Genetic screening of liver cancer:State of the art

Liver cancer,primarily hepatocellular carcinoma,remains a global health challenge with rising incidence and limited therapeutic options.Genetic factors play a pivotal role in the development and progression of liver cancer.This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer.We discuss the genetic underpinnings of liver cancer,emphasizing the critical role of risk-associated genetic variants,somatic mutations,and epigenetic alterations.We also explore the intricate interplay between environmental factors and genetics,highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy,and advancements in high-throughput sequencing technologies.By synthesizing the latest research findings,we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer,shedding light on their potential to revolutionize early detection,risk assessment,and targeted therapies in the fight against this devastating disease.

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis

Immune-checkpoint inhibitor-mediated colitis(IMC)is an increasingly recognized adverse event in cancer immunotherapy,particularly associated with immune checkpoint inhibitors(ICIs)such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies.As this revolutionary immunotherapy gains prominence in cancer treatment,understanding,diagnosing,and effectively managing IMC becomes paramount.IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications.However,a precise picture of IMC pathophysiology is currently unavailable.Therefore,we aimed to summarize the existing data while acknowledging the need for further research.This comprehensive review explores the mechanisms underlying ICIs,gastrointestinal adverse effects,and,in particular,IMC’s incidence,prevalence,and features.Our review also emphasizes the importance of recognizing IMC’s distinct clinical and histopathological features to differentiate it from other forms of colitis.Furthermore,this paper highlights the urgentneed for evolving diagnostic methods,therapeutic strategies,and a multidisciplinary approach to effectively manage IMC.

Clinical issues and challenges in imaging of gastrointestinal diseases:A minireview and our experience

Imaging techniques play a crucial role in the modern era of medicine,particularly in gastroenterology.Nowadays,various non-invasive and invasive imaging modalities are being routinely employed to evaluate different gastrointestinal(GI)diseases.However,many instrumental as well as clinical issues are arising in the area of modern GI imaging.This minireview article aims to briefly overview the clinical issues and challenges encountered in imaging GI diseases while highlighting our experience in the field.We also summarize the advances in clinically available diagnostic methods for evaluating different diseases of the GI tract and demonstrate our experience in the area.In conclusion,almost all imaging techniques used in imaging GI diseases can also raise many challenges that necessitate careful consideration and profound expertise in this field.

Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies.In this narrative review,we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease,immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following.We focused on the anti-gliadin antibodies,antibodies to different isoforms of tissue transglutaminase(TG)(anti-TG2,3,and 6 antibodies),anti-glycine receptor antibodies,anti-glutamine acid decarboxylase antibodies,anti-deamidated gliadin peptides antibodies,etc.Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction,presented as different neurological disorders.We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Controversies regarding transplantation of mesenchymal stem cells

Mesenchymal stem cells(MSCs)have tantalized regenerative medicine with their therapeutic potential,yet a cloud of controversies looms over their clinical tran-splantation.This comprehensive review navigates the intricate landscape of MSC controversies,drawing upon 15 years of clinical experience and research.We delve into the fundamental properties of MSCs,exploring their unique immuno-modulatory capabilities and surface markers.The heart of our inquiry lies in the controversial applications of MSC transplantation,including the perennial debate between autologous and allogeneic sources,concerns about efficacy,and lingering safety apprehensions.Moreover,we unravel the enigmatic mechanisms surro-unding MSC transplantation,such as homing,integration,and the delicate balance between differentiation and paracrine effects.We also assess the current status of clinical trials and the ever-evolving regulatory landscape.As we peer into the future,we examine emerging trends,envisioning personalized medicine and innovative delivery methods.Our review provides a balanced and informed perspective on the controversies,offering readers a clear understanding of the complexities,challenges,and potential solutions in MSC transplantation.

Ambispective epidemiological observational study of varicella-zoster virus infection: An 18 year-single-center Bulgarian experience

BACKGROUND Varicella(chickenpox)and herpes zoster(shingles)are outcomes of varicella-zoster virus(VZV)infection,and understanding their incidence trends is vital for public health planning.AIM To conduct an ambispective epidemiological study by analyzing the main epidemiological characteristics of VZV infection during an 18 year-period(2000-2018).METHODS We used descriptive and epidemiological methods to characterize chickenpox in Bulgaria,the city of Plovdiv and the region for a period of 18 years(2000-2018).RESULTS The average incidence of varicella-zoster infection for the period 2000–2018 in the Plovdiv region was estimated at 449.58‰.The highest relative share of the infection was assessed in the month of January at 13.6%,and the lowest in the months of August and September at 2.9%(both months).The age group most affected by the infection was 1-4 years,followed by 5-9 years.This corresponds to the so-called"pro-epidemic population"-a phenomenon typical for airborne infections,confirming their mass impact on the perpetuation of VZV infection.CONCLUSION Our findings reveal significant insights into VZV epidemiology,including age-specific incidence rates,clinical manifestations,and vaccination impact.This comprehensive analysis contributes to the broader understanding of VZV infec-tion dynamics and may inform evidence-based preventive measures.

Effectiveness and safety of COVID-19 vaccines in patients with oncological diseases:State-of-the-art

Although the coronavirus disease 2019(COVID-19)pandemic was declared to be no longer“a public health emergency of international concern”with its wide range of clinical manifestations and late complications,severe acute respiratory syndrome coronavirus 2 infection proved to be a serious threat,especially to the elderly and patients with comorbidities.Patients with oncologic diseases are vulnerable to severe infection and death.Indeed,patients with oncohematological diseases have a higher risk of severe COVID-19 and impaired post-vaccination immunity.Unfortunately,cancer patients are usually excluded from vaccine trials and investigations of post-vaccinal immune responses and the effectiveness of the vaccines.We aimed to elucidate to what extent patients with cancer are at increased risk of developing severe COVID-19 and what is their overall case fatality rate.We also present the current concept and evidence on the effectiveness and safety of COVID-19 vaccines,including boosters,in oncology patients.In conclusion,despite the considerably higher mortality in the cancer patient group than the general population,countries with high vaccination rates have demonstrated trends toward improved survival of cancer patients early and late in the pandemic.

Multinucleated giant cells of bladder mucosa are modified telocytes:Diagnostic and immunohistochemistry algorithm and relation to PDL1 expression score

BACKGROUND Multinucleated giant cells(MGCs)in bladder carcinomas are poorly studied.AIM To describe the function,morphogenesis,and origin of mononuclear and MGCs in urothelial carcinoma(UC)of the bladder in Bulgarian and French patients.METHODS Urothelial bladder carcinomas(n=104)from 2016-2020 were analyzed retrospectively using immunohistochemical(IHC)and histochemical stain examination.Giant cells in the bladder stroma were found in 35.6%of cases,more often in highgrades.RESULTS We confirm that MGCs in the mucosa in UC of the bladder were positive for both mesenchymal and myofibroblast markers(vimentin,smooth muscle actin,Desmin,and CD34)and the macrophage marker CD68.Furthermore,IHC studies revealed the following profile of these cells:Positive for p16;negative for epithelial(CK AE1/AE3 and GATA-3),vascular(CD31),neural(PS100 and CKIT),cambial,blastic(CD34-blasts and C-KIT),and immune markers(IG G,immunoglobulin G4,and PD-L1);no proliferative activity,possess no specific immune function,and cannot be used to calculate the Combined Positive Score scale.CONCLUSION In conclusion,the giant stromal cells in non-tumor and tumor bladder can be used as a characteristic and relatively constant,although nonspecific,histological marker for chronic bladder damage,reflecting the chronic irritation or inflammation.Likewise,according to the morphological and IHC of the mono-and multinucleated giant cells in the bladder,they are most likely represent telocytes capable of adapting their morphology to the pathology of the organ.

Future of prostate imaging:Artificial intelligence in assessing prostatic magnetic resonance imaging

Prostate cancer(Pca;adenocarcinoma)is one of the most common cancers in adult males and one of the leading causes of death in both men and women.The diagnosis of Pca requires substantial experience,and even then the lesions can be difficult to detect.Moreover,although the diagnostic approach for this disease has improved significantly with the advent of multiparametric magnetic resonance,that technology has certain unresolved limitations.In recent years artificial intelligence(AI)has been introduced to the field of radiology,providing new software solutions for prostate diagnostics.Precise mapping of the prostate has become possible through AI and this has greatly improved the accuracy of biopsy.AI has also allowed for certain suspicious lesions to be attributed to a given group according to the Prostate Imaging-Reporting&Data System classification.Finally,AI has facilitated the combination of data obtained from clinical,laboratory(prostate-specific antigen),imaging(magnetic resonance),and biopsy examinations,and in this way new regularities can be found which at the moment remain hidden.Further evolution of AI in this field is inevitable and it is almost certain to significantly expand the efficacy,accuracy and efficiency of diagnosis and treatment of Pca.

Application of Information Technology in Institutions and Challenges of Human Resources-Case Study: Administration of the Municipality of Ferizaj

This study aims to investigate how information technology is applied in the administration of the municipality of Ferizaj and what are the challenges with human resources, the work was carried out through a case study in the municipality. This paper highlights that the use of information technology provides higher efficiency for the performance of daily work in the municipality, thus also the provision of better services to citizens. However, the level of use of information technology in the Municipality of Ferizaj leaves much to be desired in terms of efficiency because a significant number of employees have not attended adequate training for the effective and efficient use of various IT applications and have not are still adapted to the digital environment in the municipality. Therefore, the recommendation derived from this paper is that the information technology environment in the municipality of Ferizaj needs to be improved by providing staff with adequate qualifications, while for those who are currently engaged in the municipality and who do not have adequate qualifications, training should be provided in a way that all users of IT applications are fully integrated into the digitized environment in order to be effective and efficient in providing services to citizens. This simultaneously gives the municipal staff job security and motivation for better services for citizens. Also, information technology enables a better control over the activity of the municipality because every action is recorded as data which can then be used to analyze the performance of the municipality.

Model for Short - Term Forecast on Vehicles in Bitola Town

The contemporary lifestyle leads to rapid increase of number of motorized traffic participants thus,there is a need of traffic planning,which requires forecast.Considering the fact that contemporary software packages exist,based on modern technology and long-term experience it is decided to rely on the software package PTV Vision-VISUM,for forecast in the traffic in Bitola town.Synthetic model is designed by this software package,modeling is done on existing situation,model’s calibration and in this article output results are presented from forecast on vehicles in Bitola town,for next 5 years.

Vaccination for solid organ transplanted patients:Recommendations,efficacy,and safety

Solid organ transplant recipients face unique challenges in managing their im-munosuppressed status,making vaccination a critical consideration.This review aimed to comprehensively analyze current recommendations,evaluate the effi-cacy of vaccinations in this population,and assess safety concerns.We explored the latest evidence on vaccine types,timing,and potential benefits for transplant patients,highlighting the importance of individualized approaches for routinely used vaccines as well as coronavirus disease 2019 vaccines.By synthesizing avai-lable data,this review underscored the pressing need to optimize vaccination strategies,ensuring that transplant recipients can obtain the full protection against many pathogens while minimizing risks associated with their post-transplant immunosuppression.

Artificial intelligence as a tool in drug discovery and development

The rapidly advancing field of artificial intelligence(AI)has garnered substantial attention for its potential application in drug discovery and development.This opinion review critically examined the feasibility and prospects of integrating AI as a transformative tool in the pharmaceutical industry.AI,encompassing machine learning algorithms,deep learning,and data analytics,offers unprecedented opportunities to streamline and enhance various stages of drug development.This opinion review delved into the current landscape of AI-driven approaches,discussing their utilization in target identification,lead optimization,and predictive modeling of pharmacokinetics and toxicity.We aimed to scrutinize the integration of large-scale omics data,electronic health records,and chemical informatics,highlighting the power of AI in uncovering novel therapeutic targets and accelerating drug repurposing strategies.Despite the considerable potential of AI,the review also addressed inherent challenges,including data privacy concerns,interpretability of AI models,and the need for robust validation in realworld clinical settings.Additionally,we explored ethical considerations surrounding AI-driven decision-making in drug development.This opinion review provided a nuanced perspective on the transformative role of AI in drug discovery by discussing the existing literature and emerging trends,presenting critical insights and addressing potential hurdles.In conclusion,this study aimed to stimulate discourse within the scientific community and guide future endeavors to harness the full potential of AI in drug development.

Method“Monte Carlo”in healthcare

In public health,simulation modeling stands as an invaluable asset,enabling the evaluation of new systems without their physical implementation,experimentation with existing systems without operational adjustments,and testing system limits without real-world repercussions.In simulation modeling,the Monte Carlo method emerges as a powerful yet underutilized tool.Although the Monte Carlo method has not yet gained widespread prominence in healthcare,its technological capabilities hold promise for substantial cost reduction and risk mitigation.In this review article,we aimed to explore the transformative potential of the Monte Carlo method in healthcare contexts.We underscore the significance of experiential insights derived from simulated experimentation,especially in resource-constrained scenarios where time,financial constraints,and limited resources necessitate innovative and efficient approaches.As public health faces increasing challenges,incorporating the Monte Carlo method presents an opportunity for enhanced system construction,analysis,and evaluation.

Harnessing immunity:Immunomodulatory therapies in COVID-19

An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.

Gastrointestinal mucosal immunity and COVID-19

As the gastrointestinal tract may also be a crucial entry or interaction site of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the role of the gut mucosal immune system as a first-line physical and immunological defense is critical.Furthermore,gastrointestinal involvement and symptoms in coronavirus disease 2019(COVID-19)patients have been linked to worse clinical outcomes.This review discusses recent data on the interactions between the virus and the immune cells and molecules in the mucosa during the infection.By carrying out appropriate investigations,the mucosal immune system role in SARS-CoV-2 infection in therapy and prevention can be established.In line with this,COVID-19 vaccines that stimulate mucosal immunity against the virus may have more advantages than the others.

Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19

patients with or without preexisting liver disorders,posing a significant complication and mortality risk.During coronavirus disease 2019(COVID-19),abnormal liver function is typically observed.However,liver injury may occur because of the treatment as well.Ischemia,cytokine storm,and hypoxia were identified as the three major factors contributing to liver damage during COVID-19.Indeed,raised liver enzymes during hospitalizations may be attributed to medications used,as well as sepsis and shock.As a result,the proportion of hospitalized patients afflicted with COVID-19 and pathological liver biomarkers varies from 14%to 53%.Aminotransferases and bilirubin are found most often elevated.Usually,increased gamma-glutamyltransferase,alkaline phosphatase,and decreased serum albumin levels are demonstrated.Additionally,although there is no specific treatment for COVID-19,many of the drugs used to treat the infection are hepatotoxic.In this mini-review,we focus on how liver dysfunction can be one of the features associated with the COVID-19 cytokine storm.Furthermore,data show that liver injury can be an independent predictor of severe COVID-19,the need for hospitalization,and death.

Bulgarian Intellectuals and Students and Their Notion of the Age of Socialism

In the years of the Bulgarian transition from Soviet-style state socialism to parliamentary democracy and market economy,the notions of the recent past experience profound changes.This process is predetermined by the new political imperative—the need to reorient the country from the Eastern bloc to the Western world.Changing the attitude of the Bulgarian society towards the socialist past is accomplished first through the change of curricula and textbooks,but also with the help of the media,which give floor to critics of socialism.Over time,however,especially since the neo-liberal economic transformations that took place under the so-called Washington Consensus led to deindustrialisation and high unemployment,a change in social attitude towards socialism began.In the 21st century,the attitude towards socialism changed.The total denial that prevailed in the 1990s gave way to a more nuanced picture—alongside the shortcomings and crimes,there are also talks about positive features of socialism such as social security and stability.This is evident both in the positions of the Bulgarian intellectuals and in the views of Bulgarian students about the socialist past.

Post-Crisis Remodeling of the Economy for the Sustainable Growth of South Eastern European （SEE） Countries

Every bigger economic crisis, as the current one, to separate national economies as well. However, leaves behind a huge material damage to the world economy and such crises remind national authorities of the mistakes done in the past while creating and running macroeconomic policy and teach them how they should overcome these crises in the upcoming period. The economic growth model of the selected South Eastern European （SEE） economies （Albania, Bosnia, Macedonia, Serbia, Slovenia, Croatia, Bulgaria, and Montenegro） during pre-global economic crisis was based mainly on foreign demand and capital inflows which created big external imbalances in those countries. It was the main reason why those countries were exposed to big vulnerability of external shocks. But, the crisis reshapes the world economic map. Competition on world markets gets new forms and players. The lessons learnt from economic crisis say that there is a need for revising the pre-crisis economic growth model in the selected countries as they are less vulnerable to external shocks. New economic model will enable their long-lasting and more sustainable economic growth in the future. One approach of remodeling their economy is presented in this paper. The main finding of this research is that instead of experiencing external ＂push＂ factors for economic growth by the governments, a promotion of internal resources is needed in order to enable ＂the catching up＂ process of these countries to continue. But, all those countries are members or candidates for becoming European Union （EU） members. That means there is no room for application on entirely new economy growth model, since those countries have to create economic model which has to be convergent to the EU one. There must be different approaches by individual countries in remodeling their economies. The findings of this survey are intended to remind the policy makers of the selected SEE countries of the mistakes they made before and during the economic crisis and the need and directions for remodeling their economies in the post-crises period that will enable their long-lasting and more sustainable economic growth in the future. The position assumed for this research is interpretative using qualitative methods of research. In order to ensure comparability among results, the proposed methodological design will be multiple-case study research on the selected SEE economies.

Solving Systems of Transcendental Equations Involving the Heun Functions

The Heun functions have wide application in modern physics and are expected to succeed the hypergeometrical functions in the physical problems of the 21st century. The numerical work with those functions, however, is complicated and requires filling the gaps in the theory of the Heun functions and also, creating new algorithms able to work with them efficiently. We propose a new algorithm for solving a system of two nonlinear transcendental equations with two complex variables based on the Müller algorithm. The new algorithm is particularly useful in systems featuring the Heun functions and for them, the new algorithm gives distinctly better results than Newton’s and Broyden’s methods. As an example for its application in physics, the new algorithm was used to find the quasi-normal modes (QNM) of Schwarzschild black hole described by the Regge-Wheeler equation. The numerical results obtained by our method are compared with the already published QNM frequencies and are found to coincide to a great extent with them. Also discussed are the QNM of the Kerr black hole, described by the Teukolsky Master equation.