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Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by expert manually refined segmentations of three distinct meningioma sub-compartments: enhancing tumor, non-enhancing tumor, and surrounding non-enhancing T2/FLAIR hyperintensity. Basic demographic data are provided including age at time of initial imaging, sex, and CNS WHO grade. The goal of releasing this dataset is to facilitate the development of automated computational methods for meningioma segmentation and expedite their incorporation into clinical practice, ultimately targeting improvement in the care of meningioma patients.

Abstract Background The dilution-replicate experimental design for qPCR assays is especially efficient. It is based on multiple linear regression of multiple 3-point standard curves that are derived from the experimental samples themselves and thus obviates the need for a separate standard curve produced by serial dilution of a standard. The method minimizes the total number of reactions and guarantees that Cq values are within the linear dynamic range of the dilution-replicate standard curves. However, the lack of specialized software has so far precluded the widespread use of the dilution-replicate approach. Results Here we present repDilPCR, the first tool that utilizes the dilution-replicate method and extends it by adding the possibility to use multiple reference genes. repDilPCR offers extensive statistical and graphical functions that can also be used with preprocessed data (relative expression values) obtained by usual assay designs and evaluation methods. repDilPCR has been designed with the philosophy to automate and speed up data analysis (typically less than a minute from Cq values to publication-ready plots), and features automatic selection and performance of appropriate statistical tests, at least in the case of one-factor experimental designs. Nevertheless, the program also allows users to export intermediate data and perform more sophisticated analyses with external statistical software, e.g. if two-way ANOVA is necessary. Conclusions repDilPCR is a user-friendly tool that can contribute to more efficient planning of qPCR experiments and their robust analysis. A public web server is freely accessible at https://repdilpcr.eu without registration. The program can also be used as an R script or as a locally installed Shiny app, which can be downloaded from https://github.com/deyanyosifov/repDilPCR where also the source code is available.

In this article, we present a clinical case of a 63-year-old patient who was treated in the COVID unit of the Clinic for Internal Diseases of UMBALSM (University General Hospital for Active Care and Emergency Medicine) “N. I. Pirogov” on the occasion of a proven coronavirus infection with a PCR positive test for SARS-CoV2-virus, clinical symptoms of severe coronavirus pneumonia, and with accompanying disease - lymphoma with skin localization, condition after lower right lobectomy, chemotherapy and checkpoint therapy for squamous cell carcinoma of the lung. We also examined the role of the transcription factor NF-kB in the course of the coronavirus infection in a patient with the indicated lymphoproliferative disease and a history of active smoking. We tried to clarify questions such as “Do severe forms of coronavirus infection and the relatively rare disease lymphoma with cutaneous localization have a common pathogenesis?” Is it possible to effectively pharmacotherapeutically influence two, at first glance, so heterogeneous diseases?’’ The conclusions drawn can help us to specify certain nosological units as “more vulnerable” to severe forms of COVID19 infection.

The cytokine storm has been identified as one of the leading causes of the severe course and, in some cases, the fatal outcome of COVID-19 infection. Other factors aggravating the course of the disease are accompanying disorders such as cardiovascular diseases, diabetes mellitus, diseases of the respiratory system, and oncological diseases. In this article, we present the course of the coronavirus infection in patients with an accompanying malignant disease, chronic lymphocytic leukemia (CLL), namely. The study included 8 patients with proven PCR-positive tests for SARS-CoV2 and confirmed chronic lymphocytic leukemia as a comorbidity. The course of the coronavirus infection in the CLL group was compared with that in the control group of 100 patients. In both groups, we compared subjective complaints such as tiredness, fatigue, and joint and muscle pain with objective criteria such as temperature, laboratory markers of inflammation, X-ray imaging, and frequency of necessary intubation. Despite the expected poor prognosis in patients with concomitant oncological disease, in the case of chronic lymphocytic leukemia, our results showed a quite different milder coronavirus infection course. Obviously, patients with CLL cannot develop a pronounced cytokine storm, most probably due to certain immunosuppression related to the pathogenesis and drug treatment options for the comorbidity of CLL.

Abstract To provide the information needed for a detailed monitoring of crop types across the European Union (EU), we present an advanced 10-metre resolution map for the EU and Ukraine with 19 crop types for 2022, updating the 2018 version. Using Earth Observation (EO) and in-situ data from Eurostat’s Land Use and Coverage Area Frame Survey (LUCAS) 2022, the methodology included 134,684 LUCAS Copernicus polygons, Sentinel-1 and Sentinel-2 satellite imagery, land surface temperature and a digital elevation model. Based on this data, two classification layers were developed using a Random Forest machine learning approach: a primary map and a gap-filling map to address cloud-covered gaps. The combined maps, covering 27 EU countries, show an overall accuracy of 79.3% for seven major land cover classes and 70.6% for all 19 crop types. The trained model was used to derive the 2022 map for Ukraine, demonstrating its robustness even in regions without labelled samples for model training.

Upper blepharoplasty has significantly evolved over the past two decades from the unified routine excision of skin, muscle, and fat to a sophisticated and individualized to the patients’ needs surgical intervention. The contemporary techniques aim to correct age-related changes while preserving or even improving anatomy and function.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a severe progressive disease, more common than previously expected. The main objectives were to evaluate hereditary and wild type ATTR-CM frequency and clinical manifestations. Material and methods: One hundred seventy-eight patients at mean age 68 ± 13 years (129 males), referred by cardiologists with suspected cardiac amyloidosis (left ventricular wall thickness ≥ 12 mm and red flags) were evaluated. Pyrophosphate scintigraphy (99mTc-PYP) grade 2-3 myocardial uptake in the absence of monoclonal protein confirmed the diagnosis. Genetic test differentiated variant from wild type ATTR-CM. Endomyocardial biopsy with amyloid typing was performed in two patients. Results: Cardiac amyloidosis was diagnosed in 69 patients: light chain in 24 (13%) and ATTR-CM in 45 patients (25%). Wild type (ATTRwt) was found in 21 (12%) male patients at mean age 81 ± 6 years and variant type (ATTRv) in 24 patients (13%) at mean age 58 ± 7 years (15 males). In all ATTRv-CM patients some degree of peripheral polyneuropathy was found. The most common clinical red flags at diagnosis in both ATTRv and ATTRwt were heart failure in all patients, atrial fibrillation (16; 36%), pacemaker (5; 11%), and carpal tunnel syndrome (8; 18%). Severe aortic stenosis (4; 19%), spinal stenosis (2;10%), biceps tendon rupture (1; 5%) were characteristic for the wild type. At follow up, four patients needed a pacemaker for high degree AV block, six patients developed new onset atrial fibrillation, seventeen patients needed either initiation or an increase of the dose of loop diuretic, another 7 patients were hospitalized for heart failure exacerbation. Eight patients (18%) died, 7 (33%) with ATTRwt-CM and 1 (4%) with ATTRv-CM, all with advanced heart failure, 4 with concomitant severe aortic stenosis. Conclusions: This study provides the first nationwide estimates of the frequency and the clinical manifestations of ATTR-CM. Confirming the severity of the disease and poor prognosis, a low threshold for screening is needed for early diagnosis and timely treatment.

Background: In the last two decades, tyrosine kinase inhibitors (TKIs) and advances in molecular diagnostics have revolutionized management and long-term clinical outcomes in chronic myeloid leukemia (CML). Real-world data from different countries allow for the identification of country-specific issues in the clinical management and development of specific plans for improvement. Here, we aimed to analyze the trend in overall survival in Bulgarian CML patients since 2000. Methods: We retrieved publicly available Bulgarian CML data from several sources such as the Bulgarian National Cancer Registry, Bulgarian National Statistical Institute, and National Health Insurance Fund since 2000. We used the retrieved data of a total of 1513 Bulgarian CML patients to describe the trends in overall survival (OS), conditional overall survival, life expectancy, and life years lost over five time periods. We also described the trends in healthcare expenditures for TKIs and CML patients’ coverage with TKIs since 2014. Results: In both uni- and multivariate models, we found a constant increase in OS over the three 5-year periods until 2014. The period 2015–2019 was not associated with an additional increase in OS. Identical dynamics in the improvement in life expectancy (LE) and in life years lost (LYLs) was observed. Additionally, conditional 5-year survival did not improve during 2015–2019 in comparison to 2010–2014. Population-level data did not show consistent changes in the documented number of deaths due to CML since 2013. The period after 2013 is marked by a constant increase in the annual expenditures for TKIs, reaching to about 2.0 EUR/capita. The number of patients who received at least one TKI also increased during that period. Conclusions: After the initial significant improvement in the clinical outcomes for Bulgarian CML patients until 2014, subsequent periods did not bring further benefit in spite of the improved coverage with second- and third-line TKIs. Multiple factors may contribute to these suboptimal outcomes. Therefore, one can propose several additional measures at the country level, which could lead to additional improvement in the OS of Bulgarian CML patients.

Abstract Background Chronic subdural haematoma (CSDH) drainage is a common neurosurgical procedure. CSDHs cause excess mortality, which is exacerbated by frailty. Sarcopenia contributes to frailty – its key component, low muscle mass, can be assessed using cross‐sectional imaging. We aimed to examine the prognostic role of temporal muscle thickness (TMT) measured from preoperative computed tomography head scans among patients undergoing surgical CSDH drainage. Methods We retrospectively identified all patients who underwent CSDH drainage within 1 year of February 2019. We measured their mean TMT from preoperative computed tomography scans, tested the reliability of these measurements, and evaluated their prognostic value for postoperative survival. Results One hundred and eighty‐eight (122, 65% males) patients (median age 78 years, IQR 70–85 years) were included. Thirty‐four (18%) patients died within 2 years, and 51 (27%) died at a median follow‐up of 39 months (IQR 34–42 months). Intra‐ and inter‐observer reliability of TMT measurements was good‐to‐excellent (ICC 0.85–0.97, P

Pricing and reimbursement in the European Union (EU) are unified by Directive 89/105/EEC/21.12.1988. The directive has a framework nature; it defines deadlines for decision-making, legal protection, publicity of information, tacit consent, etc. The specific mechanisms are subject to national measures, leading to differences in Member States. The aim of the study is a comparative analysis of the regulatory measures for pricing and reimbursement of medicinal products in Bulgaria and Italy. We looked at four main pricing and reimbursement measures: positive drug lists, reference pricing, health technology assessment, and innovative schemes. We used documentary analysis and synthesis, comparative, and statistical methods. The two countries’ pricing and reimbursement systems are fundamentally different. Italy’s system has long traditions and guarantees stability in the availability and affordability of medicinal products for the population. Since 2000, the regulations concerning the pricing and reimbursement system in Bulgaria have been amended more than 42 times, which characterizes the Bulgarian pricing and reimbursement policy as regulatoryly unstable.

Systemic vasculitides are rare and heterogeneous diseases affecting different organs and systems with varying degrees of severity depending on the type of vessels affected. The etiology and pathogenesis are unclear. Immunе mechanisms play a role in the pathogenesis: deposition of immune complexes, autoantibodies (anti-endothelial and anti-neutrophil cytoplasmic antibody, cellular and molecular responses, granulomas, and endothelial cell damage. All vasculitides are “rare diseases”. ANCA- associated vasculitis has an incidence of 20 cases/1 million population. Without treatment, mortality is >90% within up to 5 years. We conducted a two-centre, retrospective, observational, non- interventional, epidemiological, health-demographic, clinical-pharmacological study to evaluate ANCA-associated vasculitis in Bulgaria. From 2018 to 2021, we screened 12 individuals with Wegener’s granulomatosis. The analyzed population is approximately 60% of the patients in Bulgaria. The time from symptom onset to diagnosis is short, but the diagnosis is made at an advanced stage of the disease - the measured BVAS version 3 activity is moderate-severe.

There are no specific recommendations for evaluating the Ki-67 index in heterogeneous breast carcinomas. This study aimed to evaluate the applicability of currently accepted recommendations for Ki-67 evaluation in breast cancer in the context of intratumor heterogeneity. Twelve cases of heterogeneous breast carcinomas obtained from 110 patients were retrospectively studied. Ki-67 staining was performed according to protocols provided by the reagent manufacturer. Results for Ki-67 of the separate components in each tumor were obtained, described, and analyzed statistically using a paired t-test. Values of p < 0.05 were considered as statistically significant. SPSS software was used for statistical analysis. Results from the comparison of the Ki-67 index evaluation in each heterogeneous component of the studied tumors demonstrated no statistically significant difference of mean values t = 0.4802, p = 0.6405. The anticipation of an average Ki-67 score in the evaluated cases would have changed the molecular subtype from Luminal B to Luminal A (due to the Ki-67 index below 14%) in two of the cases. Heterogeneous tumors had a different Ki-67 index in their separate components. Our observations suggest that Ki-67 in heterogeneous breast carcinoma is evaluated and reported separately for the distinguishable tumor components.

Background: Laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair is a relatively new method of inguinal hernia surgical repair that, at theory, provides a good view of the inguinal anatomy and sac contents and, as a laparoscopic procedure, is considered less invasive and with fewer complications compared to total extraperitoneal (TEP) inguinal hernia repair. Purpose: This study aims to assess the short-term outcome of laparoscopic transabdominal preperitoneal inguinal hernia (TAPP) repair. Material and methods: The retrospective clinical data for 138 patients with unilateral and bilateral hernia, operated in the Department of General, Visceral, and Emergency Surgery of the University Emergency Medicine Hospital ‘N. Pirogov’ from 01 January 2022, to 01 January 2023, were included. The risk profile of the patients, the intraoperative and postoperative complications, the duration of hospital stay, the frequency, and the type of analgesics used were analyzed. Results: Forty-one women (29.7%) were included; men comprised 97 (70.29%) of the cohort. Of the selected group, 63 (45.7%) patients had indirect inguinal hernias, 34 (24.6%), and 25 (18.1%) were diagnosed with direct inguinal hernia and accreta inguinal hernia, respectively. A history of repeatedly occurring hernias was found in 16 patients (11.6%). The average hospital stay was 32 hours (or 1.3 days) and ranged from 24 hours (1 day) to 48 hours (2 days). Complications occurred in 11 (7.97%) patients. The need for analgesics and anti-inflammatory agents was reliably reduced compared to the patients undergoing conventional surgical treatment of inguinal hernia. The patients were followed for three months post-discharge for the occurrence of surgical morbidity associated with the TAPP hernia repair. None of the patients used an antimicrobial agent, as indicated by a possible complicating bacterial infection. Rehabilitation was started within the first 12 hours after the operation, thus contributing to a significantly shorter hospital stay compared to patients undergoing conventional surgical repair of an inguinal hernia. Conclusion: Our results demonstrate that TAPP inguinal hernia repair is a safe procedure with reduced postoperative pain. It has fewer complications, with no significantly longer operative time and a shorter overall hospital stay.

Background: The scientific interest in dominant Candida species colonizing the surface of conventional and double-layer dentures (D-LCDs) is still topical. Numerous studies are comparing fungal colonization in both types of removable dentures. Aim: Performing a comparative analysis of the colonization of Candida spp. on the dentures surfaces of the conventional (CCDs) and the double-layer dentures (soft-lined) complete dentures (D-LCDs) over six months, placing them under the same intraoral in vivo conditions. Methods: For isolating Candida spp., specimens were obtained from inner denture surfaces using two sterile swabs, one for the upper complete denture (n=28) and one for the lower complete denture (n=28). The culture-based Candida detection method with CHROM agar was used to identify Candida species. Results: In the third month after dentures delivery C. Albicans is the predominant Candida spp. found on both types of complete dentures surface and isolated in 46 % of the patients with conventional complete dentures and 43 % with double-layer dentures (p>0.05). In the sixth month of the finished prosthetic treatment, combinations of C. Albicans and non-albicans Candida, predominantly C. Tropicalis, C. Glabrata and C. Parapsilosis, were found in 43 % of D-LCDs and 45 % of CCDs (p>0.05). Conclusion: There was no difference in colonization based on the different materials used for denture fabrication. However, there is a significant proportional change for all studied Candida spp. over the period (3-6 months after delivery), irrespective of the denture material used.

Working with patients with Anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (AAV) requires a clear understanding of their current health status. In the scientific literature, there is not enough data on their quality of life with the different therapeutic regimens. No generic tools have been developed to assess functional indicators and health status. The aim of the study is to measure the health-related quality of life (physical, psychological and social functioning) in a Bulgarian population of patients with systemic vasculitis associated with ANCA undergoing treatment with rituximab using a common tool. Design – retrospective-prospective, observational, non- interventional, controlled study in two periods, in two rheumatology centers in Bulgaria. Treatment with rituximab leads to qualitative and quantitative improvement in all components of physical health, mental and social components. All measured parameters are within the normal range for the general population. Rituximab treatment of AAV is the best therapeutic alternative in current rheumatology practice.

Woody biomass serves as a renewable resource for various industries, including pulp and paper production, construction, biofuels, and electricity generation. However, the molecular mechanisms behind biomass traits are poorly understood, which significantly curtails the speed and efficiency of their improvement. We used activation tagging to discover genes that can positively affect tree biomass-associated traits. We generated and screened under greenhouse conditions a population of 2,700 independent activation tagging lines. A total of 761 lines, which had significantly and positively affected at least one biomass-associated trait, were discovered. The tag was positioned in the genome for forty lines which were affected in multiple traits and activation of proximal genes validated for a subset. For two lines we fully recapitulated the phenotype of the original lines through overexpression. Moreover, the overexpression led to more pronounced and additional improvements, not observed in the original lines. Importantly, the overexpression of a Fasciclin-like gene (PtaFLA10) and a Patatin-like gene (PtaPAT) was found to substantially improve biomass, with a 40% increase in dry-stem weight, and enhance drought tolerance, respectively. Additionally, PtaPAT overexpression increased cellulose content, which is crucial for biofuel production. Our work shows that the activation tagging approach applied even on a non-genome saturation scale in a poplar tree can be successfully used for the discovery of genes positively modify biomass productivity. Such dominant forward genetics approaches can aid in biotechnological manipulation of woody biomass traits and help unravel the functions and mechanisms of individual genes, gene families, and regulatory modules.

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge.Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(η5-C5H4CHO)(Me2bipy)(PPh3)]+ (RT150) and [Ru(η5-C5H4CH2OH)(Me2bipy)(PPh3)][CF3SO3] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin.To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile.

Deforming osteoarthritis of the knee joint alters the mechanical axis of the lower limb. This, combined with extra articular deformity of the tibia or femur leads to serious dysfunction of the limb and great disability for the patient. These rare cases present great challenge for the orthopedic surgeon. Most of the cases with mild to moderate deformities can be successfully managed by adjusting intra articular resections, but in those with severe extra articular deformity, an extra articular correctional osteotomy may be required in order to achieve good flexion-extension balance of the knee. We report a case of total knee replacement performed together with correctional osteotomy of the tibia due to extra articular deformity of about 20 degree varus.

During the period of 2022 and 2023, 10 patients with early infection following joint arthroplasty were admitted to the Clinic of Orthopedics and Traumatology at Sofiamed. Among them were 8 women and 3 men, with an average age of 69 years. All patients were readmitted between 18-21 days after the primary joint arthroplasty. Laboratory and microbiological investigations were conducted for all patients, followed by surgical intervention and prolonged antibiotic therapy. At a mean follow-up of 1 year and 2 months, all patients showed excellent results, except for one who died and one who was lost to follow-up.

Collinear laser spectroscopy measurements were performed on 68−74Ge isotopes (Z=32) at ISOLDE-CERN, by probing the 4s24p2P13→4s24p5sP1o3 atomic transition (269 nm) of germanium. Nuclear charge radii are determined via the measured isotope shifts, revealing a larger local variation than the neighboring isotopic chains. Nuclear density functional theory with the Fayans functionals Fy(Δr,HFB) and Fy(IVP), and the SV-min Skyrme describes the experimental data for the differential charge radii δ〈r2〉 and charge radii Rc within the theoretical uncertainties. The observed large variation in the charge radii of germanium isotopes is better accounted for by theoretical models incorporating ground state quadrupole correlations. This suggests that the polarization effects due to pairing and deformation contribute to the observed large odd-even staggering in the charge radii of the Ge isotopic chain.