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This study tackles the critical challenge of medication non-adherence in healthcare by pinpointing indicators related to medication adherence (IRMAs) across 39 European countries and Israel. Utilizing a structured expert survey methodology within the European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE; COST Action CA19132), our research identified key country-specific IRMAs and collected data on these indicators to understand the multifaceted nature of medication adherence. The research was conducted in two phases: firstly, defining key IRMAs through a two-round expert survey, and secondly, gathering country-specific data on these IRMAs through literature reviews and additional expert surveys. The study revealed a diverse range of 26 top-ranked IRMAs, including six related to country characteristics, four to social/economic factors, three each to therapy-related and patient-related factors, one to condition-related factors, and nine to healthcare system-related factors. The availability of country-specific data on these IRMAs varied among the countries, highlighting the need for more comprehensive data collection and research. The findings from this study not only underscore the complexity of predicting medication adherence but also lay the groundwork for developing targeted, country-specific interventions to improve adherence. Moreover, this research offers valuable insights for policymakers, highlighting the importance of understanding the multifaceted nature of medication adherence and offering a valuable resource in formulating targeted health policies to enhance health outcomes and reduce the economic burden associated with medication non-adherence.

Aim: This study aimed to construct prognostic mathematical models utilizing multifactorial regression analysis to assess the risk of developing drug-induced neutralizing antibodies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with tumor necrosis factor alpha blockers. Materials and methods: Over a four-year period, we enrolled 213 patients in this study and divided them into three groups: the rheumatoid arthritis group (n=121), the ankylosing spondylitis group (n=50), and the psoriatic arthritis group (n=42). The study included also a group of healthy controls consisting of 31 healthy subjects who matched the patient groups in age, sex, body mass index, and conditions typical for rheumatology patients. Prognostic mathematical models based on statistically significant factors determined through univariate correlation and regression analyses incorporated patient medical history and serological and immunological data. Results: The study encompassed all 213 patients and 31 healthy controls. Data analysis was conducted at 12 and 24 months after commencing treatment. During this follow-up, the patients exhibited the highest percentage of antidrug antibodies. At 6 months, 6.57% of patients had confirmed neutralizing antibodies, which increased to 12.69% at 12 months and 17.72% at 24 months. Multivariate logistic regression analysis revealed that factors such as age over 55 years, excess weight, smoking, and absence of methotrexate treatment at a dose less than 7.5 mg per week had the highest predictive value. Conclusions: Investigating clinical and biological markers with predictive value for individual patients’ therapeutic responses is a complex task. This complexity arises from the interplay of at least three distinct parameters: the patient’s disease state, drug bioavailability, and pathophysiological changes within the patient’s body, all of which are influenced by various factors.

This study aimed to investigate the transferability of novel artificial intelligence (AI) methods for prediction modelling of diabetes based on real-world data (RWD) between early and late adopters of emerging health technologies from the perspective of developers and health technology assessment (HTA) experts. A two-step approach was used. Developers of the new AI methods within HTx consortium completed a survey about the benefits, usability, barriers associated with implementing the new prediction models in routine HTA practices. Then, HTA experts from Central and Eastern European (CEE) countries participated in a focus group discussion. Developers generally expressed optimism regarding the transferability of the methods, while acknowledging potential disparities across CEE countries. Key benefits that were identified included enhanced understanding of diabetes, improved cost-effectiveness modelling, and refined patient stratification, all of which could contribute to clinical and reimbursement decisions across various jurisdictions. The focus group underscored the value of real-world data for diabetes prediction modelling, serving as a beneficial resource for both clinicians and HTA agencies. However, there was a recognized need to clarify the processes of integrating randomized clinical trial data with real-world data. For the other stakeholders, the advancement of the methodology will improve the diagnosis and therapy during the process of decision making. Experts from CEE countries recognized the potential of artificial intelligence-based methods employing real-world data for diabetes modelling. These methods are seen as instrumental in elucidating the heterogeneous nature of the disease, supporting clinician decision-making and holding promises for HTA purposes.

Adherence is the degree to which the patient’s behaviour and actions correspond to the physician’s established treatment regimen regarding timing, dose and frequency. Patient counselling by both oncologists and pharmacists and optimization of the therapeutic regimen can critically impact decision-making and adherence to therapy. We performed a two-step study to identify factors influencing adherence to therapy from the perspective of oncology hospital pharmacists in Bulgaria. The results show that the major factors affecting anticancer therapy adherence are the manifestation of adverse drug reactions and distrust in therapy. These could be overcome with improved communication between patients, oncologists and pharmacists on therapy aspects and more active involvement of the hospital pharmacists in therapy monitoring with a main focus on identifying possible drug-related problems based on safety profile, drug-drug interactions and non-adherence.

AbstractThere is a global call for action for cervical cancer elimination as a public health problem—WHO Strategy 90-70-90. One of the strategic pillars, alongside vaccination, is cervical cancer screening. This aims to assess the economic consequences and cost-effectiveness of primary DNA-HPV testing for cervical cancer screening in Bulgaria. Combined cost-effectiveness (CEA) and cost-benefit (CBA) analysis was performed to evaluate the net benefit of the HPV genotype testing program among women aged 30–54 in Bulgaria and to compare its cost-effectiveness with the current practice. ICER was presented separately for only direct costs and direct + indirect costs. The CBA analysis for the age group 30-54 shows that the benefit/cost ratio of DNA-HPV primary screening is 1.03 and the net present benefit accounts for 373,023 euro thus making the program beneficial for the healthcare system. CEA shows that HPV screening is cost-effective over the current practice of PAP testing with ICER 1634 euro/LYG when considering only direct costs and—8020 euro/LYG for direct and indirect costs. The ICER in terms of the sensitivity rate of the testing methods is 1316 euros. The LYG earned with the HPV testing account for 4989 for the observed women. Primary hrHPVDNA-based screening is an important scientific and clinical advance since it offers better reassurance of low cancer risk compared to cytology-only screening conducted at the same interval. Primary hrHPV screening can be considered as a dominant alternative to current cytology-based cervical cancer screening approaches including cytology alone and contesting and providing better benefit.

Objectives: The present study aimed to examine the role of two-dimensional shear wave elastography (SWE) in the assessment of the vascular wall of the carotid arteries and atherosclerotic plaques in patients with rheumatoid arthritis with moderate and low disease activity versus healthy controls. Methods: An observational case–control study was carried out at the University Medical Hospital “Kaspela” in Plovdiv, Bulgaria, from June 2023 to August 2024. This study included 24 patients with rheumatoid arthritis (RA) and 25 healthy controls. We employed two-dimensional SWE (2D-SWE) to examine the vessels around the plaques. The potential links with the degree of stenosis, plaque type, and cardiovascular risk were analyzed. Results: In the RA group, the 2D-SWE values showed significant positive correlations with the severity of the atherosclerotic plaques (rs = 0.461; 95% CI: 0.049 to 0.739; p = 0.023) and the degree of stenosis (rs = 0.920; 95% CI: 0.793 to 0.970; p < 0.001). Based on 2D-SWE, a ROC curve analysis distinguished higher severity plaques from lower severity plaques with an AUC = 0.818, 95% CI: 0.683 to 0.913. The optimal cut-off value of 2D-SWE > 32.40 kPa was associated with a sensitivity of 96%, a specificity of 56%, a positive predictive value (PPV) of 66.70%, and a negative predictive value (NPV) of 92.90%. Conclusion: Elastography can be an effective technique for assessing and stratifying atherosclerotic plaques in patients with RA, as well as for aiding in the early detection and subsequent prevention of future complications.

Imaging of microscopic objects is of fundamental importance, especially in life sciences. Recent fast progress in electronic detection and control, numerical computation, and digital image processing, has been crucial in advancing modern microscopy. Digital holography is a new field in three-dimensional imaging. Digital reconstruction of a hologram offers the remarkable capability to refocus at different depths inside a transparent or semi-transparent object. Thus, this technique is very suitable for biological cell studies in vivo and could have many biomedical and biological applications. A comprehensive review of the research carried out in the area of digital holographic microscopy (DHM) for live-cell imaging is presented. The novel microscopic technique is non-destructive and label-free and offers unmatched imaging capabilities for biological and bio-medical applications. It is also suitable for imaging and modelling of key metabolic processes in living cells, microbial communities or multicellular plant tissues. Live-cell imaging by DHM allows investigation of the dynamic processes underlying the function and morphology of cells. Future applications of DHM can include real-time cell monitoring in response to clinically relevant compounds. The effect of drugs on migration, proliferation, and apoptosis of abnormal cells is an emerging field of this novel microscopic technique.

Objective: Hypertensionis one of the most common chronic diseases, affecting more than 20% of the population. The side effects experienced due to antihypertensive medications, such as tiredness, muscle pain, and insomnia, are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSRs) and following differentiation of messages found in more than one patient. Methods: We conducted a retrospective analysis of the reported adverse drug reactions (ADRs) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) inhibitors, and sartans for the period 2017–2021. Each ICSR form was observed, and data for suspected medicine and type of adverse reaction was analyzed. Results: The total number of processed notifications for adverse drug reactions (ADRs) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29). Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on the Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusions: Cardiovascular medicines from the groups of ACE inhibitors, sartans, and statins have a high share of reported ADRs in the BDA system. Some of them are severe and need further investigation.

Evaluation of rational drug utilization (RDU) through WHO indicators is used to provide information about the level of development of national policy and to identify the necessity of further regulatory, patients or healthcare professionals -centered measures. The current study aims to investigatethe patients’ perspective about medicines utilization by implementing the WHO’s "followup" indicators in the Bulgarian practice. A prospective, cross -sectional, online inquiry study was conducted among Bulgarian population. The population above 18 years of age is 5.8 million of people and 400 people sample was considered sufficient with 95% CI. The study methodology is based on a modified version of the WHO "followup" indicators. The total number of answers was 467. The majority of patients aged over 56 years responded that they did not receive enough information about the side effects and interactions of the prescribed medicines and the most often they used the leaflet as a source of information. Most of the patients responded they always check the expiry date (61%), while 23 % of patients check it sometimes. In the group of patients over 65 years, 24% responded that they never check the expiry date. The results of our study suggest that rational medicines utilization is a broader concept depending on patients' knowledge and pharmacists and patients relation. It suggests that there is a need to educate both parties, mainly to increase health literacy and promote general aspects of rational medicines utilization.

Posner-Schlossman syndrome (PSS) is a unilateral ocular disease, characterized by recurrent non-granulomatous anterior uveitis and increased intraocular pressure (IOP), leading to chronic secondary glaucoma. In this case report, we present the case of a 46-year-old man with chronic, hypertensive anterior uveitis in the left eye and frequent recurrences over the last two years. The patient suffers from Posner-Schlossman syndrome with chronic secondary glaucoma, unresponsive to medication therapy. After trabeculectomy with ExPress implantation and, later on, cataract surgery with implantation of an intraocular lens in the left eye, the IOP varied between 10 and 12 mmHg over a period longer than a year without any medication therapy. Patients with PSS are at risk of developing secondary glaucoma and irreversible complications. Trabeculectomy with ExPress implantation is a reliable and effective treatment of IOP unresponsive to medication therapy.

The most common primary cardiac tumors are myxomas, while cardiac hamartomas are rare. Cardiac hamartomas may constitute manifestation of a genetic disorder such as tuberous sclerosis, or could be diagnosed independently as a solitary lesion. We present two rare cases of primary cardiac tumors detected via diagnostic imaging and subsequent histopathology examination. The first described case is that of a male preterm foetus with multiple rhabdomyomas in the heart, discovered during foetal echocardiography. The finding was later confirmed by autopsy, which also revealed presence of cortical tubers with typical balloon cells constituting well known epileptogenic lesions in the foetal brain. The second case describes an even rarer benign cardiac lesion – a hamartoma of mature cardiomyocytes – which was discovered by chance in a 49-year old female patient during echocardiography. The performed CT scan revealed a 37 x 16 x 12 mm tumor in the right atrium obstructing the superior vena cava inlet. The malformation was surgically removed and examined histologically revealing disorganized hypertrophic mature cardiomyocytes, partly separated by fibrous strands and admixed with mature adipocytes. Differential diagnosis was performed to rule out other benign tumors with myocyte differentiation – cardiac rhabdomyoma, histiocytoid cardiomyopathy and adult cellular rhabdomyoma.

Acute retinal necrosis (ARN) is a devastating viral infection commonly associated with varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 (HSV-1, HSV-2). Typically, ARN affects individuals without immune status disorders between the ages of 50-70. In two-thirds of the cases, one-eye involvement is observed and the inflammation can be presented as panuveitis. The most characteristic clinical manifestations are vitreitis, occlusion of the retinal arterioles, and peripheral necrotizing retinitis. Retinitis presents with the appearance of deep, multifocal, yellowish-white foci, typically localized in the peripheral retina. Systemic antivirals are the first treatment of choice for ARN. The goal of the therapy is to stop the viral replication and disease progression in the affected eye, as well as to prevent involvement of the healthy eye. The other eye can be attacked in an interval of 5 days to 30 years. The visual prognosis after illness is poor. Early diagnosis and timely initiation of treatment play an important role in maintaining visual acuity and preventing the other eye from being affected.

AbstractCholine is an essential nutrient involved in the synthesis of acetylcholine in the cholinergic neurons. The pharmacokinetic properties of choline are well described; however, there is a lack of data about its activity toward the CYP450 superfamily of enzymes. Therefore, the aim of this study was to conduct in silico and in vitro activity assessments of choline against three major CYP450 isoforms—CYP1A2, CYP2D6, and CYP3A4. Preliminary in silico modeling was performed on a specialized DL-CYP Prediction Server to evaluate the affinity of choline toward the enzymes. The in vitro study contained specific cytochrome P450 isoform inhibitors and substrates (for CYP1A2, CYP2D6, and CYP3A4) to determine the inhibition performance of choline at five different concentrations (0.150 − 1 µmol/L). The potential interactions of choline and CYPs were displayed after molecular docking with Glide (Schrödinger). In addition, induced-fit simulations and binding free energy calculations MM/GBSA (Molecular Mechanics-Generalized Born Surface Area) were applied to predict the accessibility in each CYP isoform. The initial in silico simulations revealed that choline lacks inhibition potency against the aforementioned enzymes. The in vitro evaluations confirmed that choline possessed no effect against CYP1A2; however, at 1 µmol/L choline exerted 22% and 27% blocking capacity against CYP2D6 and CYP3A4, respectively. Furthermore, there was good correlation between the in vitro results and the complexes’ free binding energy recalculations. Overall, the assessments indicated that choline is a weak CYP2D6 and CYP3A4 inhibitor. The latter results should be considered as a source of future unwanted drug–drug interactions.

AbstractThis study analysed the changes in the reimbursed cost, prices and utilization of biological medicines for a 5-year time horizon, encompassing three major arthropathic diagnoses, rheumatoid arthritis (RA), psoriatic arthropathies (PsA) and ankylosing spondylitis (AS), from the point of view of the third-party payer in Bulgaria. National; population based; macroeconomic; top-down budget analysis was performed based on official data about the number of inhabitants, reimbursed diagnoses and medicines, reimbursed cost, treated patients, and prices of medicines. The utilization of medicines was calculated in DDD per 1000/inh/day. There was an increase of 41% in the number of patients treated with biological medicines. The reimbursement cost of biologicals increased by 21%; however, the per-patient reimbursement costs per diagnosis fell by 40% due to price decreases. Out of 21 reimbursed diagnoses, we saw a significant difference in prevalence (612 SD in 2016 to 1216 SD in 2020; p

IntroductionMeaningful patient involvement in health technology assessment (HTA) is essential in ensuring that the interests of the affected patient population, their families, and the general public are accurately reflected in coverage and reimbursement decisions. Central and Eastern European (CEE) countries are generally at less advanced stages of implementing HTA, which is particularly true for patient involvement activities. As part of the Horizon2020 HTx project, this research aimed to form recommendations for critical barriers to patient involvement in HTA in CEE countries.MethodsBuilt on previous research findings on potential barriers, a prioritisation survey was conducted online with CEE stakeholders. Recommendations for prioritised barriers were formed through a face-to-face workshop by CEE stakeholders and HTx experts.ResultsA total of 105 stakeholders from 13 CEE countries completed the prioritisation survey and identified 12 of the 22 potential barriers as highly important. The workshop had 36 participants representing 9 CEE countries, and 5 Western European countries coming together to discuss solutions in order to form recommendations based on best practices, real-life experience, and transferability aspects. Stakeholder groups involved in both phases included HTA organisation representatives, payers, patients, caregivers, patient organisation representatives, patient experts, health care providers, academic and non-academic researchers, health care consultants and health technology manufacturers/providers. As a result, 12 recommendations were formed specified to the CEE region’s context, but potentially useful for a broader geographic audience.ConclusionIn this paper, we present 12 recommendations for meaningful, systematic, and sustainable patient involvement in HTA in CEE countries. Our hope is that engaging more than a hundred CEE stakeholders in the study helped to spread awareness of the importance and potential of patient involvement and that the resulting recommendations provide tangible steps for the way forward. Future studies shall focus on country-specific case studies of the implemented recommendations.

Background: Within the last years, excessive utilization of food supplements for prevention and prophylaxis in different chronic diseases is observed. In order to extend the control on the arrangement of the market, utilization, and safety of food supplements, the European Commission took genuine regulatory steps to harmonize the criteria for FS and to guarantee that they are not giving deceiving information. However, excessive use, uncontrolled patients consumption, exposure to higher than recommended intakes, and even interaction with specific medicines can cause toxicity risks and pose serious health concerns. The aim of this study is to examine the tendency of pharmacists to correctly recommend food supplements to chronically ill patients in order to extend the pharmaceutical care and prevent side effects. Materials and methods: The used method is an anonymous survey that was conducted by using the direct questionnaire method among master pharmacists and assistant pharmacists working in community pharmacies in Bulgaria. Results: The results show that the majority of the pharmacists are willing to recommend food supplements and that they could participate in the monitoring of chronically ill patients with food supplements intake. On the other side, the survey shows that most of the patients are seeking for food supplements and do ask for advice. Conclusion: In conclusion, pharmacists as the most accessible health care professionals can provide more detailed information concerning food supplements in order to avoid negative effects on the safety of chronically ill patients, especially with additional training in the field.

Se estudian algunos rasgos del estilo comunicativo de los jóvenes a base de las manifestaciones lingüísticas de las funciones expresiva, apelativa y fática del lenguaje. Se analizan los recursos lingüísticos pertenecientes a los niveles léxico-semántico y sintáctico, donde se hacen más patentes las peculiaridades del habla juvenil.

Aim: Real-world data and real-world evidence (RWE) are becoming more important for healthcare decision making and health technology assessment. We aimed to propose solutions to overcome barriers preventing Central and Eastern European (CEE) countries from using RWE generated in Western Europe. Materials & methods: To achieve this, following a scoping review and a webinar, the most important barriers were selected through a survey. A workshop was held with CEE experts to discuss proposed solutions. Results: Based on survey results, we selected the nine most important barriers. Multiple solutions were proposed, for example, the need for a European consensus, and building trust in using RWE. Conclusion: Through collaborationwith regional stakeholders, we proposed a list of solutions to overcome barriers on transferring RWE from Western Europe to CEE countries.

IntroductionBreast cancer is the most common type of cancer affecting women in Europe. Advanced breast cancer (ABC) poses a significant therapeutic challenge, and therefore, timely access to treatment is crucial. The aim of the present study was to evaluate the treatment patterns and patients' access to new therapies for ABC in Bulgaria.MethodsWe conducted a retrospective study in the period 2008–2021. Based on the European Medicines Agency (EMA) database, we analyzed a number of medicinal products with marketing authorization for ABC in the last 13 years. Time to market access was evaluated as the degree of availability, which is measured by the number of medicines that are available to patients (availability index, AI), and the average time elapsed between obtaining a marketing authorization and time to inclusion in the Positive Drug List. Data were analyzed through descriptive statistics via Microsoft Excel version 10.ResultsThe average time to access was 564 days for targeted therapy. The availability and compliance index for chemotherapy and hormonal therapy in advanced breast cancer was 1, while the average AI for targeted therapy was 0.67. Patient access to targeted oncology therapy of ABC is above average for Europe and takes 1–2 years.ConclusionFaster access is more evident for biosimilars. National regulatory requirements for pricing and reimbursement have a major impact on market access.

Objectives: The present study aimed to examine the role of two-dimensional shear wave elastography (SWE) in the assessment of the vascular wall of the carotid arteries and atherosclerotic plaques in patients with rheumatoid arthritis with moderate and low disease activity versus healthy controls. Methods: An observational case–control study was carried out at the University Medical Hospital "Kaspela" in Plovdiv, Bulgaria, from June 2023 to August 2024. This study included 24 patients with rheumatoid arthritis (RA) and 25 healthy controls. We employed two-dimensional SWE (2D-SWE) to examine the vessels around the plaques. The potential links with the degree of stenosis, plaque type, and cardiovascular risk were analyzed. Results: In the RA group, the 2D-SWE values showed significant positive correlations with the severity of the atherosclerotic plaques (rs = 0.461; 95% CI: 0.049 to 0.739; p = 0.023) and the degree of stenosis (rs = 0.920; 95% CI: 0.793 to 0.970; p < 0.001). Based on 2D-SWE, a ROC curve analysis distinguished higher severity plaques from lower severity plaques with an AUC = 0.818, 95% CI: 0.683 to 0.913. The optimal cut-off value of 2D-SWE > 32.40 kPa was associated with a sensitivity of 96%, a specificity of 56%, a positive predictive value (PPV) of 66.70%, and a negative predictive value (NPV) of 92.90%. Conclusion: Elastography can be an effective technique for assessing and stratifying atherosclerotic plaques in patients with RA, as well as for aiding in the early detection and subsequent prevention of future complications. [ABSTRACT FROM AUTHOR]

Imaging of microscopic objects is of fundamental importance, especially in life sciences. Recent fast progress in electronic detection and control, numerical computation, and digital image processing, has been crucial in advancing modern microscopy. Digital holography is a new field in three-dimensional imaging. Digital reconstruction of a hologram offers the remarkable capability to refocus at different depths inside a transparent or semi-transparent object. Thus, this technique is very suitable for biological cell studies in vivo and could have many biomedical and biological applications. A comprehensive review of the research carried out in the area of digital holographic microscopy (DHM) for live-cell imaging is presented. The novel microscopic technique is non-destructive and label-free and offers unmatched imaging capabilities for biological and bio-medical applications. It is also suitable for imaging and modelling of key metabolic processes in living cells, microbial communities or multicellular plant tissues. Live-cell imaging by DHM allows investigation of the dynamic processes underlying the function and morphology of cells. Future applications of DHM can include real-time cell monitoring in response to clinically relevant compounds. The effect of drugs on migration, proliferation, and apoptosis of abnormal cells is an emerging field of this novel microscopic technique. [ABSTRACT FROM AUTHOR]

Objective: Hypertensionis one of the most common chronic diseases, affecting more than 20% of the population. The side effects experienced due to antihypertensive medications, such as tiredness, muscle pain, and insomnia, are often a significant predictor of poor adherence to therapy. The goal of the current study is to present the frequency, type, seriousness, and severity of adverse drug reactions reported to the BDA via Individual Case Safety Reports (ICSRs) and following differentiation of messages found in more than one patient. Methods: We conducted a retrospective analysis of the reported adverse drug reactions (ADRs) reported in the Bulgarian Drug Agency database after treatment with antihyperlipidemic medicines, angiotensin-converting enzyme (ACE) inhibitors, and sartans for the period 2017–2021. Each ICSR form was observed, and data for suspected medicine and type of adverse reaction was analyzed. Results: The total number of processed notifications for adverse drug reactions (ADRs) included in the database is 142. The highest number of ADRs was reported for ARB (58), followed by antihyperlipidemic medicines (55) and ACE inhibitors (29). Most of the assessed adverse events experienced by more than one patient fall into the probable and related categories based on the Global Introspection method classification. Therefore, they have been investigated and are consistent with exposure in the population. Conclusions: Cardiovascular medicines from the groups of ACE inhibitors, sartans, and statins have a high share of reported ADRs in the BDA system. Some of them are severe and need further investigation. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) inhibitors have heralded a paradigm shift in the management of immune-mediated diseases. While their efficacy is well-established, the safety concerns associated with these agents, particularly regarding thromboembolic events (TE), remain a focus of extensive research and clinical scrutiny. This comprehensive literature review embarks on an exploration of the multifaceted landscape of JAK inhibitors, providing insights into their safety profiles across diverse immune-mediated diseases. The introduction highlights the transformative influence of JAK inhibitors in the treatment of immune-mediated diseases. Historically, the therapeutic arsenal for these conditions included corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologics. The advent of JAK inhibitors has revolutionized this landscape, although concerns about their safety persist. This review strives to comprehensively evaluate their safety, amalgamating knowledge from multiple studies and trials. The subsequent sections delve into the safety of specific JAK inhibitors in the context of rheumatoid arthritis, inflammatory bowel diseases, and dermatologic conditions and their associations with venous thromboembolism. The evolving understanding of TE risk, particularly the intricate relationship between these agents and immune-mediated diseases, is meticulously unravelled. The concluding remarks underscore the dynamic nature of TE risk assessment with regard to immune-mediated diseases involving JAK inhibitors. It underscores that risk assessment is multifactorial, influenced not only by the choice of JAK inhibitor but also by the nuances of the underlying immune-mediated disease and the unique patient characteristics. This review offers a holistic perspective on TE risks associated with JAK inhibitors and contributes to the ongoing dialogue regarding their safety in the realm of immune-mediated diseases.

Febuxostat, initially developed as a xanthine oxidase inhibitor to address hyperuricemia in gout patients, has evolved into a versatile therapeutic agent with multifaceted applications. This review provides a comprehensive overview of febuxostat’s mechanism of action, its effectiveness in gout management, its cardiovascular safety profile, renal and hepatic effects, musculoskeletal applications, safety considerations, and emerging research prospects. Febuxostat’s primary mechanism involves selective inhibition of xanthine oxidase, resulting in reduced uric acid production. Its pharmacokinetics require personalized dosing strategies based on individual characteristics. In gout management, febuxostat offers a compelling alternative, effectively lowering uric acid levels, relieving symptoms, and supporting long-term control, especially for patients intolerant to allopurinol. Recent studies have demonstrated its cardiovascular safety, and it exhibits minimal hepatotoxicity, making it suitable for those with liver comorbidities. Febuxostat’s potential nephroprotective effects and kidney stone prevention properties are noteworthy, particularly for gout patients with renal concerns. Beyond gout, its anti-inflammatory properties hint at applications in musculoskeletal conditions and a broader spectrum of clinical contexts, including metabolic syndrome. Emerging research explores febuxostat’s roles in cardiovascular health, neurological disorders, rheumatoid arthritis, and cancer therapy, driven by its anti-inflammatory and antioxidative properties. Future directions include personalized medicine, combination therapies, mechanistic insights, and ongoing long-term safety monitoring, collectively illuminating the promising landscape of febuxostat’s multifaceted therapeutic potential.

Introduction: Filtration surgery is the most effective method of lowering intraocular pressure (IOP) in patients with insufficient medical control. It consists in facilitating the drainage of the intraocular fluid (IOF) from the anterior chamber to the subconjunctival space and subsequent lowering of IOP. The formation of filtration blebs (FB) and the processes of scarring occurring in the conjunctiva are of particular importance in glaucoma surgery. In many cases, the appearance of FB does not match the IOP values, and what causes the failure after trabeculectomy often remains unclear. Often, over time, there is a change in the structure of the FB, as fibrous tissue grows, which prevents the IOF drainage. Laser scanning in vivo confocal microscopy is a non-invasive study allowing the production of layered images at the microstructural level with high resolution of both the cornea and other structures of the anterior ocular surface.Aim: To evaluate the morphological structure and function of filtering blebs after trabeculectomy using in vivo confocal microscopy taking into account the type of implant and when the surgery was performed.Materials and methods: The study included 33 patients, 46 eyes with glaucoma. Twenty-six of the eyes had primary open-angle glaucoma (POAG), 18 eyes had pseudoexfoliative glaucoma and 2 eyes had juvenile glaucoma. All patients underwent trabeculectomy with fornix-based flap, and three of the eyes underwent retrabeculectomy. Mitomicyn C (MMC) was administered intraoperatively to all patients. The study of the filtering bleb was performed by in vivo confocal microscopy (CFM) (Heidelberg Retina Tomograph II (HRT II) /Rostock Cornea Module/ (Heidelberg Engineering GmbH, Heidelberg, Germany), the period from trabeculectomy and examination being from 1 year to 22 years. An Express implant was placed in 14 eyes, Ologen implant in 7 eyes, and 25 eyes had no implant placed. In the analysis of the morphological structure of the filtering blebs, three indicators were evaluated: the type of epithelium, the type of stroma, and blood vessels.Results: Statistical significance was established with regard to the function and morphological structure of the filtering bleb (p=0.009). Blebs with fine collagen mesh and dense collagen mesh demonstrate good function. In the case of blebs with insufficient function, those with a dense collagen network and hyper-reflective tissue predominated and there were no blebs with a fine collagen network, and in non-functioning blebs most common were those with a pronounced collagen network and hyper-reflective tissue. With regard to vascularization, we found that the functioning blebs in the shortest postoperative period were dominated by those with one blood vessel (stage 1) and there was no stage 3, with weak tortuosity, while in non-functioning blebs in the late postoperative period, there was moderate to severe vascularization and tortuosity (p=0.037), (p=0.043), (p=0.047), (p=0.021). The type of implant affects the tortuosity of the blood vessels of the filtering bleb (p=0.026). The blebs with Express implants show a slight tortuosity, followed by the blebs with Ologen implants. The highest percentage of highly kinked blood vessels occurred in blebs without an implant.Conclusions: In vivo confocal microscopy is an innovative method which allows visualization of the internal structure of the filtering blebs at a cellular level, giving us a new insight into the ongoing healing processes, premising the function of the filtering blebs after glaucoma surgery.

Central and Eastern European countries (CEEC) have among the highest rates of increase in healthcare expenditure. External reference pricing, generics and biologics price capping, regressive scale for price setting, health technology assessment (HTA), and positive drug lists for reimbursed medicines are among the variety of implemented cost-containment measures aimed at reducing and controlling the rising cost for pharmaceuticals. The aim of our study was to analyze the influence of a recently introduced measure in Bulgaria—budget capping in terms of overall budget expenditure. A secondary goal was to analyze current and extrapolate future trends in the healthcare and pharmaceutical budget based on data from 2016 to 2021. The study is a retrospective, observational and prognostic, macroeconomic analysis of the National Health Insurance Fund's (NHIF) budget before (2016–2018) and after (2019–2021) the introduction of the new budget cap model. Subgroups analysis for each of the three new budget groups of medicines (group A: medicines for outpatient treatment, prescribed after approval by a committee of 3 specialists; group B: all other medicines out of group A; and group C: oncology and life-saving medicines out of group A) was also performed, and the data were extrapolated for the next 3 years. The Kruskal–Wallis test was applied to establish statistically significant differences between the groups. During 2016–2021, healthcare services and pharmaceutical spending increased permanently, observing a growth of 82 and 80%, respectively. The overall healthcare budget increased from European €1.8 billion to 3.3 billion. The subgroup analysis showed a similar trend for all three groups, with similar growth between them. The highest spending was observed in group C, which outpaced the others mainly due to the particular antineoplastic (chemotherapy) medicines included in it. The rising overall healthcare cost in Bulgaria (from European €1.8 billion to 3.3 billion) reveals that implementation of a mechanism for budget predictability and sustainability is needed. The introduced budget cap is a relatively effective measure, but the high level of overspending and pay-back amount (from European €34 billion to 59 billion during 2019–2021) reveals that the market environmental risk factors are not well foreseen and practically implemented.

Abstract Chalcogenide glasses are one of the most versatile materials that have been widely researched because of their flexible optical, chemical, electronic, and phase change properties. Their application is usually in the form of thin films, which work as active layers in sensors and memory devices. In this work, we investigate the formulation of nanoparticle ink of Ge–Se chalcogenide glasses and its potential applications. The process steps reported in this work describe nanoparticle ink formulation from chalcogenide glasses, its application via inkjet printing and dip-coating methods and sintering to manufacture phase change devices. We report data regarding nanoparticle production by ball milling and ultrasonication along with the essential characteristics of the formed inks, like contact angle and viscosity. The printed chalcogenide glass films were characterized by Raman spectroscopy, X-ray diffraction, energy dispersive spectroscopy and atomic force microscopy. The printed films exhibited similar compositional, structural, electronic and optical properties as the thermally evaporated thin films. The crystallization processes of the printed films are discussed compared to those obtained by vacuum thermal deposition. We demonstrate the formation of printed thin films using nanoparticle inks, low-temperature sintering and proof for the first time, their application in electronic and photonic temperature sensors utilizing their phase change property. This work adds chalcogenide glasses to the list of inkjet printable materials, thus offering an easy way to form arbitrary device structures for optical and electronic applications.

Стандартные протоколы ультразвукового исследования включают исследования всех сосудов анализируемой области, во всех режимах сканирования, с полным набором измерений, и требуют высокой квалификации специалистов и больших временных затрат. Однако для ряда клинических задач достаточно выполнения фокусированного протокола ультразвукового исследования, т.е. ориентированного на решение конкретной проблемы и, следовательно, сокращенного по времени, тем самым позволяющего увеличить число обследуемых. Оценка сердечно-сосудистого риска с помощью выявления атеросклеротических бляшек в сонных и бедренных артериях, скрининг на наличие аневризмы аорты, выявление проксимального тромбоза глубоких вен нижних конечностей – это те направления в медицине, где фокусированные протоколы ультразвукового исследования могут повысить долю обследуемых и способствовать своевременной диагностике и профилактике заболеваний. Доступность фокусированного ультразвукового исследования и развитие образовательных структур позволят расширить круг специалистов, способных выполнять подобные исследования (кардиологи, терапевты, врачи общей практики, сосудистые хирурги). Сегодня существует много вопросов по организации проведения фокусированных протоколов в клинической практике. Данный консенсусный документ направлен на повышение информированности широкого круга специалистов о задачах, принципах проведения и применении фокусированного УЗИ.

Patients' perspectives are important to identify preferences, estimate values and appreciate unmet medical needs in the process of research and development and subsequent assessment of new health technologies. Patient and public involvement in health technology assessment (HTA) is essential in understanding and assessing wider implications of coverage and reimbursement decisions for patients, their relatives, caregivers, and the general population. There are two approaches to incorporating the patients' voice in HTA, preferably used in a mix. In the first one, patients, caregivers and/or their representatives directly participate at discussions in different stages of the HTA process, often at the same table with other stakeholders. Secondly, patient involvement activities can be supported by evidence on patient value and experience collected directly from patients, caregivers and/or their representatives often by patient groups Patient involvement practices, however, are limited in Central and Eastern European (CEE) countries without clear methodology or regulatory mechanisms to guide patient involvement in the HTA process. This poses the question of transferability of practices used in other countries, and might call for the development of new CEE-specific guidelines and methods. In this study we aim to map potential barriers of patient involvement in HTA in countries of the CEE region.

Background: Rising expenditure for new cancer medicines is accelerating concerns that their costs will become unsustainable for universal healthcare access. Moreover, early market access of new oncology medicines lacking appropriate clinical evaluation generates uncertainty over their cost-effectiveness and increases expenditure for unknown health gain. Patient-level data can complement clinical trials and generate better evidence on the effectiveness, safety and outcomes of these new medicines in routine care. This can support policy decisions including funding. Consequently, there is a need for improving datasets for establishing real-world outcomes of newly launched oncology medicines.Aim: To outline the types of available datasets for collecting patient-level data for oncology among different European countries. Additionally, to highlight concerns regarding the use and availability of such data from a health authority perspective as well as possibilities for cross-national collaboration to improve data collection and inform decision-making.Methods: A mixed methods approach was undertaken through a cross-sectional questionnaire followed-up by a focus group discussion. Participants were selected by purposive sampling to represent stakeholders across different European countries and healthcare settings. Descriptive statistics were used to analyze quantifiable questions, whilst content analysis was employed for open-ended questions.Results: 25 respondents across 18 European countries provided their insights on the types of datasets collecting oncology data, including hospital records, cancer, prescription and medicine registers. The most available is expenditure data whilst data concerning effectiveness, safety and outcomes is less available, and there are concerns with data validity. A major constraint to data collection is the lack of comprehensive registries and limited data on effectiveness, safety and outcomes of new medicines. Data ownership limits data accessibility as well as possibilities for linkage, and data collection is time-consuming, necessitating dedicated staff and better systems to facilitate the process. Cross-national collaboration is challenging but the engagement of multiple stakeholders is a key step to reach common goals through research.Conclusion: This study acts as a starting point for future research on patient-level databases for oncology across Europe. Future recommendations will require continued engagement in research, building on current initiatives and involving multiple stakeholders to establish guidelines and commitments for transparency and data sharing.

Introduction: Thyroid carcinoma is the most common endocrine cancer. Some somatic mutations in genes (BRAF, NRAS and TERT) involved in key signaling pathways and genome stability have been recently identified to play an important role in its development. Very little research has been done on their frequency and clinical relevance in Bulgarian patients with papillary thyroid cancer (PTC). This study is focused on investigating somatic mutation frequency in Bulgarian patients with PTC and their association with clinicopathologic features.

This paper compares the refusal strategies employed by English and Bulgarian native speakers in business settings with interlocutors of a higher status. The data collecting tool is a discourse - completion task (DCT). The refusals are compared in terms of frequency of the semantic formulas and adjuncts. The findings indicate that refusals towards representatives of a higher status are most frequently realized through the semantic formula Reason/Explanation, followed by Regret/Apology and Negation of the proposition for English native speakers or Statement of fact for Bulgarians. Some of the short patterns of strategies observed for Bulgarians are the combinations: Negation of the proposition and Statement of fact, Statement of fact and Warning, Statement of fact and Statement of limit and Statement of fact and Redirecting. These findings should benefit researchers, business people and negotiators who are to overcome intercultural, communicational and linguistic challenges in a globalized world.

Globally, the diffuse goiter affects more than 10% of the population and in some regions is endemic. Thyroid nodules are found in approximately 5% of the population using the oldest method for thyroid examination – palpation. When performing ultrasound screening, this percentage increases significantly and reaches between 20 and 75% of the total population. Thyroid carcinoma is a rare malignancy and accounts for up to 1% of all malignant tumors. It is the most common endocrine cancer and is clinically manifested as a thyroid nodule. Somatic mutations play an important role in its development. Differentiation of benign and malignant thyroid nodules is of great importance due to the different therapeutic approach. Therefore, new diagnostic tools are sought to help distinguish the two. Despite the progress in our knowledge of carcinogenesis in recent years, a number of key issues still remain unanswered. The establishment of new rare somatic mutations can improve pre-surgical diagnosis and optimize post-operative strategies for the treatment of thyroid carcinoma. Next-generation sequencing (NGS) allows for extensive mutation and genome rearrangements tracking. The results obtained with NGS provide the basis for the development of new approach for systematic genetic screening, at prevention, early diagnosis, accurate prognosis, and targeted therapy of this disorder.