizraženija u 36. satu merenja. Medijana  klirensa   metotreksata   bila  je 8,32   l/h. Farmakokinetički parametri  redom bili su:  medijana  volumena  centralnog  kompartmana V₁ 28,47  l, medijane konstanti k₁₀ 0,206, k₁₂ 0,0245, k₂₁ 0,1114. Najizraženiji uticaj primenjene doze na koncentracije metotreksata pokazan je u 24.  satu  merenja, dok uticaj doze na klirens  metotreksata nije  pokazan. Prisustvo produžene eliminacije metotreksata dovodi do smanjenih vrednosti konstanta k₁₀ i k₂₁. Nije pokazana statistički značajna  interakcija ispitivanih demografskih karakteristika (uzrast, telesna površina i pol)  i koncentracija metotreksata, kao ni klirensa metotreksata. Pokazana je značajna interakcija između koncentracija metotreksata i nivoa laktat dehidrogenaze, kao i klirensa metotreksata i nivoa kreatinina i laktat dehidrogenaze. Većina ispoljenih  toksičnosti bila je umerenog stepena (<3 stepena). Najzastupljeniji klinički znak toksičnosti bio je oralni mukozitis, koji je bio većeg stepena u grupi sa većom primenjenom dozom metotreksata  (5g/m²). Najzastupljeniji  laboratorijski toksični efekti  metotreksata bili su leukopenija i anemija. Najteži stepeni laboratorijskih znakova toksičnosti (leukopenija, anemija, porast  AST,  ALT i GGT) nalazili su se u grupi sa većom dozom  (5 g/m²) i  sa produženom eliminacijom metotreksata. Osnov  za  kliničko  vođenje  pacijenata  na  terapiji visokim dozama metotreksata je terapijsko praćenje leka (therapeutic drug monitoring – TDM) zbog velikih  interindividualnih i intraindividualnih  varijabilnosti  u  farmakokinetici  leka. Rutinsko praćenje koncentracija metotreksata važno je za identifikaciju pacijenata sa povećanim rizikom od razvoja toksičnosti ,  te  je TDM  standardna  praksa  za smernice spasavanja leukovorinom, naročito za pacijente za koje se zna da imaju smanjen   klirens metotreksata ili druge rizike povezane sa prolongiranim citotoksičnim koncentracijama (bubrežna ili jetrena oštećenja, kolekcije tečnosti u “trećem prostoru”, gastrointestinalna opstrukcija). Veliki  broj  istraživanja  kod pedijatrijskih pacijenata pokazao je vezu između sistemskog izlaganja metotreksatu i  efikasnosti  i  toksiĉnosti  metotreksata. Ipak, ne postoji dovoljno  informacija o farmakokinetici metotreksata kod dece obolele od akutne limfoblastne leukemije. Takođe, ova istraživanja nisu do sada sprovođena kod dece koja su lečena u našoj sredini.
Methotrexate  is  an  antifolate  drug  widely  used  for  treatment  of  various malignant  tumours.  It  is  used  at  high  doses  and  in  combination  with leucovorin rescue.  Although  high - dose  MTX  therapy  dramatically  improves  the  prognosis  of patients with malignancies, severe adverse events are constant clinical concern. The  aims  of  this  stydy  were  to  determine  the  serum  concentration  of  methotrexate  and  to  calculate  the  pharmacokinetic  parameters  of  methotrexate  in children  suffering  from  malignant  deseases  who  are  treated  with  high  doses  of metotrexate  (2  g/m² i  5  g/m² );  furthermore,  to  investigate  the  effects  of  the  applied doses of methotrexate, and demographic and clinical characteristics of the examinees on   the   concentration   and   pharmacokinetic   parameters   of   the   drug.   The   study investigated the   presence   and   the   degree   of   clinical   and   laboratory   signs   of metotrexate  toxicity,  as  well  as  the  effect  of  the  applied  doses,  and  demographic characteristics of the examinees on the appearance and the degree of toxicity. The retrospective - prospective study included 42  pediatric patients aged from 0.75  to  17.75  years  (median  5.75  years).  All  patients  were  threated  at  the  Children and Youth Health Care Institute of Vojvodina (Novi Sad, Serbia), Hemathology and Oncology  Section,  in  the  period  from  June  20 04  to  June  2012.  38  examinees diagnosed as acute lymphoblastic leukemia were treated according to two subsequent protocols,  ALL  IC - BFM  2002  and  ALL  IC - BFM  2009  of  the  International  BFM study  group „I - BFM - SG“ (International Berlin - Frankfurt - Münster  Study  Group)  for management   of   childhood   non - B   acute   lymphoblastic   leukemia.   4   examinees diagnosed  as  non - Hodgkin  lymphoma  were  treated  according  to  the  NHL - BFM  95 protocol. The study included 113 cycles of therapy with methotrexate (1-4 cycles per patient)  with  3 86  measured  serum  concentrations  of  methotrexate.  The  range  of  the applied doses was between 800 and 10,000 mg. The  concentration  of  methotrexate  was  measured  24,  36  and  42  hours  after the initiation of the methotrexate infusion, as well as in longer time intervals when needed.  To  calculate  the  pharmacokinetic  parameters,  the  study  applied  the  two - compartment  pharmacokinetic  model  after  the  termination  of  intravenous  infusion, when  relations  for  pharmacokinetic  points  existed.  Data  on  clinical  and  laboratory signs of methotrexate toxicity were collected  from medical documentation, and the Common  Terminology  Criteria  for  Adverse  Events  (CTCAE),  Version  4.0,  U.S. Department  of  health  and  human  services,  National  Institute  of  Health,  National Cancer  Institute, was  used  as  the  score  system  for  toxicity  ranking.  In  order  to determine  the  effects  of  the examinees’  characteristics, applied  doses  and  the presence  of  prolonged  elimination on  the  parameters  of  interest,  three  groups  of patients were  compared (2 g/m² dose without prolonged elimination, 5 g/m² without prolonged elimination and 5 g/m² with prolonged elimination of methotrexate). In the  entire  group of  examinees, the median  concentration of methotrexate was  25.82 μmol/l in the 24th hour, 0.68 μmol/l in the 36th  hour  and 0.24 μmol/l in the 42nd hour of  observation. The largest inter - individual variability of methotrexate concentration  was  observed  in  the  24th  hour  while  the  largest  intra - individual variability  was  recorded  in  the  36th  hour  of  observation.  The  median  clearance  of methotrexate  was  8.32l/h.  Pharmacokinetic  parameters  were  the  following:  median volume  of  the  central  compartment V₁ 28.47  l,  median  constants k₁₀ 0,206, k₁₂ 0,0245, k₂₁ 0,1114, respectively. The   strongest   influence   of   the   applied   dose   on   the   methotrexate concentration was recorded in the 24th hour of observation while no influence on the methotrexate  clearance  was  found.  The  presence  of  prolonged  elimination  of methotrexate   causes   lower  constants k₁₀ and   k₂₁. There   was   no   statistically significant  interaction  between  the  investigated  demographic  characteristics  (age, body  surface  and  gender)  and  the  methotrexate  concentration,  nor  between  the demographic   characteristics   and   the   methotrexate   clearance.   A   significant interaction was found between methotrexate concentration and lactat dehydrogenase level, as   well   as   between   methotrexate   clearance   and   creatinine   and   lactate dehydrogenase level, respectively. Most of the observed toxicities were of moderate degree (< 3 degrees). Oral mucositis  was  the  most  represented  clinical  sign  of  toxicity,  and  it  was  of  higher degree  in  the  group  where  the  applied  dose  of  methotrexate  was  higher  (5  g/m² ). Leucopenia  and  anemia  were  the  most  represented  laboratory  toxic  effects.  The most severe laboratory signs of toxicity  (leucopenia, anemia, increase in AST, ALT and  GGT  activity)  were  observed  in  the  group  with  the  higher  dose  (5  g/m² )  and prolonged methotrexate elimination. Due to high inter- and   intra-individual    variability  of  the drug pharmacokinetics,  the  basis  for  the  clinical  care  of  patients  on  high  methotrexate dosage  therapy  is  therapeutic  drug  monitoring – TDM.  Routine  monitoring  of methotrexate serum concentration is important for the identification of patients with a high  risk  of  toxicity,  and  thus  TDM  is  used  as  a  standard  procedure  which  provides guidelines  for  leucovorin  rescue,  particularly  for  patients  with  a  lower  methotrexate clearance or other risks associated with prolonged cytotoxic concent rations (kidney or liver  damage,  body  fluid  accumulation  in  the  “third  space”,  gastrointestinal obstruction). Numerous studies involving pediatric patients have documented the link between  a  systemic  methotrexate  exposure  on  one  hand,  and  the  efficiency  and toxicity of  ethotrexate on the other hand. However, there is no sufficient data on the methotrexate    pharmacokinetics   in   children   suffering   from   acute   lymphoblastic leukemia.   Moreover,   this   type   of   research,   involving   children   treated   in   the geographical region of this study, have not been conducted.

Streptococcus pneumoniae (pneumokok) je  jedan  od  vodećih  uzroka morbiditeta i mortaliteta širom sveta, kada su u pitanju infektivne bolesti. Pretežno izaziva infekcije gornjih respiratornih puteva (sinuzitis, otitis) i konjunktivitis. Vodeći je uzročnih vanbolničkih pneumonija, bakterijskog meningitisa i sepse. Lekovi izbora u terapiji pneumokoknih bolesti su beta laktamski antibiotici i makrolidi. Iako se makrolidni antibiotici uveliko koriste u lečenju pneumokoknih infekcija širom sveta, porast rezistencije na makrolide  bi  mogao  da  kompromituje  njihovu  upotrebu. Rezistencija pneumokoka na makrolide je posredovana putem dva glavna mehanizma: modifikacija ciljnog mesta delovanja leka  i aktivni efluks leka. Metilaciju 23S ribozomalne ribonukleinske kiseline (rRNK) obavlja enzim metilaza, čiju sintezu kodira ermB gen. Kod ovog tipa rezistencije dolazi do ukrštene rezistencije na makrolide (M), linkozamide (L) i streptogramine B (Sb). Ovakav vid rezistencije se ispoljava kao MLS_b - fenotip i karakteriše ga visok nivo rezistencije. Može se javiti kao konstitutivni (cMLS) i inducibilni (iMLS). Drugi mehanizam rezistencije na makrolide je aktivni efluks leka, kodiran od strane mefA  gena. Efluks antibiotik a determiniše rezistenciju samo na 14-člane i 15-člane makrolide, bez ukrštene rezistencije. Ispoljava se kao M-fenotip, a karakteriše ga niži stepen rezistencije. Cilj ove studije je bio  da  se  odredi u čestalost  makrolidne  rezistencije Streptococcus pneumoniae među invazivnim i neinvazivnim izolatima kod dece i odraslih, da se odrediti u čestalost korezistencije i multiple rezistencije kod makrolid rezistentnih sojeva  Streptococcus pneumoniae, da se fenotipski odredi tip rezistencije na makrolide i da se ispita genska osnova makrolidne rezistencije (detektovati prisustvo ermB i mefA gena). Analizirani su podaci o 326 sojeva Streptococcus pneumoniae rezistentnih na makrolide (MRSP) sakupljenih širom  Srbije  u  periodu  od  januara  2010.  do  decembra  2012.  godine. Sakupljeni  MRSP  izolati  su  transportovani  u  Nacionalnu  referentnu laboratoriju za streptokok radi daljih ispitivanja. Identifikacija je vršena na osnovu mikroskopskih, kulturelnih i biohemijskih osobina. Konzervacija je vršena u moždano-srčanom bujonu sa 10% sadržajem glicerola na -80°C. Dvostruki  disk  difuzioni  test,  kombinovani  difuzion odilucioni  test  i automatizovani VITEK 2 sistem su korišćeni za određivanje fenotipova rezistencije na makrolide. Geni koji kodiraju rezistenciju na makrolide su detektovani PCR metodom. Ukupna rezistencija sojeva S.pneumoniae na makrolide u Srbiji je iznosila 34%. Sojevi S.pneumoniae rezistentni na makrolide su češće bili izolovani kod dece (36%) u odnosu na odrasle (29%) osobe, i češće su izolovani iz neinvazivnih (35,5%) u odnosu na invazivne (27,4%) materijale. Dominantan fenotip rezistencije na makrolide je bio MLS_b fenotip (78,5%). Konstitutivan MLS fenotip je bio zastupljen kod 73,9%, a inducibilan MLS kod 4,6% MRSP izolata. Potvrđena je udruženost mefA  gena i M fenotipa; ermB gena i iMLS fenotipa, kao i ermB gena i cMLS fenotipa. Prisustvo oba ermB i mefA gena rezistencije je potvrđeno kod 43,9 % izolata. Svi izolati sa koji su imali oba gena rezistencije su ispoljili  MLS_b fenotip.  Istovremena  neosetljivost  na  penicilin  je bila zastupljena kod 16% MRSP sojeva. Visok nivo rezistencije na penicilin je imalo svega 5,8% MRSP izolata. Među MRSP sojevima je bio prisutan visok nivo  rezistencije  na  tetraciklin  (81,3%)  i  trimetoprim-sulfametoksazol (74,3%). Multirezistenti sojevi, koji su bili rezistentni na tetracikline i trimetoprim-sulfametoksazol su predstavljali dve trećine (66,1%) MRSP izolata.  Zastupljenost  udružene  rezistencije  MRSP  na  tetraciklin i trimetoprim-sulfametoksazol je bila veća kod sojeva sa MLS fenotipom (73,1%)  u  odnosu  na  sojeve  sa  M  fenotipom  (36,7%). Zastupljenost istovremene rezistencije na makrolide i druge antibiotike među kojima su penicilin, amoksicilin, cefotaksim, tetraciklin, trimetoprim-sulfametoksazol, kao  i  multirezistentnih  sojeva  je  bila  veća  kod pedijatrijskih  izolata pneumokoka  u  odnosu  na  sojeve  dobijene  kod  odraslih.  U čestalost istovremene rezistencije na makrolide i druge antibiotike među kojima su tetraciklin i ofloksacin je bila više prisutna među neinvazivnim u odnosu na invazivne MRSP izolate. Invazivni MRSP izolati iz likvora su pokazivali veću rezistenciju na beta laktamske antibiotike u odnosu neinvazivne sojeve. MRSP sojevi su pokazali veoma visok nivo osetljivosti na levofloksacin (99,6), telitromicin (98,4%), cefotaksim (93,5%), i mipenem (97,3%). MRSP sojevi su u potpunosti bili osetljivi na vankomicin, linezolid, moksifloksacin, sparfloksacin, rifampicin  i  pristinamicin.  Među  invazivnim  sojevima S.pneumoniae rezistentnim na makrolide je nađeno 12 različitih serotipova. Polovina izolata je pripadala serotipovima 19F (25%) i 14 (23%), dok su sledeći po učestalosti bili 6A (10,4%) i 23F (8,3%). Istovremena rezistencija na makrolide, penicilin, tetracikline i trimetoprim-sulfametoksazol je nađena kod serotipova 19F, 14 i 23F, dok su serotpovi 12F i 31 bili neosetljivi samo na makrolide. Naše istraživanje predstavlja prvu detaljnu analizu fenotipskih i  genotipskih  osobina  sojeva  pneumokoka  rezistentnih  na  makrolidne antibiotike u Srbiji. Dobijeni rezultati ukazuju na  potrebu za aktivnim nadzorom nad pneumokoknim infekcijama u Srbiji.
Streptococcus pneumoniae (pneumococcus) is one of the leading morbidity and  mortality  causes  all  over  the  world  with  respect  to  infectious  diseases. Streptococcus  pneumoniae is  a  leading  cause  of upper  respiratory  tract infections  (  sinusitis,  otitis)  and  conjunctivitis. It  is  also  the  most  common cause  of  community-acquired  pneumonia, bacterial  meningitis  and  sepsis. Beta lactam and  macrolide antibiotics remained a first choice for empirical treatment of pneumococcal infections. Although macrolides are widely used for   treatment   of   pneumococcal   infections, an   increase   in   macrolide resistance  might compromise  their use. Pneumococcal  macrolide resistance is  mediated  by  two  major  mechanisms:  target  site  modification  and  active drug  efflux.  Methylation  of  the  23S  ribosomal  ribonucleic  acid  (rRNA)  is performed   by   the   enzyme   methylase,   encoded   by   the ermB gene. Modification  of  ribosomal  targets  leads  to  cross-resistance to  macrolides (M),  lincosamides  (L)  and  streptogramins  B  (Sb). It  is  expressed  as  the MLS_b –phenotype,  which  confers  a  high-level  resistance. This  phenotype  can   be   either   constitutively   (cMLS)   or   inducibly   (iMLS). expressed. Another macrolide resistance mechanism is the active drug efflux, encoded by  the mefA  gene.  The  drug  efflux  confers  resistance  to  14-  and  15-membered  macrolides  only,  with  no  cross-resistance.  It  is  expressed  as  the M-phenotype,  which  confers  low-level  resistance.  The  objective of  this study   was   :   1) to   examine   the   prevalence of   macrolide   resistant Streptococcus   pneumoniae (MRSP) among   invasive   and   noninvasive isolates in children and adults, 2) to examine the prevalence of coresistance and multiple-resistance among MRSP strains, 3) to examine the prevalence of  macrolide  resistant  phenotypes,  and  4)  to  examine  the  prevalence  of macrolide  resistant  genotypes  (detect  the  presence of  the ermB   and mefA gene).  A  total  of   326  MRSP  strains  were  analyzed,  which  were  collecte dall  over  Serbia  in  the  period  from  January,  2010  - December,  2012.  The collected   MRSP   isolates   were   referred   to   the   National  Reference Laboratory  for  streptococci  and  pneumococci for  further  investigation. Identification based on microscopic, culture and biochemical features of the isolates. Conservation was performed in the brain-heart infusion broth with a  10%  glycerol  content  at  -80°C.  Macrolide  resistance  phenotypes  were determined by a double disc diffusion test, combine d diffusion-dilution test and   automatized   VITEK  2 system. Macrolide   resistance   genes   were  determined by PCR. Overall, macrolide nonsusceptibility rate in Serbia was 34%.  MRSP  isolates  were  more  prevale nt  among  children  (36%)  than adults  (29%),  and  were  more  prevalent  among   noninvasive  (35.5%)  than invasive  (27.4%)  samples.  Predominant  macrolide  resistance  phenotype was  the  MLS b  phenotype  (78.5%),  from  which  73.9 %  belonged  to  cMLS and  4.6%  to  iMLS  phenotype.  All  the  strains  assigne d  to  the  MLS_b phenotype harbored ermB gene, while all the strains with M phenotype had the mefA gene.  The  presence  of  both ermB and mefA resistance  genes  was confirmed  in  43.9  %  of  isolates. All  the  isolates  which  harbored  both resistance genes expressed the MLS_b phenotype. Among macrolide resistant strains,  penicillin  nonsusceptiblility  was  observed   in  16% .  A  high  level resistance was confirmed in 5. 8% of MRSP isolates. MRSP strains showed high  resistance rates to tetracyclin  (81.3%) and  trimethoprim-sulfamethoxazole  (74.3%).  Multiresistant  strains,  resistant  to  tetracyclines and  trimethoprim-sulfamethoxazole,  made  two  thirds  (66.1  %)  of  MRSP isolates.  Among  MRSP,  co-resistance  to  tetracycline  and  trimethoprim-sulfamethoxazole  was  more  prevalent  among  MLS  phenotypes  (73.1%) than  M  phenotypes  (36.7%).  Co-resistance  strains  to  macrolides  and  other antibiotics including    penicillin,   amoxicillin,    cefotaxime,  tetracyclin, trimethoprim-sulfamethoxazole and multiresistant  strains  were more prevalent among children than adult. Coresistance to macrolides and other antibiotics  including  tetracycline  and  ofloxacin  was  more  prevalent  among noninvasive   than   invasive   strains.   Invasive   MRSP   isolates   from   the cerebrospinal fluid showed a higher resistance rate to beta lactam antibiotics than  noninvasive  strains.  MRSP  strains  had  a  high  susceptibility  rates  to levofloxacin   (99.6),   telithromycin   (98.4%),   cefotak sime   (93.5%)   and imipenem  (97.3%).  MRSP  strains  were  fully  susceptible  to  vancomycin, linezolid, moxifloxacin, sparfloxacin, rifampicin a nd pristinamycin. Among macrolide   resistant S.pneumoniae strains,   12 different   serotypes   were identified.  One  half  of  these  isolates  belonged  to the  19F  (27.1%)  and  14 (22.  9%)  serotype,  followed  in  frequency  by  the  6A  (10.41%)  and  23F (8.3%)  serotype .  Multiresistant  strains  (macrolides,  penicillin,  tetracyclines and  trimethoprim-sulfamethoxazole)  belonged  to  serotypes 19F,  14  and 23F, while the 12F and 31 serotype were resistant to macrolides only. This in vestigation   represents   the   first   detailed   analysis of   phenotypes   and genotypes  of  macrolide  resistant  pneumococcal  strains  in  Serbia.  The obtained  results suggest  the need for an active surveillance  of pneumococcal infections in Serbia.

Medical research requires detailed and accurate information on individual patients. This is especially so in the context of pharmacovigilance which amongst others seeks to identify previously unknown adverse drug reactions. Here, the clinical stories are often the starting point for assessing whether there is a causal relationship between the drug and the suspected adverse reaction. Reliable automatic de-identification of medical case narratives could allow to share this patient data without compromising the patient’s privacy. Current research on de-identification focused on solving the task of labelling the tokens in a narrative with the class of sensitive information they belong to. In this Master’s thesis project, we explore an inverse approach to the task of de-identification. This means that de-identification of medical case narratives is instead understood as identifying tokens which do not need to be removed from the text in order to ensure patient confidentiality. Our results show that this approach can lead to a more reliable method in terms of higher recall. We achieve a recall of sensitive information of 99.1% while the precision is kept above 51% for the 2014-i2b2 benchmark data set. The model was also fine-tuned on case narratives from reports of suspected adverse drug reactions, where a recall of sensitive information of more than 99% was achieved. Although the precision was only at a level of 55%, which is lower than in comparable systems, an expert could still identify information which would be useful for causality assessment in pharmacovigilance in most of the case narratives which were de-identified with our method. In more than 50% of the case narratives no information useful for causality assessment was missing at all.
Tillgång till detaljerade kliniska data är en förutsättning för att bedriva medicinsk forskning och i förlängningen hjälpa patienter. Säker avidentifiering av medicinska fallbeskrivningar kan göra det möjligt att dela sådan information utan att äventyra patienters skydd av personliga data. Tidigare forskning inom området har sökt angripa problemet genom att märka ord i en text med vilken typ av känslig information de förmedlar. I detta examensarbete utforskar vi möjligheten att angripa problemet på omvänt vis genom att identifiera de ord som inte behöver avlägsnas för att säkerställa skydd av känslig patientinformation. Våra resultat visar att detta kan avidentifiera en större andel av den känsliga informationen: 99,1% av all känslig information avidentifieras med vår metod, samtidigt som 51% av alla uteslutna ord verkligen förmedlar känslig information, vilket undersökts för 2014-i2b2 jämförelse datamängden. Algoritmen anpassades även till fallbeskrivningar från biverkningsrapporter, och i detta fall avidentifierades 99,1% av all känslig information medan 55% av alla uteslutna ord förmedlar känslig information. Även om denna senare andel är lägre än för jämförbara system så kunde en expert hitta information som är användbar för kausalitetsvärdering i flertalet av de avidentifierade rapporterna; i mer än hälften av de avidentifierade fallbeskrivningarna saknades ingen information med värde för kausalitetsvärdering.

Uvod: U našoj zemlji nema smernica za lečenje bakterijskih infekcija u tercijarnim zdravstvenim ustanovama. Odabir antibakterijskih lekova je empirijski, što nije uvek u skladu sa preporučenom terapijom prema međunarodnim smernicama. Zbog toga su na Klinici za infektivne bolesti Kliničkog centra Vojvodine u januaru 2013. godine usvojeni međunarodni protokoli i primenjivani za lečenje infektivnih bolesti bakterijske etiologije. Cilj istraživanja bio je da se ispita i uporedi efikasnost lečenja pojedinih antibiotskih tretmana za lečenja infektivnih bolesti bakterijske etiologije prema kliničkom iskustvu ordinirajućeg lekara, prema međunarodno prihvaćenim protokolima i prema modifikovanim međunarodnim protokolima na osnovu stanja lokalne rezistencije. Materijal i metode: Ispitivanje je bilo retrospektivno-prospektivno u trajanju od tri godine od  01.01.2012-31.12.2014.godine, sprovedeno je na Klinici za infektivne bolesti Kliničkog centra Vojvodine. U studiju je uključeno 1147 pacijenata sa dijagnozom infektivne bolesti bakterijske etiologije (sepsa, infekcija urinarnog trakta, bakterijski meningitis, infekcije kože i mekih tkiva, bakterijski tonzilofaringitisi, pneumonija, febrilni gastroenteritis i spondilodiscitis). U retrospektivnom delu, tokom 2012. godine ustanovljena je efikasnost lečenja prema kliničkom iskustvu ordinirajućeg lekara, kod 459 pacijenata. U drugom delu ispitivanja koje je bilo prospektivno, tokom 2013. godine, kod 487 pacijenata, ustanovljena je efikasnost lečenja prema međunarodnim protokolima i upoređena sa lečenjem prema kliničkom iskustvu ordinirajućeg lekara. Tokom 2012. i 2013. godine, ustanovljena je struktura uzročnika i rezistencija na antimikrobne lekove, i prema stanju lokalne rezistencija modifikovani su međunarodni protkoli i primenjivani su tokom 2014. godine. U trećem delu ispitivanja koje je bilo prospektivno, tokom 2014. godine, kod 201 pacijenta ustanovljena je efikasnost lečenja prema modifikovanim međunarodnim protokolima i upoređena sa lečenjem prema usvojenim međunarodnim protokolima. Efikasnost lečenja praćena je na osnovu vrednosti telesne temperature i na osnovu laboratorijskih parametara (leukocita, C reaktivnog proteina, fibrinogena, sedimentacije eritrocita i prokalcitonina), prvog i sedmog dana hospitalizacije. Za upoređivanje efikasnosti terapijskih režima napravljen je sistem skorovanja telesne temperature i laboratorijskih parametara. Za statističku obradu podataka korišćen je programski paket Statistical Package for Social Sciences - SPSS 21. Statistički značajnim se smatraju vrednosti nivoa značajnosti p<0.05. Rezultati: Praćenjem rezistencija bakterija u našoj sredini modifikovani su međunarodni protokoli za lečenje infekcija izazvanih E.coli i S aureus-om. Rezistencija E. coli iz urinokultura tokom 2012. i 2013. godine na ciprofloksacin (koji je preporučen prema međunarodnim protokolima za lečenje infekcija urinarnog trakta) je bila u 2012. godini 38,8% i u 2013. godini 57,1%, a na levofloksacin 27,7% u 2012. godini i u 2013. godini 28,6%. Rezistencija S. aureus-a izolovanog iz brisa rana na cefazolin (koji je preporučen prema međunarodnim protokolima za lečenje infekcija kože i mekih tkiva) u prve dve godine ispitivanja bila je 25% a na klindamicin nije zabeležena rezistencija. Rezistencija S. aureus-a na cefazolin (koji je preporučen prema međunarodnim protokolima za lečenje bakterijskih tonzilofaringitisa) iz brisa grla bila je u 2012. godini 18,1%, u 2013. godini 14,2% a na klindamicin u ovom periodu nije zabeležena rezistencija. Tako da je preporuka u modifikovanom kliničkom protokolu za lečenje infekcija urinarnog trakta levofloksacin, za lečenje bakterijskih tonzilofaringitisa i lečenje infekcija kože i mekih tkiva izazvanih S aureus-om klindamicin.Poredeći ukupan skor kliničkih i laboratorijskih parametara, lečenje pacijenata prema usvojenim međunarodnim protokolima, statistički značajno je efikasnije u odnosu na lečenje prema kliničkom iskustvu lekara kod lečenja pacijenata sa infekcijom urinarnog trakta (p=0,034) i infekcijom kože i mekih tkiva (p=0,032). U lečenju ostalih ispitivanih bakterijskih infekcija prema kliničkom iskustvu lekara i usvojenim međunarodnim protokolima nema statički značajne razlike (p>0,05). Lečenje pacijenata sa infekcijom urinarnog trakta, prema modifikovanim međunarodnim protokolima je statistički značajno efikasnije u odnosu na efikasnost lečenja prema usvojenim međunarodnim protokolima (p=0,025) poredeći ukupan skor kliničkih i laboratorijskih parametara. Lečenje pacijenata sa tonzilofaringitisima i infekcijama kože i mekih tkiva prema modifikovanim međunarodnim protokolima podjednako je efikasno u odnosu na lečenje prema usvojenim međunarodnim protokolima (p=0,100) poredeći ukupan skor kliničkih i laboratorijskih parametara. Zaključak: Upoređivanjem dobijenih rezultata, omogućeno je određivanje najoptimalnijeg načina lečenja bolesti bakterijske etiologije, uvažavajući preporuke prema međunarodnim smernicama. Dobijeni rezultati ukazuju na to da je praćenjem lokalne strukture uzročnika i stanja lokalne rezistencije omogućeno određivanje optimalnijeg načina lečenja infekcija urinarnog trakta i infekcije kože i mekih tkiva, uvažavajući međunarodne preporuke i modifikaciju međunarodnih smernica prema stanju rezistencija bakterija na antimikrobne lekove u našoj sredini
Introduction:In our country,there are noguidelines for the treatment of bacterial infections in tertiary health institutions. The choice of antibiotic is empirical and it does not always comply with the recommended treatment according to international guidelines. For this reason, international protocols were adopted at the Clinic for infectious diseases of the Clinical Center of Vojvodinain January 2013. and implemented in therapy of infectious diseases caused by bacteria. The aim of the study was to compare different regimens and to evaluate their effectiveness in therapy of the bacterial infections: one based on the clinical experience of the prescribing physician, another based on international guidelines and the third, modified international protocoladapted to comply with the local antibacterial resistance. Material and methods: Thisretrospective-prospective study was conducted at the Clinic for Infectious Diseases of the Clinical Center of Vojvodina and it covered the period of three years, from 01.01.2012.-31.12.2014. 1,147 patients diagnosed with infectious diseases of bacterial etiology (sepsis, urinary tract infections, bacterial meningitis, skin and soft tissue infections, bacterial tonsillopharyngitis, pneumonia, febrile gastroenteritis and spondylodiscitis) were included in the study. In the first, retrospective part of the study, the efficacy of therapy based on the clinical experience of the prescribing physician was analyzed from medical records of 459 patients treated in 2012. In 2013, during the second, prospective part of the study, the efficacy of treatment according to the international guidelines was evaluated in 487 patients and the results were compared to the data obtained from the patients treated according to the clinical experience of the prescribing physician. The types of organism isolated in 2012/2013 were analyzed as well as their resistance to antimicrobials, the international protocols were subsequently modified according to the state of local resistance and implemented during 2014. In 2014, during the third, prospective part of the study, the efficacy of therapy according to modified international protocols was established in 201 patients, and the results were compared to the ones obtained by therapy according to original international protocols. The efficacy of the treatment was estimated by body temperature measurements and laboratory parameters (leukocytes, C-reactive protein, fibrinogen, erythrocyte sedimentation rate and procalcitonin) on day 1 and day 7 of hospitalization. The scoring system for body temperature and laboratory parameters was designed to compare therapeutic regimes efficiency. For statistical analysis, we used a software package Statistical Package for Social Sciences- SPSS 21. The values of p<0.05were considered statistically significant. Results.Monitoring of antibiotic resistance patterns in our community led to modification international protocols for treating infections caused by E. coli and S aureus. Resistance of E.coli to ciprofloxacin (recommended for the treatment of urinary tract infectionsby international protocols) from urine culture in 2012 and 2013 was 38.8% and 57.1% respectively, while resistance to levofloxacin in 2012 and 2013 was 27.7% and 28.6%, respectively. Resistance of S. aureus to cefazolin (recommended by international protocols for the treatment of the skin and soft tissue infections) from wound cultures in 2012 and 2013 was 25% while the resistance to  clindamycin was not present. Resistance to cefazolin (recommended for the treatment of bacterial tonsillopharyngitisby international protocols) from throat culture in 2012 and 2013 was 18,1% and 14,2%, respectively,and the resistance to clindamycin was not present in the same period. Accordingly, clinical therapeutic protocols were modified, levofloxacin was recommended for urinary tract infections and clindamycin was recommended for treatment of tonsillopharyngitis and skin and soft tissues infections caused by S. aureus. Comparing the total score of clinical and laboratory parameters, the treatment of patients according to the adopted international protocols was statistically significantly more effective compared to the one based on clinical experience of physicianin urinary tract infections (p = 0.034) and skin and soft tissue infections(p = 0.032). No statically significant difference (p>0.05) was observed in efficiency of treatment options for other studied bacterial infections. In therapy of urinary tract infections, modified international protocols proved to be significantly more efficient than the adopted international protocols (p = 0.025) when the total score of clinical and laboratory parameters was compared.  Comparing the total score of clinical and laboratory parameters, both adopted international protocols and modified international protocols proved to be equally efficient (p=0,100) in therapy of bacterial tonsillopharyngitis and skin and soft tissue infections. Conclusion:Comparison of the obtained results made possible to develop the optimal way of treating diseases of bacterial etiology, taking into account recommendations by international guidelines.The results suggest that the monitoring of the local structure of pathogens and their resistance pattern enabled the determination of optimal treatment options for urinary tract infections and skin and soft tissue infections, respecting international recommendations and modifying the international guidelines to match bacterial resistance pattern in our community.

UVOD: Savremenim dijagnostičkim i terapijskim dostignućima, kao i unapređenjem preventivnih mera produžen je životni vek ljudi. Starenje stanovništva je fenomen koji zahvata ceo svet. Povećanje broja starijeg stanovništva je udruženo sa porastom broja obolelih od karcinoma u ovoj starosnoj grupi, jer je starenje samo po sebi riziko faktor za nastanak karcinoma. Incidenca pojave karcinoma naglo raste od 50-te godine života sa vrhom u 80-toj godini života. U osoba starijih od 65 godina se dijagnostikuje 58% svih karcinoma, a 30% u starijih od 70 godina. Godine starosti nisu kontraindikaciija za sprovođenje hemioterapije kod starih bolesnika sa karcinomom. Starenje je povezano sa izmenjenom farmakodinamikom i farmakokinetikom antitumorskih lekova i povećanom osetljivošću normalnog tkiva na toksične komplikacije, te je odluka kliničara kod davanja hemioterapije ovoj starosnoj kategoriji bolesnika sa karcinomom uvek vrlo kompleksna i zahteva dobru procenu i odgovarajuću selekciju bolesnika za ovaj tretman. MATERIJAL I METODE: Doktorska disertacija obuhvata rezultate delom restrospektivnog, a delom prospektivnog opservacionog istraživanja sprovedenog u periodu 01.01.2011. do 31.12.2013.godine u Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici, u kojem je praćeno 152 bolesnika starosti 65 i više godina kod kojih je dijagnostikovan nemikrocelularni karcinom bronha u uznapredovalom stadijumu bolesti, a koji su lečeni kombinovanim hemioterapijskim režimom na bazi platine. Kao prognostički faktori su uzeti: starosna dob bolesnika (grupa mlađih od 75 godina i starih 75 i više godina), pol, navika pušenja cigareta (pušač, nepušač, bivši pušač), navika konzumiranja alkohola, performans status (prema ECOG-Eastern Cooperative Oncology Group skali) u momentu postavljanja dijagnoze, patohistološki tip tumora (adenokarcinom, skvamozni karcinom, drugo), stadijum bolesti (IIIb, IV), veličina tumora (manje od 6 cm i 6 cm i više), TNM status prema klasifikaciji tumora (7.revizija), parametri krvne slike (vrednosti leukocita, hemoglobina, trombocita), biohemijski parametri (vrednosti laktat-dehidrogenaze (LDH), alkalne fosfataze, aspartat- aminotransferaze (AST), alanin-aminotransferaze (ALT), kalijuma, natrijuma, bilirubina) na početku terapije, komorbiditeti u momentu postavljanja dijagnoze (broj komorbiditeta po sistemima, Charlson index), simptomi bolesti (kašalj, hemoptizije, otežano disanje, bol u grudnom košu, promuklost, smetnje gutanja, sindrom gornje šuplje vene, bol u kostima, simptomi od strane centralnog nervnog sistema, povišena telesna temperatura), gubitak na telesnoj masi (više od 5% u prethodnih 6 meseci), indeks telesne mase (<18,5kg/m² pothranjen, 18,5-24,9kg/m² normalno uhranjen, 25-29,9kg/m² prekomerna telesna masa, ˃30kg/m² gojaznost). Svi potencijalni prognostički faktori su evaluirani univarijantnom analizom, a potom su svi faktori rizika za koje je utvrđena značajnost analizirani primenom multivarijantne logističke regresije, u cilju prepoznavanja nezavisnih prediktora za dvogodišnje preživljavanje. Za otkrivanje nezavisnih prediktora preživljavanja na dve godine je primenjena binarna logistička regresiona analiza, a kao potencijalni prediktori su bile sledeće varijable: starost ispod 75 godina, pušačka navika, patohistološki tip karcinoma, stadijum bolesti IV, T4 status, M1b status, prisustvo respiratornog komorbiditeta, otežano disanje, bol u grudima. Kumulativno preživljavanje je prikazano Kaplan-Meier-ovim krivama. Primenom multivarijantne Cox- regresione analize su dobijeni nezavisni prediktori kumulativnog preživljavanja. Iz dobijenih prognostičkih faktora koji se izdvajaju kao nezavisni prediktori za preživljavanje su kreirani matematički modeli za dvogodišnje preživljavanje. CILJ ISTRAŽIVANJA: Utvrditi uticaj pojedinih prognostičkih faktora na dvogodišnje preživljavanje ovih bolesnika i iz toga izvesti matematički model za stratifikaciju ovih bolesnika u odnosu na dvogodišnje preživljavanje. REZULTATI: Analizom prognostičkih faktora je utvrđeno da grupa bolesnika starih 75 godina i više ima nešto duže dvogodišnje preživljavanje od grupe bolesnika mlađih od 75 godina, ali bez statističke značajnosti, bolesnici sa tumorom veličine 6 cm i više imaju kraće dvogodišnje preživljavanje u odnosu na bolesnike sa tumorom manjim od 6 cm, bolesnici kod kojih je u momentu postavljanja dijagnoze T status tumora bio T4, a M status M1b imaju kraće dvogodišnje preživljavanje, bolesnici kod kojih je na početku tretmana u laboratorijskim nalazima bila prisutna anemija i povišene vrednosti LDH imaju kraće dvogodišnje preživljavanje, prisustvo više komorbiditeta utiče na kraće preživljavanje, bolesnici sa gubitkom na telesnoj masi većim od 5% u periodu 6 meseci pre postavljanja dijagnoze bolesti imaju kraće dvogodišnje preživljavanje. Kreirana su dva matematička modela (jedan za preživljavanje na 2 godine i jedan za kumulativno preživljavanje) za stratifikaciju gerijatrijskih bolesnika sa uznapredovalim stadijumom nemikrocelularnog karcinoma bronha lečenih hemioterapijom na bazi platine u odnosu na dvogodišnje preživljavanje. ZAKLJUČAK: Dobijeni matematički modeli za preživljavanje gerijatrijskih bolesnika sa uznapredovalim stadijumom nemikrocelularnog karcinoma bronha lečenih hemioterapijom na bazi platine na jednostavan način stratifikuju bolesnike u odnosu na preterapijske prognostičke faktore za razliku od sveobuhvatne gerijatrijske procene koja je vremenski zahtevna procedura i zahteva obučen kadar.
INTRODUCTION: Nowadays life expectancy is prolonged due to modern diagnostic and therapy achievements, as well as promotion of preventive measurements. Aging of population is a phenomenon in the whole world. Increasing number of elderly population is accompanied with the increased number of diagnosed cancer in this age group, because the aging themselves is a risk factor for development of cancer. The appearance of cancer rapidly rises from the age of fifty with the peak at the age of eighty. 58% of cancer diagnoses are in the people older than sixty-five years and 30% in people older than seventy years. The age is not contraindication for chemotherapy treatment in older patient with cancer. The aging is associated with disturbed pharmacodynamics and pharmacokinetics of antitumor drugs and increased susceptibility of normal tissue for toxic complications, therefore clinical decision for introducing chemotherapy is very complex and requires good assessment and proper selection of the patients for this treatment. MATERIAL AND METHODS: This doctoral thesis includes results of partly retrospective and partly prospective observational research conducted in the period 01.01.2011. until 31.12.2013. at the Institute for pulmonary diseases of Vojvodina in Sremska Kamenica, which includes 152 lung cancer patients 65 and more years old with diagnosed non-small cell lung cancer in advanced stage treated with combined platinum based chemotherapy regimen. These prognostic factors are included: age of patients (group <75 years, group ≥75 years old), sex, smoking cessation (smoker, former smoker, non smoker), alcohol consuming habit, performance status (according to the ECOG-Eastern Cooperative Oncology Group scale) in the moment of confirmed diagnosis, pathohistological type of tumor (adenocarcinoma, squamous cell carcinoma, other), stage of disease (IIIb, IV), tumor size (<6cm and ≥6cm), TNM status according tumor classification (7th revision), blood count parameters (leucocyte, hemoglobin level, thrombocyte), biochemical parameters (lactate-dehydrogenase level (LDH), alkaline phosphatase level, aspartate aminotransferase level (AST), alanine aminotransferase level (ALT), potassium level, sodium level, bilirubin level) on the start of the chemotherapy, comorbidities at the moment of diagnosis (number of comorbid conditions, Charlson index), symptoms of the disease (cough, hemoptysis, dyspnea, chest pain, hoarseness, swallowing difficulties, caval venae compression symptoms, bone pain, central nervous symptoms, increased body temperature), weight loss (˃ 5% in the previous 6 months), body mass index (<18,5kg/m² underweight 18,5-24,9kg/m² normal weight, 25-29,9kg/m² overweight , ˃30kg/m² obese). All potential prognostic factors were evaluated with univariante analysis, and after that all factors with confirmed significance were analysed with multivariante logistic regression, in order to identify independent predictors for 2-year survival. Binary logistic regression analysis was applied for identifying independent predictors for 2-years survival and those variables were analysed : age <75 years, smoking cessation, pathohistological type of cancer, stage of disease IV, T4 status, M1b status, presence of respiratory comorbidity, dyspnea, chest pain. Cumulative survival of those patients was shown with Kaplan-Meier prognostic curves. Two mathematical model for 2-year survival was created from the factors confirmed as independent predictors for survival. AIM: This research objectives were to determine the influence of certain prognostic factors on 2-years survival of those patients and to create mathematical model for stratification of those patients related to 2-years survival. RESULTS: Univariante analysis confirmed that the group of patients older than 75 years and more have had better 2-year survival than group of patient younger than 75 year, but without the statistically significance, patients with tumor size ≥6cm have had worst 2-year survival in comparison with patients with tumor size <6cm, patients with tumor status T4 at the moment of diagnosis and M status M1b have had the shorter 2-year survival, patients with anemia and increased LDH level on the start of the chemotherapy treatment have had shorter 2-year survival, the presence of more comorbid conditions at the moment of diagnosis influence on shorter 2-year survival, patients with weight loss more than 5% in the previous 6 months have had shorter 2-year survival. Two mathematical models were created (one for 2-year survival and the other for the cumulative survival) for stratification of elderly patients with advanced staged non-small cell lung cancer treated with combined platinum based chemotherapy regimen related to 2-year survival. CONSLUSION: Created mathematical models for stratification of elderly patients with advanced staged non-small cell lung cancer treated with combined platinum based chemotherapy regimen more easily stratify patients compared to pretreatment prognostic factors as opposed to comprehensive geriatric assessment which is time-consuming procedure and requires trained personnel.

Escherichia coli i Klebsiella pneumoniae su među najznačajnijim uzročnicima infekcija kod ljudi. Problem predstavljaju multirezistentni sojevi koji se javljaju ne samo u bolničkom nego i u vanbolničkom okruženju. Karbapenemi, beta-laktami sa najširim spektrom delovanja, spadaju u lekove poslednje linije odbrane. Rezistencija na karbapeneme među enterobakterijama je u porastu širom sveta. Može nastati usled prisustva karbapenemaza, enzima koji degradiraju karbapeneme, ili usled hiperprodukcije AmpC cefalosporinaza ili beta-laktamaza proširenog spektra uz gubitak porina. Geni koji kodiraju karbapenemaze se nalaze na mobilnim genetičkim elementima koji im omogućavaju brz prenos. Najčešće karbapenemaze su KPC, NDM, VIM, IMP i OXA-48 enzimi. Detekcija sojeva koji produkuju karbapenemaze nije moguća samo na osnovu profila rezistencije izolata, s obzirom da minimalne inhibitorne koncentracije karbapenema mogu biti u referentnom opsegu. Svaki izolat sa smanjenom osetljivošću na karbapeneme bi trebalo ispitati kako bi se sprečilo njihovo širenje. Detekcija karbapenemaza može da se zasniva na fenotipskim i genotipskim metodama. Ciljevi istraživanja su bili da se utvrdi postojanje rezistencije na karbapeneme kod multirezistentnih izolata Escherichia coli i Klebsiella pneumoniae iz kliničkih uzoraka, da se dokaže produkcija karbapenemaza korišćenjem fenotipskih i genotipskih testova, kao i da se analizira osetljivost izolata Escherichia coli i Klebsiella pneumoniae sa molekularno dokazanim karbapenemazama. Istraživanje je sprovedeno kao prospektivna studija u periodu 01.11.2013. do 01.11.2014. godine u Centru za mikrobiologiju Instituta za javno zdravlje Vojvodine u Novom Sadu. U istraživanje je bilo uključeno 300 multirezistentnih izolata Escherichia coli i Klebsiella pneumoniae konsekutivno izolovanih iz kliničkih uzoraka (krv, punktat, sekret iz donjeg respiratornog trakta, urin i sekret rana) hospitalizovanih pacijenata. Identifikacija do nivoa vrste je vršena klasičnim bakteriološkim metodama. Za ispitivanje osetljivosti korišćeni su disk difuziona metoda i gradijent testovi. Vrednosti minimalnih inhibitornih koncentracija su ispitane automatizovanim Vitek 2 sistemom (BioMérieux, Francuska), a interpretacija izvršena u skladu sa preporukama CLSI (Clinical Laboratory Standards Institute). Za fenotipsko testiranje prisustva betalaktamaza proširenog spektra korišćen je kombinovani disk test. Za fenotipsko testiranje prisustva karbapenemaza kod sojeva rezistentnih na karbapeneme korišćen je kombinovani disk test i test sinergizma sa dva diska. Detekcija gena za beta-laktamaze blaCTXM, gena za karbapenemaze blaKPC, blaVIM, blaNDM, blaIMP i blaOXA-48-like izvršena je metodom lančane reakcije polimeraze. Genotipizacija odabranih izolata Klebsiella pneumoniae izvršena pomoću repetitivne lančane reakcije polimeraze korišćenjem DiversiLab sistema (BioMérieux, Francuska). Od 300 multirezistetntnih izolata, bilo je 242 (80,7%) Klebsiella pneumoniae i 58 (19,3%) Escherichia coli izolovanih iz kliničkih uzoraka. Smanjenu osetljivost na bar jedan karbapenem (imipenem, meropenem, ertapenem) pokazalo je 179 (59,7%) izolata. Fenotipski test za dokazivanje produkcije betalaktamaza proširenog spektra bio je pozitivan kod 87/171 (50,9%) izolata. Gen blaCTX-M je dokazan kod 111/121 (91,7%) izolata. Fenotipski test za dokazivanje karbapenemaza bio je pozitivan kod 65/179 (36,3%) izolata, kod 63 (96,9%) je ukazivao na prisustvo metalo-beta laktamaza, a kod 2 (3,1%) na prisustvo karbapenemaza iz grupe A. Senzitivnost fenotipskog testa za dokazivanje karbapenemaza klase A i B iznosila je 100,0%, specifičnost 96,6%, a ukupna tačnost 97,6%. Karbapenemaze su nađene kod 79/179 (44,1%) izolata rezistentnih na karbapeneme. Gen blaNDM nađen je kod 58 (32,4%) izolata, blaOXA- 48-like kod 11 (6,1%), a blaKPC kod 2 (1,1%) izolata. Geni blaVIM i blaIMP nisu detektovani. Kod 8 (4,5%) izolata nađena su 2 gena koja kodiraju karbapenemaze, blaNDM i blaOXA-48-like. Određivanjem osetljivosti disk difuzionom metodom i automatizovanim Vitek 2 sistemom, izolati koji produkuju karbapenemaze pokazivali su smanjenu osetljivost na sve testirane beta-laktame i gentamicin, odnosno tobramicin. Visok procenat rezistenicije izolati su pokazali u odnosu na ciprofloksacin, levofloksacin i trimetoprim/sulfametoksazol. Najefikasniji antibiotski lekovi su bili amikacin, tigeciklin, fosfomicin i kolistin. Poređenjem minimalnih inhibitornih koncentracija izolata koji produkuju i izolata koji ne produkuju karbapenemaze utvrđena je statistički značajna razlika za meropenem, imipenem, ertapenem, amikacin, gentamicin. Genotipizacijom odabranih izolata Klebsiella pneumoniae korišćenjem DiversiLab sistema klonalno širenje je dokazano među izolatima koji produkuju NDM i OXA-48-like karbapenemaze u okviru iste zdravstvene institucije, ali i među različitim zdravstvenim ustanovama. Među izolatima rezistentnim na karbapeneme Klebsiella pneumoniae se češće izoluje od Escherichia coli. Kod izolata koji su pokazali smanjenu osetljivost prema bar jednom karbapenemu, karbapenemaze su detektovane u manje od polovine izolata. Kod ostalih izolata dokazane su beta-laktamaze proširenog spektra koje uz gubitak porina mogu uzrokovati rezistenciju na karbapeneme. Kod izolata Klebsiella pneumoniae sa dokazanim genima koji kodiraju karbapenemaze detektovani su pojedinačni blaKPC, blaNDM i blaOXA-48-like geni, kao i kombinacija gena blaNDM i blaOXA-48-like. Kod izolata Escherichia coli nađeni su samo blaNDM geni. Najefikasniji antibiotski lekovi za izolate koji produkuju karbapenemaze su amikacin, tigeciklin, fosfomicin i kolistin. Izolati sa dokazanim karbapenemazama pokazuju rezistenciju na veći broj antibiotika u odnosu na izolate koji ne produkuju karbapenemaze. Dokazano je klonalno širenje izolata Klebsiella pneumoniae koji produkuju karbapenemaze. Testove za fenotipsku detekciju karbapenemaza bi trebalo koristiti i u rutinskim mikrobiološkim laboratorijama u skladu sa EUCAST (European Committee on Antimicrobial Susceptibility Testing) preporukama, a konačnu potvrdu treba izvršiti molekularnim metodama u referentnoj laboratoriji.
Escherichia coli and Klebsiella pneumoniae are among the most common human pathogens. Multiresistant strains are emerging not only in hospital settings, but also in the community representing a major concern. Carbapenems, beta-lactams with the broadest spectrum of activity are considered to be antibiotics of last resort. Resistance to carbapenems among enterobacteria is spreading worldwide. It is mainly caused by carbapenemases, enzymes capable of degrading carbapenems or by hyperproduction/overexpression of AmpC betalactamases or extended spectrum betalactamases with porin loss. Carbapenemaseencoding genes are usually located on mobile genetic elements providing their fast transfer. The most common carbapenemases are KPC, NDM, VIM, IMP and OXA-48. The detection of carbapenemase-producer cannot rely only on the resistance profile as their minimal inhibitory concentration values may sometimes lay within the susceptibility range. Therefore, every multidrug-resistant isolates with lower susceptibility to carbapenems should be tested for the presence of carbapenemases in order to prevent further spreading. The detection of carbapenemases is based on phenotypic and genotypic methods. The aims of the study were to determine the occurrence of carbapenem resistance in multidrug-resistant Escherichia coli and Klebsiella pneumoniae isolated from clinical samples, to detect carbapenemase production using both phenotypic and genotypic methods and to analyze the susceptibility of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae. The study was conducted from 1st November 2013 to 1st November 2014 at the Center for Microbiology in the Institute for Public Health of Vojvodina, Novi Sad, Serbia. The study included 300 nonrepetitive multidrug-resistant strains of Escherichia coli and Klebsiella pneumoniae isolated from clinical specimen (blood, aspirates, lower respiratory tract secretions, urine and wound secretion) of hospitalized patients. Identification of isolated strains was done using conventional bacteriological methods. Antimicrobial susceptibility was tested using the disk diffusion method and MIC test strips. Minimal inhibitory concentrations were determined using Vitek 2 Compact automated system (BioMérieux, France), interpreted according to the CLSI (Clinical and Laboratory Standards Institute) recommendations. Phenotypic testing of extended-spectrum beta-lactamases production was done using combined disk test. Phenotypic testing of carbapenemase production was done by combined disk test and double-disk synergy test. Detection of blaCTX-M, gene encoding extended-spectrum beta-lactamases and blaKPC, blaVIM, blaNDM, blaIMP i blaOXA-48-like, genes encoding carbapenemases was done using PCR. Genotyping of selected Klebsiella pneumoniae isolates was done by repPCR using DiversiLab system (BioMérieux, France). From the total of 300 multiresistant isolates, 242 (80.7%) were Klebsiella pneumoniae and 58 (19.3%) were Escherichia coli obtained from clinical samples. Reduced susceptibility to at least one carbapenem (imipenem, meropenem, ertapenem) was found in 179 (59.7%) isolates. Phenotypic test for extended-spectrum betalactamases production was positive in 87/171 (50.9%) isolates. A total of 111/121 (91.7%) isolates harbored blaCTX-M. Phenotypic test for carbapenemase production was positive in 65/179 (36.3%) isolates, 63 (96.9%) indicating the presence of metallo-beta-lactamases and 2 (3.1%) indicating the presence of class A carbapenemases. Sensitivity of the phenotypic test for carbapenemase production of class A and B was 100.0%, specificity 96.6% and overall accuracy 97.6%. Carbapenemases were detected in 79/179 (44.1%) carbapenemresistant isolates. Gene blaNDM was found in 58 (32.4%) isolates, blaOXA-48-like in 11 (6.1%) and blaKPC in 2 (1.1%) isolates. Genes blaVIM and blaIMP were not detected. In 8 (4.5%) isolates 2 genes encoding carbapenemases were found, blaNDM and blaOXA-48-like. Using both disk diffusion method and Vitek 2 automated system for antimicrobial susceptibility testing carbapenemase-producing isolates were resistant to all beta-lactams and also to gentamicin and tobramicin respectively. Resistance rates were high for ciprofloxacin, levofloxacin and cotrimoxazole. Good activity maintained for amikacin, tigecycline, fosfomycin and colistin. Comparing minimal inhibitory concentrations of carbapenemaseproducing isolates and non-carbapenemase producers, significant difference was found for meropenem, imipenem, ertapenem, amikacin and gentamicin. Genotyping of selected Klebsiella pneumoniae isolates using DiversiLab system, revealed the clonal spread of NDM- and OXA-48-like-producers not only within one healthcare-setting, but also between different healthcare centers. Among carbapenem-resistant isolates, Klebsiella pneumoniae was found more often than Escherichia coli. Carbapenemases were detected in less than 50% of isolates resistant to at least one carbapenem. In other carbapenem resistant isolates extended-spectrum betalactamases were confirmed most likely causing carbapenem-resistance with porin deficiency or porin loss. Among carbapenemase-producing Klebsiella pneumoniae blaKPC, blaNDM and blaOXA-48-like genes were detected, as well as combination of 2 genes blaNDM and blaOXA-48-like. In carbapenemase-producing Escherichia coli only blaNDM was found. The most efficient antimicrobial drugs among tested carbapenemase-producing isolates were amikacin, tigecycline, fosfomycin and colistin. Carbapenemase-producing isolates were resistant to more antimicrobial agents compared to non-carbapenemase producers. Clonal dissemination of carbapenemase-producing Klebsiella pneumoniae was confirmed. Phenotypic detection of carbapenemase production should be done in routine microbiology laboratories according to EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations. Final confirmation should be done by molecular methods in the reference laboratory.

Uvod: Infekcija krvi izazvana multirezistentnim bakterijama roda Acinetobacter (MDRA) je praćena značajnim letalitetom i visokim troškovima bolničkog lečenja. Ciljevi istraživanja: Ustanoviti učešće izolata Acinetobacter spp. u strukturi pozitivnih hemokultura i kretanje procenta rezistencije na antibiotike u zdravstvenim ustanovama sekundarnog i tercijarnog nivoa na teritoriji AP Vojvodine u periodu 2013-2015. godina; Utvrditi kod kojih pacijenata se najčešće javljaju infekcije krvi izazvane MDRA; Utvrditi faktore rizika za nastanak bolničke infekcije (BI) krvi izazvane MDRA i uticaj BI krvi izazvane ovim uzročnicima na dužinu trajanja hospitalizacije i na ishod lečenja pacijenata hospitalizovanih u zdravstvenim ustanovama sekundarnog i tercijarnog nivoa u AP Vojvodini. Materijal i metode: Podaci iz protokola mikrobiološke laboratorije Centra za mikrobiologiju Instituta za javno zdravlje Vojvodine su korišteni za retrospektivnu analizu učestalosti izolata Acinetobacter spp. u strukturi hemokultura i za praćenje kretanja procenta rezistentnih izolata Acinetobacter spp. na posmatrane vrste antibiotika u zdravstvenim ustanovama sekundarnog i tercijarnog nivoa u AP Vojvodini u periodu od 01.01.2013. do 31.12.2015. godine. Utvrđivanje faktora rizika za nastanak infekcije krvi izazvane MDRA je sprovedeno kao prospektivna kohortna studija u jedinicama intenzivnih nega (JIN) u zdravstvenim ustanovama u AP Vojvodini u periodu od 01.01.2013. do 31.03.2016. godine. Grupu 1 (n=164), studijsku grupu kohortne studije su činili ispitanici sa BI krvi izazvanom MDRA. Grupu 2 (n=328), kontrolnu grupu kohortne studije, sačinjavali su pacijenti JIN bez izolata Acinetobacter spp. u hemokulturi. Kontrole su bile uključene u istraživanje samo ako je dužina njihovog boravka u JIN (dužina trajanja hospitalizacije do otpusta) bila ista ili duža od dužine boravka para iz studijske grupe do izolacije MDRA iz hemokulture. Kontrole su bile uparene sa slučajem iz studijske grupe u odnosu (1:2) prema: uzrastu (+/-5 godine), vrsti JIN i vremenu (isti kalendarski mesec u kojem je kod para iz studijske grupe izolovana pozitivna hemokultura). U cilju utvrđivanja predisponirajućih faktora za letalni ishod (14-dnevni letalitet) pacijenata u JIN sa infekcijom krvi izazvanom MDRA sprovedena je anamnestička studija. Rezultati: Učešće izolata Acinetobacter spp. u strukturi hemokultura pacijenata uzrasta 18 i više godina hospitalizovanih u zdravstvenim ustanovama u AP Vojvodini u periodu 2013-2015. godina iznosilo je 13,9%. Primoizolati Acinetobacter spp. iz uzoraka hemokultura pacijenata su u 96,1% (198/204) bili multirezistentni. Analizom kretanja rezistencije izolata Acinetobacter spp. na ispitivane antibiotike jedino je na cefepim ustanovljeno statistički značajno smanjenje učešća rezistentnih izolata (od 98,5% u 2014. godini do 83,3% u 2015. godini), (p=0,025). Izolati Acinetobacter spp. su najčešće registrovani kod pacijenata hospitalizovanih u JIN (71,1% (145/204)). Multivarijantnom analizom izdvojili su se nezavisni prediktori za nastanak infekcije krvi izazvane MDRA: prijem iz drugog odeljenja/bolnice, prijemne dijagnoze politrauma i opekotina, prethodna kolonizacija gornjeg respiratornog trakta MDRA, prisustvo dva i više komorbiditeta, prethodna primena mehaničke ventilacije, viši indeks invazivnih procedura, prethodna primena derivata imidazola i prethodna primena četiri i više klasa antibiotika. Pacijenti sa infekcijom krvi izazvanom MDRA su statistički značajno duže boravili u JIN (24.5±17,5) u odnosu na neinficirane kontrole (19,7±12,6), (p=0,001) i statistički značajno češće su imali letalan ishod (51,2% (84/164) u odnosu na pacijente bez infekcije krvi izazvane ovim mikroorganizmom (25,0% (82/328), (p<0,0001). Multivarijantnom analizom, kao nezavisni prediktori letalnog ishoda pacijenata, izdvojili su se: starija životna dob, prijemnom dijagnoza akutne respiratorne insuficijencije i primena neadekvatne antimikrobne terapije nakon izolacije uzročnika iz hemokulture. Zaključak: Učestalost i struktura faktora rizika je ukazala da je snižavanje prevalencije i snižavanje letaliteta moguće ostvariti kombinovanom primenom mera koje obuhvataju racionalnu upotrebu antibiotika širokog spektra u empirijskoj antimikrobnoj terapiji i striktno poštovanje procedura vezanih za primenu invazivnih nastavaka.
Aim: Establish the participation of Acinetobacter spp. isolates in the structure of positive hemocultures and the percentage range of resistance to antibiotics in the health institutions of secondary and tertiary level on the territory of AP of Vojvodina in the period from 2013 to 2015; determine which patients most commonly get BSI caused by MDRA; determine risk factors for the occurrence of healthcare-associated infection (HAI) of blood caused by MDRA and the impact of HAI of blood caused by these pathogens to the duration of hospitalization, and the treatment outcome of patients admitted to the health care institutions of secondary and tertiary levels in the AP of Vojvodina. Material and Methods: Data from the protocol of the microbiological laboratory of the Center for Microbiology, Institute of Public Health of Vojvodina were used for retrospective analysis of the frequency of isolates of Acinetobacter spp. in the structure of positive hemocultures and for monitoring the percentage isolates of Acinetobacter spp. resistant to the observed type of antibiotics in health institutions of secondary and tertiary levels in AP of Vojvodina in the period from January 1, 2013 to December 31, 2015. Determining the risk factor for the occurrence of BSI induced by MDRA was conducted as a prospective cohort study in intensive care units (ICU) in the health institutions in AP of Vojvodina in the period from January 1, 2013 to March 31, 2016. Group 1 (n=164), study group of the cohort study included the patients with HAI of blood induced by MDRA. Group 2 (n=328), control group of the cohort study consisted of ICU patients without isolates of Acinetobacter spp. in the hemoculture. Controls were included in the study only if the length of their stay in the ICU (duration of hospitalization until discharge) was the same or longer than the length of the stay of their study group counterparts until the isolation of MDRA from blood culture. Controls were matched with the cases of the study group in the ratio (1: 2) according to: age (+/- 5 years), type of ICU and time (the same calendar month in which positive hemoculture was isolated in the the study group pair). In order to determine the predisposing factors of lethal outcome (14-day lethality) of patients in the ICU with the BSI caused by MDRA, anamnestic study was conducted. Results: Participation of Acinetobacter spp. isolates in the structure of hemocultures of patients, aged 18 and older, hospitalized in medical institutions in AP of Vojvodina in the period from 2013 to 2015 amounted to 13.9%. Acinetobacter spp. primoisolates from the patients' hemoculture samples were in 96.1% (198/204) multi-drug resistant. Analysing the Acinetobacter spp. isolates resistance to the tested antibiotics, Cefepime was the only to prove to cause statistically significant decrease in the share of resistant isolates (from 98.5% in the year 2014 to 83.3% in 2015), (p=0.025). Isolates of Acinetobacter spp. are most frequently registered in patients hospitalized in ICU (71.1% (145/204)). Multivariate analyses separated independent predictors for the occurrence of blood infection caused by the MDRA: patient transfers from another ward/hospital, admission diagnoses of polytrauma and burns, previous colonization of the upper respiratory tract MDRA, the presence of two or more co-morbidity, previous use of mechanical ventilation, higher index of invasive procedures, previous use of Imidazole derivates and the previous use of four or more classes of antibiotics. Patients with BSI caused by MDRA stayed statistically much longer in the ICU (24.5±17.5) as compared to uninfected controls (19.7±12.6), (p=0.001) and significantly more likely to have the lethal outcome (51.2% (84/164)) compared to patients without bloodsteram infections caused by this micro-organism (25.0% (82/328) (p<0.0001). Using multivariate analysis, independent predictors of death of patients, were found to be: advanced age, admission diagnosis of acute respiratory insufficiency and the application of inadequate antibiotic therapy after the isolation of pathogens from the hemoculture. Conclusion: The frequency and the structure of the risk factors suggested that the reduction of the prevalence and lowering of lethality can be achieved by combined administration of measures that include the rational use of broad spectrum antibiotics in the empirical antimicrobial treatment and strict compliance with the procedures related to the use of invasive follow-ups.

The large amounts of clinical data generated by electronic health record systems are an underutilized resource, which, if tapped, has enormous potential to improve health care. Since the majority of this data is in the form of unstructured text, which is challenging to analyze computationally, there is a need for sophisticated clinical language processing methods. Unsupervised methods that exploit statistical properties of the data are particularly valuable due to the limited availability of annotated corpora in the clinical domain. Information extraction and natural language processing systems need to incorporate some knowledge of semantics. One approach exploits the distributional properties of language – more specifically, term co-occurrence information – to model the relative meaning of terms in high-dimensional vector space. Such methods have been used with success in a number of general language processing tasks; however, their application in the clinical domain has previously only been explored to a limited extent. By applying models of distributional semantics to clinical text, semantic spaces can be constructed in a completely unsupervised fashion. Semantic spaces of clinical text can then be utilized in a number of medically relevant applications. The application of distributional semantics in the clinical domain is here demonstrated in three use cases: (1) synonym extraction of medical terms, (2) assignment of diagnosis codes and (3) identification of adverse drug reactions. To apply distributional semantics effectively to a wide range of both general and, in particular, clinical language processing tasks, certain limitations or challenges need to be addressed, such as how to model the meaning of multiword terms and account for the function of negation: a simple means of incorporating paraphrasing and negation in a distributional semantic framework is here proposed and evaluated. The notion of ensembles of semantic spaces is also introduced; these are shown to outperform the use of a single semantic space on the synonym extraction task. This idea allows different models of distributional semantics, with different parameter configurations and induced from different corpora, to be combined. This is not least important in the clinical domain, as it allows potentially limited amounts of clinical data to be supplemented with data from other, more readily available sources. The importance of configuring the dimensionality of semantic spaces, particularly when – as is typically the case in the clinical domain – the vocabulary grows large, is also demonstrated.
De stora mängder kliniska data som genereras i patientjournalsystem är en underutnyttjad resurs med en enorm potential att förbättra hälso- och sjukvården. Då merparten av kliniska data är i form av ostrukturerad text, vilken är utmanande för datorer att analysera, finns det ett behov av sofistikerade metoder som kan behandla kliniskt språk. Metoder som inte kräver märkta exempel utan istället utnyttjar statistiska egenskaper i datamängden är särskilt värdefulla, med tanke på den begränsade tillgången till annoterade korpusar i den kliniska domänen. System för informationsextraktion och språkbehandling behöver innehålla viss kunskap om semantik. En metod går ut på att utnyttja de distributionella egenskaperna hos språk – mer specifikt, statistisk över hur termer samförekommer – för att modellera den relativa betydelsen av termer i ett högdimensionellt vektorrum. Metoden har använts med framgång i en rad uppgifter för behandling av allmänna språk; dess tillämpning i den kliniska domänen har dock endast utforskats i mindre utsträckning. Genom att tillämpa modeller för distributionell semantik på klinisk text kan semantiska rum konstrueras utan någon tillgång till märkta exempel. Semantiska rum av klinisk text kan sedan användas i en rad medicinskt relevanta tillämpningar. Tillämpningen av distributionell semantik i den kliniska domänen illustreras här i tre användningsområden: (1) synonymextraktion av medicinska termer, (2) tilldelning av diagnoskoder och (3) identifiering av läkemedelsbiverkningar. Det krävs dock att vissa begränsningar eller utmaningar adresseras för att möjliggöra en effektiv tillämpning av distributionell semantik på ett brett spektrum av uppgifter som behandlar språk – både allmänt och, i synnerhet, kliniskt – såsom hur man kan modellera betydelsen av flerordstermer och redogöra för funktionen av negation: ett enkelt sätt att modellera parafrasering och negation i ett distributionellt semantiskt ramverk presenteras och utvärderas. Idén om ensembler av semantisk rum introduceras också; dessa överträffer användningen av ett enda semantiskt rum för synonymextraktion. Den här metoden möjliggör en kombination av olika modeller för distributionell semantik, med olika parameterkonfigurationer samt inducerade från olika korpusar. Detta är inte minst viktigt i den kliniska domänen, då det gör det möjligt att komplettera potentiellt begränsade mängder kliniska data med data från andra, mer lättillgängliga källor. Arbetet påvisar också vikten av att konfigurera dimensionaliteten av semantiska rum, i synnerhet när vokabulären är omfattande, vilket är vanligt i den kliniska domänen.
High-Performance Data Mining for Drug Effect Detection (DADEL)

Poslednjih godina je prisutan trend povratka prirodi i upotrebi biljnih lekova, kako u prevenciji tako i u lecenju razlicitih bolesti. Timijan (Thymus vulgaris L.) se u narodnoj medicini koristio u lecenju respiratornih oboljenja kao što su kašalj, bronhitis i astma. Rezultati novijih istraživanja pokazuju da timijan poseduje i druga potencijalno korisna farmakološka svojstva (antimikrobna, antiinflamatorna, antioksidativna, spazmoliticka, antidijabetesna i anksioliticka). Ciljevi ovog istraživanja su bili da se ispitaju farmakodinamske osobine preparata timijana, njihove interakcije sa lekovima koji deluju na centralni nervni sistem, uticaj na funkciju jetre i parametrem oksidativnog stresa kod životinja izloženih ugljentetrahloridu, kao sadržaj karvakrola i timola u sirupu timijna, pri razlicitim uslovima cuvanja. U farmakodinamskim ispitivanjima kao eksperimentalne životinje korišceni su miševi soja NMRI, a u svim drugim ispitivanjima pacovi soja Wistar. Tinktura timijana je primenjena u dozi od 0,4mk/kg, a sirup u dozi od 12,08 ml/kg, na miševima. Primenjene doze na pacovima su bile 0,18 ml/kg za tinkturu i 5,6 ml/kg za sirup timijana. Za ispitivanje analgetickog dejstva korišceni su metod vrele ploce i test sircetne kiseline. Za procenu motorne koordinacije korišcen je test rotirajuceg štapa, a za procenu hipnotickog delovanja mereno je vreme spavanja. Prilikom ispitivanja uticaja preparata timijana na farmakokinetiku paracetamola, odre_ivana je koncentracija ovog leka HPLC metodom, a nakon toga su odreeni farmakokinetski parametri paracetamola. Antioksidantna aktivnost preparata timijana odre_ivana je pomocu in vitro i in vivo testova. Nakon žrtvovanja životinja ra_ena je histopatološka analiza jetrenog tkiva, a u serumu su odre_ivani biohemijski parametri, kao i pokazatelji bubrežene i jetrene funkcije. Sadržaj timola i karvakrola i sirupu timijana odre_en je GC/MS metodom. Sirup i tinktura timijana su pokazali analgeticki efekat u testu vrele ploce, kao i smanjenje broja grceva izazvano primenom sircetne kiseline. Sedmodnevna primena preparata timijana smanjila je analgeticko dejstvo kodeina, a pojacala analgeticki efekat paracetamola. Sirup timijana je potencirao diazepamom izazvan poremecaj motorne koordinacije. Ispitivanjem uticaja preparata timijana na hipnoticko delovanje pentobarbitala, postignuti su razliciti rezultati u zavisnosti od dužine trajanja pretremana. Sedmodnevna primena timijana je produžila vreme trajanja spavanja, dok je jednokratna primena timijana skratila vreme trajanja spavanja. Nakon i intravenske i peroralne primene paracetamola, grupe životinja koje su bile pretretirane preparatima timijana imale su krace poluvreme eliminacije i vecu konstantu eliminacije. Upotreba samo preparata timijana nije imala uticaj na biohemijske i histološke promene jetrene funkcije. S druge strane, upotreba tincture timijana u kombinaciji sa ugljen-tetrahloridom dovela je do porasta vrednosti AST i ALT enzima u serumu, dok je sirup timijana u kombinaciji sa ugljentetrahloridom smanjio aktivnost aminotransferaza. Najvece odstupanje u koncentracijama aktivnih komponenti timola i karavkrola, pokazali su sirupi cuvani na sobnoj temperaturi (20°C), u sekundarnoj ambalaži i na svetlom mestu. Rezultati dobijeni u toku ovog istraživanja ukazuju da preparati timijana uticu na farmakodinamske osobine kodeina, paracetamola, diazepama i pentobarbitala, kao i na farmakokinetiku paracetamola. Upotreba preparata timijana ispoljila je analgeticki efekat i umanjila posledice izloženosti oksidativnom stresu. Uslovi cuvanja sirupa timijana uticali su na njegovu stabilnost.
In recent years is present trend of return to nature and the use of herbal medicines in prevention and treatment of different diseases. Thyme (Thymus vulgaris L.) was used in folk medicine in the treatment of respiratory diseases such as cough, bronchitis and asthma. The new research results have demonstrated that thyme has many others potentially useful pharmacological properties (antimicrobial, antiinflammatory, antioxidant, antispasmodic, antidiabetic and anxiolytic). The aims of this research were to determine the pharmacodynamic properties of thyme preparations and their interactions with central nervous system drugs, influence on liver function and oxidative stress parameters of animals exposed to carbon tetrachloride, as well as concentration of thymol and carvacrol in thyme syrup, at different storage conditions. In pharmacodynamics examination as experimental animals were used NMRI mice, while in all other test were used Wistar rats. Applied dose of thyme tincture was 0.4 ml/kg and of syrup 12.08 ml/kg, for mice. For rats, applied doses of tincture and syrup were 0.18 ml/kg and 5.6 ml/kg, respectively. The analgesic activity was examined by the hot plate test and acetic acid test. The Rotarod test was used to evaluate the motor coordination and to evaluate hypnotic activity sleeping time was mesaured. In order to examine the influence of thyme preparations on pharmacokinetics of paracetamol, the concentracion of this drug was measured by HPLC metods, and after that pharmocokinetic parameters of paracetamol were determined.The antioxidant acivity of thyme preparations was determined by using in vitro and in vivo tests. After animals sacrificing, histopathological analysis of liver tissue were peroformed, in serum were determined biochemical parameters and renal and hepatic function parameters. Quantification of thymol and carvacrol in syrup was carried out by GC/MS method. Thyme syrup and thyme tincture exhibited analgesic activity in hot plate test and reduced the number of writhes induced by acetic acid. Seven-day pretreatment with thyme preparations reduced analgesic activity of codeine and increased analgesic effect of paracetamol. Thyme syrup potentiated diazepam induced motor coordination impairment. Examining the impact of thyme preparations on hypnotic effect induced by pentobarbital, different results were achieved depending on the duration of pretreatment. Seven-day pretreatment with thyme had prolonged the sleeping time, while after single dose of thyme the sleeping time was decreased. After intravenous and after oral administration of paracetamol, groups pretreated with thyme preparations had decreased elimination half-life and increased elimination constant rate. Administration of thyme preparations alone did not change biochemical nor histological markers of hepatic function. On the other hand, co-administration of thyme tincture and carbon tetrachloride resulted in exacerbation of AST and ALT values in serum, while thyme syrup in coadministration with carbon tetrachloride managed to reduce activities of aminotransferases. The concentration of major active compounds, thymol and carvacrol, was mostly changed when syrups were stored at room temperature (20°C), in secondary containers and in light place. Results obtained in this study demonstrated that thyme preparations do affect pharmacodynamic properties of codeine, paracetamol, diazepam and pentobarbital and pharmacokinetics of paracetamol. Administration of thyme preparations exhibited analgesic activity and reduced the effects of exposure to oxidative stress. Storage conditions of thyme syrup did affect its stability.

In Günter Grass's Danzig Trilogy and novella, Im Krebsgang, an antagonistic female type makes a repeated appearance. She appears in the guise of Susi Kater and Luzie Rennwand in Die Blechtrommel, and as Tulla Pokriefke in the other works, Katz und Maus, Hundejahre, and Im Krebsgang. This antagonistic female type is not like other women in these works. A review of Le Deuxième Sexe by feminist Simone de Beauvoir reveals several crucial components contributing to woman's position in society. Most essentially, a woman's natural attributes and (dis)abilities and the conventions of society have enforced her historical submission to man. This thesis analyzes how the antagonistic female type, or villain, compares and contrasts with other female figures in these works by Grass, according to a paradigm derived from Beauvoir's description of woman. From this analysis, a better understanding of the female villain's nature emerges. Indeed, such a comparison demonstrates that certain female figures in the works of Grass transcend their historically oppressed or subdued status by refusing to submit to those natural handicaps and societal restrictions identified by Beauvoir, and thus become a threat to man's status or security as an antagonistic female type, or villain. However, the villain figure is not always inherently evil, but possesses the capacity to change. The villain and victim can reconcile their differences and may even form a friendly relationship. This evolving villain-victim duality becomes most clear in Grass's work, Im Krebsgang, and suggests the possibility of assuaging contemporary conflicts as educators sympathize with the experiences of both extremist groups and victimized parties and help them come to terms with their differences.

Mnogi lekovi registrovani za razne druge indikacije mogu da deluju selektivno na tumorske receptore, signalne puteve, metaboličke procese, bioenergetske faktore, enzime, proteine, gene koji regulišu proliferaciju, apoptozu i neoangiogenezu tumora ne pogađajući ove procese kod zdravih ćelija. Uvođenje novih lekova je izrazito dug, složen i skup proces istraživanja. Korišćenjem principa otkrivanja antikancerskog efekta kod već registrovanih lekova za druge indikacije, direktno se utiče na skraćivanje vremena i troškova istraživanja. Eksperimentalno je ispitana efikasnost antitumorskog delovanja mebendazola, metformina, itrakonazola, diklofenaka, nitroglicerina i deoksiholne kiseline na fibrosarkom hrčka izazvan BHK21/C13 tumorskom ćelijskom linijom praćenjem veličine i histologije lečenih tumora. Eksperimentalno je ispitana mogućnost primene deoksiholne kiseline, nitroglicerina, kofeina i itrakonazola kao adjuvansa u kombinaciji sa pojedinim ispitivanim lekovima (metformin, itrakonazol, diklofenak) za lečenje fibrosarkoma hrčka. Kako je ispitivanje vršeno na mladuncima imladim hrčkovima i kako su sarkomi najčešći u dečijem uzrastu, definisanje potencijalne antikancerske uloge ispitivanih lekova se odnosi prvenstveno na njihovu primenu u pedijatriji. Pokazano je da metformin, kombinacije metformina sa kofeinom, metformina sa itrakonazolom i metformina sa nitroglicerinom deluju u pogledu svih ispitivanih parametara tumora antitumorski na fibrosarkom hrčka. Kofein, itrakonazol i nitroglicerin pojačavaju antitumorsko dejstvo metformina na fibrosarkom hrčka. Tokom svih eksperimenata realizovanih u okviru ove disertacije, pokazalo se da nije bilo delotvornog tretmana, koji ne sadrži metformin.
Many drugs registered for various other indications can act selectively to tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins, genes that regulate proliferation, apoptosis, and neoangiogenesis of the tumor without affecting these processes in the healthy cells. The introduction of new drugs is a very long, complex and expensive process of research. Using the principle of detecting the anticancer effect in already registered drugs for other indications, directly affects the reduction of time and cost of research. The efficacy of mebendazole, metformin, itraconazole, diclofenac, nitroglycerin and deoxycholic acid antitumor activity on hamster fibrosarcinoma induced experimentally by the BHK21/C13 tumor cell line was tested by monitoring the size and histology of the treated tumors. The possibility of using deoxycholic acid, nitroglycerin, caffeine and itraconazole as an adjuvant in combination with investigated drugs (metformin, itraconazole, diclofenac) for the treatment of hamster fibrosarcoma has been experimentally tested. As the examination was carried out on young cubs and young hamsters and that sarcomas are the most common in childhood, defining the potential anti-cancer role of the investigated drugs relates primarily to their application in pediatrics. Metformin, combinations of metformin with caffeine, metformin with itraconazole and metformin with nitroglycerin have shown antitumor action on the hamster fibrosarcoma in terms of all tested tumor parameters. Caffeine, itraconazole and nitroglycerin increase the antitumor effect of metformin on the hamster fibrosarcoma. During all the experiments carried out within this dissertation, there has been no effective treatment, which does not contain metformin.

Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najčešće koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najčešće prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodišnjeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiološka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistološki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim oštećenjem. Što se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (<1 μg/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih širom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23±17,11 mg, 47,11±16,79 mg, 50,00±17,55 mg i 78,63±18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92±10,47 mg, 33,89±9,23 mg, 28,33±11,55 mg i 28,12±11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44±111,51 ng/ml, 157,43±112,39 ng/ml, 176,77±118,56 ng/ml i 342,86±181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00±537,89 ng/ml, 923,76±739,96 ng/ml, 560,74±436,72 ng/ml i 1045,32±932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87±27,22 ms, tj. 414,64±29,38 ms 8. dana STM, 416,97±26,39 15. dana, i 425,20±17,71 ms nakon 1. meseca tj. 423,50±14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi muškog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi muškog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori – koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi muškog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi muškog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog oštećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije došlo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razjašnjenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.
Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias – torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals’ control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (<1 μg/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23±17.11 mg, 47.11±16.79 mg, 50.00±17.55 mg and 78.63±18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92±10.47 mg, 33.89±9.23 mg, 28.33±11.55 mg and 28.12±11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44±111.51 ng/ml, 157.43±112.39 ng/ml, 176.77±118.56 ng/ml and 342.86±181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00±537.89 ng/ml, 923.76±739.96 ng/ml, 560.74±436.72 ng/ml and 1045.32±932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87±27.22 ms, 414.64±29.38 ms on the 8th day of MMT, 416.97±26.39 on the 15th day of MMT, after 1 month of MMT 425.20±17.71 ms and after 6 months of MMT 423.50±14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.

Ruzmarin Rosmarinus officinalis L. (Lamiaceae) je biljka koja se u tradicionalnoj medicini na našem području koristi za postizanje analgetičkog, holeretičkog i hepatoprotektivnog delovanja. Prema Evropskoj agenciji za lekove (2010 godine), indikacije za sistemsku primenu etarskog ulja ruzmarina su lečenje dispepsije i spazama gastrointestinalnog trakta, a za spoljašnju primenu se preporučuje u lečenju umereno jakih bolova u zglobovima i mišićima i u lečenju poremećaja periferne cirkulacije. Imajući u vidu da komponente etarskog ulja ruzmarina ispoljavaju i druga, potencijalno korisna farmakološka svojstva, postoji potreba da se ova delovanja detaljnije ispitaju. Ciljevi ispitivanja su bili da se utvrdi: 1) analgetički efekat etarskog ulja ruzmarina i njegov uticaj na farmakodinamske osobine paracetamola, kodeina, diazepama i pentobarbitala kao i na farmakokinetske osobine paracetamola; 2) antioksidativni i hepatoprotektivni efekat u uslovima hemijski izazvanog oksidativnog stresa. Metodom gasne hromatografije (GC/MS i GC/FID) utvrđen je kvantitativni sastav etarskog ulja. Najzastupljenije komponente ulja koje je korišćeno u našem ispitivanju su oksidovani monoterpeni 1,8-cineol (43.77%) i kamfor (12.53%) i monoterpenski ugljovodonik α-pinen (11.51%). Suspenzija etarskog ulja ruzmarina primenjivana je miševima u dozama 10 i 20 mg/kg tm tokom sedam dana i jednokratno u farmakodinamskim testovima: test vrele ploče, test „uvijanja“ (posle intraperitonealne primene sirćetne kiseline), test za procenu motorne koordinacije životinja na rotirajućem štapu i test merenja vremena trajanja spavanja. Za ispitivanje uticaja etarskog ulja ruzmarina na farmakokinetske osobine paracetamola i za biohemijska i toksikološka ispitivanja, korišćeni su pacovi koji su tokom sedam dana tretirani suspenzijom etarskog ulja ruzmarina u dozi 5 i 10 mg/kg tm, a sedmog dana su primili paracetamol i.v. ili p.o.. Za praćenje farmakokinetskih parametara korišćeni su uzorci krvi dobijeni iz repne vene pacova u kojima su HPLC metodom merene koncentracije paracetamola, na osnovu kojih su potom određeni farmakokinetski parametri ovog leka. Antioksidativna aktivnost etarskog ulja ruzmarina je određivana in vitro (DPPH i Folin-Ciocaulteu testovima) i in vivo. Nakon žrtvovanja životinja iz prikupljenih uzoraka krvi određivani su iz seruma biohemijski parametri, pokazatelji bubrežne i jetrene funkcije, a u homogenatu tkiva jetre određivani su parametri oksidativnog stresa. Samo etarsko ulje ruzmarina ispoljava analgetičko delovanje i smanjuje visceralnu bol izazvanu sirćetnom kiselinom. Pored toga, potencira analgetički efekat kodeina i paracetamola. Etarsko ulje ruzmarina značajno smanjuje hipnotičko delovanje pentobarbitala i sprečava poremećaj motorne koordinacije nakon primene diazepama. Etarsko ulje ruzmarina ne utiče značajnije na oralnu biološku raspoloživost paracetamola. Višekratna primena različitih doza etarskog ulja ruzmarina ne izaziva toksične promene u krvi i jetri ispitivanih životinja. Primena etarskog ulja ruzmarina štiti životinje od reaktivnih kiseoničnih vrsta, umanjuje posledice izloženosti oksidativnom stresu i ispoljava značajno hepatoprotektivno delovanje.
Rosemary Rosmarinus officinalis, L.(Lamiaceae) is traditionally used in folk medicine for its analgetic, choleretic and hepatoprotective properties. According to the recommendation of European Medicines Agency from 2010, rosemary essential oil can be used for treating dyspepsia and mild spasmodic disorders of the gastrointestinal tract, and also externally as an adjuvant in the relief of minor muscular and articular pain and minor peripheral circulatory disorders. Different studies conducted with rosemary essential oil show other pharmacological effects of main components of the oil. The aim of this study was to examine: 1) analgetic effects of rosemary essential oil and its influence on the pharmacodynamic properties of paracetamol, codeine, diazepam and pentobarbital, and also its influence on the pharmacokinetic properties of paracetamol; 2) antioxidant and hepatoprotective effects on the parameters of chemicaly induced oxidative stress. The quantification of chemical constituents of the essential oil was carried out by gas chromatography (GC/FID and GC/MS). The major compounds that were identified and quantitated by GC-FID and GC-MS were oxygenated monoterpens 1,8-cineole (43.77%), camphor (12.53%) and monoterpene hydrocarbon α-pinene (11.51%). The suspension of rosemary essential oil was applied to mice orally (doses: 10 and 20 mg/kg b.w.) for seven days and in single dose for the pharmacodynamic tests: hot plate, writhing, rotharod and sleeping time. Rats treated with suspension of rosemary essential oil for seven days orally (doses: 5 and 10 mg/kg b.w.) were used for the examination of influence of essential oil on the pharmacokinetic properties of paracetamol. Then on the 7th day the paracetamol was applied to them p.o. or i.v.. The parameters of pharmacokinetic were analyzed in blood samples obtained from rats tail veins. The HPLC method was used for measurement of concentration of paracetamol in blood samples. Those concentrations were used for calculation of the pharmacokinetic parameters. The antioxidant activity of the rosemary essential oil was evaluated in vitro (with DPPH and Folin-Ciocaulteu tests) and in vivo. The animals were sacrificed and the samples of blood and liver were taken. The obtained serum was used for determination of standard biochemical parameters and the parameters of oxidative stress were analyzed in obtained liver homogenates. The essential oil of rosemary shows analgetic properties and it decreases visceral pain induced with intraperitoneally injected acetic acid. The rosemary essential oil increases pharmacological effects of codeine and paracetamol. Also, this oil reduces pentobarbital-induced sleeping time and diminishes diazepam-induced disorder of psychomotor coordination. The essential oil of rosemary does not change paracetamol bioavailability. The rosemary essential oil applied in multiple doses does not induce toxic changes in blood and liver samples obtained from animals. The use of rosemary essential oil protects animals from reactive oxygen species, decreases the effects caused by oxidative stress and shows significant hepatoprotective effect.

Globally, approximately 208 million people aged 15 and older used illicit drugs at least once in the last 12 months; 2 billion consumed alcohol and tobacco consumption affected 25% (World Drug Report, 2008). In the United States, 20.1 million (8.0%) people aged 12 and older were illicit drug users, 129 million (51.6%) abused alcohol and 70.9 million (28.4%) used tobacco (SAMHSA/OAS, 2008).Usually considered a problem specific to men (Lynch, 2002), 5.2% of pregnant women aged 15 to 44 are also illicit drug and substance abusers (SAMHSA/OAS, 2007). During pregnancy, illicit drugs and substance abuse (ID/SA) can significantly affect a woman and her infant contributing to developmental and communication delays for the infant and influencing parenting abilities (Budden, 1996; March of Dimes, 2006b; Rossetti, 2000). Feelings of guilt and shame and stressful experiences influence approaches to parenting (Ashley, Marsden, & Brady, 2003; Brazelton, & Greenspan, 2000; Ehrmin, 2000; Johnson, & Rosen, 1990; Kelley, 1998; Rossetti, 2000; Velez et al., 2004; Zickler, 1999). Parenthood is an expanded role that can be a trying time for those lacking a sense of self-efficacy and creates a high vulnerability to stress (Bandura, 1994). Residential treatment programs for ID/SA mothers and their children provide an excellent opportunity for effective interventions (Finkelstein, 1994; Social Care Institute for Excellence, 2005). This experimental study evaluated whether teaching American Sign Language (ASL) to mothers living with their infants/children at an ID/SA residential treatment program increased the mothers’ self-efficacy and decreased their anxiety. Quantitative data were collected using the General Self-Efficacy Scale and the State-Trait Anxiety Inventory showing there was both a significant increase in self efficacy and decrease in anxiety for the mothers. This research adds to the knowledge base concerning ID/SA mothers’ caring for their infants/children. By providing a simple low cost program, easily incorporated into existing rehabilitation curricula, the study helps educators and healthcare providers better understand the needs of the ID/SA mothers. This study supports Bandura’s theory that parents who are secure in their efficacy can navigate through the various phases of their child’s development and are less vulnerable to stress (Bandura, 1994).

Ispitana je direktna i indirektna fotoliza alprazolama (ALP) i amitriptilina (AMI)primenom UV, vidljivog  i simuliranog sunčevog zračenja (SSZ). Takođe, praćena je stabilnost vodenih rastvora ALP i AMI u mraku.  U okviru ispitivanja fotokatalitičke  razgradnje ALP,ispitana je efikasnost ZnO i TiO₂  Degussa P25 primenom UV i SSZ.  Takođe, proučavan je  utica jmasene koncentracije fotokatalizatora, pH, kao iuticaj hvatača radikala/šupljina  i elektron-akceptora.  Praćen je stepen mineralizacijemerenjem ukupnog organskog ugljenika i primenom  jonske hromatografije. Takođe,detaljno su ispitani reakcioni intermedijeri.  Dalje,ispitano  je ponovno korišćenje ZnO u tri uzastopna procesa razgradnje ALP. U cilju praćenja citotoksičnosti ALP, ispitan je  in vitro rast dve ćelijske linije: Neuro-2a i MRC-5. Zatim,proučavana je efikasnost sintetisanih ZnO (ZnO modifikovani mlevenjem i kalcinacijom, ZnO dopirani jonima Mg(II), ternarni i  mešani  cink-kalaj-oksidi) i TiO₂  (anatas  TiO₂  nedopirani  i dopirani La(III)-jonima, brukitni TiO2) nanoprahova u razgradnji ALP primenom UV i SSZ. U okviru fotokatalitičke razgradnje AMI, ispitana  je  efikasnost  razgradnje  pri različitim eksperimentalnim uslovima  (uticaj vrste fotokatalizatora i zračenja, masene  koncentracije fotokatalizatora, početne koncentracije supstrata, uticaj prisustva  kako  hvatača radikala i šupljina, tako  i elektron-akceptora). Praćen je stepen mineralizacije merenjem ukupnog organskog ugljenika i  primenom  jonske hromatografije.  U cilju praćenja citotoksičnosti  AMI, ispitan je  in vitro  rast četiri ćelijske linije: Neuro-2a, MRC-5, H-4-II-E i HT-29.  Zatim, proučavana je efikasnost sintetisanih TiO₂/polianilin nanokompozitnih prahova, kao i  prevlaka  čistog TiO₂  i WO₃/TiO₂  u razgradnji AMI primenom UV i SSZ. Takođe, ispitan je uticaj  strukture  supstrata  na efikasnost  fotokatalitičke razgradnje kroz ispitivanje  efikasnosti sintetisanih TiO₂  nanoprahova dopiranih jonima W(VI), zatim mešanih  cink-kalaj-oksid  nanoprahova, kao i  indijum-cink-oksid nanoprahova primenom UV i SSZ.
Direct and indirect photolysis of alprazolam (ALP) and amitriptyline (AMI) were studied using UV, visible,  and simulated solar irradiation (SSI). Also, the stability of the ALP and AMI aqueous solutions in the dark were monitored. Photocatalytic degradation of ALP was studied in  the  presence of  ZnO and TiO₂ Degussa  P25  using UV and SSI. Also, the influence of the photocatalyst  loading, pH, as well as the influence of the radical  and  holes scavengers  and electron acceptors  were studied. The  degree of mineralization was monitored by measuring  of  total organic carbon and  using  ion chromatography. Also, reaction intermediates were examined in detail. Further, reusabillity  of ZnO was investigated in three consecutive degradation processes of ALP. In order to  get insight into the  cytotoxicity of the ALP  and intermediates formed during photocatalytic degradation, their influence on the growth of two cell lines: Neuro-2a and MRC-5 were investigated. Then, the efficacy of synthesized ZnO (ZnO modified with milling  and calcination, ZnO doped with Mg(II) ions, ternary and coupled binary  tin-zinc-oxide) and TiO₂  (anatase  TiO₂  undoped and  doped  with  La(III) ions  and  brookite TiO₂) nanopowders in ALPdegradation using UV and  SSI  were investigated. Within the photocatalytic degradation of AMI, the  degradation efficiency under different experimental conditions was studies (influence of the photocatalyst and irradiation type, photocatalyst  loading, initial  substrate concentration, the effect of the presence of radical and  holes scavengers, and electron acceptors). The degree of mineralization was monitored by measuring  of  total organiccarbon and  using  ion chromatography.  In order to  study  the cytotoxicity of AMI  and degradation intermediates, their influence on the  growth of four cell lines: Neuro-2a, MRC-5, H-4-II-E,  and HT-29  were investigated. Then, the efficacy of synthesized TiO2/polyaniline nanocomposite powders, as well as photocatalysts of pure TiO₂  and WO₃/TiO₂  in the form  of  films   in AMI degradation using UV and SSI were studied. In addition, the effect of the  substrate  structure on the efficiency of photocatalytic degradation was studied by testing the activity  of synthesized TiO₂  nanopowders doped with W(VI)  ions, then  coupled binary tin-zinc- oxide  nanopowders, as well as coupled binary  indium-zinc- oxide nanopowders using UV and SSI.

Sukcinimidi su jedinjenja koja pokazuju višestruke farmakološke efekte uključujući i antiproliferativnu aktivnost, zahvaljujući prisustvu farmakofore sa dva hidrofobna regiona i dva regiona bogata elektronima. Savremeni dizajn lekova ima za cilj da se modifikacijama u strukturi (promena vrste, položaja i orijentacije supstituenata) i in silico računarskim metodama predvide i optimizuju farmakokinetske osobine i bezbednosni profil kandidata za lek. U ranoj fazi razvoja lekova se koriste postojeće baze podataka o molekulskim, farmakokinetskim i toksikološkim parametrima već ispitanih jedinjenja i pomoću matematičkih modela i algoritama predviđaju se osobine novih molekula, eliminišu se neodgovarajući kandidati i postiže se ušteda u vremenu i materijalnim sredstvima. Da se ispitaju fizičko-hemijske karakteristike 11 novosintetisanih metil-etil-N-aril-sukcinimida na osnovu strukture, primenom različitih softverskih paketa; da se na osnovu strukture odrede farmakokinetski i toksikološki parametri, primenom različitih softverskih paketa; da se ispita retenciono ponašanje, odnosno odrede retencione konstante za svako jedinjenje primenom visokoefikasne hromatografije na tankom sloju (HP-TLC) i ispita mogućnost primene retencionih konstanti kao mere lipofilnosti ispitivanih jedinjenja; da se ispita antiproliferativna aktivnost na odabranim kulturama ćelija karcinoma i na zdravim ćelijama fibroblasta pluća; da se analizom molekulskog dokinga ustanovi vezivanje za estrogene receptore. Ispitano je retenciono ponašanje 11 novosintetisanih derivata sukcinimida primenom visokoefikasne hromatografije na tankom sloju (HP-TLC) obrnute faze uz primenu dvokomponentne smeše vode i organskog rastvarača (metanola, acetonitrila ili acetona), sa odgovarajućim zapreminskim udelom organskog rastvarača kao mobilne faze. Iz razvijenih hromatograma su izračunate retencione konstante RM0 i S. Logaritam podeonog koeficijenta (logP) određen je in silico, korišćenjem različitih računarskih programa. In silico su određene fizičko-hemijske karakteristike, farmakokinetski parametri, toksikološki parametri, akvatična toksičnosti i afinitet vezivanja za estrogene receptore. Izračunate su vrednosti afiniteta za 4 vrste receptora (G-protein spregnuti receptori, jonski kanali, inhibitori kinaza, nuklearni receptori). Antiproliferativna aktivnost ispitivanih derivata sukcinimida određena je primenom kolorimetrijskog testa sa tetrazolijum solima (MTT testa) na komercijalnim kulturama ćelija (MRC-5, A549, HeLa, MDA-MB-231, MCF-7, HT-29) i izračunate su IC50 vrednosti. Urađena je i doking analiza sukcinimida prema ERA (estrogen receptor alfa) i ERB (estrogen receptor beta) i dobijene su vrednosti energije formiranja kompleksa sa posmatranim receptorima (MolDock Score). Statistički najznačajnije linearne korelacije dobijene su između eksperimentalno određenih hromatografskih parametara (RM0 i S) i in silico parametara lipofilnosti MlogP i ClogP. Ispitivanjem uticaja promene RM0 i S na farmakokinetske karakteristike dobijeni su rezultati koji pokazuju paraboličnu zavisnost konstante apsorpcije (Ka) i procenta vezivanja za proteine plazme (PPB) od posmatranih retencionih konstanti, dok je zavisnost sa volumenom distribucije (Vd) i sposobnošću prolaska kroz krvno-moždanu barijeru (logBBB) bila linearnog tipa. Toksičnost ispitivanih jedinjenja, procenjena na osnovu in silico dobijenih LD50 vrednosti, nije bila viša od toksičnosti već registrovanih lekova sa strukturom sukcinimida, i dala je parabolične zavisnosti u odnosu na RM0 i S vrednosti. Eksperimentalno nijedno od ispitivanih jedinjenja nije pokazalo aktivnost u odnosu na zdrave fibroblaste pluća. Najznačajniju antiproliferativnu aktivnost (najniže IC50) su pokazala jedinjenja 6 i 7 u odnosu na ćelije linije MCF-7 i jedinjenje 11 u odnosu na A549 ćelijsku liniju. Doking analiza je pokazala niže energije formiranja kompleksa sa ERA, u odnosu na ERB. Eksperimentalno određeni parametri RM0 i S se mogu koristiti kao alternativne i pouzdane mere lipofilnosti analiziranih sukcinimida. Ispitivana jedinjenja pokazuju povoljne fizičko-hemijske karakteristike, predviđene in silico metodama i povoljne farmakokinetske karakteristike: male vrednosti konstante apsorpcije, umeren volumen distribucije, povoljan afinitet vezivanja za proteine plazme, favorizovan prolazak kroz krvno-moždanu barijeru za lipofilnija jedinjenja. Procenjuje se da sva ispitivana jedinjenja, izuzev derivata sa –CN supstituentom, imaju zahtevani nizak stepen toksičnosti. Po antiproliferativnoj aktivnosti u odnosu na ćelije ER-zavisnog karcinoma dojke (MCF-7) izdvajaju se jedinjenja sa metil i nitro supstituentom u para položaju. Na osnovu malih energija formiranja kompleksa sa ERA, koji su eksprimirani na ćelijama MCF-7 linije, pretpostavlja se da bi mehanizam njihovog delovanja delimično mogao biti objašnjen uticajem na ERA, ali su potrebna dodatna istraživanja na tom polju.
Succinimides have exhibited various pharmaceutical effects including antiproliferative activity due to an important structural fragment (a pharmacophore) presented in form of two hydrophobic regions and two electron-rich centers. Current development of new drugs involves modifications in structure (type, position and orientation of substituents) and usage of in silico computational programs to predict and optimize pharmacokinetic and safety profile of drug candidates. In early phase of drug development, databases regarding the molecular, pharmacokinetic and toxicological parameters of already tested compounds are used, mathematical models and algorithms are applied for predicting the properties of new molecules and inadequate candidates are eliminated saving time and resources. Determination of physico-chemical properties of the analyzed methyl-ethyl-N-phenilsuccinimide derivatives by software packages; virtual pharmacokinetic and toxicology screening; investigation of retention behavior of the compounds by the reversed-phase HPTLC analysis and calculation of retention constants and their correlation with lipophilicity; in vitro evaluation of antiproliferative activity toward five carcinoma cell lines and normal fetal lung cell line; molecular behavior study on target estrogen receptors by molecular docking and correlation of antiproliferative activity toward ER+ breast carcinoma cell lines and in silico estrogen receptor affinity binding. Retention behavior of 11 newly synthesized succinimide derivatives was determined by reversed phase high performance thin layer chromatography (RP HPTLC) with the application of two-component mixtures water - organic solvent (methanol, acetonitrile or acetone) with adequate volume fractions of the organic modifier. After chromatographic development RM0 and S parameters were calculated. The logarithm of partition coefficient, logP for the analyzed compounds were calculated by different softwares. Physico-chemical properties, pharmacokinetic and toxicological parameters, aquatic toxicity and relative affinity to estrogen receptors were predicted in silico. The affinity toward 4 types of receptors (G-proteine coupled receptors, ion channels, kinase inhibitors, nuclear receptors) were calculated as well. Standard MTT assay was applied to evaluate cytotoxic activities of the analyzed succinimides after cells were exposed. Antiproliferative activity were investigated toward commercial MRC-5, A549, HeLa, MDA-MB-231, MCF-7, HT-29 cell lines and IC50 values were calculated for each compound. MolDock Score that represents energy of binding to estrogen alfa and estrogen beta receptors was determined by molecular docking. Statistically significant linear correlations were determined between the chromatographic retention constants (RM0 and S) and calculated logP, and the best two were obtained in correlation of retention constants with MlogP and ClogP. The examination of RM0 and S influence on pharmacokinetics indicated parabolic dependence of the absorption constant (Ka) and plasma protein binding predictor (PPB) from the observed constants while the volume of distribution (Vd) and the ability to cross the brain blood barrier (logBBB) had linear association with the retention parameters. The toxicity of the analysed compounds evaluated in silico as LD50 on rodents was lower in comparison with the drugs with succinimide structure that are on the market and had parabolic correlation with the RM0 and S values. The experiments indicated that none of the compounds examined had cytotoxic activity toward the healthy lung fibroblast cells. The results of the in vitro assay shown that none of the investigated compounds demonstrated antiproliferative activity toward fetal lung cells. The most potent antiproliferative agents were compounds 6 and 7 toward MCF-7 cell line, and compound 11 toward A549 cell line. Molecular docking shown lower energy for binding to ERA in comparison to ERB.

In addition to coverage in the national and international media of the ongoing violence in Mexico related to the drug trade, there has been growing interest in fictional representations of the Mexican drug trade, its origins and social context. There is now a considerable body of written narratives that have been christened narconovelas. A small number of academic works has charted the emergence of the narconovela and sought to examine how drug traffickers have been represented and evaluated in fiction. However, very little attention has been paid to the aesthetic qualities of ‘narco-literature’. This study examines four of the most highly-regarded works in detail: Balas de plata (2008), by Élmer Mendoza; Los minutos negros (2006), by Martín Solares; Contrabando (2008), by Víctor Hugo Rascón Banda; and Trabajos del reino (2004), by Yuri Herrera. So embedded is the phenomenon of drug trafficking in northern Mexican culture, so suffused with cliché is its representation in other media, that to write about the topic with originality and ethical nuance is difficult. This thesis accounts for the distinct choices made by the four authors in question to address this difficulty of representation in the structure, style and tone of their novels. The self-awareness exhibited by these works of fiction regarding the challenges of representing their subject matter render them the most sophisticated examples yet created of the so-called narconovela.

The subject of this dissertation is the representation of temporality, trauma and sexuality in Antanas Škėma’s fiction. The chapter “Temporal structures” examines temporal order in the writer’s novella “Isaac” according to Genettes narratology. The analysis reveals deliberately inserted mechanisms in the construction of the text, which disrupt the narrative investigation. A survey of temporal structures exposes invented events in the text and the definitions of “factual reality” and “imaginary reality” are introduced. The narrative analysis results in a hypothesis that Škėma’s text has been constructed as an imitation of human memory and as a representation of the factual reality outside the text. The chapters “Representation of trauma” and “Representation of sexual perversion” use Freud’s trauma theory and sexual theory as a method. Trauma appears to constitute the construction of the narrator and his urge to distort temporal links between the narrative and the story. When the narrator in Škėma’s “Isaac” focuses on the depiction of sexually perverted consciousness, the text affects the reader by forcing him to break off his horizons of expectation. The depiction of rape in Škėma’s fiction links the themes of sexuality and power and of sexuality and trauma. The writer detaches the representation of sexuality from the definition of love: sexuality, portrayed in the analyzed texts, appears to create its own norms. This is one of many ways to transform the depiction of sexual perversion into a social norm in Škėma’s narrative. The chapter “Škėma’s Autobiography and literary critics” provides a re-reading of the writer’s autobiography and his journalistic texts. The chapter ”Publication and reception of Škėma’s fiction” provides a compiled reading of earlier research and a survey of the writer’s books published in exile.

L’objectif principal de notre travail consiste à mettre en évidence de manière systématique le lexique régional propre à une aire délimitée du domaine d’oïl, à savoir l’aire sud-orientale comprenant les régions de la Lorraine, de la Bourgogne, de la Franche-Comté et de la Champagne. Notre recherche consistera en premier lieu en l’identification des mots régionaux dans un corpus de textes médiévaux des 13e et 14e siècles. Une fois cette identification réalisée, nous rédigerons des articles lexicographiques élaborés permettant de traiter de la manière la plus adéquate la régionalité médiévale. Ces articles s’appuieront non seulement sur le corpus mais aussi sur l’intégralité de la documentation disponible dans la lexicographie de référence. Ils rendront ainsi possible une réflexion sur la genèse et l’évolution des régionalismes en question. Le travail interprétatif qui accompagnera l’identification et le traitement des matériaux consistera en une analyse de l’ensemble du vocabulaire régional identifié
This study aims to describe and analyse the linguistic variation of Medieval French, focusing on lexicon. The geographical area that I analyse includes the North-Eastern regions of France: Lorraine, Bourgogne, Franche-Comté and Champagne. First, I will identify the words who reveal a regional distribution in a corpus of texts from the 13–14th centuries; I will analyse each regional word though a lexicographical article with a focus on the etymology and the semantic changes. Secondly, I will categorize the regional vocabulary aiming at identifying its origin and its spread in the medieval linguistic space

This paper researches the use of conceptual metaphors in rap and country song lyrics. It looks specifically at conceptual metaphors for the concepts of LOVE and SADNESS, focusing on what source domains are proposed in each genre, what similarities there are in source domains between the genres and the style of language found in the linguistic expressions in the two genres. Song lists and lyrics were obtained from internet sites and then, using the Metaphor Identification Procedure (MIP), linguistic expressions were identified which were then subjected to a qualitative analysis. Those relating to SADNESS and LOVE were grouped according to proposed source domains for comparison. The results show that there are similarities, and some differences in the source domains identified within the genres and that they have a wide variety of sub-domains. Concrete concepts common to both genres do not exhibit the same mapping of correspondences to the target domains. There is no discernible difference in the style of language used in the linguistic expressions of the two genres. Nevertheless, the rap expressions tend to be more in the present, dynamic and at times sexually provocative whereas in country expressions they tend to be more reflective, virtuous and at times, depressing.

Les travaux décrits dans cette thèse portent sur la détection et l'extraction trans- et multilingue des effets indésirables des médicaments dans des textes biomédicaux rédigés par des non-spécialistes. Dans un premier temps, je décris la création d'un nouveau corpus trilingue (allemand, français, japonais), centré sur l'allemand et le français, ainsi que le développement de directives, applicables à toutes les langues, pour l'annotation de contenus textuels produits par des utilisateurs de médias sociaux. Enfin, je décris le processus d'annotation et fournis un aperçu du jeu de données obtenu. Dans un second temps, j'aborde la question de la confidentialité en matière d'utilisation de données de santé à caractère personnel. Enfin, je présente un prototype d'étude sur la façon dont les utilisateurs réagissent lorsqu'ils sont directement interrogés sur leurs expériences en matière d'effets indésirables liés à la prise de médicaments. L'étude révèle que la plupart des utilisateurs ne voient pas d'inconvénient à décrire leurs expériences quand demandé, mais que la collecte de données pourrait souffrir de la présence d'un trop grand nombre de questions. Dans un troisième temps, j'analyse les résultats d'une potentielle seconde méthode de collecte de données sur les médias sociaux, à savoir la génération automatique de pseudo-tweets basés sur des messages Twitter réels. Dans cette analyse, je me concentre sur les défis que cette approche induit. Je conclus que de nombreuses erreurs de traduction subsistent, à la fois au niveau du sens du texte et des annotations. Je résume les leçons apprises et je présente des mesures potentielles pour améliorer les résultats. Dans un quatrième temps, je présente des résultats expérimentaux de classification translingue de documents, en anglais et en allemand, en ce qui concerne les effets indésirables des médicaments. Pour ce faire, j'ajuste les modèles de classification sur différentes configurations de jeux de données, d'abord sur des documents anglais, puis sur des documents allemands. Je constate que l'incorporation de données d'entraînement anglaises aide à la classification de documents pertinents en allemand, mais qu'elle n'est pas suffisante pour atténuer efficacement le déséquilibre naturel des classes des documents. Néanmoins, les modèles développés semblent prometteurs et pourraient être particulièrement utiles pour collecter davantage de textes, afin d'étendre le corpus actuel et d'améliorer la détection de documents pertinents pour d'autres langues. Dans un cinquième temps, je décris ma participation à la campagne d'évaluation n2c2 2022 de détection des médicaments qui est ensuite étendue de l'anglais à l'allemand, au français et à l'espagnol, utilisant des ensembles de données de différents sous-domaines. Je montre que le transfert trans- et multilingue fonctionne bien, mais qu'il dépend aussi fortement des types d'annotation et des définitions. Ensuite, je réutilise les modèles mentionnés précédemment pour mettre en évidence quelques résultats préliminaires sur le corpus présenté. J'observe que la détection des médicaments donne des résultats prometteurs, surtout si l'on considère que les modèles ont été ajustés sur des données d'un autre sous-domaine et appliqués sans réentraînement aux nouvelles données. En ce qui concerne la détection d'autres expressions médicales, je constate que la performance des modèles dépend fortement du type d'entité et je propose des moyens de gérer ce problème. Enfin, les travaux présentés sont résumés, et des perspectives sont discutées
The work described in this thesis deals with the cross- and multi-lingual detection and extraction of adverse drug reactions in biomedical texts written by laypeople. This includes the design and creation of a multi-lingual corpus, exploring ways to collect data without harming users' privacy and investigating whether cross-lingual data can mitigate class imbalance in document classification. It further addresses the question of whether zero- and cross-lingual learning can be successful in medical entity detection across languages. I describe the creation of a new tri-lingual corpus (German, French, Japanese) focusing on German and French, including the development of annotation guidelines applicable to any language and oriented towards user-generated texts. I further describe the annotation process and give an overview of the resulting dataset. The data is provided with annotations on four levels: document-level, for describing if a text contains ADRs or not; entity level for capturing relevant expressions; attribute level to further specify these expressions; The last level annotates relations to extract information on how the aforementioned entities interact. I then discuss the topic of user privacy in data about health-related issues and the question of how to collect such data for research purposes without harming the person's privacy. I provide a prototype study of how users react when they are directly asked about their experiences with ADRs. The study reveals that most people do not mind describing their experiences if asked, but that data collection might suffer from too many questions in the questionnaire. Next, I analyze the results of a potential second way of collecting social media data: the synthetic generation of pseudo-tweets based on real Twitter messages. In the analysis, I focus on the challenges this approach entails and find, despite some preliminary cleaning, that there are still problems to be found in the translations, both with respect to the meaning of the text and the annotated labels. I, therefore, give anecdotal examples of what can go wrong during automatic translation, summarize the lessons learned, and present potential steps for improvements. Subsequently, I present experimental results for cross-lingual document classification with respect to ADRs in English and German. For this, I fine-tuned classification models on different dataset configurations first on English and then on German documents, complicated by the strong label imbalance of either language's dataset. I find that incorporating English training data helps in the classification of relevant documents in German, but that it is not enough to mitigate the natural imbalance of document labels efficiently. Nevertheless, the developed models seem promising and might be particularly useful for collecting more texts describing experiences about side effects to extend the current corpus and improve the detection of relevant documents for other languages. Next, I describe my participation in the n2c2 2022 shared task of medication detection which is then extended from English to German, French and Spanish using datasets from different sub-domains based on different annotation guidelines. I show that the multi- and cross-lingual transfer works well but also strongly depends on the annotation types and definitions. After that, I re-use the discussed models to show some preliminary results on the presented corpus, first only on medication detection and then across all the annotated entity types. I find that medication detection shows promising results, especially considering that the models were fine-tuned on data from another sub-domain and applied in a zero-shot fashion to the new data. Regarding the detection of other medical expressions, I find that the performance of the models strongly depends on the entity type and propose ways to handle this. Lastly, the presented work is summarized and future steps are discussed
Die in dieser Dissertation beschriebene Arbeit befasst sich mit der mehrsprachigen Erkennung und Extraktion von unerwünschten Arzneimittelwirkungen in biomedizinischen Texten, die von Laien verfasst wurden. Ich beschreibe die Erstellung eines neuen dreisprachigen Korpus (Deutsch, Französisch, Japanisch) mit Schwerpunkt auf Deutsch und Französisch, einschließlich der Entwicklung von Annotationsrichtlinien, die für alle Sprachen gelten und sich an nutzergenerierten Texten orientieren. Weiterhin dokumentiere ich den Annotationsprozess und gebe einen Überblick über den resultierenden Datensatz. Anschließend gehe ich auf den Schutz der Privatsphäre der Nutzer in Bezug auf Daten über Gesundheitsprobleme ein. Ich präsentiere einen Prototyp zu einer Studie darüber, wie Nutzer reagieren, wenn sie direkt nach ihren Erfahrungen mit Nebenwirkungen befragt werden. Die Studie zeigt, dass die meisten Menschen nichts dagegen haben, ihre Erfahrungen zu schildern, wenn sie um Erlaubnis gefragt werden. Allerdings kann die Datenerhebung darunter leiden, dass der Fragebogen zu viele Fragen enthält. Als nächstes analysiere ich die Ergebnisse einer zweiten potenziellen Methode zur Datenerhebung in sozialen Medien, der synthetischen Generierung von Pseudo-Tweets, die auf echten Twitter-Nachrichten basieren. In der Analyse konzentriere ich mich auf die Herausforderungen, die dieser Ansatz mit sich bringt, und zeige, dass trotz einer vorläufigen Bereinigung noch Probleme in den Übersetzungen zu finden sind, sowohl was die Bedeutung des Textes als auch die annotierten Tags betrifft. Ich gebe daher anekdotische Beispiele dafür, was bei einer maschinellen Übersetzung schiefgehen kann, fasse die gewonnenen Erkenntnisse zusammen und stelle potenzielle Verbesserungsmaßnahmen vor. Weiterhin präsentiere ich experimentelle Ergebnisse für die Klassifizierung mehrsprachiger Dokumente bezüglich medizinischer Nebenwirkungen im Englischen und Deutschen. Dazu wurden Klassifikationsmodelle an verschiedenen Datensatzkonfigurationen verfeinert (fine-tuning), zunächst an englischen und dann an deutschen Dokumenten. Dieser Ansatz wurde durch das starke Ungleichgewicht der Labels in den beiden Datensätzen verkompliziert. Die Ergebnisse zeigen, dass die Einarbeitung englischer Trainingsdaten bei der Klassifizierung relevanter deutscher Dokumente hilft, aber nicht ausreicht, um das natürliche Ungleichgewicht der Dokumentenklassen wirksam abzuschwächen. Dennoch scheinen die entwickelten Modelle vielversprechend zu sein und könnten besonders nützlich sein, um weitere Texte zu sammeln. Dieser wiederum können das aktuelle Korpus erweitern und damit die Erkennung relevanter Dokumente für andere Sprachen verbessern. Nachfolgend beschreibe ich die Teilnahme am n2c2 2022 Shared Task zur Erkennung von Medikamenten. Die Ansätze des Shared Task werden anschließend vom Englischen auf deutsche, französische und spanische Korpora ausgeweitet, indem Datensätze aus verschiedenen Teilbereichen verwendet werden, die auf unterschiedlichen Annotationsrichtlinien basieren. Ich zeige, dass die mehrsprachige Übertragung gut funktioniert, aber auch stark von den Annotationstypen und Definitionen abhängt. Im Anschluss verwende ich die besprochenen Modelle erneut, um einige vorläufige Ergebnisse für das vorgestellte Korpus zu zeigen, zunächst nur für die Erkennung von Medikamenten und dann für alle Arten von annotierten Entitäten. Die experimentellen Ergebnisse zeigen, dass die Medikamentenerkennung vielversprechende ist, insbesondere wenn man bedenkt, dass die Modelle an Daten aus einem anderen Teilbereich verfeinert und mit einem zeroshot Ansatz auf die neuen Daten angewendet wurden. In Bezug auf die Erkennung anderer medizinischer Ausdrücke stellt sich heraus,dass die Leistung der Modelle stark von der Art der Entität abhängt. Ich schlage deshalb Möglichkeiten vor, wie man dieses Problem in Zukunft angehen könnte

This thesis examines the phenomenon of feminicide in Ciudad Juarez, Mexico, and the representation of female victims in U.S. and Mexican mainstream media and performance activism. Specifically analyzing representations of maquiladora workers and feminicide victims in film, fashion and photography, this thesis explores the simultaneous fetishization and devaluation of border women in patriarchal society. By broadening the base of pressure for justice, via performance and internet activism, misogynist governments and policies can and will change.

L’objectif de ce mémoire et d’analyser et d’observer la traduction d’Esther Sermage du livre de Leif G.W Person Faller fritt som i en dröm publié en 2011 en France sous le titre de Comme dans un rêve. Nous nous sommes concentrée sur des méthodes que la traductrice utilise de façon récurrente, à savoir l’emprunt et l’équivalence, ainsi que sa volonté d’aliéner le plus possible la traduction française pour pouvoir donner à ses lecteurs une atmosphère des plus suédoises. Ainsi, nous avons sélectionné un nombre total de douze chapitres dans le livre où nous nous observons la traduction d’Esther Sermage et nous suivons les méthodes de Venuti, Berman, J.P Vinay, J. Darbelnet et d’autres. De plus, à la fin de notre mémoire, nous avons fait une étude de réception, analysant les avis des internautes français du livre Comme dans un rêve.
The aim of this thesis was to analysis Esther Sermage’s translation of Leif G.W Persson’s book Faller Fritt som I en dröm which was published in 2011 in France under the name of Comme dans un rêve. The analysis focused on the methods of translation that Esther Sermage uses in a recurrent way, as the equivalence and the borrowing methods, and on the will of the translator to foreign as much as possible the French translation to give to her readers a very Swedish atmosphere. By those means, we have selected a number of twelve chapters in the book where we observed Esther Sermage’s translation and we followed Venuti, Berman, J.P Vinay, J. Darbelnet’ and other’s methods and theories of translation. At the end of our paper, we will analyze how the french public received the book Comme dans un rêve and what they thought about it.

This essay discusses the differences in depiction of vampires between Stephenie Meyer’s Twilight (2005) and Bram Stoker’s Dracula (1897). By using examples from the novels, the essay exemplifies how genre, narration, and readership affect the description of vampires within the two novels. The essay bases its discussion on genre on the premise that the vampire genre is in fact a genre to itself, but one with a broad variation. Furthermore, the essay briefly discusses the shift within the vampire genre, where vampires during the last centuries have gone from dangerous and scary to appealing and romantic. A connection is made between the shift within the vampire genre and Anne Rice’s vampire fiction. The discussion on genre shows how the romance, fantasy, and horror genres affect the depiction of vampires.
Denna uppsats diskuterar hur vampyrer i verken Twilight (Meyer, 2005) och Dracula (Stoker, 1897) skildras på olika sätt. Skillnader i beskrivningarna illustreras med hjälp av exempel från de båda böckerna och berör genre, berättarperspektiv och läsarkrets. Diskussionen i uppsatsen baseras på att vampyrgenren är en egen genre med många olika beskrivningar av vampyren. Uppsatsen berör även förändringen i genren och lyfter kort hur vampyren från början tolkas som farlig och skrämmande för att sedan framstå som attraktiv och romantisk. En koppling görs också mellan förändringen i vampyrgenren och Anne Rices vampyrnoveller. Vidare i diskussionen kring genre berörs även hur genrerna romantik, fantasy och skräck påverkar skildringen av vampyrerna i de nämnda verken.

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Envisioning to study the mediatic discourse related to the individual / drug user, the role of the media in disseminating the discursive practices attributed to this public was investigated. In order to achieve this, the first step was to comprehend the historical process of drugs in humanity, its mechanism of criminalization and the journalistic language referring to drug addiction. It is understood that there is a discourse involving the "drug war", disseminated by the state and by the cultural industry, which depreciatingly labels the users of psychoactive substances. Therewith, mediatic discourse often directs itself to concrete ends of sale, turning into a domination instrument, focusing in culture commercialization. However, in this study, the hypothesis pointed out is that the way media discourses are represented run through the bias of prejudice and stigmatization, leading drug users to a fragmented reality behind the walls of society. This is a bibliographical and documentary research, that consists of a qualitative evaluation, ranging from 2010 to July of 2016, of two great circulation newspapers in the state of Goiás - O Popular and Diário da Manhã -, aiming to identify signals that surpass the individuals / drug users. It is also worth to mention that this study uses the Critical Theory of the Society to substantiate a critical reflection on journalistic language associated to drug users and how this can influence its individual constitution and how they are seen by society and culture. In the first chapter, the history of drugs and the National Drug Policy was investigated; the second chapter presents a discussion of the fundamentals of cultural industry and how media perceives the individuals / drug users; data collected in the newspapers O popular and Diário da Manhã are discussed in the third chapter. As a conclusion, it is possible to highlight that society still understands and sees drug users with stigmatization and prejudice. In sum, this study pretends to reveal the benefits of a look beyond in the social imaginary, when related to the stigmatized drug users, in order to provide preventive actions and develop an ethical record with these individuals / drug users, without detracting or depreciating them.
Com o estudo do discurso midiático em relação ao indivíduo usuário de drogas, investigou-se o papel da mídia na disseminação das práticas discursivas atribuídas a esse público. Para isso, procurou-se, inicialmente, compreender o processo histórico das drogas na humanidade, o mecanismo de criminalização e a linguagem jornalística sobre a temática da drogadição. Entende-se que existe um discurso de “guerra às drogas”, vinculado pelo Estado e pela indústria cultural, que rotula o usuário de substâncias psicoativas depreciativamente. Com isso, o discurso midiático muitas vezes se volta para fins concretos de venda, tornando-se um instrumento de dominação, em que o foco é a mercantilização da cultura. Contudo, a hipótese apontada neste estudo é a de que os modos de representação dos discursos midiáticos perpassam pelo preconceito e pela estigmatização, colocando os usuários de drogas em uma realidade fragmentada e atrás dos muros da sociedade. Esta pesquisa é de cunho bibliográfico e documental e consiste em uma avaliação qualitativa, tendo sido realizada de 2010 a julho de 2016, em dois jornais de grande circulação no estado de Goiás – O Popular e Diário da Manhã –, à procura de identificar as marcas que sobrepujam os indivíduos usuários de drogas. Destaca-se, ainda, que o trabalho apropria-se da Teoria Crítica da Sociedade para fundamentar uma reflexão crítica sobre a linguagem jornalística com relação ao usuário de drogas e como isso pode influenciar na sua constituição como indivíduo e na forma como a sociedade e a cultura o veem. Buscou-se investigar, no primeiro capítulo, o percurso histórico das drogas e a Política Nacional de Drogas; o segundo capítulo perpassa por uma discussão sobre os fundamentos da indústria cultural e como a mídia compreende os indivíduos usuários de drogas; o terceiro capítulo discute os dados coletados nos jornais O popular e Diário da Manhã; e, à guisa da conclusão, mostrar-se-á que a sociedade ainda compreende e vê o usuário com as marcas da estigmatização e do preconceito. Em suma, espera-se que este estudo descortine subsídios de um olhar para além de um ser nefasto e estigmatizado no imaginário social, na tentativa de propiciar uma ação preventiva e desenvolver um registro ético com esses indivíduos usuários de drogas, sem deturpá-los ou reduzi-los.

This project analyzes three examples of testimonial literature written by favela residents in Brazil to demonstrate the extent to which these accounts contest or confirm the popular news media's violent representation of favelas and their inhabitants. The literary works Quatrocentos contra um: Uma história do Comando Vermelho (1991) by William da Silva Lima and Capão pecado (2000) by Ferréz and the documentary Notícias de uma guerra particular (1999) present an insider's perspective of the violence that takes place in the favela and thus can reveal the factors that contribute to it. Through these explanations, readers and viewers become aware of the generally unheard side of the story of the repressed and ignored poor class. Lima's voice in Quatrocentos contra um serves to explain the way that crime was organized as a means of survival to combat the repression and abuse of the government, and in Capão pecado Ferréz demonstrates the difficulty that favela residents who are not involved in drug trafficking have in avoiding the violence that surrounds them because they do not have equal opportunity for education and employment. He suggests a non-violent rebellion through artistic means to build a positive image of favela inhabitants, both inside and outside of the poor community. The documentary Notícias de uma guerra particular directed by João Moreira Salles and Kátia Lund presents information that places much of the blame for violence on the lack of social structure that would integrate the poor, and more importantly allows for honest, hardworking favela residents to share their experience of trying to make a living and avoid illegal activity while suffering from the stereotype that all who live in poor communities are involved in violent activity. Together these works constitute an attempt for the violence of the favelas to be explained through the voice of favela residents themselves.

Thesis (Ph. D.)--Georgia State University, 2009.
Title from title page (Digital Archive@GSU, viewed July 22, 2010) Sheri Joseph, committee chair; John Holman, Josh Russell, committee members. Includes bibliographical references (p. 38).

Consumers of digital contents are empowered with numerous technologies allowing them to produce perfect copies of these contents and distribute them around the world with little or no cost. To prevent illegal copying and distribution, a technology called Digital Rights Management (DRM) is developed. With this technology, consumers are allowed to access digital contents only if they have purchased the corresponding licenses from license issuers. The problem, however, is that those consumers are not allowed to resell their own licenses- a restriction that goes against the first-sale doctrine. Enabling a consumer to buy a digital license directly from another consumer and allowing the two consumers to fairly exchange the license for a payment are still an open issue in DRM research area. This thesis investigates existing security solutions for achieving digital license reselling and analyses their strengths and weaknesses. The thesis then proposes a novel Reselling Deal Signing (RDS) protocol to achieve fairness in a license reselling. The idea of the protocol is to integrate the features of the concurrent signature scheme with functionalities of a License Issuer (LI). The security properties of this protocol is informally analysed and then formally verified using ATL logic and the model checker MOCHA. To assess its performance, a prototype of the RDS protocol has been developed and a comparison with related protocols has been conducted. The thesis also introduces two novel digital tokens a Reselling Permission (RP) token and a Multiple Reselling Permission (MRP) token. The RP and MRP tokens are used to show whether a given license is single and multiple resalable, respectively. Moreover, the thesis proposes two novel methods supporting fair and secure digital license reselling. The first method is the Reselling Deal (RD) method which allows a license to be resold once. This method makes use of the existing distribution infrastructure, RP, License Revocation List (LRL), and three protocols: RDS protocol RD Activation (RDA) protocol, and RD Completion (RDC) protocol. The second method is a Multiple License Reselling (MLR) method enabling one license to be resold N times by N consumers. The thesis presents two variants of the MLR method: RRP-MR (Repeated RP-based Multi-Reselling) and HC-MR (Hash Chain-based Multi-Reselling). The RRP-MR method is designed such that a buyer can choose to either continue or stop a multi-reselling of a license. Like the RD method, the RRP-MR method makes use of RP, LI, LRL, and the RDS, RDA, and RDC protocols to achieve fair and secure reselling. The HC-MR method allows multiple resellings while keeping the overhead on LI at a minimum level and enable a buyer to check how many times a license can be further resold. To do so, the HC-MR utilises MRP and the hash chain cryptographic primitive along with LRL, LI and the RDS, RDA and RDC protocols. The analysis and the evaluation of these three methods have been conducted. While supporting the license reselling, the two methods are designed to prevent a reseller from (1) continuing using a resold license, (2) reselling a non-resalable license, and (3) reselling one license a unauthorised number of times. In addition, they enable content owners of resold contents to trace a buyer who has violated any of the usage rights of a license bought from a reseller. Moreover, the methods enable a buyer to verify whether a license he is about to buy is legitimate for re-sale. Furthermore, the two methods support market power where a reseller can maximise his profit and a buyer can minimise his cost in a reselling process. In comparison with related works, our solution does not make use of any trusted hardware device, thus it is more cost-effective, while satisfying the interests of both resellers and buyers, and protecting the content owner's rights.

The work of this thesis was focused on the development of high-performance algorithms for a new generation of molecular descriptors, with many advantages with respect to its predecessors, suitable for diverse applications in the field of drug design, as well as its implementation in commercial grade scientific software (Pentacle). As a first step, we developed a new algorithm (AMANDA) for discretizing molecular interaction fields which allows extracting from them the most interesting regions in an efficient way. This algorithm was incorporated into a new generation of alignmentindependent molecular descriptors, named GRIND-2. The computing speed and efficiency of the new algorithm allow the application of these descriptors in virtual screening. In addition, we developed a new alignment-independent encoding algorithm (CLACC) producing quantitative structure-activity relationship models which have better predictive ability and are easier to interpret than those obtained with other methods.
El trabajo que se presenta en esta tesis se ha centrado en el desarrollo de algoritmos de altas prestaciones para la obtención de una nueva generación de descriptores moleculares, con numerosas ventajas con respecto a sus predecesores, adecuados para diversas aplicaciones en el área del diseño de fármacos, y en su implementación en un programa científico de calidad comercial (Pentacle). Inicialmente se desarrolló un nuevo algoritmo de discretización de campos de interacción molecular (AMANDA) que permite extraer eficientemente las regiones de máximo interés. Este algoritmo fue incorporado en una nueva generación de descriptores moleculares independientes del alineamiento, denominados GRIND-2. La rapidez y eficiencia del nuevo algoritmo permitieron aplicar estos descriptores en cribados virtuales. Por último, se puso a punto un nuevo algoritmo de codificación independiente de alineamiento (CLACC) que permite obtener modelos cuantitativos de relación estructura-actividad con mejor capacidad predictiva y mucho más fáciles de interpretar que los obtenidos con otros métodos.

This dissertation explores how written discourses of Drum editors' and readers' letters linguistically construct social identities of the Drum audience, and how this identity construction is intimately linked with socio-historical, socio-cultural and socio-political contexts in which Drum appears in 1951 and 2001. Basically, this study is a contrastive analysis of the audience construction at two significant dates in the life of a South African publication, Drum magazine: March 1951, when the magazine was first published, and 7 June 2001, fifty years later when the magazine is read in a vastly changed socio-politico-cultural context. Data collection was based on the "Readers' Page" in two copies of Drum, one published in March 1951 and the other in 7 June 2001. In each copy of the magazine, the focus is on the editor's letter which asks for the readers' contributions and gives recommendations on the types of letters he is hoping to attract, and one reader's letter from each of the same chosen copies of Drum which the editor publishes. The cover pages of both copies of Drum are used to investigate whether they foreground or reinforce the images of Drum readers. Another set of data comes from an unstructured interview of the current Drum magazine editor. Findings in this study indicate that the ideal Drum audience in 1951 is the African middle class scholar who is a good writer, whereas in 2001, good quality writing is compromised for an advertising community of consumers. In addition, the black educated, urban Drum audience in 1951 see themselves as having power to resist the education system which is characterised by racial segregation. In 2001, the young people regard the attainment of higher education in institutions of higher learning as valuable for black economic empowerment. Educators/therefore, need to teach learners the skills of reading a text critically, so that the learners are able to identify ways in which language choices channel their interpretation, and also the ways in which texts are linked to their socio-historical contexts.
Thesis (M.A.)-University of Natal, Durban, 2002.

Indiana University-Purdue University Indianapolis (IUPUI)
Polypharmacy is a general clinical practice, there is a high chance that multiple administered drugs will interfere with each other, such phenomenon is called drug-drug interaction (DDI). DDI occurs when drugs administered change each other's pharmacokinetic (PK) or pharmacodynamic (PD) response. DDIs in many ways affect the overall effectiveness of the drug or at some times pose a risk of serious side effects to the patients thus, it becomes very challenging to for the successful drug development and clinical patient care. Biomedical literature is rich source for in-vitro and in-vivo DDI reports and there is growing need to automated methods to extract the DDI related information from unstructured text. In this work we present an ontology (PK ontology), which defines annotation guidelines for annotation of PK DDI studies. Using the ontology we have put together a corpora of PK DDI studies, which serves as excellent resource for training machine learning, based DDI extraction algorithms. Finally we demonstrate the use of PK ontology and corpora for extracting PK DDIs from biomedical literature using machine learning algorithms.

This thesis investigated the memory skills of young adults with and without language and learning disabilities (LLD) using the Deese-Roediger-McDermott word recall paradigm (Roediger & McDermott, 1995). Three types of word lists were presented: semantic lists consisted of words that are related to a non-presented critical item (CI) (e.g., bad) in meaning (good, rotten, harmful, worse); phonological lists included words related to the CI in sound (e.g., had, lad, bat, bag); and hybrid lists included words related to the CI in both meaning and sound (e.g., good, lad, rotten, bat). Individuals with diagnoses of LLD were classified as "true LLD" or "compensated LLD" based on language test scores and a discriminating composite score, while those without LLD were considered the "typical language" (TL) group. Hypotheses were made regarding veridical recall and memory intrusions, including intrusions of the non-presented critical item (CI). For veridical recall, the compensated LLD and TL groups were expected to have higher recall accuracy than the true LLD group. As for CI intrusions, two possible outcomes were considered: the true LLD group may recall more CIs due to inability to discriminate between presented and non-presented words (Kirchner & Klatzky, 1985); or they may recall fewer CIs due to difficulties forming traces of the gist of the word list (Weekes et al., 2005). Data from 30 participants (ages 18 to 25) -- 12 true LLD, 8 compensated LLD, and 10 TL -- were included in this thesis. Results indicated that the true LLD group showed a non-significant tendency to have lower recall accuracy scores than the other two groups, and a higher number of CI intrusions. List-type also affected accuracy and CI intrusions, as semantically-related lists increased recall accuracy and hybrid semantic-phonological lists increased CI intrusions. Possible conclusions from these data are presented along with recommendations for future research.
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This report investigated the various types of memory intrusion errors of adults with language learning disability (LLD) in comparison to age- and gender-matched typically developing (TD) adults using lists that are specifically designed to induce memory intrusions adapted from Roediger and McDermott (1995) and modified by Watson et al. (2001; 2003). The 28 participants between the ages of 18:9 - 24:3 listened to pre-recorded lists of twelve words that converged on a critical lure either semantically, phonologically, or dually with a hybrid list. This report tested the hypotheses that 1) hybrid lists would be more likely to induce memory intrusions of the critical lure than either semantic or phonological lists for each group; 2) adults with LLD would demonstrate more intrusion errors than their TD counterparts; 3) the error profiles of the LLD and TD groups should be largely similar; however, the adults with LLD might show deficits in extracting the semantic gist of word lists in light of such patterns in children with specific language impairment (Sheng & McGregor, 2010a). Results showed that the hybrid lists induced the greatest number of critical lure intrusions producing a super-additive effect. Contrary to our hypothesis, the LLD group did not produce more memory intrusions than the TD group. The fact that the two groups performed similarly on all standardized measures suggests that the participants with LLD may have outgrown their disability. Results also revealed that interference and intrusions increased when there was an increase in phonological similarity among words for both groups. Lastly, our preliminary evidence suggests that adults with LLD are not as efficient as their TD counterparts at extracting the gist of semantically-related words. The inclusion of a greater number of participants may provide stronger support for the hypothesis that lexical-semantic organization is less efficient in young adults with LLD.
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碩士
元智大學
資訊管理學系
94
The molecule simulation can be used to help to build the molecule mode, predict, and explain physical character or chemical character. Docking simulation, moreover, can be used to move or help medicine to develop fast, and to observe the interaction between the ligand and the biomacromolecuar. In this thesis, the molecule docking method will be stated, including Rigid-body docking、Flex-rigid docking and Full-flexible docking. We will also use Scripting Language BCL (Biosym Command Language) to create automatic processes and to predict the interaction of ligand with biomacromolecular targets on an infrastructure of Insight II. There will be two approaches mentioned in this thesis – ZDOCK and MolD (Molecule Dynamics). We will use ZDOCK first to search and to compare conformational space, and to find a probable position. Then, we will use MolD (Molecule Dynamics) to calculate the part energy and RMSD of this probable position.

abstract: Proliferation of social media websites and discussion forums in the last decade has resulted in social media mining emerging as an effective mechanism to extract consumer patterns. Most research on social media and pharmacovigilance have concentrated on Adverse Drug Reaction (ADR) identification. Such methods employ a step of drug search followed by classification of the associated text as consisting an ADR or not. Although this method works efficiently for ADR classifications, if ADR evidence is present in users posts over time, drug mentions fail to capture such ADRs. It also fails to record additional user information which may provide an opportunity to perform an in-depth analysis for lifestyle habits and possible reasons for any medical problems. Pre-market clinical trials for drugs generally do not include pregnant women, and so their effects on pregnancy outcomes are not discovered early. This thesis presents a thorough, alternative strategy for assessing the safety profiles of drugs during pregnancy by utilizing user timelines from social media. I explore the use of a variety of state-of-the-art social media mining techniques, including rule-based and machine learning techniques, to identify pregnant women, monitor their drug usage patterns, categorize their birth outcomes, and attempt to discover associations between drugs and bad birth outcomes. The technique used models user timelines as longitudinal patient networks, which provide us with a variety of key information about pregnancy, drug usage, and post- birth reactions. I evaluate the distinct parts of the pipeline separately, validating the usefulness of each step. The approach to use user timelines in this fashion has produced very encouraging results, and can be employed for a range of other important tasks where users/patients are required to be followed over time to derive population-based measures.
Dissertation/Thesis
Masters Thesis Computer Science 2016

This thesis is an expansion of an ongoing examination of gist and verbatim memory in young adults with language-learning disabilities (LLD) using the DRM paradigm (Deese, 1959; Roediger & McDermott, 1995). This study uses lists based on situation semantic features in addition to DRM lists based on backwards associative strength (BAS), which were categorized as strong-, mid-, and low-BAS (Stadler, Roediger, & McDermott, 1999). Items in each list (e.g., bacon, toast, cereal, muffin) related to a non-presented word (e.g., breakfast): the critical lure (CL). BAS is a measure of the likelihood that a list item will elicit the CL. Thirty young adults participated in this study and were divided into three groups: true LLD, compensated LLD, and typically developing (TD). Participants listened to word lists and verbally recalled the words they remembered hearing. Accurate recall was an indicator of verbatim memory; CL recall was an indicator of gist memory. The true LLD group recalled CL at a significantly higher rate than the other groups in the case of the situation lists; additionally, the compensated LLD group recalled CL for the low-BAS lists at a significantly higher rate than the other groups. These findings suggest that the LLD participants may process semantic information differently or may rely on gist memory to a greater extent than the TD controls. Results also indicated list type differences for both verbatim and gist recalls, supporting the effects of both semantic features and BAS together with other factors.
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