Clear cell Renal Cell Carcinoma (ccRCC) is profoundly angiogenic, characterised by complex yet heterogenous vascular networks. Blood vessels are an important constituent part of the tumour microenvironment (TME) and, in addition to immune cells, are the target of drug therapies in advanced disease. The TME plays an important role in determining disease progression and response to therapy, acting as a selective pressure on the tumour cells thus influencing evolutionary trajectory. This selective pressure is sculpted by cross-talk between blood vessels, immune cells and the tumour cells themselves. Whilst the details of these carefully orchestrated cellular interactions is not understood their final read-out is reflected in tissue morphology, which can be assessed using an H&E-stained slide, a fundamental component of clinical diagnostic histopathological workflows. A computational pathology approach to assess vascular networks from digital H&E whole slide images (H&E WSIs) would present a powerful tool to understand disease biology. It would permit high-throughput analysis of large cohorts where routine multi-regional sampling captures disease heterogeneity. Such work would lay the foundations for developing a computational pathology biomarker to predict survival outcomes that could be easily implemented into existing clinical workflows. Intricacy of vascular network structures makes reproducible analysis challenging, which can be approached either using morphology, a qualitative evaluation of a shape, or using topography to quantify feature dimensions. Here we reconcile the two methods to develop an interpretable computational pathology solution to study the blood vessels in ccRCC. Further, we have built a deep-learning attention UNET model to segment blood vessels from H&E WSIs. By combining these tools we have developed a computational pathology pipeline able to robustly characterise vascular networks directly from H&E WSIs. We leverage 1064 tumour regions from 82 ccRCC tumours of the TRACERx Renal dataset where ex-vivo multi-regional sampling with closely linked specimens for histological and genomic analysis permits interrogation of the histo:genomic relationship contextualised within the evolutionary dynamics of each tumour. We demonstrate that vascular intratumoral heterogeneity is pervasive and we link different vascular topologies to genetic alterations associated with opposing evolutionary trajectories (PBRM1 and BAP1 mutations) and the acquisition of metastatic competence (loss of 9p). Finally, we show that progressive accumulation of genetic alterations alters vascular network structure, suggesting that vascular topology could be used to assess tumour evolution. Our pipeline is a powerful tool to study ccRCC vasculature in large cohorts with multi-regional sampling to capture intratumoral heterogeneity and ultimately could form the basis of a computational pathology biomarker to predict outcome to therapy. Citation Format: Charlotte E. Spencer, Graham Ross, Thomas Mead, Amy Strange, Anna Song, Katie Bentley, Samra Turajlic. Interpretable computational pathology reveals that vascular networks reflect evolutionary dynamics in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR015.

Aim Lung adenocarcinoma (ADC) is a leading subtype of lung cancer, histologically defined with five different architectural growth patterns: lepidic, acinar, papillary, solid and micropapillary. The aim of this study was to explore the prevalence of epidermal growth factor receptor (EGFR) mutation and a relationship between the specific histological patterns of lung ADC in the population of Bosnia and Herzegovina. Methods The study included tumour tissue from 102 patients with completely resected lung ADC from 2015 to 2020. Molecular testing for the presence of EGFR mutations was performed by real-time PCR method. The relationship between EGFR mutation status and clinicopathological parameters was analysed. Results The EGFR mutation was detected in 12 (11.8%) cases of ADC, more often in non-smokers (p=0.007). A higher percentage of solid growth pattern presented in ADC may be an indicator of EGFR negativity (p=0.039), while a higher percentage of micropapillary growth pattern more common in the presence of EGFR mutation (p=0.047). Conclusion The prevalence of EGFR mutation is in accordance with the expected prevalence considering our studied population, Caucasians from South Europe. Better understanding of the relationship between histological patterns and molecular characteristics of lung ADC will enable earlier diagnosis and optimal treatment for patients.

liver

Aim To create a predictive score based on functional parameters of the liver and determine its prognostic value in survival of patients with decompensated cirrhosis. Methods Retrospective observational study included 91 consecutive patients with decompensated cirrhosis. Functional parameters (bilirubin, AST - aspartate aminotransferase, ALT - alanine aminotransferase, ALP - alkaline phosphatase, GGT - gammaglutamyltranferase, albumin, prothrombin time, platelet count, haematocrit and creatinine), Child-Pugh (CP) and Model of EndStage Liver Disease (MELD) scores have been measured at first hospitalization and at every exacerbation episode over follow-up period of 24 months. Results Using Cox regression analysis, we found that age (OR=1.206; p=0.03; 95% CI=1.019-1.428), serum bilirubin (OR=1.017; p=0.003; 95% CI=1.006-1.029), INR (International normalized ratio) (OR=6.262; p=0.002; 95% CI=1.924-20.378) and serum creatinine (OR=1.019; p=0.005; 95% CI=1.006- 1.032) had statistically strong association with the incidence of a six-month mortality. Age (OR=1.120; p=0.006; 95% CI=1.033- 1.214), serum bilirubin (OR=1.021; p=0.0001; 95% CI=1.010- 1.032), GGT (OR=1.007; p=0.023; 95% CI=1.001-1.014), INR (OR=9.571; p=0.001; 95% CI=2.610-35.098), haematocrit (OR=0.695; p=0.001; 95% CI=0.559-0.864) and serum creatinine (OR=1.023; p=0.0001; 95% CI=1.011-1.035) showed an increased the risk for a 24-month lethal outcome. Predictive score derived from liver functional parameters, CP and MELD scores, each independently has shown a high degree of death prediction after 6 or 24 months in patients with end-stage liver disease. Conclusion Predictive score derived from liver functional parameters had a better prognostic value for short-term and long-term mortality comparing to MELD and Child-Pugh score.

Aim To investigate the association between type 2 diabetes mellitus (T2DM) and pulmonary embolism, as well as to determine the prognostic value of troponin, D-dimer, prothrombotic, and proinflammatory markers in patients with T2DM. Methods The retrospective cohort study included 305 patients with pulmonary embolism, divided into two groups: the first group with type 2 diabetes mellitus (n=165) and the control group without type 2 diabetes mellitus (n=140). Data were collected from May 2018 to May 2023. In all patients the following parameters were analysed: anthropometric parameters, laboratory parameters (troponin, D-dimer, CRP, fibrinogen, uric acid, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), arterial blood pressure, antiphospholipid antibodies, HOMA-IR index, CT angiography of the pulmonary artery, rate of adverse clinical events in pulmonary embolism (need for inotropic catecholamine support, fibrinolysis, cardiopulmonary resuscitation) and the rate of intrahospital mortality from pulmonary embolism. Results Patients with T2DM had elevated troponin, D-dimer, CRP, uric acid, fibrinogen, HOMA-IR and more severe clinical complications with higher mortality rates within 10 days of hospital admission. Significant predictors of PE in T2DM patients were found. Patients with pulmonary embolism in T2DM had a 4.38 times higher chance of death compared to patients with pulmonary embolism without T2DM. Conclusions Troponin, D-dimer, prothrombotic, and proinflammatory markers have good prognostic value for short-term outcomes in PE among patients with T2DM.

Introduction: The no-reflow phenomenon (persistent microvascular hypoperfusion despite macrovascular angiographic reperfusion) represents an explanation to poor outcome despite successful thrombectomy. There remains no universally-accepted definition to standardise future studies. We aim to compare the clinical features and outcomes of patients identified as having no-reflow using different perfusion MRI/CT definitions. Methods: We performed a pooled analysis of thrombectomy patients who underwent 24-hour follow-up perfusion MRI or CTs in the EXTEND-IA, EXTEND-IA TNK part 1 and 2 RCT. Presence of no-reflow was defined according to four definitions identified from a meta-analysis of 13 studies (Definition A = eTICI2c-3 and >15% asymmetry in CBV or CBF within the infarct on follow-up perfusion MRI/CT; definition B = mTICI2c-3 and >40% CBF asymmetry, definition C = mTICI2b-3 and presence of a Tmax>6s lesion; Definition D = mTICI2b-3 and >90% reduction of baseline Tmax>6s lesion). Receiver Operating Characteristics (ROC) analysis was performed with the outcome variable being poor functional outcome at 90 days (mRS≥3). Results: Of 325 patients analysed, the prevalence of no-reflow varied between definitions from 1.9 to 29.3% (p<0.001). There was poor agreement between definitions (kappa 0.062-0.745, 5 out 6 comparisons <0.196). Among patients identified as exhibiting no-reflow by any definition, there were significant differences in the intralesional interside differences in CBF (p=0.006), CBV (p<0.001) and MTT (p=0.005). Definition A yielded the highest Area Under the ROC Curve (AUC=0.679) for discrimination of 90-day functional outcome (Definitions C=0.649, D=0.597, B=0.515; p<0.0001). Sensitivity analyses testing across the eTICI≥2b, eTICI≥2c and eTICI3 strata showed consistent results. Conclusions: Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, suggesting that patients classified as having no-reflow by various definitions differ in their underlying pathophysiological processes. Definition A (eTICI2c-3 & >15% CBV/CBF asymmetry) discriminated prognostic performance best, supporting its use as the reference no-reflow imaging definition.

Background and Purpose: Cancer increases the risk for acute ischemic stroke (AIS) and deep venous thrombosis. The role of paradoxical embolization as a stroke etiology in patients with cancer is uncertain. Our study investigated the relationship between cancer-related stroke and the presence of a patent foramen ovale (PFO). Methods: We included AIS patients hospitalized at our comprehensive stroke center between January 2015 and December 2020 with available PFO status as detected on transesophageal echocardiography. Active cancer, including cancer known at the time of stroke as well as occult cancer newly diagnosed within one year after stroke, were retrospectively identified. The association between PFO status and active cancer was assessed with multivariable logistic regression and reported using adjusted odds ratios (aOR) and their 95% confidence intervals (CI). Results: Among 2236 AIS patients (median age 68.3 years, female sex 36.4%), 103 (4.6%) had active cancer, of whom 24 (23%) were diagnosed with PFO. This included 32 patients (1.4%) with occult cancer, of whom 19% were diagnosed with PFO. Conversely, among 2133 AIS patients without active cancer, 774 were diagnosed with PFO (36%). In multivariable analysis (Fig 1), the absence of PFO was associated with active cancer (aOR 2.62, 95% CI 1.28-5.38). This association appeared stronger when patients older than 80 years of age were excluded (aOR 3.06, 95% CI 1.42 - 6.58) and persisted among patients with occult cancer at the time of AIS (aOR 5.39, 95% CI 1.18-24.74). Conclusions: In patients with AIS, PFO was diagnosed more commonly among patients without cancer than those with cancer. This might be due to cancer-related stroke being related to arterial coagulopathy rather than paradoxical emboli resulting from venous thrombi. Further studies are needed to confirm these findings and to assess the diagnostic role of PFO in patients with cancer and AIS.

The paper describes the factorial design of the experiment with three input factors that change on two levels. For given values of the input parameters, it is shown how to obtain a variance analysis table and which factors and interactions between factors are significant. The example was done in the software intended for the design of the experiment and in the software R. It is shown how to use the software R to arrive at the final solution of the given example.

Remote driving plays an essential role in coordinating automated vehicles in some challenging situations. Due to the changed driving environment, the experiences and behaviors of remote drivers would undergo some changes compared to conventional drivers. To study this, a continuous real-life and remote driving experiment is conducted under different driving conditions. In addition, the effect of steering force feedback (SFF) on the driving experience is also investigated. In order to achieve this, three types of SFF modes are compared. According to the results, no SFF significantly worsens the driving experience in both remote and real-life driving. Additionally, less force and returnability on steering wheel are needed in remote driving, and the steering force amplitude appears to influence the steering velocity of remote drivers. Furthermore, there is an increase in lane following deviation during remote driving. Remote drivers are also prone to driving at lower speeds and have a higher steering reversal rate. They also give larger steering angle inputs when crossing the cones in a slalom manoeuvre and cause the car to experience larger lateral acceleration. These findings provide indications on how to design SFF and how driving behavior and experience change in remote driving.

Purpose- The purpose of this study is to investigate whether regional variations exist in the development of the digital economy and how they impact growth in the four global regions where Muslims predominate. Methodology- The study employs empirical examination of 48 countries with Muslim majority divided in four regions (Middle East and North Africa region, Europe and Eurasia region, South Asia, East Asia region and the Pacific and Africa region) between 2000 to 2021. The study employs Kao Residual Cointegration Test, and the Long-run Valuation of Fully Modified Ordinary Least Squares (FMOLS/DOLS-Dynamic). A certain number of specific variables in the econometric model will be employed to measure the level of digitization on economic growth, such as: Digital economy infrastructure proxied by Individuals using the internet, Digital economic openness proxied by ICT product exports and Digital technology competitiveness proxied by Research and Development as share of GDP. Findings- The analysis reveals that despite the fact that the digital economy made a positive contribution to economic growth in both Sub-Saharan Africa and Europe and Euroasia, the impact on these regions is less than that on the Middle East and North Africa, South Asia, East Asia, and the Pacific countries due to the underdeveloped infrastructure of the digital economy The least effect of digitalization on growth was found in Sub-Saharan African countries with low incomes.. Conclusion- Based upon the analysis, it may be concluded that digitalization can considerably boost economic growth, but its benefits may differ depending on how developed a nation is. There is a clear geographical imbalance in the development of the digital economy across 48 nations with a majority of Muslims .To increase overall GDP growth, those countries need to look into policies that will help increase ICT and the digital economy use. Keywords: Digital economy, economic growth, ICT, the Muslim Word, panel cointegration model. JEL Codes: O40, O47, E22.

We report on an ongoing measles outbreak in the Federation of Bosnia and Herzegovina with 141 cases notified between week 52 2023 and week 6 2024. Among those with known vaccination status, 97% were unvaccinated and the most affected group is children under the age of 5 years (n = 87) who were not vaccinated during the pandemic years. Sixty-eight cases were hospitalised, the most common complications were measles-related pneumonia and diarrhoea. The sequenced measles viruses from four cases belonged to genotype D8.

Background: Frequent episodes of nasal symptoms are the usual clinical manifestations (CM) of allergic rhinitis (AR) and have a significant negative impact on health-related quality of life (HRQoL) in adolescents. The purpose of this cross-sectional study was to test the hypothesis that cytokines in nasal mucus may be associated with HRQoL in adolescents with AR. Methods: European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L), “The Adolescent Rhinoconjunctivitis Quality of Life Questionnaire” (AdolRQLQ) and the Total 4 Symptom Score (T4SS) scoring system were administered to 113 adolescents with AR, nonallergic rhinitis (NAR) and to healthy control subjects. Nasal secretions were sampled and tested for 13 cytokines using a multiplex flow cytometric bead assay. Results: The AR group had significantly lower EQ-5D-3L (0.661 ± 0.267 vs. 0.943 ± 0.088; p < 0.001) and higher AdolRQLQ total scores (2.76 ± 1.01 vs. 1.02 ± 0.10; p < 0.001) compared to the control group. The AR group had higher concentrations of IL-1β (p = 0.002), IL-6 (p = 0.031), IL-8 (p < 0.001), IL17-A (p = 0.013) and IL-18 (p = 0.014) compared to the control group, and IL-1β, IL-6, IL17-A and IL-18 were significantly (p < 0.050) increased with disease progression. Cytokines IL-1β, IL-6, as well as severe CM, were identified as significant predictors of lower HRQoL in adolescents with AR. Conclusions: This study identified IL-1β, IL-6, as well as severe CM, as predictors of lower HRQoL in adolescents with AR. However, these results should only serve as a starting point for additional confirmation research.

Simple Summary Mastitis is defined as the inflammation of the mammary gland and is one of the most widespread and economically important diseases of dairy cows. Bacteria are the most reported mastitis-causative agents, while other pathogens are often overlooked because they are not routinely investigated. Incomplete diagnosis may result in inappropriate antimicrobial therapy, treatment failure, antimicrobial resistance, dissemination of pathogens, and mastitis recurrences. Thus, this study aimed to investigate the presence of not only bacteria but also other microorganisms associated with cattle mastitis on dairy farms in Bosnia and Herzegovina, a country that lacks an effective mastitis control programme and bacteriological analysis of mastitic milk. The current study revealed Mycoplasma bovis as the main pathogen and a variety of other mastitis-causing agents in cattle: bacteria (Escherichia coli, Staphylococcus aureus, coagulase negative staphylococci, Streptococcus agalactiae, Streptococcus uberis, and others), fungi (Candida spp.), and algae (Prototheca zopfii). The finding of mastitis cases requiring currently unavailable treatment and vaccines emerges in the broader scope of etiological agents in routine mastitis diagnosis. These measures applied at the herd and national levels are crucial for more effective mastitis control, animal health and welfare, the dairy industry, and public health. Abstract To obtain improved insights into the complex microbial aetiology of bovine mastitis, this study investigated the pathogens involved in cattle mastitis in Bosnia and Herzegovina. A total of 179 milk samples from cows with clinical mastitis (CM) and subclinical mastitis (SCM), as well as eight bulk tank milk (BTM) samples from 48 dairy farms, were analysed by standard bacteriological and mycological methods. Mycoplasma detection and identification were performed using culture techniques and real-time polymerase chain reaction (PCR). A total of 88 (49.2%) mastitis samples were positive for known mastitis pathogens at 32 of 47 farms (68.1%). Mycoplasma bovis was a predominant pathogen (25/187; 13.4%) in the majority of herds (14/48; 29.2%) and accounted for 48.9% of positive CM samples. Escherichia coli was the second most dominant CM pathogen (34%), followed by Streptococcus agalactiae (10.6%), whereas Staphylococcus aureus and coagulase-negative staphylococci were the most common in SCM samples (17.1%). Other mastitis pathogens included Candida spp. and Prototheca zopfii. Two BTM samples were positive for M. bovis only, and one was positive for a mixed culture of S. aureus and Streptococcus uberis. The finding of various causative agents of bovine mastitis, with M. bovis emerging as the main pathogen, emphasizes the significance of comprehensive testing that includes not only common mastitis pathogens but also mycoplasmas, fungi, and algae.