Toxicity-related antiretroviral drug treatment modifications in individuals starting therapy: a cohort analysis of time patterns, sex, and other risk factors.

BackgroundModifications to combination antiretroviral drug therapy (CART) regimens can occur for a number of reasons, including adverse drug effects. We investigated the frequency of and reasons for antiretroviral drug modifications (ADM) during the first 3 years after initiation of CART, in a closed cohort of CART-naïve adult patients who started treatment in the period 1998-2007 in Croatia.Material and methodsWe calculated differential toxicity rates by the Poisson method. In multivariable analysis, we used a discrete-time regression model for repeated events for the outcome of modification due to drug toxicity.ResultsOf 321 patients who started CART, median age was 40 years, 19% were women, baseline CD4 was <200 cells/mm3 in 71%, and viral load was ≥100 000 copies/mL in 69%. Overall, 220 (68.5%) patients had an ADM; 124 (56%) of these had ≥1 ADM for toxicity reasons. Only 12.7% of individuals starting CART in the period 1998-2002 and 39.4% in the period 2003-2007 remained on the same regimen after 3 years. The following toxicities caused ADM most often: lipoatrophy (22%), gastrointestinal symptoms (20%), and neuropathy (18%). Only 5% of drug changes were due to virologic failure. Female sex (hazard ratio [HR], 2.42 95%; confidence intervals, 1.39-4.24) and older age (HR, 1.42 per every 10 years) were associated with toxicity-related ADM in the first 3 months of a particular CART regimen, but after 3 months of CART they were not.ConclusionsLess toxic and better-tolerated HIV treatment options should be available and used more frequently in Croatia

Assessment of soil erosion potential by application of USLE and PESERA models on the territory of Prvonek catchment

Губитак земљишта изазван процесом ерозије је озбиљан проблем у Републици Србији, a процена губитака земљишта као и систем заштите од ерозије представљају неопходни услов за одрживи развој привреде и друштва. Предвиђање губитка земљишта је важно за процену опасности од ерозије и детерминацију одговарајућих мера конзервације и коришћења земљишта у сливу. Широк спектар модела је данас доступан за процену ризика од ерозије земљишта. Избор одређеног модела у великој мери зависи од сврхе истраживања, доступности података, времена и потребних материјалних средстава за његову реализацију. Степен угрожености земљишта процесима ерозије у овој докторској дисертације, оцењен је применом USLE и PESERA моделима, док је транспорт неких микроелемената са наносом услед ерозионог процеса процењен применом WaTEM/SEDEM модела. Применом USLE и PESERA модела добили су се релативно уравнотежени резултати, са вредностима класификованим у групу умерене угрожености од ерозионих процеса. На основу добијених резултата транспортованих микроелемената применом WaTEM/SEDEM модела, ризична подручја са нешто вишим вредностима транспортованих микроелемената се углавном јављају на локалитетима где су забележене веће укупне количине тешких метала у земљишту, односно, близу подручја са израженијим интензитетом ерозије. Резултати добијени применом USLE и PESERA модела у проучаваним условима пружају могућност око националног концензуса за избор ерозионог модела. Међутим, ниво њихове примене је првенствено условљен размерама подручја. Резултати указују да је примена USLE модела прикладнија када се ради о процени ерозионих губитака земљишта на мањим сливовима, пре свега због могућности модела да врши процену на детаљнијим резолуцијама. С друге стране, PESERA модел има предност када се ради о проценама губитака земљишта на регионалном нивоу, зато што боље одражава хидроеколошке параметре, који су од значаја за развој ерозионих процеса. На овакав закључак упућују и резултати примене оба модела, према анализираној литератури, у различитим подручјима у Европи

Solidary liability of debtors in obligations

Kada u jednom obligacionom odnosu na poverilačkoj ili dužničkoj strani ima više subjekata, tada njihovi pravni odnosi mogu biti regulisani po načelu podeljenog dugovinskog odnosa (svako za svoj deo potraživanja odnosno dugovanja) ili po načelu solidarnosti (jedan za sve i svi za jednog). Prema tome, obligacija sa više subjekata preduslov je svake solidarnosti. Predmet ove disertacije čini solidarnost dužnika (pasivna solidarnost) koja je u poređenju sa aktivnom solidarnošću daleko značajnija, kako sa stanovišta prakse, tako i sa stanovišta zakonodavstva i pravne nauke. Mnoge kodifikacije komparativnog građanskog prava, posebno evropske pravne kulture, poverilačkoj solidarnosti posvećuju daleko manji prostor u odnosu na solidarnost dužnika. Razlog tome, pre svega, leži u činjenici, da je solidarnost dužnika jedno od značajnih sredstava ličnog obezbeđenja izvršenja dugovane prestacije. Tekst ove doktorske disertacije pod naslovom “Solidarnost dužnika u obligacionim odnosima”, posle uvodnih obeležja, izložen je u šest celina (poglavlja), i unutar svake od njih obuhvaćena su srodna pitanja u vidu pojedinih odseka. Tekst disertacije iznosi preko tri stotine stranica sa oko sedam stotina fusnota, posebno zakonskih izvora, obimne literature i sudske prakse u oblasti solidarnih dužnika. Tehnika pisanja je prilagođena uputstvu Univerziteta u Beogradu o načinu, obliku i sadržaju doktorske disertacije. Prva glava disertacije posvećena je istorijskom razvoju solidarnih obligacija, počev od antičkog i naročito rimskog prava, pa preko srednjovekovne evolucije, sve do savremenih kodifikacija građanskog prava u krugu evropske familije prava gde su izložena rešenja solidarnih obligacija u više od dvadeset pravnih sistema. Posle ovog istorijskog razvoja solidarnih obligacija, naučno su obrađena pitanja koja se odnose na široko polje primene ovih obligacija kao što je njihovo prisustvo u materiji ugovorne i deliktne odgovornosti, imovinskih odnosa u porodičnom pravu, stvarnom pravu (naročito kod svojinskih zajednica), a zatim u privrednom pravu (ortačko društvo, komanditno društvo, društvo sa ograničenom odgovornošću, akcionarsko društvo). Pored toga, na ovom mestu su analizirana izvesna pitanja koja su značajna za solidarnost dužnika: deljive i nedeljive obligacije, novčane i nenovčane obligacije, obligacije intuitu personae, neutužive (naturalne) obligacije. Na ovom mestu su obrađene i kumulativne, alternativne i fakultativne obligacije i njinova primena u kontekstu solidarnosti dužnika.When there are several subjects in an obligatory relation on the creditor’s or debtor’s side, their legal relations can be regulated based on the principle of divided debt relationship (to each of them belongs his part of the claim, i.e. of the debt), or on the principle of solidarity (one for all and all for one). Therefore, an obligation with several subjects is a prerequisite for any solidarity. The subject of this doctoral dissertation is the solidarity of debtors (passive solidarity), which, compared to active solidarity, is far more significant from the point of view of practice, as well as from the point of view of legislation and jurisprudence. Many codifications of comparative civil law, especially in the European legal culture, devote far smaller attention to the solidarity of creditors compared to the solidarity of debtors. The reason for this lies, above all, in the fact that the solidarity of debtors constitutes one of the more significant means of personal security for the execution of the owed debt. After some introductory remarks, the text of this PhD thesis, entitled "Solidary Liability of Debtors in Obligations", has been exposed in six units (chapters), each of them covering related questions in the form of particular sections. The text of the thesis has more than three hundred pages with about seven hundred footnotes, especially from legal sources, an extensive literature and jurisprudence in the field of solidary debtors. The writing technique is adapted to the instructions of the University of Belgrade about the writing style, the form and the contents of a PhD thesis. The first chapter of the thesis is devoted to the historical development of solidary obligations, starting from the antique and, especially, the Roman law, through medieval evolution, up to the contemporary civil law codifications in the circle of the European law family, exposing solutions of solidary obligations in more than twenty legal systems. After this overview of the historical development of solidary obligations, questions related to the wide application scope of these obligations have been dealt with scientifically, such as their presence in the matter of contractual and delinquent responsibility, property relations in family law, the Real Estate law (especially in the case of community ownerships), and in the commercial law (partnership, limited partnership, limited liability company, joint-stock company). In addition, some issues, important for the solidarity of debtors, have been analyzed vi here: divisible and indivisible obligations, monetary and non-monetary obligations, obligations intuitu personae, obligations which cannot be enforced in a court of justice (natural obligations). Cumulative, alternative and facultative obligations and their application in the context of the solidarity of debtors have also been elaborated in this part

Radionuclides and heavy metals in soil, vegetables, and medicinal plants in suburban areas of the cities of Belgrade and Pancevo, Serbia

The content of radionuclides (K-40 , U-238 , Ra-226 , Th-232, and Cs-137) and heavy metals (As, Cd, Cu, and Pb) was determined in samples of soil, vegetables and medicinal plants collected in the period 2007-2017, from two suburban areas of Belgrade - the municipalities of Palilula and Surcin, and Pancevo - the Dr Josif Pancic Institute for the Study of Medicinal Herbs. During the research period, activity concentration of Cs-137 in soil decreased from 16 Bqkg(-1) to 3.9 Bqkg(-1) (Palilula, Belgrade) and from 18 Bqkg(-1) to 12 Bqkg(-1) (Surcin, Belgrade). Mean activity concentrations of natural radionuclides in the soil were higher than the global average. lkend for heavy metal levels, according to the average concentrations found in the soil, were as follows: Cu >Pb >As >Cd for Palilula, Pb >Cu >As >Cd for Surcin and Dr Josif Pancic Institute, Pancevo. The obtained results indicate that the industrial pollution has no impact on food production in the study area and that the main anthropogenic source of radionuclides and heavy metals in soil are mineral phosphorous fertilizers, often used in agricultural fields

New age for alignment-free methods for sequence analyses

Progress in a wide range of fields ranging from population genetics to precision medicine may be attributed to availability of big biological data. Alignment-free sequence comparison is the methodology of choice in data-intensive applications given that it is significantly faster and requires less resources compared to traditional sequence comparison based on pairwise or multiple sequence alignment. The symbiosis of alignment-free methods with machine learning is a paradigm of new age in bioinformatics, as it ensures the much needed boost to quicken the complex predictions on large datasets, particularly of molecules with low sequence identity. In this talk, I will present two stories in which I will describe approaches to predict functional consequences of gene variants and imperfect tandem repeats in protein sequences.Special Edition of Book of Abstract

Repurposing of antiparasitic drugs for Candidate SARS-CoV-2 Main Protease Inhibitors by combined in silico Method

The SARS-CoV-2 outbreak that is spreading rapidly around the world requires urgently effective treatments. Therefore, in silico drug repurposing represents a powerful strategy to enable the acceleration of the identification of drug candidates with already known safety profiles. The SARS-CoV-2 main protease is essential for viral replication and an attractive drug target. This study used the virtual screening protocol with both long-range and short-range interactions to select candidate SARS-CoV-2 main protease inhibitors. The Informational spectrum method developed for small molecules was first applied for searching the Drugbank database of antiparasitic agents and further followed by molecular docking. After in silico screening of drug space, we propose several drugs as potential SARS-CoV-2 main protease inhibitors for further experimental testing.Special Edition of Book of Abstract

Feature-Based Classification of Amino Acid Substitutions outside Conserved Functional Protein Domains

There are more than 500 amino acid substitutions in each human genome, and bioinformatics tools irreplaceably contribute to determination of their functional effects. We have developed feature-based algorithm for the detection of mutations outside conserved functional domains (CFDs) and compared its classification efficacy with the most commonly used phylogeny-based tools, PolyPhen-2 and SIFT. The new algorithm is based on the informational spectrum method (ISM), a feature-based technique, and statistical analysis. Our dataset contained neutral polymorphisms and mutations associated with myeloid malignancies from epigenetic regulators ASXL1, DNMT3A, EZH2, and TET2. PolyPhen-2 and SIFT had significantly lower accuracies in predicting the effects of amino acid substitutions outside CFDs than expected, with especially low sensitivity. On the other hand, only ISM algorithm showed statistically significant classification of these sequences. It outperformed PolyPhen-2 and SIFT by 15% and 13%, respectively. These results suggest that feature-based methods, like ISM, are more suitable for the classification of amino acid substitutions outside CFDs than phylogeny-based tools

Can We Use Standard Tools to Predict Functional Effects of Missense Gene Variations Outside Conserved Domains? TET2 Example

The most common genetic variations in humans are Single Nucleotide Polymorphisms (SNPs), so predicting their associations with cancers is a significant issue. Here, we were particularly interested in SNPs occurring outside protein Conserved Domains (CDs) of TET2, a recently discovered epigenetic regulator involved in leukemogenesis. Functional effects of TET2 gene variations were assessed with four publicly available tools: PhD-SNP, MutPred, PolyPhen-2 and SIFT. The methods were tested on the dataset of 166 SNPs and somatic TET2 mutations, and separately on the subset of 69 variations outside TET2 CDs. Abilities of tested tools to separate neutral SNPs from pathogenic mutations were similar to previously reported on complete TET2 dataset. However, we observed significantly lower accuracy of predictions outside CDs, ranging from 0.54 to 0.62. Also, areas under the ROC curves were low, 0.51-0.55. Correlations between predictions and positions of variations inside/outside CDs were significant and high, 0.46-0.78. Low efficiency of commonly used tools in predicting functional effects of variations outside CDs emphasize the need for new or modified algorithms.Proceedings available at: [http://www.tabis2013.ipb.ac.rs/tabis2013.pdf

Fatty acid in colorectal cancer in adult and aged patients of both sexes

Purpose: Colorectal cancer represents the second most common type of cancer in Serbia. Alteration of lipid metabolism begins early, and can represent a central hallmark in cancer evolution. Fatty acids have various important functions as building components of cell membranes, as signaling molecules in immune responses and also manage the general cancer signaling network. The purpose of this study was to investigate the difference of various fatty acids content between colorectal cancer and adjacent healthy intestinal tissue in adult and aged patients of both sexes. Methods: 52 subjects participated in this study. Healthy colon mucosa and tumor tissue samples were obtained from patients previously diagnosed with colorectal carcinoma. Simplified method of Berstad et al was used for direct transesterification of total lipids in tumor and healthy mucosa tissue samples and separations of the methyl esters was carried out using a gas chromatograph equipped with a split/ splitless injector and a flame ionization detector. Results: 18 0, 18 1 n7, 20 3, 20 4, 20 5, 22 4, 22 5 22 6, SFA, PUFA, n6, n3 and AA/EPA were significantly higher in tumor tissue. On the other hand, 18 1 n9, 18 2, 18 3 n3, MUFA, n6/ n3 were significantly higher in healthy tissue. Conclusions: Saturation index (SI) could be a valuable tool to delineate robust immune response and worse prognosis in patients with colorectal cancer. Our study demonstrated significant differences in fatty acid profiles between tumor tissue and healthy mucosa. Parameters, such as gender, age, stage and mucinous component didn't influence altered fatty acid content

Alignment-free method for functional annotation of amino acid substitutions: Application on epigenetic factors involved in hematologic malignancies

For the last couple of decades, there has been a significant growth in sequencing data, leading to an extraordinary increase in the number of gene variants. This places a challenge on the bioinformatics research community to develop and improve computational tools for functional annotation of new variants. Genes coding for epigenetic regulators have important roles in cancer pathogenesis and mutations in these genes show great potential as clinical biomarkers, especially in hematologic malignancies. Therefore, we developed a model that specifically focuses on these genes, with an assumption that it would outperform general models in predicting the functional effects of amino acid substitutions. EpiMut is a standalone software that implements a sequence based alignment-free method. We applied a two-step approach for generating sequence based features, relying on the biophysical and biochemical indices of amino acids and the Fourier Transform as a sequence transformation method. For each gene in the dataset, the machine learning algorithm–Naïve Bayes was used for building a model for prediction of the neutral or disease-related status of variants. EpiMut outperformed state-of-the-art tools used for comparison, PolyPhen-2, SIFT and SNAP2. Additionally, EpiMut showed the highest performance on the subset of variants positioned outside conserved functional domains of analysed proteins, which represents an important group of cancer-related variants. These results imply that EpiMut can be applied as a first choice tool in research of the impact of gene variants in epigenetic regulators, especially in the light of the biomarker role in hematologic malignancies. EpiMut is freely available at https://www.vin.bg.ac.rs/180/tools/epimut.php.EpiMut is freely available at [https://www.vin.bg.ac.rs/180/tools/epimut.php]