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Diagnostic ultrasound in monitoring patients with rheumatoid arthritis compared to standard clinical disease activity indices
Unatoč ACR/EULAR preporukama o korištenju dijagnostičkog UZV u RA, UZV pregled za sada nije dio standardnih indeksa kojima se prati aktivnosti bolesti, niti je uključen u kriterije remisije. Cilj ovog istraživanja je bio procijeniti vrijednost dijagnostičkog UZV u praćenju bolesnika s RA u odnosu na standardne metode praćenja. Ispitati odnos UZV nalaza s kliničkim, laboratorijskim, radiološkim pokazateljima aktivnosti bolesti, kliničkim indeksima aktivnosti bolesti, funkcionalnim upitnicima te ACR/EULAR kriterijima kliničke remisije. Predložiti model hrvatskog zglobnog bodovnog sustava te novi kompozitni bodovni sustav. Od uključenih 117 RA bolesnika koji su praćeni tokom 3 mjeseca, ukupno ih je 88 završilo istraživanje. UZV pregled je učinjen na predefiniranom setu zglobova i tetiva, a UZV promjene su bodovane prema posljednjim publiciranim konsenzusima stručnih društava. Broj otečenih zglobova, procjena aktivnosti bolesti na VAS skali od strane liječnika, CRP, radiološki verificirane erozivne promjene, CDAI i SDAI indeks su bili najsnažnije značajno povezani s objektiviziranjem upale pomoću UZV. UZV aktivnost je utvrđena kod do 75% (Boolean) odn. 57,1% (SDAI) ispitanika koji su bili u remisiji prema ACR/EULAR kliničkim kriterijima. Kreiran je i validiran CroUS koji obuhvaća RC, MCP2, MCP3, PIP3, koljena, MTP5 zglobove i tetive ECRL/ECRB, EDC, ECU,
tibialis posterior, PB/PL bilateralno. Rezultat kreiranog kompozitnog SonoFIA indeksa (CroUS, HAQ, DAS 28 SE) >8, uz osjetljivost od 83,33% i specifičnost od 61,54% upućuje na visoko aktivnu bolest. Potvrdili smo nužnost implementiranja UZV pregleda u redovni klinički pregled i njegovu dodatnu vrijednost i superiornost u objektiviziranju aktivnosti bolesti i remisije. Smatramo kako bi UZV praćenje aktivnosti RA, temeljem reduciranih bodovnih sustava i kompozitnih bodovnih sustava baziranih na UZV, svoju glavnu primjenu u praksi trebalo naći u dvojbenim kliničkim slučajevima, posebice kod bolesnika u stabilnoj remisiji kod kojih se razmatra redukcija terapije.Although ACR/EULAR recommends using diagnostic US in RA, it is still not incorporated into disease activity indices or remission criteria. The aim was to determine the value of diagnostic US in monitoring RA regarding standard methods
of monitoring. To examine the relationship of US finding with clinical, laboratory, radiological disease activity indicators, clinical disease acitivity indices, functional questionnaires, ACR/EULAR remission criteria. To propose a model of a Croatian
joint scoring system and a novel composite scoring system. 117 RA patients were included and 88 finished the study during the 3 month follow up. US examination was conducted on a predefined joint and tendon set and scored according to the
latest published consensus. SJC, evaluator GDA, CRP, X-ray erosive changes, CDAI and SDAI had the strongest correlation with US findings. US activity was found in up to 75% (Boolean) and 57,1% (SDAI) patients in remission. CroUS (RC, MCP2, MCP3, PIP3, knee, MTP5, ECRL/ECRB, EDC, ECU, tibialis posterior, PB/PL bilateraly) was developed and validated. Composite SonoFIA index (CroUS, HAQ, DAS28 SE) > 8 indicates high disease activity with 83,33% sensitivity and 61,54% specificity. We confirmed the necessity of US implementation into RA monitoring and it's added value and superiority in objectifying disease activity and remission. US monitoring using reduced joint counts and US based composite scoring systems should take place in questionable clinical cases and patients in sustained remission with perspecitve of drug tapering
The possibility of torque reduction in drilling of horizontal wells placing protection ring on the drill pipes joint : doctoral dissertation
Tijekom izrade horizontalne bušotine mogu se pojaviti različiti tehnološki problemi, a najčešće su oni posljedica povećanih vrijednosti momenta torzije i sile natega. Kontakt između niz bušaćih alatki i zaštitnih cijevi/stijenki kanala bušotine uzrokuje povećanje sile trenja, što rezultira povećanom silom natega i momentom torzije tijekom izrade kanala bušotine osobito tijekom izrade zakrivljenih i horizontalnih dionica kanala bušotina. Osim spomenutog trenja također dolazi i do intenzivnog trošenja spojnica bušaćih šipki, s obzirom da je spojnica najširi dio niza bušaćih alatki pa samim tim i u neprestanom kontaktu sa stijenkama kanala bušotine. Najbolji je način za smanjenje momenta torzije i sile natega tijekom bušenja korištenje isplaka na bazi ulja ili sintetičkih isplaka umjesto isplake na bazi vode. Međutim, smanjenje momenta torzije i sile natega može se efikasno postići i na način da se u isplaku na bazi vode, koja je ekološki prihvatljivija dodaju komercijalni podmazivači koji imaju zadatak smanjenje koeficijenta trenja. Budući da se tijekom izrade horizontalnih bušotina velikog dosega najveći dio bušenja odvija kroz ležište, za ovo ispitivanje odabrana je polimerna isplaka (engl. drill-in fluid) odnosno fluid na bazi vode posebno namijenjen za bušenje kroz ležišta. Jedno od mogućih rješenja ovog problema je upotreba zaštitnih kliznih prstenova koji bi bili postavljeni na spojnicu bušaćih šipki u kombinaciji sa aditivima (podmazivačima) u polimernoj isplaci u cilju smanjenja momenta torzije i sile natega. Stoga su za ova istraživanja odabrana tri materijala odnosno poliamid 6 (PA6), politetrafluoretilen (PTFE – u nastavku teksta - Teflon) i polioksimetilen (POM), koji bi se potencijalno mogla koristili kao materijali za izradu zaštitnih kliznih prstenova i koji bi se postavili na spojnicu bušaćih šipki. Također, tijekom ispitivanja korištena su tri komercijalna podmazivača Z, X i Y od dva različita proizvođača, kako bi se ocijenio kumulativni utjecaj podmazivača i zaštitnih kliznih prstenova na smanjenje momenta torzije i sile natega tijekom bušenja. U okviru ovog doktorskog rada laboratorijska ispitivanja su provedena u dvije faze. Prva je faza ispitivanja provedena u Laboratoriju za bušotinske fluide na Rudarsko-geološko-naftnom fakultetu, Sveučilišta u Zagrebu gdje su ispitana osnovna fizikalna svojstva polimerne isplake te je provedeno ispitivanje na uređaju za određivanje podmazivosti isplake. Prva faza ispitivanja podijeljena je na tri dijela gdje su u prvom dijelu ispitana svojstva polimerne isplake u koju je dodan podmazivač Z, u drugom dijelu korišten je podmazivač X, dok je u trećem dijelu provedeno ispitivanje na polimernoj isplaci s podmazivačem Y. Na temelju dobivenih rezultata o podmazivosti polimerne isplake u koju je dodan jedan od tri podmazivača Z, X i Y II u različitim koncentracijama odlučeno je koristiti teflon za nastavak ispitivanja u drugoj fazi s obzirom da su kod njega izmjerene najmanje vrijednosti sile trenja. U drugoj fazi ispitivanja ispitano je trošenje ispitnog bloka izrađenog od teflona na uređaju za mjerenje trošenje strojnih elemenata koji su u kontaktu (Timken) na Fakultetu strojarstva i brodogradnje, Sveučilišta u Zagrebu. Ispitano je trošenje ispitnog bloka izrađenog od teflona u polimernoj isplaci sa i bez oteživača u koju je dodan jedan od tri podmazivača u koncentraciji 2% i 4%, pri sobnoj i povišenoj temperaturi. Nakon analiziranja svih podataka dobivenih na uređaju za mjerenje trošenja strojnih elemenata koji su u neposrednom kontaktu može se zaključiti da je trošenje ispitnog bloka izrađenog od teflona minimalno, odnosno u rasponu od 0,08 do 2,79%, te uglavnom posljedica konstrukcije samog laboratorijskog uređaja na kojem je provedeno laboratorijsko istraživanje kao i postupka ispitivanja. Temeljem provedenih sveobuhvatnih laboratorijskih ispitivanja ostvarena su oba postavljena cilja te su potvrđene postavljene hipoteze, odnosno postavljene dobre osnove za daljnja ispitivanja koja bi trebala voditi ka komercijalizaciji ovog tehničkog rješenja za konkretni problem iz prakse.During the drilling of a horizontal well, various technological problems may occur, and most often they are the result of increased values of torsion moment and drag force. The contact between the drill string and the casing/wellbore causes an increase in the frictional force, which results in an increased drag force and torsional moment while drilling the borehole especially during the drilling of curved and horizontal sections of the borehole. In addition to the mentioned friction, there is also wear and tear of the tool joint of drill pipe, considering that the tool joint is the widest part of a drill string and therefore in constant contact with the borehole of the well. The best way to reduce torsional moment and drag force during drilling is to use oil-based or synthetic muds instead of water-based muds. However, the reduction of the torsional moment and drag force can also be effectively achieved by adding commercial lubricants to the water-based mud, which have the task of reducing the friction coefficient. Since during the drilling of extended reach wells, most of the drilling takes place through the reservoir section, a polymer mud was chosen for this test. One of the possible solutions to this problem is the use of protective sliding rings that would be placed on the tool joint of the drill pipe in combination with additives (lubricants) in the polymer mud to reduce the torsional moment and drag force. Therefore, three materials were selected such as polyamide 6 (PA6), polytetrafluorethylene (PTFE – in the following text - Teflon) and polyoxymethylene (POM), from which it was intended to create a protective sliding ring that would be placed on the drill joint of a drill pipe. Also, three commercial lubricants Z, X and Y from two different manufacturers were used, which have the role of reducing the friction factor and thus the torsional moment and drag force. As part of this doctoral thesis, laboratory tests were carried out in two phases. The first phase of testing was carried out in the Laboratory for Drilling Fluids at the Faculty of Mining, Geology and Petroleum Engineering, University of Zagreb, where the basic physical properties of the polymer mud were tested, and a test was carried out on a device for determining the lubricity of the mud. The first phase is divided into 3 parts where in the first part the properties of the polymer mud to which lubricant Z has been added are tested, in the second part lubricant X, while in the third part lubricant Y is tested. In the first part basic physical properties testing was conducted on polymer mud with weighing agents in which lubricant Z was added in different concentrations from 1% to 6% and the lubricity of the mud using metal block and blocks made from Teflon, PA6 and POM. After analysing the data, it was concluded that increasing the concentration of lubricants to 5% and 6% it did not provide additional decrease IV in friction force, so it was decided to continue with concentrations from 1 to 4%. By this conclusion, same tests were conducted using polymer mud without weighing agents in which lubricant Z was added in different concentrations from 1% to 4%. From the obtained data, it has been decided for the second and third part of testing to use polymer mud with and without weighing agents in which lubricant X or Y was added in a concentration of 0,5% as a minimum value, 2% as a mean value and 4% as a maximum value. In the second and third part of testing same tests were conducted as in the first part. In the second part polymer mud with and without weighing agents in which lubricant X was added in concentrations of 0,5%, 2% and 4%. In the third part of first phase polymer mud with and without weighing agents in which lubricant Y was added in concentrations of 0,5%, 2% and 4%. After analysing all the obtained data on the friction force and mud lubricity, it was observed that the value of the friction force created by using test blocks made of Teflon is the lowest compared to all other test materials such as metal, POM and PA6. Based on this, it was decided to continue the laboratory tests in second phase using test blocks made of Teflon and polymer mud with and without weighing agents in which one of three lubricants Z, X and Y was added in concentrations of 2% and 4%. Second phase of testing is divided in two parts, and it was conducted at the Faculty of Mechanical Engineering and Naval Architecture, University of Zagreb, on a machine that measures mechanical wear of mechanical elements that are in direct contact (Timken) and provide the value of friction factor. The first part was testing mechanical wear of blocks made from Teflon in a polymer mud without weighing agents in which one of three lubricants Z, X and Y was added in concentration of 2% and 4%. To simulate real parameters, the test was conducted at room temperature and at higher temperature (50 °C). The second part was testing mechanical wear of blocks made from Teflon in a polymer mud with weighing agents in which one of three lubricants Z, X and Y was added in concentration of 2% and 4%. After completing all the tests as part of this doctoral thesis, it can be concluded that the use of a test block made of Teflon significantly reduces the friction factor compared to a metal block. Also, after analysing all the data obtained on the device for measuring the mechanical wear of mechanical elements that are in direct contact, it can be concluded that the mechanical wear of the test block made of Teflon is minimal (0.08-2.79%) and considering the imagined idea of placing sliding protective rings on the tool joint of drill pipe should reduce their mechanical wear, i.e. in this specific case, the protective sliding ring will wear out and not the tool join of the drill pipe
The role of aminoacyl-tRNA synthetases in cellular oxidative stress response
Aminoacil-tRNA-sintetaze (AARS) su enzimi koji kataliziraju nastanak kovalentne veze između pripadne aminokiseline i tRNA pri čemu nastaje aminoacil-tRNA, supstrat u procesu translacije. Citosolne AARS zbog redukcijskog okoliša inače nemaju disulfidnu vezu, no pronađena je u kristalnoj strukturi citosolne seril-tRNA-sintetaze (SerRS) iz biljke Arabidopsis thaliana. U ovom radu dizajnirane su jednostruko (SerRS_C213S, SerRS_C244S) i dvostruko mutirane inačice (SerRS_C213S/C244S) i pokazano je da dolazi do reverzibilnog nastajanja disulfidne veze što omogućuje enzimu nepromijenjenu aktivnost u oksidacijskom stresu. Također je istražen utjecaj mistranslacije uzrokovane ugradnjom valina (Val) ili norvalina (Nva) umjesto izoleucina na odgovor na oksidacijski stres. U tu svrhu korišteni su sojevi bakterije Escherichia coli koji eksprimiraju izoleucil-tRNA-sintetazu s inaktiviranom domenom za popravak pogreške (PS7066 i ED-). Rezultati su pokazali da prethodni uzgoj stanica u mistranslatirajućim uvjetima do stacionarne faze uzrokuje bolje preživljenje i rast u oksidacijskom stresu u odnosu na stanice koje nisu rasle u mistranslatirajućim uvjetima. Nadalje, uočeno je da uzgoj stanica s inaktiviranim RpoS-om u mediju s višim koncentracijama valina ili norvalina izaziva adaptaciju na oksidacijski stres koja je neovisna o RpoS-u, dok stanice uzgojene pri nižim koncentracijama valina ili norvalina ne preživljavaju u uvjetima oksidacijskog stresa.Aminoacyl-tRNA synthetases (AARS) are enzymes that catalyze covalent bond formation between cognate amino acid and tRNA to produce aminoacyl-tRNA - substrate in the translation process. Due to the reductive environment, cytosolic AARSs do not have disulfide bonds, however, one was found in the crystal structure of cytosolic seryl-tRNA synthetase (SerRS) from the plant Arabidopsis thaliana. In this study, point (SerRS_C213S, SerRS_C244S) and double mutants (SerRS_C213S/C244S) were designed and it was shown that the reversible disulfide bond formation allows unchanged enzyme activity under oxidative stress. Also, the effect of isoleucine-to-valine (Val) or norvaline (Nva) mistranslation on oxidative stress response was investigated. For this purpose, Escherichia coli strains expressing isoleucyl-tRNA synthetase with a mutation in the editing domain were used (PS7066 and ED-). The results show that prior cell growth in mistranslating conditions to stationary phase leads to higher survival and growth rates under oxidative stress compared to cells that were not grown in mistranslating conditions. Furthermore, it was shown that prior growth of cells with inactivated RpoS in media with higher concentrations of Val or Nva leads to adaptation to oxidative stress that is RpoS- independent, while the cells grown with lower concentrations of Val or Nva do not survive in oxidative stress conditions
Distribution of organic pollutants in the air, total deposited matter, and soil in the city of Zagreb and its surroundings
Onečišćenje zraka je globalni problem koji uzrokuje brojne posljedice po ljudsko zdravlje i okoliš. Dokazano štetne učinke imaju lebdeće čestice u zraku, osobito one ekvivalentnog aerodinamičkog promjera manjeg od 10 μm (PM10) i 2,5 μm (PM2,5), koje mogu u svom sastavu sadržavati brojne toksične tvari. Policiklički aromatski ugljikovodici (PAU) su spojevi od posebnog interesa zbog svog štetnog kancerogenog djelovanja, dok poliklorirani bifenili (PCB) i organoklorovi pesticidi (OCP) pripadaju grupi postojanih organskih onečišćujućih tvari koje karakterizira postojanost, bioakumulacija i toksičnost. Atmosfersko taloženje, uključujući suho i mokro taloženje, koje je ključno za uklanjanje onečišćujućih tvari iz zraka, može imati negativne učinke na ekosustave i posredno na ljudsko zdravlje. Štetni organski spojevi dospijevaju u tlo putem prirodnih procesa taloženja i ljudskom aktivnošću kao što je izlijevanje nafte, neodgovarajuće odlaganje otpada ili uslijed požara. U prvom dijelu istraživanja provedena su preliminarna ispitivanja koja su obuhvatila različite metode priprave uzoraka za određivanje PAU-a, PCB-a i OCP-a u lebdećim česticama u zraku, ukupnoj taložnoj tvari (UTT) i tlu. Postupci kojima je bilo moguće optimalno istovremeno odrediti spojeve iz sve tri grupe primijenjeni su na uzorke UTT-a, frakcije lebdećih čestica PM10 i tla s različitih lokacija u Gradu Zagrebu i okolici. Tijekom tri godine (2020. – 2023. godina) kontinuirano su sakupljani mjesečni uzorci UTT-a na deset lokacija, a tjedni uzorci frakcije lebdećih čestica PM10 sakupljani su na jednom mjernom mjestu tijekom 2022. godine. Kompozitni uzorci površinskog sloja tla uzeti su na istim lokacijama 2022. godine te je provedena fizikalno-kemijska karakterizacija tla i određen sadržaj elemenata. Pronađene su razlike u tokovima taloženja PAU-a između mjernih mjesta, ali su se pokazale statistički značajne samo za PAU-e s četiri aromatska prstena i benzo[a]piren u UTT-u na nekim mjernim mjestima. Za PCB-e i OCP-e u UTT-u nije pronađena statistički značajna razlika između mjernih mjesta. Značajne sezonske razlike u tokovima taloženja uočene su za PAU-e, pojedine heksa- i hepta-PCB-e te izomere HCH, pri čemu su najviše vrijednosti zabilježene zimi. Masene koncentracije spojeva PAU, HCH, DDT i njegovih razgradnih produkata u frakciji lebdećih čestica PM10 bile su značajno više zimi, dok se kod PCB-a sezonski minimum i maksimum razlikovao ovisno o stupnju kloriranja kongenera. Dijagnostički omjeri PAU-a i rezultati faktorske i rojne analize te analize glavnih komponenti, pokazuju prisutnost različitih izvora onečišćenja, ovisno o mjernom mjestu i godišnjem dobu (izgaranje biomase, nafte i fosilnih goriva, emisije iz prometa), dok se prisutnost PCB-a i OCP-a povezuje s povijesnim ili prekograničnim unosima. Primijenjeni statistički alati upućuju na kompleksne međusobne odnose između spojeva te su različito grupirali mjerna mjesta, ovisno o promatranoj sastavnici okoliša. Uz karakter mjernog mjesta i lokalne izvore, na razine PAU-a, PCB-a i OCP-a utječe i sam geografski položaj mjernog mjesta, što je vjerojatno povezano s različitim režimom oborina i strujanja zraka. Značajne linearne korelacije između PAU-a u UTT-u i frakciji lebdećih čestica PM10 te između PCB-a s višim stupnjem kloriranja u UTT-u i frakciji lebdećih čestica PM10 upućuju na zaključak da suho taloženje vjerojatno ima značajnu ulogu u uklanjanju tih spojeva iz atmosfere. Odnosi između pojedinih PAU-a, PCB-a i OCP-a u tlu i UTT-u ukazuju na složene mehanizme kruženja tih spojeva u okolišu.Air pollution is a global issue that leads to various negative outcomes to human health and the environment. Particulate matter in the air, especially that with an equivalent aerodynamic diameter of less than 10 μm (PM10) and 2.5 μm (PM2.5), has been proven to have harmful effects and can contain various toxic substances. Polycyclic aromatic hydrocarbons (PAHs) are compounds of particular interest due to their harmful carcinogenic effects, while polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) belong to the group of persistent organic pollutants characterized by persistence, bioaccumulation, and toxicity. Atmospheric deposition, including dry and wet deposition, is crucial for removing pollutants from the air, but it can have negative effects on ecosystems and, indirectly, on human health. Harmful organic compounds enter the soil through natural deposition processes, as well as due to local events such as oil spills, improper waste disposal, and fires. In the first part of this study, preliminary investigations were conducted, covering various sample preparation methods for determining PAHs, PCBs, and OCPs in particulate matter, total deposited matter (TDM), and soil. Procedures that showed optimal results for the simultaneous determination of all three groups of compounds were selected. The optimized methods were applied to samples of PM10, TDM, and soil at various polluted locations in the city of Zagreb and its surroundings. Over three years (2020–2023), monthly TDM samples were continuously collected at ten locations, and weekly samples of the PM10 fraction of airborne particles were collected at one measurement site in 2022. Additionally, composite samples of the surface soil layer were collected at the same locations in 2022, and the physical and chemical characteristics of the soil and the elements present were determined. Differences in PAHs deposition fluxes between measurement sites were found, but were statistically significant only for PAHs with 4 aromatic rings and benzo[a]pyrene in TDM at some locations.
No statistically significant difference between locations was found for PCBs and OCPs in TDM. Significant seasonal differences in deposition fluxes were observed for PAHs, some hexa- and hepta-PCBs, and HCH isomers, with the highest values recorded in winter. The mass concentrations of PAHs, HCH, DDT and its degradation products in the PM10 were significantly higher in winter, while the seasonal minimum and maximum for PCBs differed depending on the chlorination degree of the compound. The diagnostic ratios of PAHs and results of factor analysis, cluster analysis, and principal component analysis indicated the presence of different pollution sources, depending on the location and season (biomass burning, petroleum and fossil fuel combustion, traffic emissions), while PCBs and OCPs were associated with historical or transboundary inputs. The applied statistical tools indicated complex relationships between compounds and differently grouped locations depending on the observed environmental compartment. In addition to local sources, the geographical location of the measurement site also affects the levels of PAHs, PCBs, and OCPs, likely related to different precipitation regimes and airflow patterns. Significant linear correlation between PAHs in TDM and PM10, as well as between PCBs with higher degrees of chlorination in TDM and PM10, suggested that dry deposition likely played a significant role in removing these compounds from the atmosphere. Relationships between individual PAHs, PCBs, and OCPs in soil and TDM indicated the complex circulation mechanisms of these compounds in the environment
The organization of lithic technology at the site of Campanož in the context of the middle palaeolithic of the Adriatic region
U arheološkim kontekstima litička tehnologija često je informativan izvor o raznim aspektima ljudskog ponašanja. Povezanost litičke tehnologije i sustava korištenja okoliša u vrijeme srednjeg paleolitika dobro je zabilježeni fenomen.
Cilj ovog rada je proučavanje organizacije proizvodnje i ekonomije litičkih artefakata na srednjopaleolitičkom nalazištu Campanož. Nadalje, cilj rada je shvatiti odnos između organizacije proizvodnje i ekonomije te sustava mobilnosti i korištenja okoliša skupina koje su koristile nalazište, u kontekstu poznatog srednjopaleolitičkog ponašanja na Jadrana. Campanož je stratificirano nalazište na otvorenom na prostoru južnog dijela istarskog poluotoka, koje je pronađeno zajedno u kontekstu s prirodnim izvorištem kamene sirovine. U teorijskom smislu analiza se temelji na kombinaciji pristupa lanca operacija, tehnološke organizacije i ljudske bihevioralne ekologije, a iz teorijskih postavki iznesena su očekivanja o odnosu korištenja izvorišta rožnjaka i karakteristika skupa artefakata. Istraživanje je provedeno tehno-tipološkom analizom, koristeći se i rezultatima tafonomske i sirovinske analize.
Rezultati analize pokazuju da su na nalazištu uglavnom korišteni varijeteti sirovine koja potječe sa samog izvorišta. Cijeli postupak proizvodnje, od razokorivanja jezgara do dodatne obradbe oruđa, provođen je na nalazištu. Osim toga, jezgre su odbacivane u različitim stupnjevima redukcije, a razlike u stupnju redukcije mogu se između ostalog povezati i s razlikama u kvaliteti sirovine. Načini proizvodnje odbojaka su raznoliki, a prevladaju diskoidni i centripetalni proizvodni postupci. Rjeđe su zastupljeni dodirujući naizmjenični ortogonalni, jednosmjerni plošni, ortogonalni plošni, višesmjerni višeplošni i volumetrijski postupci. Levaloaški postupak rijetko je zastupljen. Jedan dio artefakata pretvoren je u oruđa, a uglavnom se radi o komadima na lokalnoj sirovini. Osim toga, nekoliko primjeraka svjedoči o donošenju već gotovih artefakata na nalazište. Tafonomski procesi znatno su utjecali na skup, selektivno transportirajući artefakte malih dimenzija, dovodeći do fragmentacije artefakata te ostavljajući brojne površinske modifikacije. Nalazište je posjećivano kroz dugi vremenski period, o čemu svjedoče razlike u površinskim modifikacijama artefakata.
Usporedba s određenim nalazištima s prostora Jadrana pokazuje da su s obzirom na prosječne dimenzije jezgara i nizak stupanj redukcije odbojci i oruđa relativno malih dimenzija. Uz to, poredba s nalazištima na otvorenom iz sjeverne Dalmacije pokazuje da je i udio odbojaka iz rane faze redukcije nešto slabije zastupljen. Ovi podaci sugeriraju da je s nalazišta odnesen dio odbojaka, ponajprije većih primjeraka koji su često bili i okorinski. Osim toga, usporedba s drugim nalazištima koja su smještena na izvorištima sirovine ukazuje na relativno visoki udio oruđa u skupu s Campanoža, što zajedno s korištenjem svrsishodnih proizvodnih postupaka sugerira da je samo izvorište bilo nastanjivano.
Navedeni podaci interpretirani su kao rezultat aktivnosti rezidencijalno vrlo mobilnih skupina neandertalaca, koje su izvorište koristile za opskrbu pokretnim priborima oruđa. Pri tome je nalazište možda korišteno i kao rezidencijalni kamp. Pri posjeti nalazištu osim sirovine iskorištavani su i otpadci ranijih posjeta, što je vidljivo iz recikliranih artefakata. Osim toga, zasad su dostupni samo dokazi za korištenje lokalnog okoliša, u rasponu do 8 km. Iznesen je preliminarni model o mogućim okolišnim uvjetima na prostoru istarske krške zaravni tijekom pleistocena u kojima bi navedeni sustav korištenja okoliša bio moguć. Naposljetku, u radu se u kontekstu geomorfoloških karakteristika istarske krške zaravni stavlja naglasak na buduće perspektive rada na srednjopaleolitičkim nalazištima na otvorenom.In archaeological contexts, lithic technology is often seen an informative source about various aspects of human behaviour. The relationship between lithic technology and land use systems during the Middle Palaeolithic is a well-documented phenomenon.
The aim of this thesis is to study the organization of production and the economy of lithic artifacts at the Middle Palaeolithic site of Campanož. Furthermore, the goal of the paper is to understand the relationship between the organization of production and economy, and the mobility patterns and land use systems of the groups that used the site, framed within the context of the known Middle Palaeolithic behaviour on the Adriatic. Campanož is a stratified open-air site located in the southern part of the Istrian Peninsula, found in association with a natural source of stone raw material. The site was excavated in 2010 and 2011, revealing a rich assemblage of more than 100.000 chert finds, among which artefacts were found. More than 6.000 artefacts were recognized among the finds, and among these a sample of about 1.500 finds was selected for analysis.
The theoretical background of the research was based on an approach combining aspects of chaîne opératoire, technological organization, and human behavioural ecology. Borrowing concepts from these approaches, theoretical assumptions were made about the relationship between the use of the chert source and the characteristics of the resulting artefact assemblage. The research was conducted through techno-typological analysis, while also utilizing results from taphonomic and raw material analyses. More specifically, quantitative-based attribute analysis of the artefacts was combined with a techno-economic analysis, as well as a classification of cores according to a reading of the flaking orientations, their chronological relationships and the roles of different core parts in the reduction process.
The results of the analysis show that the varieties of raw material used at the site mainly came from the source itself. The raw materials are residual, as they were released into the soil by the dissolution of the underlying limestone and subsequently exposed on the surface by erosional processes, thereby becoming available to hominin exploitation. The entire reduction process, from core decortication to the retouching of tools, was conducted on-site. Cortical elements are well represented and show that both whole and fragmented pieces of raw material were used. Raw materials of different shapes were used, and examples of nodules, lenticular nodules, thin platy pieces and fosill sponges. There is a variation among the raw material in terms of silicification, and the better-quality raw materials make up only a minor part of the entire assemblage. The differences in reduction among artefacts can, among other things, be linked to variations in the quality of the raw material.
Cores were discarded at different stages of reduction, which included cores in the strict sense, as well as cores on flakes. The ways of producing flakes were diverse, with discoid and centripetal methods predominating. Less common were secant alternating orthogonal, unidirectional unifacial, orthogonal unifacial, multidirectional multiplatfom, and volumetric methods. The Levallois method is rarely represented. Discoid and centripetal cores display the greatest size ranges, while some core types are only found in small sizes. Additionally, there are differences in the utilized raw material forms among the different production methods. Thus, some of the variation in core reduction may be due to the application of similar methods on different raw material forms. Likewise, some methods may represent the final exploitation phases of other production methods. The application of different methods accounts for a certain degree of variability in flake form.
Some of the artefacts were retouched into tools, and these were also almost entirely made from local raw material. Scrapers predominate, but the proportion of notches and denticulates, Upper Palaeolithic types and retouched flakes are significant. Several tools were made by directly retouching natural pieces. Interestingly, some of the typological variation in the assemblages is accounted for by differences in original flake form. Tools are significantly larger than unretouched flakes in the assemblage. Additionally, several specimens suggest that finished artefacts were brought to the site.
Taphonomic processes significantly impacted the assemblage. Data on patination, frost damage. abrasion and edge damage suggest that artefacts were exposed on the surface for a long period. Furthermore, differences in the frequency of these surface alterations suggests that different parts of the assemblage experienced different amount of exposure to taphonomic processes. Thermal damage and trampling are responsible for fragmenting a significant proportion of artefacts. A small percentage of artefacts were exposed to fire, but there is no clear indication whether that was due to natural fires or from hominin activity. Particle-size analysis suggests that small-sized artefacts, i.e. those smaller than 15 mm have been selectively transported from the analysed area. Therefore, erosional processes, primarily overland flow, acting on a slightly inclined slope, resulted in the modification of the assemblage by systematically removing smaller artefacts downslope from the studied area.
A comparison with certain sites in the Adriatic region shows that, considering the average dimensions of the cores and the low degree of reduction, the flakes and tools from Campanož are relatively small in size. Furthermore, comparison with open-air sites from northern Dalmatia, some of which are associated with raw material sources, indicates that the flakes from the early reduction phases are somewhat underrepresented. These data suggest that some flakes, particularly larger specimens, were likely removed from the site, and these were often cortical. The practice of transporting flakes from the site corresponds to the strategy of provisioning individuals with tools. That type of strategy is indicative of residentially highly mobile groups, which rely on portable personal toolkits for performing activities in their daily lives. On the other hand, a comparison with other case studies of open-air sites located at raw material sources indicates a relatively high proportion of tools in the Campanož assemblage, which, together with the use of expedient production techniques, suggests that the source itself might have been inhabited.
The lithic assemblage of Campanož is interpreted as resulting from activities by residentially highly mobile Neanderthal groups, who used the source to supply their portable toolkits. During visits to the site, not only natural pieces of raw material were utilized but also the knapping waste from previous visits, as seen in the occurrence of recycled artifacts. In addition, raw material source sites could have been occupied occasionally, when the conditions were favourable. So far there is only evidence for the use of the local environment, within a range of up to 8 km. A preliminary model of possible environmental conditions in the Istrian karst peneplain during the Pleistocene in which the described system of environmental use would have been feasible is proposed, revolving around the sequential exploitation of resource concentrations around karstic wetland features. Also emphasized is the topographic uniformity of the area, which given the relative paucity of sites with strategic importance in monitoring animal movement, could have made open-air sites more attractive for settlement, including raw material sources. Finally, the paper emphasizes future perspectives for research on open-air Middle Paleolithic sites in the context of favourable geomorphological characteristics of the Istrian karst peneplain
Ograničavanje nuklearne energije simetrije koristeći kulonsko pobuđenje izotopa kositra bogatih neutronima pri relativističkim energijama
Relativistic Coulomb excitation of neutron-rich nuclei can be utilized to study the symmetry energy - a crucial yet still fairly enigmatic ingredient of the nuclear equation of state. Projectile nuclei are accelerated to relativistic velocities in inverse kinematics towards the Coulomb field of a high-Z target. Collective Coulomb excitations arise in projectile nuclei, whereby neutron and proton densities are displaced with respect to each other. An isospin imbalance forms in the system, which makes a suitable environment to probe the slope of the symmetry energy L, i.e., the linear coefficient in the expansion of the symmetry energy around the saturation density. An experiment aiming to constrain the parameter L was carried out using the large acceptance spectrometer R⌃3B-GLAD at the GSI accelerator facility, as a part of the FAIR Phase-0 campaign. Tin isotopes in the mass range A = 124 − 134 were produced as a secondary beam via fragmentation and fission reactions at energies close to 1 GeV/u and impinged onto the lead target to induce Coulomb excitations. After the deexcitation process, during which neutrons and γ-rays are emitted, the outgoing particles – including the residual fragment – were detected using the R⌃3B setup. This allowed for the measurement of the Coulomb-excitation cross section σ_C above the one-neutron separation threshold. In this work, an approach to constrain the slope of the symmetry energy, first suggested by A. Horvat and collaborators at GSI, was studied. Namely, σ_C of neutron-rich nuclei at relativistic energies correlates with the dipole polarizability α_D, owing to their similar functional dependence on excitation energy. Through the established correlation between α_D and L, measurement of the said cross section enables placing constraints on the slope of the symmetry energy via comparison with theoretical calculations. Coulomb-excitation cross sections were determined for the tin isotopes 124⌃Sn, 130⌃Sn and 132⌃Sn. The dipole response, characterized by the transition strengths B(E1) and B(E2), was computed using the Quasiparticle Random Phase Approximation with a variety of energy density functionals. Based on these inputs, Coulomb-excitation cross sections were subsequently evaluated using both first-order perturbation theory and the coupled-channel approach. A comparison between theoretical predictions and experimental measurements revealed a systematic discrepancy, with the theoretical calculations consistently overestimating the observed cross sections. Potential sources of this discrepancy are discussed in detail. It is concluded that resolving this inconsistency is necessary to give a reliable constraint on L. This will require close and continued collaboration between theoretical and experimental efforts.Relativisticko kulonsko pobuđenje jezgara bogatih neutronima može se koristiti u svrhu proučavanja energije simetrije – ključne, ali još uvijek nedovoljno poznate komponente nuklearne jednadžbe stanja. Takvi eksperimentalni uvjeti zahtijevaju korištenje inverzne kinematike. Nestabilne jezgre akceleriraju se do relativističkih brzina kao projektili i sudaraju s metom velikog atomskog broja Z. Dolazi do kulonskog pobuđenja projektila prilikom kojeg se u dotičnoj jezgri razdvajaju protonska i neutronska gustoća. Drugim riječima, u sustavu nastaje izospinska neravnoteža, što predstavlja pogodno okruženje za ispitivanje nagiba energije simetrije L, odnosno linearnog koeficijenta u Taylorovom razvoju energije simetrije oko gustoće saturacije. U svrhu proučavanja nuklearne jednadžbe stanja, proveden je eksperiment koristeći postav R⌃3B-GLAD na akceleratorskom postrojenju GSI, u sklopu kampanje FAIR Phase-0. Izotopi kositra u masenom rasponu A = 124 − 134 proizvedeni su kao sekundarni snop putem fragmentacijskih i fisijskih reakcija pri energijama oko 1 GeV/u. Kulonska pobuđenja inducirana su u električnom polju olovne mete, a izlazne čestice detektirane su pomoću postava R⌃3B-GLAD, što je omogućilo mjerenje udarnog presjeka kulonskih pobuđenja iznad energije separacije jednog neutrona. U ovom radu istraživan je pristup ograničavanja nagiba energije simetrije preko korelacije s udarnim presjekom kulonskih pobuđenja σ_C koji su prvi put predložili A. Horvat i kolaboratori na institutu GSI. Naime, σ_C u jezgrama bogatim neutronima pri relativističkim energijama korelira s dipolnom polarizabilnošću α_D , što proizlazi iz njihove slične funkcijske ovisnosti o energiji pobuđenja. Uzevši u obzir dobro poznatu korelaciju između α_D i parametra L, očekivana je korelacija između σ_C i L što omogućuje ograničavanje spomenutog parametra usporedbom mjerenja udarnog presjeka i teorijskih izračuna. Udarni presjeci kulonskih pobuđenja izmjereni su za izotope kositra 124⌃Sn, 130⌃Sn i 132⌃Sn. Dipolni odziv, opisan reduciranim vjerojatnostima prijelaza B(E1) i B(E2), izračunat je koristeći aproksimaciju nasumičnih faza uz primjenu različitih energijskih funkcionala gustoće. Zatim su udarni presjeci kulonskih pobuđenja, koristeći dobivene B(E1,E2) vrijednosti, izračunati pomoću prvog reda računa smetnje te metodom vezanih kanala. Između teorijskih predviđanja i izmjerenih udarnih presjeka za sva tri proučavana izotopa uočeno je značajno odstupanje pri čemu teorijski izračuni sustavno precjenjuju mjerenja. Mogući uzroci tog odstupanja detaljno i su diskutirani. Zaključeno je da, uz ovakvo neslaganje eksperimentalnih mjerenja i teorijskih izračuna, nije moguće pouzdano ograničavanje nagiba energije simetrije. Bliska i kontinuirana suradnja između teorijskih i eksperimentalnih istraživanja neophodna je za pronalaženje uzroka ovom neslaganju
UTJECAJ ISTOVREMENE MANIPULACIJE DNA I HISTONA NA EKSPRESIJU GENA UKLJUČENIH U EPITELNO-MEZENHIMSKU TRANZICIJU PRIMJENOM SUSTAVA CRISPR/dCas9
Interplay between epigenetic modifications is essential for regulation of gene expression.
The adaptation of CRISPR/Cas9 technology for epigenetic research by introducing dead Cas9
(dCas9) fused to epigenetic effector domains (ED) has enabled significant advancements in this
field. I expanded the CRISPR/dCas9 modular system with five histone modifying domains
(G9a, G9a-me3, LSD1, KDM5A, macro1.1) and DNMT3L domain, as well as the multi-guide
module to accommodate up to 11 gRNAs. From a set of candidate genes involved in epithelial
to mesenchymal transition (EMT), ZEB1 and SNAI1 were selected for further epigenetic
manipulations in HepG2 cell line. Their CpG islands were simultaneously targeted with dCas-
DNMT3A combined with specific dCas9-ED fusions to understand the interplay of DNA
methylation and histone modifications. The combinations had synergistic effect on gene
expression and affected the EMT phenotype. Interplay between introduced modifications was
also observed as a locus specific synergistic increase in DNA methylation, and was not
disrupted by global histone acetylation increase after sodium butyrate treatment. The
combinatorial epigenetic effects were not replicated in A549 cell line, suggesting specificity of
epigenetic regulatory pathways.Međudjelovanje epigenetičkih modifikacija je neophodno regulaciju ekspresije gena.
Korištenje CRISPR/Cas9 tehnologije u epigenetičkim istraživanjima pomoću inaktivnog Cas9
(dCas9) fuzioniranog s epigenetičkim efektorskim domenama (ED) omogućilo je značajan
napredak u ovom području. Proširila sam modularni sustav CRISPR/dCas9 s pet domena za
modifikaciju histona (G9a, G9a-me3, LSD1, KDM5A, makro1.1) i domenom DNMT3L, te
„multi-guide“ modul koji može primiti do 11 gRNA. Od nekoliko kandidat gena koji sudjeluju
u epitelno-mezenhimskoj tranziciji (EMT), odabrala sam ZEB1 i SNAI1 za daljnje epigenetičke
manipulacije u staničnoj liniji HepG2. Njihovi CpG otoci su istovremeno ciljani s DNMT3AdCas9
u kombinaciji s određenom dCas9-ED fuzijom kako bi se istražilo među-djelovanje
DNA metilacije i modifikacija histona. Kombinacije su imale sinergistički učinak na ekspresiju
gena i utjecale su na EMT fenotip. Simultano uvedene modifikacije pokazale su sinergistički
efekt na razini metilacije DNA na određenom lokusu, koji nije bio osjetljiv na povećanje
globalne acetilacije histona. Kombinacije dCas9 fuzija nisu djelovale na ekspresiju ciljanih
gena u A549 staničnoj liniji, što ukazuje na specifičnost epigenetičkih regulatornih putova
IMMUNOGLOBULIN G GLYCOSYLATION IN DOWN SYNDROME
Glikozilacija je jedna od najčešćih ko- i posttranslacijskih modifikacija proteina. Glikani vezani na imunoglobulin G (IgG) utječu na njegovu strukturu i funkciju i mijenjaju se s dobi te u brojnim fiziološkim i patološkim stanjima organizma. Znakovi preuranjenog starenja, kao i brojne druge bolesti, česti su kod Downova sindroma (DS). Tekućinskom kromatografijom ultravisoke učinkovitosti analizirana je glikozilacija IgG-a u tri populacije osoba s DS-om za koje su postojali klinički podaci o najčešćim komorbiditetima i uspoređena s onom njihovih zdravih vršnjaka. Proučen je utjecaj produkata gena kromosoma 21 B3GALT5, RUNX1 i DYRK1A na glikozilaciju IgG-a u DS-u digestijom glikana IgG-a egzoglikozidazama te kemijskom inhibicijom produkata gena u limfoblastoidnim staničnim linijama. Pokazano je kako glikozilacija IgG-a osoba s DS-om neovisno o učestalim komorbiditetima odgovara kronološki starijim zdravim osobama. U korištenim eksperimentalnim sustavima RUNX1 ima izravan utjecaj na glikozilaciju IgG-a u DS-u, dok B3GALT5 i DYRK1A nemaju.Glycosylation is one of the most common co- and posttranslational modifications. Glycans attached to immunoglobulin G (IgG) affect its function and change with age and in numerous physiological and pathological conditions. Signs of premature aging, along with many other diseases, are common in Down syndrome (DS). IgG glycosylation of three DS populations that had clinical data on the most common comorbidities was analyzed by ultra-high performance liquid chromatography and compared to their healthy peers. The impact of chromosome 21 gene products B3GALT5, DYRK1A and RUNX1 on IgG glycosylation was studied using enzymatic digestions of IgG glycans and IgG-producing lymphoblastoid cell lines obtained from individuals with and without DS. IgG glycosylation was revealed to be significantly shifted in the direction of aging in DS, showing a ubiquitous trend independent of comorbidities, and an insight into the effect of gene products B3GALT5, DYRK1A and RUNX1 on IgG glycosylation was provided
Selective degradation of misfolded proteins in quiescent yeast Saccharomyces cerevisiae
Kako bi se zaštitile od nakupljanja pogrešno smotanih proteina, stanice su razvile mehanizme za kontrolu kvalitete proteina, uključujući put selektivne razgradnje sustavom ubikvitin-proteasoma. Prethodna istraživanja kontrole kvalitete proteina uglavnom su provedena u stanicama koje se aktivno dijele, međutim mnoge stanice, poput neurona i matičnih stanica u mirovanju, se ne dijele. U ovoj disertaciji istražili smo puteve selektivne razgradnje proteina u stanicama u mirovanju, koristeći modelni organizam, kvasac Saccharomyces cerevisiae. Po ulasku stanica kvasca u mirovanje aktivira se autofagija, a veliki dio proteasoma reorganizira se u granule u kojima proteasomi vjerojatno nisu aktivni, stoga nije bilo jasno oslanjaju li se stanice u mirovanju na sustav ubikvitin-proteasoma za eliminaciju pogrešno smotanih proteina. U ovom radu uspostavili smo ekspresiju modelnih pogrešno smotanih proteina tGnd1, stGnd1 i Ubc9ts u stanicama u mirovanju, koristeći PIR3- i Z-promotore. Pokazali smo da stanice u mirovanju prepoznaju pogrešno smotane proteine te ih usmjeravaju u selektivnu razgradnju, čak i u kasnijim fazama mirovanja. Nadalje, razgradnja je ovisila o aktivnosti E3 ligaza ubikvitina Ubr1 i San1, te proteasomu, što upućuje na sličan put razgradnje kao u proliferirajućim stanicama. Sveukupno rezultati pokazuju da stanice kvasca u mirovanju zadržavaju funkcionalnu kontrolu kvalitete proteina, te da se ona primarno temelji na selektivnoj razgradnji proteina.To prevent the negative impact of misfolded protein accumulation, cells have developed protein quality control pathways, including selective degradation by the ubiquitin-proteasome system. Previous research on protein quality control has mostly been conducted in actively dividing cells. However, many cells, such as neurons and quiescent stem cells, are non-dividing. In this thesis, we investigated selective protein degradation in quiescent cells, using yeast Saccharomyces cerevisiae as a model organism. Upon entry into quiescence, yeast cells induce autophagy, and a large portion of the proteasomes relocalizes into cytoplasmic granules, presumably in an inactive form. Therefore, it has been unclear whether quiescent cells rely on the ubiquitin-proteasome system for the elimination of misfolded proteins. In this study, we established an expression system of model misfolded proteins tGnd1, stGnd1, and Ubc9ts in quiescent cells using PIR3- and Z-promoters. We show that quiescent cells recognize misfolded proteins and direct them to selective degradation, even in the later stages of quiescence. Furthermore, degradation was dependent on the E3-ubiquitin ligases Ubr1 and San1 and the proteasome, suggesting a similar pathway as in proliferating cells. Overall, the results show that quiescent yeast cells maintain functional protein quality control, which is primarily based on selective protein degradation
Assessment of cognitive functions in psoriatic arthritis patients
Uvod: Cilj istraživanja bio je procijeniti kognitivne funkcije u bolesnika sa psorijatičnim artritisom (PsA).
Ispitanici i metode: U istraživanje presječnog tipa konsekutivno su uključeni bolesnici sa PsA (N= 67) i zdravi ispitanici (N= 69).
Kognitivne funkcije procijenjene su pomoću Montrealskog testa kognitivne procjene (MoCA) i testa utiranja puta (TMT) A i B. Simptomi depresije i anksioznosti testirani su pomoću Beckovog inventara depresije-II te Upitnika anksioznosti kao stanja i osobine ličnosti. Učinjena je standardna klinička procjena PsA i psorijaze.
Rezultati: Bolesnici sa PsA imali su značajno lošije rezultate na TMT-A testu (p˂0,01). Nije bilo razlike između skupina u rezultatima MoCA i TMT-B testa. Svi testovi procjene kognitivnih funkcija korelirali su s dobi ispitanika, a TMT-B dodatno s obrazovnim statusom. Nije nađena korelacija između testova procjene kognitivnih funkcija i kliničkih parametara psorijatične bolesti, depresije i anksioznosti. U regresijskoj analizi, dob ispitanika pokazala se značajnom u predviđanju rezultata MoCA testa, objašnjavajući oko 18% varijance. U bolesnika sa PsA primijećene su značajno više razine depresivnosti, anksioznosti i umora (p=0,02; 0,015; odnosno 0,004).
Zaključak: Bolesnici sa PsA potencijalno imaju povišen rizik kognitivnog oštećenja. Potrebna su daljnja istraživanja kako bi se preciznije odredio rizik kognitivnog propadanja u PsA.Objective: The objective of this study was to assess cognitive functions in patients with psoriatic arthritis (PsA).
Methods: Patients with PsA (N= 67) and healthy subjects (N= 69) were consecutively enrolled in this cross-sectional study. Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) and the Trail Making Test (TMT) A and B. Depression and anxiety were evaluated using the Beck Depression Inventory-II and the State-Trait Anxiety Inventory. A standard clinical assessment of PsA and psoriasis was performed.
Results: Patients with PsA scored significantly worse on the TMT-A test (p˂0.01). No differences in the MoCA and TMT-B scores were found. All cognitive assessment tests correlated with age, and TMT-B also correlated with educational status. No correlation was found between cognitive assessment tests and PsA disease-related parameters, depression or anxiety. In the regression analysis, age was found to be a significant predictor of the MoCA score, explaining 18% of the variance. Patients with PsA exhibited significantly higher levels of depression, anxiety and fatigue (p=0.02, 0.015, and 0.004, respectively).
Conclusion: Patients with PsA may be at an increased risk of cognitive impairment. Further research is needed to specify the risk of cognitive decline in PsA