Introduction Immune checkpoint inhibitors (ICIs) such as ipilimumab (ipi), nivolumab (nivo) and pembrolizumab (pembro) and the combination of ipi +nivo have improved response rates and survival in patients (pts) with advanced melanoma. Nivo was recently approved by the FDA as an adjuvant therapy. Responses may be durable, however associated immune-related adverse events may result in significant morbidity. Current treatment algorithms suggest that pts treated with ICIs who develop corticosteroid (CS)-refractory (CSrefr) irD/C are prescribed anti-TNF alpha antibodies such as infliximab (IFX). Little is known about the clinical features and outcomes of pts who receive IFX. Methods Pts with advanced melanoma from the Royal Marsden NHS Foundation Trust who received CS and IFX were identified from an ethically approved irD/C database (pts treated with ICIs from 2011–2016) and their medical records were reviewed, including flexible sigmoidoscopy (FS) results. Descriptive statistics and percentages were used to summarise the features of the CSrefr versus CS-responsive (CSresp) groups. Results Rates of all-grade irD/C by course of treatment were as follows: ipi 77/285 (27%), nivo or pembro 17/166 (10%), ipi +nivo 23/68 (34%). CS were prescribed in 72 (62%). 17 (15%) received IFX; 9 received 2 doses and 3 received 3 doses. 76% responded to IFX within a week; median time to improvement was 4 days (range 1–28). Table 1 outlines clinical information for the CSrefr and CSresp groups. Infection occurred in 10 episodes of IFX prescription (59%), 9 requiring antibiotics, including 2 cases of Pneumocystic jirovecii pneumonia. Conclusions 35% of irD/C due to ipi +nivo is CS-refractory. In the CSrefr group, CS duration was longer, macroscopic colitis was more common and most pts developed an infection. Interestingly time to progression of disease was longer in the CSrefr group. Prospective clinical trials are warranted to evaluate whether early IFX may reduce the burden of CS in the management of irD/C without compromising disease control.Abstract PTU-005 Table 1 CS-refractory versus CS-responsive patients CSrefr (n= 17) CSresp (n= 54) N (range) % N (range) % Ipi 8 47 30 56 Nivo/pembro 1 6 9 16 Ipi+nivo 8 47 11 20 Days from start ICI to onset of irD/C 41 - 45 - Grade 1/2 1 6 14 26 Grade 3/4 16 94 40 74 Median days from start of D/C to CS (range) 5 - 5 - Days from start CS to IFX 14(1–100) - NA - Median duration CS - - Grade 1/2 160(160–160) - 49(6–295) - Grade 3/4 79(28–279) - 47(6–204) - Extra treatment 1(vedolizumab) 6 0 0 Macroscopic abnormality on FS 13/17 76 22/41 54 Microscopic abnormality only on FS 1/17 6 9/41 22 Normal FS 2/17 12 7/41 17 Unknown FS result 1/17 6 3/41 7 Disease progression 12 67 42 79 Median days to progressive disease 170 - 101 - NB: 1 patient who had CS but unknown status re IFX is not included

Introduction Immune Checkpoint inhibitors (ICPi) have revolutionised the management of melanoma, non-small cell lung cancer and renal cancer. They block receptors expressed by immune cells that reduce immune activation. ‘Turbo-charged’ immune cells deliver augmented anti-tumour immunity (hence the striking efficacy of these anti-cancer agents), but comes at the cost of immune mediated side effects. Immune-mediated damage to the gut is a common and serious side effect of ICPi therapy. Endoscopic and histological findings in the lower gastrointestinal (GI) tract have been described (colitis is a common feature), but little is known about manifestations in the upper GI tract. Methods We performed a retrospective analysis of all patients presenting with diarrhoea following treatment with ICPis (ipilimumab, nivolumab, pembrolizumab or combination therapy) who had been investigated with OGD. Endoscopic and histopathological data were recorded. Lower GI findings in this cohort were also analysed. Results We reviewed 40 OGDs performed in our unit for melanoma patients who developed diarrhoea after starting treatment with ICPi patients. In all cases flexible sigmoidoscopy or colonoscopy was also performed. Inflammatory changes were common, including gastritis (40%) and duodenitis (17.5%). Importantly, even in the absence of macroscopically visible mucosal injury, there was a significant burden of microscopic inflammation, especially in the duodenum. In patients with a normal duodenoscopy, significant microscopic changes were present in 28% of patients. Significant histological abnormalities included chronic inflammation and/or increased intraepithelial lymphocytes (86%) and villous atrophy (71%), consistent with pathologically relevant mucosal immune activation. Abnormalities in the oesophagus were also common (32%), but were dominated by candidiasis (15%), likely secondary to high-dose steroids used to treat this challenging condition. All patients in this cohort of ICPi-induced diarrhoea patients investigated with OGD additionally underwent lower GI endoscopy, which confirmed the presence of colitis in 65% of patients. Importantly, upper GI disease was just as common in patients with a normal lower GI investigation (57%) as those with overt colitis (54%). Conclusions There is a significant burden of upper GI pathology, including macroscopic and microscopic mucosal injury and excessive immune accumulation, most notably in the duodenum, in patients with diarrhoea secondary to ICPi therapy. Additional findings that altered management included oesophageal candidiasis (likely a side-effect steroid therapy, which is usually rapidly initiated as soon as patients present with diarrhoea). Importantly, upper GI pathology is just as common in patients without colonic disease. OGD should be part of diagnostic work up of patients developing diarrhoea in the context of ICPi therapy.

Abstract The investigation of fish parasites in Bosnia and Herzegovina in recent years became significant, and therefore new records of parasitic trematodes and their hosts are important for better understanding of fish parasitology and pathology. In this study 41 parasitic specimens were collected and the basic taxonomical characters were measured (body length and width, diameter of oral and ventral sucker, length and width of pharynx, ovary length and width, testes length and width and eggs length and width). After the sampling of the parasites, they were collected and conserved in 70% ethanol. After that procedure the aforementioned characters were measured using Digimizer Image Analyzer Version 4.1. After all measurements, the trematode parasite Azygia robusta was confirmed for the first time on brown trout Salmo trutta. This first record was found in the Vrbas River near Banja Luka, Bosnia and Herzegovina (Sava River Basin). Former records of this parasite in Europe were observed on other salmonid fish species, as huchen Hucho hucho. This new record should be very important part of data of fish parasitology in Bosnia and Herzegovina.

This paper addresses the issue of modeling meanfield behavior in heterogeneous populations of linear timeinvariant SISO systems. Our analysis is conducted in the frequency domain, where the heterogeneity of input-output mappings (transfer functions) is modeled as a complex-valued Gaussian process. The mean-field model of diffusively coupled agents is obtained as a Gaussian approximation of averaged input-output behavior. It is shown that the strong coupling and the large number of agents reduce the population variance.

A variety of LQR-RRT kinodynamic motion planners are built on the idea of solving a two point boundary value problem in an LQR manner for affine systems. These planners can also be used for controllable nonlinear systems only if its linearized model at the equilibrium state is also controllable, and the cost function reflects only a time/control trade-off. We propose a class of RRT planners based on the SDRE (State Dependent Riccati Equation) control paradigm. The SDRE control is used both for finding the nearest state in the tree and for the tree expansion. By solving an LQR tracking problem for nonlinear systems within the SDRE framework, instead of a two point boundary value problem, the proposed planners deal with a wider range of controllable nonlinear systems and cost functions. We compare the proposed planners with LQR-RRT-like algorithms by observing the results obtained from the three specific benchmark examples.

Th e analysis of foreign trade in global trading of today requires the usage of macro-analytical activities which are based on contemporary and classical evaluation methods, trading measurements and macroeconomic indicators of economic stability and growth. Th is paper starts from the idea and the need to evaluate the infl uence of foreign trade between Bosnia and Herzegovina using the gravity model. Th e aim of this paper has been set based on this idea and is refl ected in the advantages and disadvantages of using the gravity model in evaluating foreign trade between Bosnia and Herzegovina and Montenegro.

581.19:547.56]:582.971.1 Methanol extracts obtained from the berries of three Symphoricarpos taxa (Caprifoliaceae) were used to determine their total phenols concentrations, and antioxidant and antimicrobial activities. According to our knowledge, total concentrations of phenolic compounds and antimicrobial activities for of S. × chenaultii and S. orbiculatus, as well as antioxidant activity of all three analyzed taxa are for the first time analyzed in this study. Based on obtained results, it was noticed that the highest average values of the total phenols, flavonoids and flavanols had methanol extracts of S. orbiculatus berries (3.525 mg GAE g-1 DW, and 11.037 and 0.881 mg CE g-1 DW, respectively), while methanol extracts of S. albus berries had the lowest (1.430 mg GAE g-1 DW, and 4.154 and 0.211 mg CE g-1 DW respectively). Symphoricarpos orbiculatus extract (IC50 = 5.299 mg mL-1) possessed the highest antioxidant activity while the lowest had S. albus (IC50 = 20.017 mg mL-1). The methanol extracts of analyzed Symphoricarpos taxa showed no antifungal activity against C. albicans. Moderate antibacterial activity of S. albus methanol extract is determined against five tested bacterial strains (Bacillus vulgatus, Enterococcus faecalis, Pseudomonas aeruginosa, Salmonella abony, and Staphylococcus aureus), and S. × chenaultii extract showed a low antibacterial activity only against P. aeruginosa, B. vulgatus and S. aureus. Although S. orbiculatus methanolic extract had the highest antioxidant activity it did not show any antibacterial activity at all. Analyzed Symphoricarpos extracts are potentially effective and can be used as natural antioxidant and antimicrobial preparations against test microorganisms.

Background Juvenile systemic scleroderma (jSSc) is an orphan disease with an estimated prevalence of around 3 per 1 000 000 children. There are no studies which evaluated prospectively the patient related outcomes in these patients. We report the data from juvenile scleroderma inception cohort (jSSc) regarding organ involvement and patient related outcomes. Methods The jSSc is a prospective cohort of jSSc patients. Patients were enrolled who were diagnosed with jSSc, had a jSSc onset age under 16 years and were younger as age of 18 years at the time of inclusion. The patients are prospectively assessed every 6 months according to a standardised protocol. Patients with available 12 months follow up data were included in the analyses. Results Currently 100 patients are followed in the jSSc cohort. 51 of them had available 12 months follow up data. Among those patients 37 (72.5%) had diffuse and 14 (27.5%) limited subtype. Mean age of onset of disease was 9.5 (±4.1) years and the mean disease duration at time of inclusion was 3.1 years (±3.2). The proportion of patients treated with DMARD increased from 74.5% to 88% at 12 months follow up. 86% were ANA positive at both assessments. Anti-scl70 positivity increased from 38% to 42%. Anticentromere antibody positivity was 2.4% at both assessments. Mean modified skin score decreased from 17.7 to 14.3 (p=0.151) Raynaud phenomenon occurred in 86% at enrolment and increased up to 88% at 12 months follow up. Nailfold capillary changes occurred around 70% at both assessments, but number of patients with active ulceration decreased from 28% to 16% (p=0.148). The number of patients with decreased FVC (FVC under 80%) decreased from 40.5% to 32% (p=0.497). The number of patients with pulmonary hypertension remained around 10%. No renal crisis or hypertension were reported. The gastrointestinal involvement was around 40% at both assessments. The number of patients with swollen joints decreased from 24% to 10% (p=0.06). The number of patients with muscle weakness decreased significantly from 33% to 9% (p=0.016), parallel to the number of patients with elevated CK values which decreased from 27% to 12% (p=0.074). All patient related outcomes, like global disease activity (p=0.048), global disease damage (p=0.05), Raynaud activity (p=0.003) and ulceration activity (p=0.001) improved significantly over 12 months. Physician assessed global disease activity (p=0.003) and ulceration activity (p=0.001) also improved significantly. Conclusions Our data show, that jSSc patients over a 12 months disease course stayed quite stable or improved regarding organ involvement. But patient and physician related outcomes regarding activity assessment improved significantly. Disclosure of Interest None declared

Background At present no clear evidence based guidelines exist to standardise the tapering and discontinuation of corticosteroids (CS) in juvenile dermatomyositis (JDM). Objectives To provide evidence-based recommendations for CS tapering/discontinuation through the analysis of the patients in the PRINTO new onset JDM trial. Secondary objective of the study was to identify predictors of clinical remission and CS discontinuation. Methods New onset JDM children were randomised to receive either prednisone (PDN) alone or in combination with MTX or CSA. All children were given initially intravenous methylprednisolone, and then PDN starting with 2 mg/kg/day. Gradual tapering according to a specific protocol could lead to the safe dose of 0.2 mg/kg/day by month 6, then discontinued at month 24. Major therapeutic changes (MTC) were defined as the addition or major increase in the dose of MTX/CSA/other drugs or any other reasons for which patients were dropped from the trial. Patients were divided according to clinical remission (CR) (CMAS=52 and MD global=0 for 6 continuous months) into two major groups. Group 1 included those on CR, who could discontinue PDN, with no MTC (reference group). Group 1 was compared with those who did not achieve CR, without or with MTC (group 2 and 3, respectively). JDM core set measures (CSM) were compared within the 3 groups. We also calculated the gold standard group 1 median change in the CSM in the first 6 and over 24 months and applied a logistic regression model to identify predictors of CR with PDN discontinuation. Results 139 children were enrolled in the trial: 47 on PDN, 46 on PDN +CSA and 46 on PDN +MTX. We identified 30 (21.6%) patients for group 1, 43 (30.9%) for group 2 and 66 (47.5%) for group 3. At baseline all 3 groups had no differences in the CSM. Already in the first 2 months a clear differential trend in disease activity measures, according to clinical remission status and PDN discontinuation, could be identified. From the observation of the median change in the CSM of group 1 in the first 6 months, the following recommendations could be extrapolated: decrease corticosteroids from 2 to 1 mg/kg/day in 2 months if the MD-global, parent-global, CHAQ, DAS, CMAS, MMT or Phs measures have changed of at least 50%; from 1 to 0.5 mg/kg/day in the following 2 months if the MD-global, CHAQ, DAS, CMAS show a change of at least 20%; in the following 2 months (month 4–6) corticosteroids can be tapered up to the safe dose of 0.2 mg/kg/day, if the disease activity measures remain at low/normal values. We finally ran a logistic regression model that showed that the achievement of PRINTO criteria 50–70–90 at 2 months from disease onset, an age at onset >9 years and the combination therapy PDN +MTX, increase the probability of clinical remission from 4 to 7 times (table 1).Abstract OP0340 – Table 1 Logistic regression model for the outcome: achievement of remission (n/tot: 28/130; 21.5%) Conclusions We propose evidence based specific cut-offs for corticosteroid tapering/discontinuation based on the change in JDM CSM of disease activity, and to identify the best predictors for clinical remission and corticosteroid discontinuation. Disclosure of Interest None declared

Abstract The economic openness and reindustrialization. Can these two occurrences exist at the same time? The empirical experience of the East European countries tells us that they cannot. Trade liberalization in the transition countries implemented during the 1990s led to the process of deindustrialization which continued also during the 2000s. The goal of this paper is to present the possible directions for reform of the international trade system which would enable reindustrialization of the small countries in East Europe with simultaneous preservation of the achieved level of trade liberalization. Admittedly, we are separated from the win-win situation by the conviction that this is only possible if the compensation principle is applied on the global trade, according to which the winners in the global trade (developed countries with trade surplus), should compensate to the losers (small insufficiently developed countries) a part of their losses with mandatory support to programs of reindustrialization based on exports, for which the funds are chronically lacking. An alternative is reindustrialization based on import substitution i.e. strengthening of the protectionism, where all benefits of the free trade could vanish so in the end everybody would be in loss.

Abstract This paper systematically examines the influence of the level of Fe(III) doping on the crystal structure and other properties of Ni(OH)2. Reference β-Ni(OH)2 and Fe-doped Ni(OH)2 samples were synthesized by hydrothermal precipitation of mixed Ni(II) and Fe(III) nitrate aqueous solutions in a highly alkaline medium. The samples were investigated using X-ray powder diffraction (XRPD), scanning and transmission electron microscopy (FE-SEM and TEM), energy dispersive X-ray spectroscopy (EDS), Mossbauer spectroscopy, magnetic measurements, Fourier transform infrared (FT-IR) spectroscopy, ultraviolet–visible–near infrared (UV–Vis–NIR) spectroscopy, thermogravimetric analysis (TGA) and electrochemical measurements. Incorporation of Fe in β-Ni(OH)2 by cation substitution was confirmed from the shifts in position of XRPD lines due to the difference in the ionic radius of Fe3+ and Ni2+. The Fe3+-for-Ni2+ substitution in β-Ni(OH)2 caused formation of an interstratified structure with β-Ni(OH)2 and α-Ni(OH)2 structural units interconnected within the same structural layers and crystallites. Mossbauer spectra revealed the presence of Fe3+ ions in highly distorted octahedral sites, presumably at the boundary between the α-Ni(OH)2 and β-Ni(OH)2 structural units within the same structural layer. Electrochemical measurements showed significant increase in oxygen evolution reaction (OER) catalytic activity of Fe-doped Ni(OH)2 compared to pure phase.

Abstract This paper uses a DEA-VRS methodology for the estimation of municipal efficiency to provide empirical evidence of the impact of decentralization in BiH under the Dayton Peace Agreement (DPA) on overall municipal efficiency. In particular, the paper focuses on the analysis of the overall efficiency of 33 new municipalities established under DPA. The findings suggest that the average municipal efficiency in BiH is rather low, and only 23 or 16% of municipalities in BiH are efficient. The average efficiency achieved is around 0.71. This means that with the same level of inputs (budget revenue) outputs may be increased by almost 30%, on average. The results of DEA-VRS efficiency estimation suggest that new municipalities have lower average efficiency (0.60) in comparison to “older” municipalities (0.74). In our sample, only six percent of newly created municipalities are efficient, 12% exhibit some level of efficiency, while the remaining 82% are inefficient, with significant share (39%) of very inefficient municipalities