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The Dinaric Karst is a global hotspot for subterranean diversity, with two distinct peaks of species richness in the northwest and southeast, and an area of a lower species richness in the central part. In this article, we present a species list and describe the ecological conditions of the Lukina jama–Trojama cave system, located in the central part of the Dinaric Karst. This cave system is the deepest and one of the most logistically challenging cave systems sampled so far in the Dinaric Karst. Repeated sampling resulted in a list of 45 species, including 25 troglobionts, 3 troglophiles, 16 stygobionts, and 1 stygophile. Most of the recorded species are endemic to the Velebit Mountain, while three species are endemic to the Lukina jama–Trojama cave system. Within the system, species richness peaks in the deepest third of the cave, most likely reflecting the harsh ecological conditions in the upper parts, including ice, cold winds, and occasional waterfalls. Milder and more stable deeper parts of the cave contain a rich subterranean species community, part of which is associated with two very distinct aquatic habitats, the cave hygropetric and the phreatic zone. The newly recognized hotspot of subterranean biodiversity in the central Dinaric Karst, which has emerged between the two known centers of biodiversity, further highlights the species richness in large cave systems, but also challenges the diversity patterns in the Dinaric Karst overall.

Animals that are not fully troglomorphic are often neglected in cave biology studies. However, they can provide important insights into the early stages of cave colonization. This is especially true when a surface population is also present and available for comparative studies. Although fishes are not uncommon in caves of the Dinaric Karst, it is generally believed that there are no cave-adapted fishes in this region. Several genera of fishes, such as Delminichtys, Telestes, and Phoxinellus, are known to be associated with caves, as they have been reported to retreat to caves during dry periods and spend several months underground until favorable conditions return. Data on such populations and their occurrence in caves are sparse, but during recent intensive surveys of Sušik Cave, Velika Kapela Mt, Croatia, cavers have frequently encountered fish. Sušik cave is a sinkhole of the small stream inhabited by a single endemic fish species, Telestes karsticus. Therefore, we set out to investigate whether T. karsticus lives permanently in Sušik Cave, how large the cave population is, and whether it exhibits any cave-adaptive characteristics. Our results show that T. karsticus lives in Sušik Cave throughout the year and its population is estimated to be several hundred individuals. Moreover, we found morphological and physiological characteristics that clearly distinguish it from the neighboring surface population. Therefore, Telestes karsticus forms a permanent cave population and the presence of a conspecific surface population makes it a potentially important model system for understanding the initial adaptive processes that occur during cave colonization.

Monografija životinja pronađenih u Gornjoj i Donjoj Baraćevoj špilji.

Builds on different theoretical paradigms and traces a variety of haunted spaces in horror film and literature. Explores the unique role of human geography in the process of mapping a genre. Comprehensive reading of a space/place-based experience as it relates to the birth of the American horror genre.

Many aspects of the biology of cave animals cannot be understood simply by in situ observations. This is especially true for comparative evolutionary and developmental studies. For example, for studying physiological and behavioral adaptations or the role of phenotypic plasticity in the evolution of adaptations, animals must be kept under controlled laboratory conditions. For this reason, we have established an animal facility in our laboratory where we plan to culture cave species from different taxonomic groups and their close surface relatives. The available literature to help us design the facility and care for the animals in the initial stages was sparse. Fortunately, many colleagues in cave biology contributed with advice and assistance. Here we report our findings to provide some guidelines for other researchers in similar endeavors. We will briefly discuss good and bad practices related to animal care - housing, water treatment, small terrarium design, different types of food, and breeding. We will also address general protocols necessary for keeping different species closely together - decontamination of equipment and tools and quarantine. To date, we have successfully established breeding colonies of four different cave/surface species pairs and several others have survived in our facility for many months, if not years, including planarians, crustaceans, and mollusks.

Purpose: Randomized controlled clinical trials are driven by time-given protocols defined by strict exclusion and inclusion criteria. As a result, clinical trials provide the best possible outcomes regarding the efficacy and safety of investigational medical products. Nonetheless, the implementation of protocols suggested by clinical trials has been shown as non-pragmatic into standard treatment care. Not following the protocols recommended by clinical trials in our standard routine treatment care does not provide the benefits of therapy as clinical trials suggest. Therefore, we wanted to investigate whether our proposed treatment protocols with diabetic macular oedema, designed for standard treatment of care, may achieve non-inferior results compared to clinical trials where the non-inferiority was defined by a difference in the vision of up to 10 ETDRS letters. Methods: Manuscripts amalgamated in this doctoral thesis involved patients with fovea-involving macular oedema who were eligible for treatment with intravitreal anti-VEGF injections. All patients applied met the National Institute of Care and Excellence (NICE) criteria for treatment (center-involving diabetic macular oedema ³ 400 microns) and with baseline visual acuity (VA) equal to or less than 80 ETDRS letters. All patients were treated in Moorfields Eye Hospital NHS Foundation Trust, in London, UK. The primary cohort of interest (treatment-naive cohort) involved 89 patients (99 eyes) who were treatment-naive and funded for intravitreal aflibercept injections. We analyzed primary, secondary and tertiary outcomes in short and long terms. In addition, we wanted to see whether those patients who had started treatment on a different anti-VEGF agent (ranibizumab as another licensed anti-VEGF product in the United Kingdom) and didn't respond well to the initiated treatment may benefit from switching to intravitreal aflibercept injections, which may have more potent effect as per available pharmacokinetic data. Therefore, we formed a second cohort that involved 67 switched patients (90 eyes) who had started treatment with intravitreal ranibizumab and were switched to intravitreal aflibercept. In both cohorts, the primary outcomes were visual acuity (VA), central foveal thickness (CFT), and macular volume (MV) 12 months after treatment was commenced/after switching off a drug. The analysis of the same primary outcomes was performed for the treatment-naive cohort 36 months after initiating treatment. Then, we calculated the percentage of eyes that achieved visual acuity gain of ³ 15 ETDRS letters and the percentage of eyes that achieved improvement in CFT for 100 microns or more at the end of year 1 and year 3. As tertiary outcomes, we made a subgroup analysis according to the baseline VA (< 69 ETDRS letters or ³ 69 ETDRS letters). For switched cohorts, we analysed whether the time of switching plays a role in overall results. Results The mixed ANOVA analysis showed no statistically significant difference in baseline variables and 12-month outcomes between short- and long-term followed treatment naïve patients and switched patients. The mean change in vision after three years of initiation of treatment with intravitreal aflibercept injections was +6.89 EDTRS letters, while improvement in CFT and MV during the same time was -140 microns and – 1.38 mm3, respectively. At the end of follow-up of 36 months, 25% of patients improved vision for three or more ETDRS lines (15 letters or more). Just more than 50% of patients had improvement in central foveal thickness for 100 microns or more. Fifty-eight percent of eyes of the primary cohort had baseline visual acuity less than 69 ETDRS letters. The mean change in visual acuity in the subgroup with baseline VA less than 69 letters was +11.27 ETDRS letters (p < 0.0001). Forty-two percent of eyes from the primary cohort had baseline visual acuity ³ 69 ETDRS letters). The mean change in the visual acuity after 36 months in that subgroup was + 0.88 ETDRS letters (p = 0.6041). We sub-divided the switched eyes into two subgroups according to the duration of time between the ranibizumab being discontinued and the aflibercept commencing; 53 eyes were switched with an interval of fewer than three months after the last injection of ranibizumab, and 37 eyes were switched after three months or more had elapsed. There was no statistically significant difference in outcomes ( p > 0.05) between those subgroups. Conclusion Our short and long-term results of visual acuity and anatomical outcomes in patients with sight-impairing, center-involving diabetic macular oedema treated with intravitreal aflibercept showed a significant improvement in vision, comparable with results suggested by landmark clinical trials. Furthermore, our results were non-inferior when compared to landmark clinical trials related to the safety and efficacy of intravitreal aflibercept in the treatment of DMO (VIVID, VISTA, and Protocol T). Our subgroup analysis based on baseline visual acuity proved the importance of starting treatment when visual acuity is initially better. We achieved stable vision over three years of follow-up in those whose baseline visual acuity was 69 ETRDS letters or better (up to 80 ETDRS letters). Those patients kept their good vision which meets driving criteria. Our results are the first published results from the real world, which show the importance of planning the treatment guided by baseline vision, which was first indicated in the Protocol T study. Regarding the results in our switched cohort, we showed that switching from intravitreal ranibizumab to intravitreal aflibercept has a rationale for speeding up the visual recovery and improving the anatomical outcomes in everyday life offer patients sooner improvement and better functioning by using their vision. We proved that time of switching does not play a role in primary outcomes (VA, CFT, MV), which may indicate that indeed the reason for clinical improvement in our switched cohort relies on the mechanism and pharmacokinetics of the aflibercept molecule., Svrha: Randomizirane kliničke studije su vođene striktno vremenski određenim protokolima koji su definirani isključujućim kriterijima. To rezultira činjenicom da kliničke studije prikazuju najbolje moguće rezultate medicinskih proizvoda, koji su u fazi istraživanja. Ipak, protokoli koje predlažu randomizirane kliničke studije nepragmatičnim u standarnoj kliničkoj praksi. Ukoliko se protokoli koje predlažu randomizirane kliničke dovesti do suboptimalnih rezultata liječenja. Stoga, htjeli smo istražiti može li naš protokol za liječenje dizajniran za potrebe standardne kliničke prakse, postići neinferiorne rezultate u komparaciji sa kliničkim neinferiornost definirana razlikom u vidnoj oštrini do 10 ETDRS slova. Metodologija: Publikacije objedinjene u ovu doktorsku dizertaciju uključuju pacijente sa makularnim edemom koji zahvaća kriterije za liječenje intravitrealnim anti-VEGF injekcijama. Svi pacijenti zadovoljavaju kriterije za liječenje 400 microna) prema uputi National Insititute of Care and Excellence (NICE) i sa bazičnom vidnom oštrinom od 80 ETDRS slova. Svi pacijenti su liječeni u Moorfields Eye Hospital NHS Foundation Trust, u Londonu, Kohorta pacijenata od primarnog interesa (tretman-naivna) uključivala je 89 pacijenata (99 očiju) koji terapiju i kojima je trošak liječenja intravitrealnim injekcijama bio odobren. Analizirali smo kratkoročno sekundarne i tercijarne rezultate. Zatim, željeli smo vidjeti jeli pacijenti koji su započeli liječenje drugim je drugi licencirani anti-VEGF lijek u Ujedinjenoj Kraljevini), a koji nisu odgovorili dobro na inicijalnu terapiju, zamjene na injekcije intravitrealnog aflibercepta. Intravitrealni aflibercept bi trebao imati bolju efikasnost informacija o farmakokinetici. Stoga, formirali smo drugu kohortu pacijenata koja je uključivala 67 pacijenata primarno započeli tretmant intravitrealnim ranibizumabom, a zatim je liječenje zamijenjeno intravitrealnim U obje kohorte, primarni ishod su bili vidna oštrina (VO), centralna fovealna debljina (CFD), te makularni nakon započetog liječenja, odnosno nakon zamjene lijeka. Analiza primarnih rezultata je također napravljena kohortu pacijenata 36 mjeseci nakon započetog liječenja. Zatim, izračunali smo postotak onih očiju koje oštrine za ³ 15 ETDRS slova te poboljšanje CFD za 100 mikrona ili više na kraju prve i treće godine. Kao smo podgrupnu analizu na temelju početne vidne oštrine (< 69 ETDRS slova ili ³ 69 ETDRS slova). Za zamijenili lijek, napravili smo analizu ima li vrijeme promjene lijeka efekt na konačan ishod liječenja. Rezultati Miješana ANOVA analiza pokazala je da nema statistički signifikantne razlike u bazičnim varijablama te između pacijenata koji su analizirani u kratkoročnoj ili dugoročnoj analizi te pacijenata kod kojih je zamijenjena promjena u vidnoj oštrini tri godine nakon početka liječenja sa intravitrealnim aflibercept injekcijama je poboljšanje u CFD i MV tokom istoga razdoblja bila -140 mikrona i -1.38 mm3. Na kraju perioda praćenja od 36 mjeseci, 25% pacijenata je imalo poboljšanje vida za tri ili više ETDRS više od 50% pacijenata je imalo poboljšanje centralne fovealne debljine za 100 mikrona ili više. Pedeset i osam posto očiju u primarnoj kohorti je imalo početnu vidnu oštrinu manju od 69 ETDRS slova. oštrine u podgrupi sa početnom VO manjom od 69 slova je bila +11.27 ETDRS slova (p < 0.0001). Četrdeset kohorte je imalo početnu vidnu oštrinu ³ 69 ETDRS letters. Srednja promjena vidne oštrine nakon 36 mjeseci 0.88 ETDRS slova (p = 0.6041). One oči kod kojih je došlo do zamjene terapije podijelili smo na temelju vremenskog razmaka između zadnje početka liječenja sa intravitrealnim afliberceptom; kod 53 očiju vremenski interval je bio kraći od tri mjeseca ranibizumaba, dok je kod 37 očiju taj vremenski razmak bio tri mjeseca ili dulji. Analiza je pokazala da kod statistički signifikantna razlika u ovim podgrupama ( p > 0.05). Zaključak Naši kratkoročni i dugoročni rezultati vidne oštrine te anatomskih promjena kod pacijenata sa prijetećim dijabetičkim makularnim edemom liječenim intravitrealnim afliberceptom su pokazali signifikatno poboljšanje rezultatima značajnih randomiziranih kliničkih studija. Nadalje, naši rezultati su bili neinferiorni uspoređujući ih sa sigurnošću i efikasnošću intravitrealnog aflibercepta koje indiciraju značajne kliničke studije (VIVID, VISTA, Protokol T). Naša podgrupna analiza bazirana dokazala je značaj početka liječenja kada je vidna oštrina bolja. Postigli smo stabilan vid tokom tri godine je vidna oštrina bila 69 ETDRS slova ili bolja (do 80 ETDRS slova). Ti pacijenti su zadržali vidnu oštrinu koja upravljanje motornim vozilom. Naši rezultati su prvi publicirani rezultati iz realne kliničke prakse, koji pokazuju značaj planiranja liječenja oštrini, što su primarno indicirali rezultati Protokol T studije. Promatrajući naše rezultate kod kohorte pacijenata kod kojih smo zamijenili lijek, pokazali smo da zamjena ranibizumaba sa intravitrealnim afliberceptom ima smisla u ubrzanju oporavka vida i poboljšanja anatomskih svakodnevnoj praksi, dajući pacijentima brži oporavak i generalno bolje funkcioniranje koristeći svoj vid. zamjene lijeka ne igra ulogu u primarnim rezultatima (VO. CFD, MV), što može indicirati da razlog poboljšanja u mehanizmu te farmakokinetskim karakteristikama molekule aflibercepta.