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The effect of the two probiotic strains and policosanol combination on metabolic parameters in obese women
No full textГојазност се карактерише дисбиозом гастроинтестиналне микробиоте, те се примена пробиотика сматра обећавајућим новим приступом у третману овог обољења. Циљ наше студије је био испитати утицај нове пробиотске формулације на метаболичке, инфламаторне, епигенетске и хематолошке параметре, хормоне који утичу на апетит, као и имуномодулаторни ефекат пробиотика. У студији је коришћена комбинација пробиотика и октакозанола, једињења са хипохолестеролемијским ефектом. Истраживање је трајало 12 недеља, а спроведено је као рандомизована, двоструко слепа, плацебо-контролисана студија, у којој су учествовале испитанице са ИТМ = 30,0 – 39,9 kg m−2. Интервентна група (N = 25) је пила по 1 капсулу дневно у којој се налазило 7 x 1010 CFU Lactiplantibacillus plantarum 299v, 5 x 109 CFU Saccharomyces boulardii и 40 mg oктакозанола, док је контролна група (N = 23) пила плацебо. Примена пробиотске формулације након 12 недеља је резултовала значајно нижим концентрацијама проинфламаторних параметара, док су концентрације грелина и HDL-холестерола биле значајно више. Уочен је и регулаторни ефекат на експресију miRNA и mRNA, епигенетских маркера значајних у процесима метаболизма, инфламације и адипогенезе. Показано је да пробиотска формулација испољава позитиван ефекат на величину и облик еритроцита, као и на морфолошке карактеристике тромбоцита. Утврђен је имуномодулаторни ефекат који се огледа у смањеном проценту CD3+CD8+ и CD4+CD45RO+ Т-ћелија, као и у повећаним концентрацијама TGF-β1 након 12 недеља интервенције. Значајне промене у вредностима ИТМ између група нису забележене. Потенцијални утицај на нивое триглицерида, глукозе и инсулина захтева додатна истраживања, како би се нова дијетарна интервенција сматрала корисном адјувантном терапијом и ефикасном стратегијом у третману гојазности.Obesity is characterized by dysbiosis of the gastrointestinal microbiota, and the use of probiotics is considered a promising new approach in the treatment of this disease. The aim of this study was to examine the impact of a new probiotic formulation on metabolic, inflammatory, epigenetic and hematological parameters, appetite-related hormones, as well as the immunomodulatory effect of probiotics. Combination of probiotics and a hypocholesterolemic compound, octacosanol, was used in this study. The research lasted 12 weeks, and was conducted as a randomized, double-blind, placebo controlled study, where participated women with BMI = 30.0 - 39.9 kg m−2. Daily oral supplementation included 7 × 1010 CFU of Lactiplantibacillus plantarum 299v, 5 × 109 CFU of Saccharomyces boulardii, and 40 mg of octacosanol or placebo. After 12 weeks of the intervention significantly lower concentrations of pro-inflammatory parameters were observed, while ghrelin and HDL-cholesterol concentrations were significantly higher. A regulatory effect on the miRNA and mRNA expression, epigenetic markers important in the processes of metabolism, inflammation and adipogenesis, was also observed. It has been shown that the probiotic formulation exerts a positive effect on the size and shape of erythrocytes, as well as on the morphological characteristics of platelets. Immunomodulatory effect was was confirmed by the reduced percentage of CD3+CD8+ and CD4+CD45RO+ T-cells, as well as in increased TGF-β1 concentrations. No significant changes in BMI values between groups were noted. Potential effect on triglyceride, glucose and insulin levels requires additional research, in order to consider new dietary intervention as a useful adjuvant therapy and an effective strategy in the obesity treatment
The influence of the type and ratio of hydrophilic polymers on the pharmaceutical-technological and biopharmaceutical characteristics of solid dispersions with clopidogrel hydrogen sulfate
No full textRazvoj formulacija lekova je poslednjih godina postao posebno izazovan zbog novih aktivnih supstanci koje imaju zahtevna fizičkohemijska svojstva, zbog potrebe farmaceutskih kompanija da se lekovi što pre plasiraju na tržište, kao i zbog sve strožijih zahteva regulatornih tela. Preko 40% aktivnih supstanci, koje se koriste u terapiji i preko 60% onih koji se nalaze u nekoj od faza istraživanja, spada u grupu slabo rastvorljivih aktivnih supstanci. Formulacija čvrstih disperzija je jedan od aktuelnih pristupa za povećanje rastvorljivosti i brzine rastvaranja slabo rastvorljivih aktivnih supstanci. Klopidogrel je inhibitor aktivacije i agregacije trombocita. Najčešće se koristi u obliku soli, klopidogrel-hidrogensulfata, koja ima nisku i pH-zavisnu rastvorljivost, što ograničava njegovu bioraspoloživost i terapijsku efikasnost. Klopidogrel je pro-lek, samo oko 2% primenjene doze klopidogrela se metaboliše u aktivni oblik i dospeva u sistemsku cirkulaciju, a uz to ima i izraženu interindividualnu varijabilnost. Iz navedenih razloga, cilj istrаživаnjа ove doktorske disertаcije bila je formulаcijа, izrаdа i fаrmаceutsko-tehnološkа i biofаrmаceutskа kаrаkterizаcijа čvrstih disperzijа sа slаbo rаstvorljivom model аktivnom supstаncom, klopidogrel-hidrogensulfаtom, u cilju povećаnjа brzine rаstvаrаnjа nаvedene аktivne supstаnce.
U prvoj fazi eksperimentalnog rada formulisano je i izrađeno dvadeset čvrstih disperzija sa različitim hidrofilnim polimerima (kopovidon, makrogol 6000, poloksamer 407 i povidon K30) i različitim odnosima aktivna supstanca/polimer (1:1, 1;2; 1:3; 1:5 i 1:9), u cilju povećanja brzine rastvaranja aktivne supstance. Rezultati in vitro ispitivanja brzine rastvaranja su pokazali da vrsta i udeo hidrofilnog polimera imaju bitnu ulogu u povećanju brzine rastvaranja klopidogrel-hidrogensulfata. Najveći procenat klopidogrel-hidrogensulfata (96,38%, nakon 60 minuta) se rastvorio iz čvrste disperzije sa poloksamerom 407, pri udelu aktivna supstanca/polimer 1:9.
U drugoj fazi istraživanja sprovedena je karakterizacija odabranih čvrstih disperzija primenom metoda diferencijalne skenirajuće kalorimetrije (DSC), infracrvene spektrofotometrije sa Furijeovom transformacijom (FT-IR) i difrakcije X-zraka na prašku (PXRD), kao i određivanje sadržaja klopidogrela. U svim ispitivanim uzorcima potvrđeno je prisustvo klopidogrel-hidrogensulfata u amorfnom obliku, a sadržaj klopidogrela je bio u dozvoljenim granicama odstupanja (± 5%). Rezultati ponovljenih ispitivanja, nakon 12 meseci skladištenja uzoraka pod kontrolisanim uslovima (25 ± 2 °C i vlažnost vazduha 60 ± 5%), ukazali su na njihovu dobru stabilnost. Međutim, rezultati ispitivanja in vitro brzine rastvaranja klopidogrel-hidrogensulfata iz čvrstih disperzija sa makrogolom 6000 su pokazali da je nakon 12 meseci došlo do velikog smanjenja količine rastvorenog klopidogrel-hidrogensulfata. Ovi rezultati su ukazali na neprihvatljivu stabilnost, odnosno na neprihvatljiv kvalitet čvrstih disperzija sa makrogolom 6000, pri odnosima aktivna supstanca/polimer 1:5 i 1:9.
U trećoj fazi istraživanja ispitivane su karakteristike čvrstih disperzija prihvatljive stabilnosti (sa kopovidonom i poloksamerom 407, pri udelima aktivna supstanca/polimer 1:5 i 1:9) značajne za njihovu dalju obradu u finalni farmaceutski oblik (tablete i kapsule). Dobijeni rezultati ispitivanja veličine i raspodele veličina čestica, stvarne, nasipne i tapkane gustine, određivanja protočnosti, kompresibilnosti, poroziteta, sadržaja vlage i reoloških parametara su ukazali da ispitivane čvrste disperzije imaju prihvatljive osobine za obradu u finalni farmaceutski oblik.
U četvrtoj fazi istraživanja, primenom kompjuterskog programa GastroPlus™, uspešno je razvijen i validiran klopidogrel-specifični, fiziološki zasnovan biofarmaceutski (PBBM) model, koji na odgovarajući način opisuje apsorpciju i distribuciju klopidogrela nakon intravenske i peroralne primene. Izgrađeni PBBM model je korišćen za ispitivanje uticaja vrste i udela hidrofilnih polimera na apsorpciju, distribuciju i posledično, bioraspoloživost aktivne supstance...The development of drug formulations has become a particular challenge in recent years, as the physico-chemical properties of new active pharmaceutical ingredients are becoming increasingly complex, the pharmaceutical industry is demanding a rapid market launch and regulatory requirements are becoming ever stricter. More than 40 % of marketed active pharmaceutical ingredients and over 60 % of drug candidates in development belong to the class of poorly soluble substances. The formulation of solid dispersions is one of the current approaches to increasing the solubility and dissolution rate of poorly soluble active substances. Clopidogrel is an inhibitor of platelet activation and aggregation. It is most commonly used in the form of a salt, clopidogrel hydrogen sulfate, which has a low and pH-dependent solubility, limiting its bioavailability and therapeutic efficacy. Clopidogrel is a pro-drug, only about 2% of the clopidogrel dose administered is converted to an active form and enters the systemic circulation, and there is marked inter-individual variability. For these reasons, the research objective of this dissertation was the formulation, preparation and pharmaceutical-technological and biopharmaceutical characterization of solid dispersions with a poorly soluble model drug, clopidogrel hydrogen sulfate, in order to increase the dissolution rate of the listed active substances.
In the first phase of the experimental work, twenty solid dispersions were formulated and prepared with different hydrophilic polymers (copovidone, macrogol 6000, poloxamer 407 and povidone K30) and different drug/polymer ratios (1:1, 1;2; 1:3; 1:5 and 1:9) to increase the dissolution rate of the drug. The results of the in vitro dissolution rate test showed that the type and ratio of hydrophilic polymer play an important role in increasing the dissolution rate of clopidogrel hydrogen sulfate. The highest percentage of clopidogrel hydrogen sulfate (96.38%, after 60 minutes) was dissolved from the solid dispersion with poloxamer 407 at a drug/polymer ratio of 1:9.
In the second phase of the study, the characterization of the selected solid dispersions was carried out using the methods of differential scanning calorimetry (DSC), Fourier transform infrared spectrophotometry (FT-IR) and powder X-ray diffraction (PXRD), as well as the determination of the clopidogrel content. The presence of clopidogrel hydrogen sulfate in amorphous form was confirmed in all samples analysed, and the clopidogrel content was within the acceptable limits (± 5%). The results of repeated tests after 12 months of storage of the samples under controlled conditions (25 ± 2 °C and 60 ± 5 % RH) indicated their good stability. However, the results of testing the in vitro dissolution rate of clopidogrel hydrogen sulfate from solid dispersions with macrogol 6000 showed that there was a sharp decrease in the amount of dissolved clopidogrel hydrogen sulfate after 12 months. These results indicate an unacceptable stability, i.e. an unacceptable quality of the solid dispersions with macrogol 6000 at drug/polymer ratios of 1:5 and 1:9.
In the third phase of the research, the characteristics of solid dispersions with acceptable stability (with copovidone and poloxamer 407, at a 1:5 and 1:9 drug/polymer ratio) were studied, which are important for further processing into the final pharmaceutical form (tablets and capsules). The results of testing the particle size and distribution of particle size, true density, bulk and tapped density, determination of flowability, compressibility, porosity, moisture content and rheological parameters showed that the solid dispersions tested had acceptable properties for processing into the final dosage form.
In the fourth phase of the research, a clopidogrel-specific physiologically based biopharmaceutical model (PBBM) was successfully developed and validated using GastroPlus™ software. The model adequately described the absorption and distribution of clopidogrel after both intravenous and oral
administration..
ǂThe ǂ assumptions of correctness in epistemic democracy
No full textCilj ovog istraživanja je ispitivanje pretpostavke o postojanju razlike između ispravnih i neispravnih političkih odluka, na kojoj počiva epistemička teorija demokratije. Jedan od glavnih mehanizama kojim ova teorija dokazuje da su grupne odluke bolje od odluka koje bi donosili pojedinci je Kondorseova teorema porote, matematički model kojim se utvrđuje da su grupne odluke gotovo nepogrešive.
U istraživanju se, korišćenjem kritičko-evalutivnog metoda, pokazuje da je jedna od sastavnih pretpostavki teoreme porote – da se odlučivanje vrši između samo dve opcije – posebno problematična za epistemičku teoriju, zbog čega je potrebno pronaći adekvatan način da se ona odbaci, a da se pritom ne naruši osnovni rezultat teoreme.
Korišćenjem istorijsko-interpretativnog metoda, pokazuje se da Kondorseova teorema porote predstavlja deo Kondorseove teorije glasanja, koja sadrži dodatne elemente koji se uvode sa ciljem prevazilaženja pomenutog nedostatka. Tvrdi se da epistemička teorija demokratije treba da prihvati modifikaciju kojom se teorema porote proširuje na odlučivanje između mnoštva opcija. Takva modifikacija, međutim, dovodi u pitanju inicijalnu pretpostavku o postojanju razlike između ispravnih i neispravnih političkih odluka.
Korišćenjem metoda pojmovne analize, pokazuje se da se epistemička teorija suočava sa dva problema. Prvi problem se tiče nedostatka kriterijuma za razlikovanje ispravnih i neispravnih opcija pri demokratskom odlučivanju, a drugi problem nedostatka garancija da će ispravne opcije biti deo skupa opcija između kojih se vrši izbor. Utvrđuje se da izvor ova dva problema leži u načinima na koji se upotrebljava pojam „ispravnosti“ u kontekstu političkog odlučivanja. U završnom delu istraživanja se predlaže rešenje kojim se istovremeno odgovara na oba problema.The aim of this research is to examine the assumption underlying the epistemic theory of democracy, which holds that there is a distinction between correct and incorrect political decisions. One of the main mechanisms by which this theory demonstrates that group decisions are superior to those made by individuals is Condorcet's jury theorem, a mathematical model that establishes the near-infallibility of group decisions.
This research, using a critical-evaluative method, shows that one of the core assumptions of the jury theorem – that decisions are made between two options only – is particularly problematic for the epistemic theory. Therefore, it is necessary to find an adequate way to discard this assumption without undermining the theorem’s fundamental result.
Using a historical-interpretive method, it is shown that Condorcet's jury theorem is part of Condorcet's theory of voting, which includes additional elements aimed at overcoming the aforementioned limitation. It is argued that the epistemic theory of democracy should accept a modification that extends the jury theorem to decision-making among multiple options. However, such a modification calls into question the initial assumption about the existence of a distinction between correct and incorrect political decisions.
Through conceptual analysis, it is shown that the epistemic theory faces two problems. The first concerns the lack of criteria for distinguishing correct from incorrect options in democratic decision-making, and the second concerns the lack of guarantees that correct options will be among the set of options from which choices are made. It is established that the source of these two problems lies in the ways in which the concept of “correctness” is applied in the context of political decision-making. In the concluding part of the research, a solution is proposed that addresses both problems simultaneously
Metаllomics of benign аdrenаl glаnd diseаses
No full textOvа disertаcijа je imаlа zа cilj dа pruži uvid u koncentrаcije kljuĉnih mikro- (Mn, Co, Cu,
Zn, Аs, Se, Cd, Pb, U) i mаkroelemenаtа (Nа, K, Mg, Cа) u uzorcimа zdrаvog tkivа nаdbubregа i
uzorаkа pаtolo ki izmenjenih tkivа osobа sа dijаgnostikovаnim аdrenаlnim аdenomimа i
feohromocitomimа. Rezultаti аnаlize аdrenаlnih tkivа upotpunjeni su аnаlizom uzorаkа pune krvi, u
cilju detаljnijeg uvidа u stаtus ispitivаnih elemenаtа.
Uzorci zdrаvog аdrenаlnog tkivа (ZАT) imаli su mаnje Cu, Mn, Se, Zn, K, Mg i vi e Pb u
odnosu nа аdenomаtozno аdrenаlno tkivo (ААT), dok su suprotni rezultаti dobijeni аnаlizom pune
krvi. U odnosu nа uzorke tkivа feohromocitomа (eng. pheochromocytomа, PCC), u ZАT su uoĉene
mаnje koncentrаcije Zn, Se, Nа, K i Mg i veće Mn, Co, Pb i Аs. Kontrolnа krv imаlа je veće
koncentrаcije Mn, Cu, Zn, Se i Mg i mаnje Nа, K i Cа u odnosu nа krv PCC pаcijenаtа.
U uzorcimа ZАT uoĉene su veće kon entrаcije Ni, Nа i K i mаnje Zn, Se, Cd, Th i Mg u
odnosu nа uzorke tkivа obolelih od Ku ingovog sindromа (eng. Cushing´s syndrome tissue – CST).
Krv kontrolne grupe imаlа je mаnje koncentrаcije Mn, Ni, Аs i K, kаo i vi i Co, Cu, Se, Pb, Nа i Cа
u odnosu nа uzorke pаcijenаtа obolelih od Ku ingovog sindromа.
Uporednom аnаlizom uzorаkа zdrаvih i pаtolo ki izmenjenih tkivа uoĉаvа se većа
zаstupljenost Se, Zn, K i mаnjа Ni i Mg u svim pаtolo ki izmenjenim аdrenаlnim tkivimа: ААT,
PCC i CST. TаkoĊe, Cu, Se, Ni, Аs, K, Cа i Nа istаkli su se u rаzdvаjаnju kontrolnih uzorаkа krvi
od pаcijenаtа svih ispitivаnih pаtolo kih stаnjа.
Prikаzаni rezultаti ukаzuju nа potencijаlnu ulogu ispitivаnih elemenаtа u pаtofiziolo kim
procesimа nаdbubregа. UtvrĊene promene u kon entrаcijаmа elemenаtа mogle bi dа pomognu u
rаsvetljаvаnju pаtogeneze ispitivаnih nаdbubrežnih oboljenjа i dаju znаĉаj budućim istrаživаnjimа
metаlomike nаdbubrežnih žlezdа.This dissertаtion аimed to provide insight into the concentrаtions of key micro- (Mn, Co,
Cu, Zn, Аs, Se, Cd, Pb, U) аnd mаcro-elements (Nа, K, Mg, Cа) in heаlthy аdrenаl tissue sаmples
аnd sаmples of pаthologicаlly chаnged tissues of persons diаgnosed with аdrenаl аdenomаs аnd
pheochromocytomаs. The results of the аnаlysis of аdrenаl tissues were completed with the аnаlysis
of whole blood sаmples, in order to gаin а more detаiled insight into the stаtus of the exаmined
elements.
Heаlthy аdrenаl tissue (HАT) sаmples hаd less Cu, Mn, Se, Zn, K, Mg аnd more Pb
compаred to аdenomаtous аdrenаl tissue (ААT), while the opposite results were obtаined by whole
blood аnаlysis. In relаtion to pheochromocytomа tissue sаmples (eng. pheochromocytomа, PCC),
lower concentrаtions of Zn, Se, Nа, K аnd Mg аnd higher concentrаtions of Mn, Co, Pb аnd Аs
were observed in ZАT. Control blood hаd higher concentrаtions of Mn, Cu, Zn, Se, аnd Mg аnd
less Nа, K, аnd Cа compаred to the blood of PCC pаtients.
Higher concentrаtions of Ni, Nа, аnd K аnd lower concentrаtions of Zn, Se, Cd, Th, аnd Mg were
observed in ZАT sаmples compаred to Cushing's syndrome tissue (CST) sаmples. Control blood
hаd lower concentrаtions of Mn, Ni, Аs аnd K, аs well аs higher Co, Cu, Se, Pb, Nа аnd Cа
compаred to pаtient sаmples.
А compаrаtive аnаlysis of sаmples of heаlthy аnd pаthologicаlly аltered tissues shows а
higher prevаlence of Se, Zn, K аnd lower Ni аnd Mg in аll pаthologicаlly аltered аdrenаl tissues:
ААT, PCC аnd CST. Аlso, Cu, Se, Ni, Аs, K, Cа аnd Nа stood out in the sepаrаtion of control
blood sаmples from pаtients with аll investigаted pаthologies.
The presented results indicаte the potentiаl role of the exаmined elements in the
pаthophysiologicаl processes of the аdrenаl glаnd. Determined chаnges in the concentrаtions of
elements could help in elucidаting the pаthogenesis of the exаmined аdrenаl diseаses аnd give
importаnce to future studies of metаllomics of the аdrenаl glаnds
Photochemically catalyzed cyclizations and intramolecular [2+2] cycloadditions of allenes
No full textU okviru ove doktorske disertacije razvijene su nove sintetičke metodologije zasnovane na fotohemijski katalizovanim transformacijama alena. Istraživanje je podeljeno u dva dela.
U prvom delu razvijena je blaga metoda za aktivaciju C(sp²)–I i C(sp³)–I veza pri čemu nastali alkil/vinil/aril radikal ciklizuje na alenski fragment. U reakciji se koristi [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol%) kao fotokatalizator, DIPEA-u kao aditiv i plava svetlost (λ = 465 nm), pri čemu nastaju ciklizacioni proizvodi u prinosima od 23% do 78%. Mehanizam se odvija putem jednoelektronskog transfera (SET), gde se inicijalno redukuje C–I veza, nakon čega sledi intramolekulska adicija na alenski fragment. Reakcija je regioselektivna, i odvija se isključivo na proksimalnoj dvostrukoj vezi alena, i pokazuje visoku dijastereoselektivnost (do 95:5 u korist trans-proizvoda) kod hiralnih supstrata. Kao proizvodi u reakciji nastaju, 3-vinil indoli i 3-vinil pirolidini. Metodologija je takođe uspešno primenjena i za formiranje šestočlanih prstenova.
U drugom delu doktorske disertacije razvijena je blaga metoda za intramolekulsku [2+2] cikloadiciju enalenilamida u prisustvu plave svetlosti (λ = 465 nm) uz upotrebu Ir(ppy)₃ kao fotokatalizatora. Reakcija otpočinje procesom transfera energije (EnT), kojim se selektivno aktivira dvostruka veza cimetamidnog fragmenta koja potom selektivno napada distalnu dvostruku vezu alena formirajući isključivo trans-biciklo[4.2.0]oktanske derivate. Reakcija se odvija pod blagim uslovima i predstavlja komplementaran pristup postojećim termičkim metodama, uz znatno bolje prinse. Ustanovljeno je da supstituenti na aromatičnom prstenu značajno utiču na prinos reakcije, pa tako supstrati sa elektron-donorskim grupama daju bolje prinose (60–88%) u poređenju sa supstratima sa elektron-privlačnim grupama (39–50%). Mehanizam reakcije dodatno je potkrepljen kompjuterskim modelovanjem i analizom ključnih intermedijernih stanja korišćenjem teorije funkcionala gustine (DFT - Density functional theory).Within this doctoral dissertation, novel synthetic methodologies based on photochemically catalyzed transformations of allenes have been developed. The research is divided into two parts.
In the first part, a mild method for the activation of C(sp²)–I and C(sp³)–I bonds was developed, leading to the formation of alkyl/vinyl/aryl radicals that cyclize onto the allene fragment. The reaction employs [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol%) as a photocatalyst, DIPEA as an additive, and blue light (λ = 465 nm), yielding cyclized products in 23% to 78% yields. The mechanism proceeds via a single electron transfer (SET) process, where the C–I bond is initially reduced, followed by intramolecular addition to the allene fragment. The reaction is regioselective, occurring exclusively at the proximal double bond of the allene, and exhibits high diastereoselectivity (up to 95:5 in favor of the trans product) for chiral substrates. The products formed include 3-vinyl indoles and 3-vinyl pyrrolidines. The methodology was also successfully applied to the formation of six-membered rings.
In the second part of the dissertation, a mild method for the intramolecular [2+2] cycloaddition of enallenylamides was developed under blue light irradiation (λ = 465 nm) using Ir(ppy)₃ as a photocatalyst. The reaction starts with an energy transfer (EnT) process where the double double bond of the cinnamamide fragment is selectively activated. The formed intermediate then attacks the distal double bond of the allene, exclusively forming trans-bicyclo[4.2.0]octane derivatives. The reaction proceeds under mild conditions and represents a complementary approach to existing thermal methods, with significantly improved yields. It was found that substituents on the aromatic ring significantly influence the reaction yields, with substrates bearing electron-donating groups affording higher yields (60–88%) compared to those with electron-withdrawing groups (39–50%). The reaction mechanism was further supported by computational modeling and analysis of key intermediate states using density functional theory (DFT)
Dijagnostički značaj simptoma i znakova gripa u populaciji uzrasta 15 godina i starijih
No full textУвод: Грип представља једну од најраспрострањенијих вирусних инфекција са значајним јавноздравственим последицама, нарочито током сезонских епидемија. И поред постојања дефиниција случаја које препоручују Светска здравствена организација (СЗО) и Европски центар за превенцију и контролу болести (ECDC), идентификација оболелих на основу клиничке слике и даље представља изазов због преклапања симптома са другим респираторним инфекцијама. Иако су бројне студије испитивале предиктивну вредност појединачних симптома, већина је спроведена међу децом или без контроле коморбидитета и вакциналног статуса код одраслих. Циљеви: Ова студија има за циљ да: (1) утврди који симптоми и знаци имају највећу дијагностичку вредност за предвиђање инфекције вирусом грипа код особа старијих од 15 година; (2) испита разлике у дијагностичкој вредности предиктора у зависности од узраста испитаника, периода у току сезоне грипа, присуства коморбидитета, вакциналног статуса и епидемиолошких података о контактима са слично оболелима. Материјал и методе: Истраживање је спроведено у сезони 2022/23. и 2023/24. на територији града Новог Сада, у Дому здравља Нови Сад и Институту за јавно здравље Војводине. У студију су укључени пацијенти узраста ≥15 година који су се први пут јавили изабраном лекару са једним или више симптома респираторне инфекције. Прикупљени су епидемиолошки подаци путем стандардизованих упитника, а дијагноза инфекције вирусом грипа је потврђена PCR методом. Укупан узорак је обухватио 1240 испитаника распоређених у три старосне групе: 15–29, 30–64 и ≥65 година. Обрађене су социодемографске карактеристике, симптоми, вакцинални статус, присуство хроничних болести и епидемиолошки подаци о контактима. За статистичку анализу коришћени су χ² тест, ANOVA, т-тест и логистичка регресија. Дијагностичка вредност предиктора је изражена преко сензитивности, специфичности, позитивне и негативне предиктивне вредности и тачности (accuracy). Резултати: Најважнији предиктори лабораторијски потврђеног грипа били су: повишена телесна температура ≥38°C, суви кашаљ, малаксалост и болови у мишићима. Тачност предвиђања била је највећа код старијих од 65 година, као и код невакцинисаних особа и оних са контактима унутар породице са школском децом. Вакцинисани испитаници и они без коморбидитета имали су значајно ниже стопе лабораторијски потврђеног грипа. Поред тога, предиктивна вредност симптома је била већа у врхунцу сезоне у односу на почетне и завршне недеље надзора. Међу варијаблама, комбинација фебрилности, кашља и малаксалости показала је највећу дијагностичку тачност (>80%). Закључак: Симптоми као што су повишена телесна температура, кашаљ и општа слабост представљају кључне дијагностичке показатеље за идентификацију грипа у примарној здравственој заштити. Прецизност дијагнозе варира у зависности од старости, вакциналног статуса и постојања коморбидитета. Добијени резултати указују на потребу за ревизијом постојећих дефиниција случаја, прилагођених карактеристикама одређених подгрупа пацијената, што би допринело ефикаснијем јавноздравственом надзору и правовременој дијагностици.Influenza remains one of the most widespread viral infections with considerable public health impact, especially during seasonal epidemics. Despite the availability of standardized case definitions recommended by the World Health Organization (WHO) and the European Centre for Disease Prevention and Control (ECDC), clinical identification of cases remains challenging due to symptom overlap with other respiratory infections. While several studies have evaluated the predictive value of individual symptoms, most have focused on pediatric populations or did not consider comorbidities and vaccination status among adults. Objectives: The aim of this study was to: (1) determine which symptoms and signs have the highest diagnostic value for predicting laboratory-confirmed influenza among individuals aged 15 and older; (2) assess the differences in diagnostic performance of predictors according to age, seasonal timing, presence of comorbidities, influenza vaccination status, and epidemiological exposure. Materials and Methods: The study was conducted during the 2022/23 and 2023/24 influenza seasons in the city of Novi Sad, Serbia, at the Novi Sad Health Centre and the Institute of Public Health of Vojvodina. Participants were patients aged ≥15 years presenting for the first time with one or more symptoms of respiratory infection. Data were collected via standardized questionnaires and nasopharyngeal swabs tested by RT-PCR. A total of 1240 participants were included, divided into three age groups: 15–29, 30–64, and ≥65 years. Demographic, clinical, vaccination, comorbidity, and epidemiological data were analyzed. Statistical methods included χ² test, ANOVA, t-test, and logistic regression. Diagnostic performance of symptoms was assessed using sensitivity, specificity, positive and negative predictive values, and accuracy. Results: The most relevant predictors of laboratory-confirmed influenza were fever ≥38°C, dry cough, fatigue, and myalgia. The highest diagnostic accuracy was observed in participants aged ≥65, unvaccinated individuals, and those with household contact with school-aged children. Vaccinated individuals and those without comorbidities had significantly lower influenza positivity rates. Furthermore, the predictive value of symptoms was higher during peak influenza activity compared to early or late-season periods. The combination of fever, cough, and fatigue showed the highest diagnostic accuracy (>80%). Conclusion: Symptoms such as elevated body temperature, cough, and general malaise are key diagnostic indicators for identifying influenzacases in primary care. Diagnostic accuracy varies according to age, vaccination status, and the presence of comorbidities. These findings suggest the need to revise current universal case definitions by adapting them to patient subgroups, thereby improving influenza surveillance and clinical decision-making in public health practice.</p
Мultidimensional analysis of drilling and blasting impact on the effects of mining production
No full textУсвајање оптималних параметара бушачко-минерских радова је веома комплексан задатак, имајући у виду велики број фактора које је потребно анализирати у циљу осигурања ефикасности и безбедности извођења ових рударских операција. Адекватно изведене операције бушења и минирања обезбеђују оптималну гранулацију стенске масе, што је од велике важности за даљи ток рударске производње. Недовољно прецизно усвојени параметри ових операција могу довести до прекомерног уситњавања, повећане потрошње енергије у секундарним процесима дробљења и до нарушавања стабилности подземних просторија, што потенцијално угрожава и безбедност радне снаге. У овој докторској дисертацији развијена је методологија са мултидимензионалним приступом и савременим математичким алатима за симулацију, који имају за циљ подршку процесу одлучивања, односно прецизирања параметара бушачко-минерских радова, тако да оне буду изведене уз максималну обзирност према економским, производним и еколошким факторима. Развијена методологија се састоји од две нове методе вишекритеријумског одлучивања, које су примењене на нумеричком примеру уз дефинисање одређеног броја критеријума који служе за селекцију оптималне од више предложених алтернатива. Неодређеност неких критеријума је препозната и имплементацијом симулација у једну од две нове методе, успешно превазиђена у овом процесу подршке одлучивању. Добијена решења су упоређена и одабрано је оптимално решење. Развијена методологија је упоређена са већ признатим методама вишекритеријумског одлучивања. За верификацију је коришћен степен корелације, који је у оба случаја тестирања био преко 90 %, што се оцењује као висок степен корелације. Предложена методологија нема ограничења у својој примени, може се искористити као подршка одлучивању, на различитим рударским локацијама.Adopting optimal parameters for drilling and blasting operations is a very complex task, considering the large number of factors that need to be analyzed in detail to ensure the efficiency and safety of these mining operations. Properly executed drilling and blasting operations ensure optimal fragmentation of the mined rock mass, which is crucial for the subsequent stages of mining production. Insufficient precise parameters for these operations can lead to excessive fragmentation, increased energy consumption during secondary crushing processes, and the disruption of the stability of underground objects, potentially threatening the safety of the workforce. Тhis doctoral dissertation presents a methodology that involves a multidimensional approach and modern mathematical tools for simulation. These tools aim to support the decision-making process by specifying the parameters for drilling and blasting operations, ensuring they are performed with optimal consideration for economic, production, and environmental factors. The developed methodology consists of two novel multi-criteria decision-making methods, which were applied to a numerical example that defined several criteria to select the optimal alternative from multiple proposed options. The uncertainty of certain criteria was identified and successfully addressed in the decision-support process by implementing simulations in one of the two novel methods. The results were compared, and the optimal solution was selected. The developed methodology was also compared with existing multi-criteria decision-making methods. The degree of correlation, which was over 90% in both cases of testing, was assessed as a high degree of correlation. The proposed methodology has no limitations in its application and can be used as a decision-support tool at various mining locations
Upravnosudska stvar kao predmet upravnog spora
No full textIn addition to the Introduction, which identifies the key issues for research, and the Conclusion, which summarizes the research findings, the dissertation contains five chapters.
In the first chapter, titled “The Emergence and Development of Judicial Control over Administration”, attention is focused on the historical development of administrative disputes within continental European legal systems, with particular emphasis on the period from the early 19th century to the present day. Starting from the need for systematic and effective oversight of administrative actions, the chapter examines various models of judicial control that have developed in countries such as France, Germany, Austria, and Switzerland - representatives of the most advanced continental European legal systems. The second part of the chapter addresses the specific features of the development of judicial control in Anglo- American legal systems, focusing on the legal frameworks of the United States and the United Kingdom. Unlike the continental model, Anglo-American systems have not established separate administrative courts; instead, administrative oversight is integrated within the general court system. The third section of the chapter provides a detailed examination of the historical development of administrative disputes in Serbian law, from the earliest forms of administrative control to the modern normative and institutional framework. Particular attention is given to how the influence of the continental European legal tradition, combined with specific socio-political circumstances, has shaped the domestic model of judicial protection against administrative actions.
By applying historical and comparative methods, the analysis focuses on key institutions and legal frameworks that have influenced the formation of administrative judicial systems in the aforementioned countries. Special emphasis is placed on the characteristics and evolution of
judicial control over administration, as well as on the various mechanisms that enable citizens to seek legal protection against irregularities in the functioning of administrative bodies.
The aim of this part of the first chapter is not only to present the historical and legal aspects of the development of administrative disputes, but also to provide a broader understanding of the significance and role of administrative judiciary in building and strengthening the rule of law, through a critical examination of the advantages and shortcomings of comparative legal systems.
In the second chapter, titled “The Subject Matter of Administrative Dispute”, a more detailed analysis is conducted on the scope and content of administrative disputes in selected continental European legal systems, in Anglo-American law, as well as in the legal system of the Republic of Serbia—both historically and in its current form. Through this analysis, the aim is to explore how countries that are more advanced in this area have defined the subject matter of administrative disputes and how they resolve such disputes.
This comparative approach serves as a foundation for identifying differences and potential shortcomings in the Serbian legal system, and for proposing appropriate solutions to improve the existing framework. The objective is to examine practical examples from countries with well-developed administrative law systems, and to assess their approaches to resolving disputes between citizens and public administration.
By analyzing successful mechanisms and legal solutions that have proven effective in both continental European legal systems and Anglo-American legal traditions, this chapter seeks to provide insights that could guide the adoption of best practices to enhance the administrative dispute resolution system in the Republic of Serbia.
The third chapter addresses the necessity of distinguishing administrative matters as the subject of administrative proceedings and administrative judicial matters as the subject of administrative disputes, as well as the difference between legal matters, legal situations, and legal institutes as legal forms.
The fourth chapter discusses the legal subjects of administrative disputes in the law of Serbia, with an analysis of the legal subjects of administrative disputes both before and after World War II. The final part of this chapter is an analysis of the legal subjects of administrative disputes following the establishment of the Administrative Court of the Republic of Serbia, particularly considering the hastiness of our state, reflected in the
establishment of a court with special jurisdiction and the rapid application of the Law on Administrative Disputes, adopted in an expedited procedure, published in the "Official Gazette of the Republic of Serbia" on December 29, 2009, and which entered into force the day after publication. Furthermore, within this analysis, we explore some of the potential solutions to the problems faced by our sole Administrative Court. In this context, one of the greatest challenges the Administrative Court faced was the issue of harmonizing procedures and practices with European legal standards, as well as the needs of the domestic legal system, which was undergoing significant reform changes. Additionally, problems related to the large volume of cases and the organization of the court, which received jurisdiction over administrative disputes, required more effective mechanisms for speeding up procedures and reducing backlog. In this regard, several potential solutions are discussed, such as improving the legal and technical infrastructure of the court and applying modern technologies that could help accelerate the processing of cases and increase the transparency of the court. Furthermore, greater attention needs to be directed toward the legal education of judges and legal staff to ensure a higher quality application of new legal provisions and establish adequate standards for fair trial in administrative disputes.
The fifth chapter, titled "Administrative Judicial Matter," examines the relationship between administrative and administrative judicial matters, the relationship between administrative judicial matters and other judicial matters, with numerous characteristics of administrative judicial matters presented. The chapter also argues for the necessity of distinguishing administrative matters as the subject of administrative proceedings and administrative judicial matters as the subject of administrative disputes, suggesting that it would be correct to introduce this concept into our legislation as the subject of administrative disputes.
Namely, it is undeniable that the new Law on Administrative Disputes represents a significant step forward compared to its outdated and vague predecessor. However, considering that administrative dispute is the pinnacle of administrative law and its conclusion, and how the "testing" of the law can clearly indicate its shortcomings, primarily starting from the linguistic designation of certain institutes, the doctoral dissertation seeks to be at least a small contribution to better understanding of the law, its provisions, especially considering that administrative disputes are a delicate, diverse, and growing category of court disputes. With the adoption of the new Law on Administrative Disputes and the establishment of the Administrative Court, there was a clear intention to reform the judicial administration,
expand the scope of disputes, and respect European principles. The expected results have not materialized, and the problems that led to the reform have not been solved even today. This doctoral dissertation addresses the changes, challenges, and issues, indicating that successful reform of administrative disputes cannot be achieved by blindly adopting European legal standards and simply transplanting them into domestic legislation. Successful reform can only be achieved through a deep understanding of the legal nature of administrative disputes, with clear and precise definitions of their subject, administrative and administrative judicial matters, as this is what makes them special and different from classical court disputes. Additionally, in the context of successful reform, the author states that it is not enough to mechanically transfer European legal standards into domestic legislation. On the contrary, reforms must be based on a profound understanding of the legal nature and specificity of administrative disputes in order to ensure their efficiency and fairness. In this regard, the dissertation also explores the possibilities for further development and improvement of the system of administrative law in Serbia
Educational support in shifting from the "empty nest" parent concept to the concept of parent "emeritus"
No full textProdužen životni vek, kasnije stupanje u brak, niži natalitet, manji broj dece, produženo
ostajanje dece kod roditelja, ekonomska i socijalna nestabilnost, viši životni troškovi, uticali su na
uviđanje važnosti faze u životnom ciklusu porodice u naučnim krugovima poznate kao faze „praznog
gnezda“. Ova faza dobija dodatnu pažnju sticanjem statusa najduže faze u životnom ciklusu porodice.
Izazovi savremenog života iznedrili su potrebu za obrazovnom podrškom porodici da razvija svoje
snage, ali je obrazovanje za život u porodici i dalje više usmereno na kreiranje programa za sve ranije
faze životnog ciklusa porodice nego na fazu „praznog gnezda“.
Cilj ovog teorijsko-empirijskog istraživanja je bio da se ispita odnos između roditeljske
procene karakteristika porodičnog funkcionisanja u fazi „praznog gnezda“ u kojoj se nalaze i njihove
procene korisnosti kreiranog programa obrazovne podrške, kao i mogućnost kreiranja modela
obrazovne podrške koji bi preusmerio narativ o roditeljima „praznog gnezda“ ka konceptu roditelja
„emeritusa“. Teorijski okvir istraživanja čine sistemski pristup porodici i porodična razvojna teorija.
U istraživanju je korišćena deskriptivno-analitička metoda, a od tehnika istraživanja – anketiranje i
skaliranje. Rezultati istraživanja pokazuju da postoji povezanost između ličnih i porodičnih
karakteristika roditelja, roditeljske procene porodičnog funkcionisanja u fazi „praznog gnezda“ i
procene korisnosti kreiranog programa obrazovne podrške.
Iako mali, ovo istraživanje daje značajan doprinos razumevanju porodičnog funkcionisanja u
fazi „prazno gnezdo“ i ističe mogućnost kreiranja modela obrazovne podrške porodici tokom
celokupnog životnog ciklusa. Mnogi optimistični odgovori ispitanika po pitanju različitih elemenata
porodičnog funkcionisanja pokazuju da porodično „gnezdo“ nikada nije prazno i da je vreme da
počnemo roditelje ove životne faze porodice posmatrati kao roditelje „emerituse“.Increased life expectancy, delayed marriage, lower birth rates, having fewer children,
prolonged co-residence of children and their parents, economic and social instability, as well as higher
costs of living have all contributed to the growing recognition of the importance of the family life
cycle stage known in scientific circles as the "empty nest" stage. This stage has received extra
attention after acquiring the status of the longest stage in the family life cycle. The challenges of
modern life have created the need for educational support aimed at strengthening families, yet family
life education remains focused more on creating programs for all the earlier stages of the family life
cycle than on the "empty nest" stage itself.
The aim of this theoretical-empirical research was to examine the relationship between the
parents’ assessment of the characteristics of family functioning during the "empty nest" stage and
their assessment of the usefulness of the created educational support program, as well as the
possibility of creating an educational support model that would shift the narrative around "empty
nest" parents towards the concept of "emeritus" parents. The theoretical framework of the research is
grounded in the systemic approach to family and the Family Development Theory. The study
employed a descriptive-analytical method, utilizing survey and scaling techniques. The findings
indicate a connection between the parents’ personal and family characteristics, their assessment of
family functioning during the "empty nest" stage, and their assessments of the usefulness of the
created educational support program.
Although modest, this study makes a notable contribution to the understanding of family functioning
during the "empty nest" stage and emphasizes the possibility of developing educational support
models that encompass the entire family life cycle. Numerous optimistic responses provided by the
participants regarding various aspects of family functioning suggest that the family "nest" is never
empty, and that it is time to begin viewing parents in this life stage as "emeritus" parents
Komunikacija obuhvata vakcinom: provera pretpostavki modela sebične naspram modela socijalne racionalnosti
No full textWe explored how communicating vaccination coverage affects vaccination intentions. We compared contrasting hypotheses drawing from two theoretical models: selfish rationality and social rationality. The selfish-rational model suggests high coverage reduces motivation by encouraging free-riding on herd immunity, while the social-rational model sees high coverage as a positive descriptive norm that increases motivation. Both suggest the opposite effect at low coverage. A content analysis of 160 Serbian online news articles from the 2017 measles outbreak found that vaccination coverage was often framed negatively (e.g., “only 50% vaccinated”), lacked context and numerical precision, and rarely included explanations of herd immunity. Such reporting reinforces undesirable social norms, while failing to convey the broader societal benefits of immunization. Across all experiments (N = 1076; Hedges’ g = 0.21), communicating high country-level coverage (80–90%) generally increased vaccination intention compared to conditions when low (10–20%) or no coverage was communicated. This insight alone has limited practical use, as coverage values must be reported as they are. We therefore experimentally tested how appeals to individual (protecting oneself), social (protecting others), and collective benefits (stopping the disease) influence vaccination intentions at different levels of vaccination coverage. One effective intervention was emphasizing the social benefits of herd immunity via text and an animated infographic (N = 543; Hedges’ g = 0.23), conceptually replicating a previous finding; incorporating coverage or herd immunity threshold information had no further effect. Another successful intervention, this time in a setting of moderate coverage (60%), was appealing to individual benefits of vaccination (N = 265; Hedges’ g = 0.16). In a separate experiment (N = 217), irrespective of vaccination-coverage level, participants who opted for vaccination commonly endorsed both self-interested and prosocial reasons, while non-vaccination was typically justified by personal risk calculations and the belief that vaccination was unnecessary. Free-riding was rarely endorsed, and descriptive norms were seen as more relevant for vaccination than non-vaccination. Open-ended responses also highlighted (mis)trust in science and vaccines as an important reason. Our findings support the social-rational view more than the selfish-rational one, but also highlight the limitations of applying either model rigidly. We argue that public health messaging should reflect reasonableness, understood as a context-sensitive balancing of individual and social considerations. We discussed directions for future research, such as communicating dynamic norms (changes in coverage) and tailored messaging. By refining theoretical assumptions, using a multi-method approach, and offering practical recommendations, this work helps us better understand and support vaccination decisions in a complex, socially interdependent world.Istraživali smo kako komunikacija obuhvata vakcinom utiče na nameru da se vakcina primi. Poredili smo suprotstavljene pretpostavke proistekle iz dva teorijska modela: sebične racionalnosti i socijalne racionalnosti. Prema modelu sebične racionalnosti, visok obuhvat vakcinom smanjuje motivaciju jer podstiče grebatorstvo (eng. free-riding) o kolektivni imunitet, dok model socijalne racionalnosti visok obuhvat vidi kao pozitivnu deskriptivnu normu koja povećava motivaciju. Oba modela predviđaju suprotan efekat u slučaju niskog obuhvata. Analiza sadržaja 160 tekstova sa srpskih portal vesti tokom epidemije malih boginja 2017. godine pokazala je da se obuhvat vakcinom često uokviravao negativno (npr. „samo 50% vakcinisanih”), te da mu je nedostajao kontekst i numerička preciznost, kao i da je kolektivni imunitet retko kada pojašnjen. Takvo izveštavanje u prvi plan stavlja nepoželjne socijalne norme, dok se ne prenosi poruka o široj društvenoj koristi od imunizacije. U svim eksperimentima (N = 1076; Hedžisov g = 0,21), komunikacija visokog obuhvata (80–90%) na nivou države generalno je povećavala nameru da se primi vakcina u poređenju niskim obuhvatom (10–20%) odnosno sa situacijama kada on uopšte nije saopštavan. Ovaj uvid sam po sebi ima ograničenu praktičnu primenu jer vrednosti obuhvata vakcinom moraju biti prikazane onakvima kakve jesu. Stoga smo eksperimentalno testirali kako apeli na individualnu (zaštita sebe), socijalnu (zaštita drugih) i kolektivnu dobit (zaustavljanje bolesti) utiču na nameru da se primi vakcina na različitim nivoima obuhvata. Jedna efikasna intervencija bila je isticanje socijalnih koristi kolektivnog imuniteta putem teksta i animiranog infografika (N = 543; Hedžisov g = 0,23), čime je konceptualno repliciran prethodni nalaz; uključivanje informacija o obuhvatu ili pragu kolektivnog imuniteta nije imalo dodatni efekat. Još jedna uspešna intervencija, ovog puta u uslovima umerenog obuhvata (60%), bila je apelovanje na individualnu dobit (N = 265; Hedžisov g = 0,16). U zasebnom eksperimentu (N = 217), bez obzira na nivo obuhvata, učesnici koji su se odlučivali na vakcinaciju su obično podržavali i razloge zasnovane na ličnom interesu i prosocijalne razloge, dok je nevakcinacija pretežno opravdavana proračunima ličnog rizika i uverenjem da vakcinacija nije potrebna. Grebatorstvo je retko podržavano, a deskriptivne norme su smatrane važnijima za vakcinaciju nego za nevakcinaciju. Otvoreni odgovori su dodatno ukazali na (ne)poverenje u nauku i vakcine kao bitan razlog. Naši rezultati podržavaju pre model socijalne nego model sebične racionalnosti, ali ukazuju i na ograničenja krute primene bilo kog modela. Predlažemo da poruke u javnom zdravlju treba da odražavaju razložnost ili razumnost, shvaćenu kao kontekstualno osetljivo balansiranje individualnih i društvenih aspekata. Razmatrali smo predloge za buduća istraživanja, kao što su komunikacija dinamičkih normi (promena u obuhvatu) i ukrajanje poruka. Produbljivanjem teorijskih pretpostavki, primenom multimetodskog pristupa i davanjem praktičnih preporuka, ovaj rad nam pomaže da bolje razumemo i podržimo odluke o vakcinaciji u složenom, društveno međuzavisnom svetu