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Aims. The relationship of tumour volume, radiotherapy treatment time and other prognostic factors affecting prognosis was evaluated. Methods. 184 patients with locally advanced head and neck cancer were treated with radical intensity modulated radiotherapy (IMRT) and compared retrospectively. Results. In the multivariate analysis the overall survival was dependent on gross tumour volume (GTV), clinical stage (CS), radiotherapy treatment time (RTT) and p16 status. Local control was influenced by GTV, overall RTT and age. DFS was significantly affected by GTV, CS, RTT, p16 status and concomitant chemotherapy (CHT). Conclusions. The tumour volume and the radiotherapy treatment time were the most significant prognostic factors with the best outcomes in patients with GTV ≤ 55 cc and RTT ≤ 48 days (mean LC 8.1, DFS 7.1 and OS 6.4 years) and worst outcomes with GTV > 55 cc and RTT >48 days (mean LC 4.4, mean DFS 3.2 and mean OS 2.6 years).

Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing 9 disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis, we subsequently used canonical correlation analysis of 176 training cases to project the multidimensional space of all 26 immunophenotypic parameters into 36 2-dimensional plots for each possible pairwise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%), and mantle cell lymphoma (95.4%). Burkitt and CD10 diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD10 diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms., This work was supported by the EuroFlow Consortium, which received support from the FP6-2004-LIFESCIHEALTH-5 program of the European Commission (grant LSHB-CT-2006-018708) as Specific Targeted Research Project (STREP). The EuroFlow Consortium is part of the European Scientific Foundation for Hemato-Oncology (ESLHO), a Scientific Working Group (SWG) of the European Hematology Association (EHA).

The large amount of evidence and the renewed interest in upper and lower airways involvement in infectious and inflammatory diseases has led Interasma (Global Asthma Association) to take a position on United Airways Diseases (UAD).Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto developed by Interasma scientific network (INES) members.The manifesto describes the evidence gathered to date and defines, states, advocates, and proposes issues on UAD (rhinitis, rhinosinusitis and nasal polyposis), and concomitant/comorbid lower airways disorders (asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, obstructive sleep apnoea) with the aim of challenging assumptions, fostering commitment, and bringing about change. UAD refers to clinical pictures characterized by the coexistence of upper and lower airways involvement, driven by a common pathophysiological mechanism, leading to a greater burden on patient's health status and requiring an integrated diagnostic and therapeutic plan. The high prevalence of UAD must be taken into account. Upper and lower airways diseases influence disease control and patient's quality of life.Patients with UAD need to have a timely and adequate diagnosis, treatment, and, when recommended, referral for management in a specialized center. Diagnostic testing including skin prick or serum specific IgE, lung function, fractional exhaled nitric oxide (FeNO), polysomnography, allergen-specific immunotherapies, biological therapies and home based continuous positive airway pressure (CPAP) whenever these are recommended, should be part of the management plan for UAD. Education of medical students, physicians, health professionals, patients and caregivers on the UAD is needed.

Background. Knee osteoarthritis (OA) is a multifactorial disease resulting from the interaction of many environmental, epigenetic and genetic risk factors, and the latter account for 40% to 65%. Genetic bases of the knee OA based on genome-wide association study (GWAS) are being actively studied by many scientific teams around the world. At the same time, the results obtained are often contradictory and ambiguous, as for the conducted replicative studies of knee OA. This dictates the need for additional replicative studies in various populations, including populations of Russia. The aim of the study was to analyze genome-wide studies of knee OA and to establish GWAS-significant polymorphic loci associated with OA. Materials and Methods. The search for publications was carried out in the electronic databases PubMed, PubMedCentral, eLIBRARY, in the GWAS catalog for the period from 2008 to the present by the keywords: knee osteoarthritis, GWAS studies, candidate genes. Results. Firstly, for the period from 2008 to 2021, 15 genome-wide studies of knee OA were performed (8 GWAS, 6 meta-analyzes of GWAS data, 1 study a combination of GWAS and meta-analysis of GWAS data), as a result of which 78 polymorphic loci were found associated with the risk of developing osteoarthritis of the knee joint at p510-08. Second ly, the vast majority of these loci (62 out of 78 SNPs, 79%) showed GWAS-significant associations with OA in meta-analyzes of GWAS data and only 16 loci (21%) in GWAS studies. Third ly, almost 95% of GWAS-significant loci for knee OA (74 SNPs) were found in samples of Caucasian origin. Fourthly, 21 out of 78 GWAS-significant SNPs are associated with isolated knee OA, and 57 SNPs are associated with knee, hip and hand OA (mixed sample). Fifth, all genome-wide studies of knee OA and meta-analyzes of GWAS data were carried out abroad on samples from various foreign populations, and samples from the Russian Federation were not included in these studies. Sixth, only two GWAS-significant polymorphic loci for OA (rs143384 of the GDF5 gene for knee OA isolated localization and rs3771501 of the TGFA gene for OA of any localization) were replicated at the whole genome level of significance (p510-08) in two different studies. Conclusion. The main genome-wide studies of knee OA were reviewed and GWAS-significant polymorphisms associated with OA were identified. The obtained materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of OA in various populations of Russia, and for expanding the understanding of the molecular genetic mechanisms of the disease development.

Background and Aims. COVID-19 pandemic has impacted on all endoscopy centers in the Czech Republic, that belongs to the most affected countries in the world. The aim of our study was to analyze all procedures following routine RT-PCR testing in our tertiary center during the peak of the pandemic. Methods. We retrospectively analyzed all procedures performed from October 2020 to January 2021 after a new RT-PCR center had been set up. Main outcomes were type of scheduled procedure, indication, rate of therapeutic interventions and rate of new relevant and malignant findings. Comparison to the same period before the pandemic and SARS-CoV-2 infection in endoscopy staff are also reported. Results. A total of 1,953 procedures were performed. 624 patients were referred with a negative RT-PCR test and the remaining 1,346 patients were tested in the new center. 1,293 negative tests led to 1,329 procedures. A new relevant finding was reported in 589 (44.3%), including new malignancy in 56 (4.2%). 53 patients tested positive (3.9%). There was a reduction by 9% in the number of all procedures compared to the same period before the pandemic and an increase in the number of screening colonoscopies and ERCP procedures. In the study period, 9 of 54 staff members contracted SARS-CoV-2 infection. Conclusions. Routine RT-PCR testing of patients scheduled for elective endoscopy during the peak of COVID-19 pandemic enabled us to essentially maintain our unit productivity, including activities such as screening colonoscopy, endoscopic resection and pancreatobiliary endoscopy.

Psychogenic non-epileptic seizures (PNES) superficially resemble epileptic seizures, but are not associated with abnormal electrical activity in the brain. PNES are a heterogeneous entity and while there is increasing interest in the characterisation of PNES sub-groups, little is known about individuals with PNES who have an intellectual disability (ID). ID is a lifelong condition characterised by significant limitations in cognitive, social and practical skills. ID (commonly with comorbid epilepsy) has been identified as a risk factor for developing PNES. However, people with ID are often excluded from research in PNES. This has unfortunately resulted in a lack of evidence to help inform practice and policy for this population. This narrative review synthesises the currently available evidence in terms of the epidemiology, demographic and clinical profile of adults with PNES and ID. There is a particular focus on demographics, aetiological factors, PNES characteristics, diagnosis and treatment of the condition in this population. Throughout this article, we critique the existing evidence, discuss implications for clinical practice and highlight the need for further research and enquiry. What emerges from the evidence is that, even within the sub-group of those with ID, PNES are a heterogeneous condition. Individuals with ID and PNES are likely to present with diverse and complex needs requiring multidisciplinary care. This review is aimed at the broad range of healthcare professionals who may encounter this group. We hope that it will stimulate further discussion and research initiatives.

Background: Neurofilament light (NFL) has been increasingly recognized for prognostic and therapeutic decisions. Objective: To validate the utility of cerebrospinal fluid NFL (cNFL) as a biomarker in clinical practice of relapsing-remitting multiple sclerosis (RRMS). Methods: RRMS patients ( n = 757) who had cNFL analyzed as part of the diagnostic work-up in a single academic multiple sclerosis (MS) center, 2001–2018, were retrospectively identified. cNFL concentrations were determined with two different immunoassays and the ratio of means between them was used for normalization. Results: RRMS with relapse had 4.4 times higher median cNFL concentration (1134 [interquartile range (IQR) 499–2744] ng/L) than those without relapse (264 [125–537] ng/L, p Conclusions: cNFL is a robust and reliable biomarker of disease activity, treatment response, and prediction of disability and conversion from RRMS to SPMS. Our data suggest that cNFL should be included in the assessment of patients at MS-onset.

Background: Severe asthma is a serious condition with a significant burden on patients' morbidity, mortality, and quality of life. Some biological therapies targeting the IgE and interleukin-5 (IL5) mediated pathways are now available. Due to the lack of direct comparison studies, the choice of which medication to use varies. We aimed to explore the beliefs and practices in the use of biological therapies in severe asthma, hypothesizing that differences will occur depending on the prescribers’ specialty and experience. Methods: We conducted an online survey composed of 35 questions in English. The survey was circulated via the INterasma Scientific Network (INESNET) platform as well as through social media. Responses from allergists and pulmonologists, both those with experience of prescribing omalizumab with (OMA/IL5) and without (OMA) experience with anti-IL5 drugs, were compared. Results: Two hundred eighty-five (285) valid questionnaires from 37 countries were analyzed. Seventy-on percent (71%) of respondents prescribed biologics instead of oral glucocorticoids and believed that their side effects are inferior to those of Prednisone 5 mg daily. Agreement with ATS/ERS guidelines for identifying severe asthma patients was less than 50%. Specifically, significant differences were found comparing responses between allergists and pulmonologists (Chi-square test, p < 0.05) and between OMA/IL5 and OMA groups (p < 0.05). Conclusions: Uncertainties and inconsistencies regarding the use of biological medications have been shown. The accuracy of prescribers to correctly identify asthma severity, according to guidelines criteria, is quite poor. Although a substantial majority of prescribers believe that biological drugs are safer than low dose long-term treatment with oral steroids, and that they must be used instead of oral steroids, every effort should be made to further increase awareness. Efficacy as disease modifiers, biomarkers for selecting responsive patients, timing for outcomes evaluation, and checks need to be addressed by further research. Practices and beliefs regarding the use of asthma biologics differ between the prescriber's specialty and experience; however, the latter seems more significant in determining beliefs and behavior. Tailored educational measures are needed to ensure research results are better integrated in daily practice.

Background: Allergic asthma is the predominant phenotype in clinical practice. Allergen immunotherapy is the only curative and specific approach for the treatment of allergies with clinical benefits for several years after its discontinuation. Despite advances, the use of allergen immunotherapy in allergic asthma is still suboptimal and controversial.Objective: The purpose of this article is to review the published data about the impact of allergen immunotherapy with the most commonly used allergen extracts on allergic asthma outcomes, including both clinical parameters and patients' subjective experience (quality of life).Methods: As data sources several databases were used, including PubMed, Scopus, Web of Science (2002-2019) and search in English and Spanish languages was performed using the following terms: "allergen immunotherapy" and "asthma" in combination with "house dust mite", "birch pollen", "grass pollen", "olive tree pollen", "molds", "pets" and "asthma quality of life". Randomised control trials and meta-analysis from reviewed publications were selected.Results: Emerging data relating to the positive impact on asthma outcomes of allergen immunotherapy allows the addition of this treatment as a therapeutic option in mild to moderate asthmatics sensitized to house dust mite and pollens. Limited data are available for patients sensitized to molds and pets, as well in severe allergic asthma population.Conclusion: Allergen immunotherapy remains a potential therapeutic option for some patients with allergic asthma. Further research is needed to define the optimal period of treatment, the possible therapeutic role in the treatment of severe allergic asthma, and the cost-effectiveness of allergen immunotherapy in asthmatic patients.

Introduction. Chronic rhinitis is defined as nasal inflammation with the presence of minimum two symptoms such as nasal obstruction, rhinorrhea, sneezing and/or itching one hour daily for a minimum of 12 weeks/year. According their etiology, four groups of rhinitis are described: allergic, infectious, non-allergic non-infectious and mixed.Chronic rhinitis is frequently associated with asthma, shares similar mechanisms of the pathogenesis and has a negative impact of its outcomes sustaining the concept of unified airways disease.Areas covered. The present review summarizes the complex relationship between chronic rhinitis and asthma on the basis of recent epidemiological data, clinical characteristics, diagnosis and therapeutic management. All four groups are discussed with the impact of their specific treatment on asthma outcomes. Some medications are common for chronic rhinitis and asthma while others are more specific but able to treat the associated comorbidity.Expert opinion. The systematic assessment of chronic rhinitis in patients with asthma and its specific treatment improves both disease outcomes. Conversely, several therapies of asthma demonstrated beneficial effects on chronic rhinitis. Treating both diseases at the same time by only one medication is an interesting option to explore in the future in order to limit drugs administration, related costs and side effects.

The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine–indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood–brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood–brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.

Photodynamic therapy is a treatment modality of cancer based on the production of cytotoxic species upon the light activation of photosensitizers. Zinc phthalocyanine photosensitizers bearing four or eight bulky 2,6-di(pyridin-3-yl)phenoxy substituents were synthesized, and pyridyl moieties were methylated. The quaternized derivatives did not aggregate at all in water and retained their good photophysical properties. High photodynamic activity of these phthalocyanines was demonstrated on HeLa, MCF-7, and EA.hy926 cells with a very low EC50 of 50 nM (for the MCF-7 cell line) upon light activation while maintaining low toxicity in the dark (TC50 ≈ 600 μM), giving thus good phototherapeutic indexes (TC50/EC50) above 1400. The compounds localized primarily in the lysosomes, leading to their rupture after light activation. This induced an apoptotic cell death pathway with secondary necrosis because of extensive and swift damage to the cells. This work demonstrates the importance of a bulky and rigid arrangement of peripheral substituents in the development of photosensitizers, The work was supported by the Czech Science Foundation (19-14758Y), Charles University (PRIMUS/20/SCI/013, GAUK 1620219, SVV 260 550), and by the project EFSACDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841) cofunded by the ERDF. For affiliations ‡, ∥, and ⊥, the work was supported by MINECO-Feder funds (CTQ2017-85393-P (T.T.), CTQ-2014-53673-P and CTQ-2017-89539-P (A.d.l.E.), PCIN-2017-042/EuroNanoMed2017-191, TEMPEAT (T.T.)). Affiliation ⊥ (IMDEA Nanociencia) also acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, Grant SEV2016-0686)

Forest practices in headwater catchments are related to environmental and social contexts. The aim of this study is to analyse the changing protective functions of forests in the upper plain of the Jizera Mts. (North Bohemia, Czech Republic) since the second half of the 19th century. With time, forests have gradually changed from native stands to spruce plantations (Picea abies), introducing exotic conifers (more resistant to air pollution), and, recently, back to more diverse mixed stands. The priority in protective forest functions there shifted from flood protection to integrated control of water resources (quantity and quality). In the 1980s, forest – water interactions were degraded by consequences of extreme acid atmospheric deposition, forest die-back, and extensive clear-cut. In the Jizerka catchment, first signs of recovery were observed in the early 1990s, but, stream waters there are still affected by prolonged acidification. While reconstruction of stream water chemistry at Jizerka follows the drop of the acid deposition in some 5 years, the revival of stream biota takes 10–15 years. In 2071–2100, the projected climate change shows rising annual air temperatures by 3.0–4.6 °C, decreasing water yield by 65–123 mm, 60% drop in ‘minimum residual discharge’, and 20–30% rise in peak-flows. However, these projected environmental changes cannot substantially decline the high potential in water resource recharge, or, start reverse processes in recent recovery from acidification and radically affect the existence of planned mixed forests in the upper plain of the Jizera Mts.

Summary Human alveolar echinococcosis (AE) is a silently-progressing disorder that has become a threat in many countries. Since 2000, when the first case was recorded, the number of human AE patients in Slovakia is on continuous raise. The article presents a rare case of alveolar echinococcosis with infiltration in the adrenal gland and discusses the problems associated with differential diagnosis of the disease. In 2016, abdominal ultrasound performed due abdominal pain complaint showed the presence of cystic lesions in the right liver lobe of 54-year old female patient. During surgery, another lesion in the right adrenal gland was found, and neoplastic processes or echinococcosis were considered in the differential diagnosis. Due to unclear correlation between radiology, serology and histopathology results and endemic situation in Slovakia, molecular examination was recommended. Subsequently E. multilocularis was confirmed as etiological agent of infection. Alveolar echinococcosis is considered as a rare disease, with very few patients referred to clinicians or hospitals that sometimes have almost none existing experience with the diagnosis and treatment of the disease. Therefore, the establishment of networks or reference centres specialized on management of the disease would be suitable way to provide the patients with the best care and improve the disease diagnosis, treatment and prognosis.

Objective The aim: Is to investigate the dynamics of the morphofunctional development and physical health of students who were engaged in strength sports while studying at university. Patients and methods Materials and methods: The study involved 360 male students of different faculties between the ages of 17 and 20. Two groups of students were formed: experimental and control groups. The EG students (n=40) were engaged in strength sports (powerlifting, athletics, Crossfit); the CG students (n=320) were training according to the current program of physical education. The study of the morphofunctional development of students was carried out taking account of the indicators of body length, body weight, handgrip test, heart rate, blood pressure, and vital capacity. The level of students' health was examined according to the methodology of the assessment of the physical health level by G. L. Apanasenko. Results Results: It was established that strength sports at university affect physical development, functional abilities of the major systems of an organism, and the health state of future doctors in a more efficient way than the current program of physical education. It was found that the influence on the indicators of handgrip test, vital capacity, and heart rate of the EG students was the most prominent positive effect of sports. The evaluation of the calculated indexes (power index, life index) and the level of physical health confirmed this trend. Conclusion Conclusions: The conducted research asserts the necessity of introducing the sports-oriented form of the physical training organization at the medical higher education institutions of Ukraine to strengthen the students' health and to maintain the efficiency of the future doctors' professional activity.

The oral cavity is a biologically significant and complex site of the human body. It is a gateway into the internal environment of the organism. There are many processes, such as the beginning of digestion, speech creation, and sensory perception of taste. Oral health is closely related to the general health of a person. The oral cavity contains an enormous number of microorganisms that can cause various diseases. Oral bacteria are responsible for diseases in the mouth, but can also seriously harm human health. The oral microbiome also serves as an indicator of health, respectively morbidity of the human organism. Compared to healthy children, mentally disabled children suffer from many congenital and acquired diseases and disorders that affect their overall and oral health. These children require a specific approach to the examination, but also to the therapy. Therefore, it is necessary to pay attention to the prevention of oral diseases in children, whether healthy or mentally disabled.

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Using multishell diffusion MRI and both tract-based spatial statistics (TBSS) and probabilistic tracking of specific tracts of interest, we evaluated the neural underpinnings of the impact of a six-month dance intervention (DI) on physical fitness and cognitive outcomes in nondemented seniors. The final cohort had 76 nondemented seniors, randomized into DI and control (life as usual) groups. Significant effects were observed between the DI and control groups in physical fitness measures and in attention. We detected associations between improved physical fitness and changes in diffusion tensor imagining (DTI) measures in the whole white matter (WM) skeleton and in the corticospinal tract and the superior longitudinal fascicle despite the fact that no significant differences in changes to the WM microstructure were found between the two groups.

Despite the effective National Immunization Programme of Slovakia, some population groups are incompletely vaccinated or unvaccinated. We aimed to describe the measles outbreak spread in Eastern Slovakia between May and October 2018, affecting the Roma communities in relation to the existing immunity gaps.We defined a group of persons living in socially closed communities with low vaccination coverage.Of 439 measles cases (median age: 10 years), 264 (60.1%) were vaccinated, 137 (31.2%) received two doses and 127 (28.9%) one dose of measles vaccines, 155 (35.3%) were unvaccinated and 20 (4.6%) had an unknown vaccination status. Samples from 102 patients (with two-dose vaccination status) were additionally tested for antibodies against rubella and mumps. Of 102 cases, 68 (66.7%) cases had a positive IgM and 23 (22.5 %) IgG antibodies against measles. For rubella, only 20 (19.6%) cases had seropositive IgG levels, for mumps higher positivity was detected in 60 persons (58.8%). We could detect only a small percentage with positive serology results of rubella IgG antibodies across all age groups. We have assumed that rubella antibodies had to be produced following the vaccination. Their absence in the cases with two doses of MMR suggests that these vaccines could not have been administrated despite the fact that this data was included in the medical records. Sequential analysis of two samples showed measles genotype B3.This outbreak can outline the existence of a vulnerable group of the Roma. Low vaccinate coverage represents a serious public health threat.Kljub učinkovitemu nacionalnemu programu imunizacije na Slovaškem so nekatere skupine prebivalcev nepopolno cepljene ali necepljene. Želeli smo opisati izbruh ošpic na vzhodnem Slovaškem med majem in oktobrom 2018, ki je prizadel romske skupnosti v povezavi z obstoječimi vrzelmi v imunosti.Opredelili smo skupino ljudi, ki živijo v socialno zaprtih skupnostih z nizko precepljenostjo.Med 439 primeri ošpic (mediana starost: 10 let) je bilo 264 ljudi cepljenih (60,1 %), 137 (31,2 %) jih je prejelo dva odmerka in 127 (28,9 %) en odmerek cepiva proti ošpicam, 155 (35,3 %) jih je bilo necepljenih, pri 20 (4,6 %) pa status cepljenja ni bil znan. Vzorce 102 bolnikov (s statusom cepljenja z dvema odmerkoma) smo dodatno testirali za protitelesa proti rdečkam in mumpsu. Od 102 primerov jih je 68 (66,7 %) imelo pozitiven rezultat za protitelesa IgM in 23 (22,5 %) za protitelesa IgG proti ošpicam. Kar zadeva rdečke, smo samo pri 20 (19,6 %) primerih ugotovili seropozitivne ravni IgG, medtem ko smo za mumps odkrili večjo pozitivnost pri 60 posameznikih (58,8 %). V vseh starostnih skupinah smo odkrili samo majhen odstotek posameznikov s pozitivnimi serološkimi rezultati za protitelesa IgG proti rdečkam. Predpostavili smo, da po cepljenju zagotovo nastanejo protitelesa proti rdečkam. Njihova odsotnost v primerih z dvema odmerkoma cepiva MMR nakazuje, da to cepivo ni moglo biti uporabljeno, čeprav so bili ti podatki vključeni v zdravstveno kartoteko. Sekvenčna analiza dveh vzorcev je pokazala genotip ošpic B3.Ta izbruh lahko kaže na obstoj ranljive skupine Romov. Nizka precepljenost pomeni resno grožnjo za javno zdravje.

Introduction: Patients with asthma often have important co-morbidities which reduce the likelihood of gaining optimal asthma control. Beta2-blockers are commonly prescribed for the treatment of different clinical indications, including coronary artery disease, cardiac arrhythmia, arterial hypertension, heart failure and glaucoma. Areas covered: The aim of this reviw is to summarize current evidence on the effect of systemic and local β-blockers on asthma outcomes based on their pharmacologic properties,and to help clinicians when prescribing for patients with asthma and co-morbidities. Current data suggest that risk of asthma worsening from systemic and local use of non-selective β-blockers outweighs any potential benefits for their clinical indications. Recent studies confirm that topical and systemic prescription of cardio-selective β-blockers is not associated with a significant increased risk of moderate or severe asthma exacerbations. Expert opinion: Non-selective β-blockers should not be prescribed for the management of comorbidities in patients with asthma while cardio-selective β-blockers, preferably in low doses, may be used when strongly indicated and other therapeutic options are not available. More prospective real-life studies are needed to evaluate the risk of long-term use of β-blockers in patients with asthma.

In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.

The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitro assays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC50 ∼ 3-50 nM) than for anionic Pcs (EC50 ∼ 0.3-10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.

Introduction: Clostridium difficile infection (CDI) is the most common infectious cause of diarrhoea in hospitalised patients. It is a severe issue with increasing incidence in healtcare facilities and commmunities. Early and appropriate testing of CDI is very imortant. There are many different approaches that can be used in the CDI laboratory diagnostics. Recently performed studies evaluated diagnostic algorithms to optimize laboratory CDI diagnostics. The aim of the work was to implement an optimal algorithm of testing methods in CDI diagnostics. Materials and methods: The retrospective analysis of patients’ samples suspected on CDI was carried out in 2017. The data was analysed from the Laboratory Klinicka Biochemia in Zilina. The application of ESCMID re -commendation criteria for algorithm of testing, together with procedures in laboratory practice was carried out. Results: The analysis of the data showed that the applied algorithm or testing in CDI and highlighted the importance of preanalytic phase, and the evaluation of testing methods and results, together with clinical findings. Two- and three- step algorithm together with cultivation methods were applied. 87,6% of samples could be eva -luated with positive or negative results according to the 2-step algorhitm. Further samples were assessed and tested by ELISA test or PCR method. Conclusion: CDI represents a significant burden in healthcare facilities. An early diagnostics and interpretation helps to start the early treatment and helps in surveillence of the infection.

Novel strategies are needed that can stimulate endogenous signaling pathways to protect the heart from myocardial infarction. The present study tested the hypothesis that appropriate regimen of cold acclimation (CA) may provide a promising approach for improving myocardial resistance to ischemia/reperfusion (I/R) injury without negative side effects. We evaluated myocardial I/R injury, mitochondrial swelling, and β-adrenergic receptor (β-AR)-adenylyl cyclase-mediated signaling. Male Wistar rats were exposed to CA (8°C, 8 h/day for a week, followed by 4 wk at 8°C for 24 h/day), while the recovery group (CAR) was kept at 24°C for an additional 2 wk. The myocardial infarction induced by coronary occlusion for 20 min followed by 3-h reperfusion was reduced from 56% in controls to 30% and 23% after CA and CAR, respectively. In line, the rate of mitochondrial swelling at 200 μM Ca2+was decreased in both groups. Acute administration of metoprolol decreased infarction in control group and did not affect the CA-elicited cardiprotection. Accordingly, neither β1-AR-Gsα-adenylyl cyclase signaling, stimulated with specific ligands, nor p-PKA/PKA ratios were affected after CA or CAR. Importantly, Western blot and immunofluorescence analyses revealed β2- and β3-AR protein enrichment in membranes in both experimental groups. We conclude that gradual cold acclimation results in a persisting increase of myocardial resistance to I/R injury without hypertension and hypertrophy. The cardioprotective phenotype is associated with unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-AR pathways remains to be elucidated.NEW & NOTEWORTHY We present a new model of mild gradual cold acclimation increasing tolerance to myocardial ischemia/reperfusion injury without hypertension and hypertrophy. Cardioprotective phenotype is accompanied by unaltered adenylyl cyclase signaling and increased mitochondrial resistance to Ca2+-overload. The potential role of upregulated β2/β3-adrenoreceptor activation is considered. These findings may stimulate the development of novel preventive and therapeutic strategies against myocardial ischemia/reperfusion injury.

The aim of this retrospective analysis was to evaluate the impact of FDG-PET/CT-based target volume definition on locoregional control and survival, compared to conventional CT-based target volume definition and dose prescription. One hundred and twenty-two patients with squamous cell anal cancer were treated with curative radiotherapy (RT) alone (27%) or with RT with concurrent chemotherapy (73%) and analyzed. Forty-six percent had the early disease (stage I+II) and 54% were stage III. FDG-PET/CT-based staging was performed in 21% of the patients. The mean follow-up time was 60 months. Other risk factors affecting survival were investigated. According to initial staging in both groups (FDG-PET/CT and conventional CT) were 10% of stage IV disease, and they were excluded from radical radiotherapy and treated with palliative intent. Ninety-two percent of the patients achieved complete remission. Significant favorable factors in univariate analysis associated with disease-free survival (DFS) were PET/CT staging, T1/2 and N0 stage, and clinical stage I and II. Locoregional control (LRC) correlated with the T1/2 stage and initial performance status (PS) 0. There were no significant factors affecting overall survival (neither in univariate nor multivariate analysis). In multivariate analysis, the factor associated with better DFS was PET/CT staging and for LRC, PS 0 and concomitant chemoradiation. Acute toxicity was increased in the concurrent chemo-radiotherapy group. Two-, five- and ten-year overall survival rates were 83%, 69%, and 60%; disease-free survival rates were 76%, 73%, 73%; local control rates were 91%, 90%, and 90% and colostomy-free survival was 89%, 86%, and 81%, respectively. PET/CT staging allowed targeted dose escalation to the primary tumor and nodal metastases while decreasing dose to uninvolved regions, resulting in significantly improved DFS without compromising locoregional control.

The study aimed to compare differences of physiological acid-base balance (ABB) parameters in follicular fluid (FF) and venous blood (VB) and to evaluate ABB parameters in FF collected from different ovarian follicles in dairy cows and heifers. The ABB parameters (pH, pCO2, pO2, HCO3– and base excess (BE)) in the FF of the preovulatory follicle, of the dominant follicle on the 9th day of the cycle and of the superovulatory estrous follicles were compared to VB. Similarly, the dynamics of the ABB profile in FF and VB were monitored in repeated sampling in a group of heifers stimulated by follicle-stimulating hormone (FSH). Higher values of pH and pO2 and lower values of pCO2, HCO3– and BE were found in FF compared to VB in all experiments. Laterality of ovaries, time of sampling, ovarian activity or stimulation of the follicular development by FSH did not significantly influence ABB parameters. We found higher pH (7.392 ± 0.027 vs. 7.364 ± 0.032) and pO2 (13.83 ± 2.20 kPa vs. 4.50 ± 0.67 kPa), lower pCO2 (5.70 ± 0.39 kPa vs. 6.54 ± 0.61 kPa), HCO3– (25.51 ± 1.52 mmol/l vs. 26.86 ± 2.12 mmol/l) and BE (1.14 ± 1.57 mmol/l vs. 1.95 ± 2.2 mmol/l) in FF compared to VB in all non-stimulated cows. Similar relationships between FF and VB were found in all FSH stimulated cows. The study provides as yet unknown knowledge on the physiology of follicular fluid in cattle.

OBJECTIVES The objectives of this study were to determine the prognostic value of expression levels of selected biomarkers and their statistical analysis in relation to survival and standard histopathologic examination and other clinicopathologic variables in non-muscle invasive bladder cancer (NMIBC). BACKGROUND Worldwide, bladder cancer is a frequent malignant disease with rising incidence. Characteristic invasiveness and high recurrence rates call for more diagnostic methods to obtain more accurate information. Prognosis is affected by a significant interpersonal variability of the disease. For this reason, constant search for alternative and better diagnostic methods is essential. METHODS We analysed cancer tissue from patients with Ta and T1 bladder cancer. E-cadherin and Ki-67 expression levels were analysed using immunohistochemical staining. The expression levels quantified to a percentual amount were statistically analysed in relation to survival and their frequency distribution in the study group. RESULTS E-cadherin and Ki-67 expression levels show high association with tumor stage and grade (p

© The Author(s) 2020., Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide toward the relevant classification panel and final diagnosis. In this study, we designed and validated an algorithm for automated (database-supported) gating and identification (AGI tool) of cell subsets within samples stained with ALOT. A reference database of normal peripheral blood (PB, n = 41) and bone marrow (BM; n = 45) samples analyzed with the ALOT was constructed, and served as a reference for the AGI tool to automatically identify normal cells. Populations not unequivocally identified as normal cells were labeled as checks and were classified by an expert. Additional normal BM (n = 25) and PB (n = 43) and leukemic samples (n = 109), analyzed in parallel by experts and the AGI tool, were used to evaluate the AGI tool. Analysis of normal PB and BM samples showed low percentages of checks ( 0.95 for all cell types in PB and r2 > 0.75 in BM) and resulted in highly concordant classification of leukemic cells by our previously published automated database-guided expert-supervised orientation tool for immunophenotypic diagnosis and classification of acute leukemia (Compass tool). Similar data were obtained using alternative, commercially available tubes, confirming the robustness of the developed tools. The AGI tool represents an innovative step in minimizing human intervention and requirements in expertise, toward a “sample-in and result-out” approach which may result in more objective and reproducible data analysis and diagnostics. The AGI tool may improve quality of immunophenotyping in individual laboratories, since high percentages of checks in normal samples are an alert on the quality of the internal procedures., The EuroFlow Consortium received support from the FP6- 2004-LIFESCIHEALTH-5 program of the European Commission (grant LSHB-CT-2006-018708) as Specific Targeted Research Project (STREP). The Prague team received support from the grant number NV18-03-00343. The Salamanca team received support from the Instituto de Salud Carlos III (ISCIII) (PI16/00787-FEDER) and from Agencia Estatal de Investigación (RTC-2016-4865-1-FEDER), Ministerio de Economía y Competitividad, Madrid, Spain. AHD is supported from the program DI-17-09591 from Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain. SB is supported from the program PTQ16-08364 from Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades, Madrid, Spain. Medical University of Silesia in Katowice team was supported by the Strategmed III PersonALL grant [No. 304586/5/NCBR/2017] from the Polish National Center of Research and Development. The EuroFlow Consortium is part of the European Scientific Foundation for Hemato-Oncology (ESLHO), a Scientific Working Group (SWG) of the European Hematology Association (EHA).

Because cancer is the second leading cause of death globally, investigation of new photosensitizers for photodynamic therapy is highly desirable. In this work, different peripherally substituted subphthalocyanines (SubPcs) with either a benzocrown moiety (CE-) or a tyrosine methyl ester (Tyr-) as the axial ligand have been prepared. Target SubPcs showed high ΦΔ values, >0.50 in EtOH. Both CE- and Tyr- moieties increased substantially the hydrophilicity of the compounds (log P = 1.79-2.63, n-octanol/PBS). Uptake to cells, subcellular localization, and monitoring of the progression of cell death over time are described. Improved spectroscopic behavior of the CE- series in cell culture medium resulted in higher photodynamic activity versus that of the Tyr- series. In particular, the peripherally triethylsulfanyl SubPc-CE exhibited extraordinarily low EC50 values of 2.3 and 4.4 nM after light activation and high TC50 values of 14.49 and 5.25 μM (i.e., dark toxicity without activation) on SK-MEL-28 and HeLa cells, respectively, which rank it among the best photosensitizers ever.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn’s disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).

Mesenchymal stem cells (MSCs) represent an attractive source within the field of tissue engineering. However, their harvesting often requires invasive medical procedures. Urine-derived stem cells (UDSCs) display similar properties to MSCs, and their obtention and further processing is non-invasive for the donors as well as low cost. Here, we offer a comprehensive analysis of their biological properties. The goal of this study was to analyze their morphology, stemness, differentiation potential and cytokine profile. We have successfully isolated UDSCs from 25 urine samples. First colonies emerged up to 9 days after the initial seeding. Cell doubling time was 45 ± 0.24 SD, and when seeded at the density of 100 cells/cm2, they formed 42 ± 6.5 SD colonies within 10 days. Morphological analyzes revealed that two different types of the cell populations have been present. The first type had a rice-grain shape and the second one was characterized by a polyhedral shape. In several cell cultures, dome-shaped cells were observed as well. All examined UDSCs expressed typical MSC-like surface markers, CD73, CD90 and CD105. Moreover, conditioned media from UDSCs were harvested, and cytokine profile has been evaluated showing a significantly higher secretory rate of IL-8, IL-6 and chemokines MCP-1 and GM-CSF. We have also successfully induced human UDSCs into chondrogenic, osteogenic and myogenic cell lineages. Our findings indicate that UDSCs might have immense potential in the regeneration of the damaged tissues.

Background: Respiratory syncytial virus (RSV) infections are one of the leading causes of lower respiratory tract infections and have a major burden on society. For prevention and control to be deployed effectively, an improved understanding of the seasonality of RSV is necessary. Objectives: The main objective of this study was to contribute to a better understanding of RSV seasonality by examining the GERi multi-country surveillance dataset. Methods: RSV seasons were included in the analysis if they contained ≥100 cases. Seasonality was determined using the "average annual percentage" method. Analyses were performed at a subnational level for the United States and Brazil. Results: We included 601 425 RSV cases from 12 countries. Most temperate countries experienced RSV epidemics in the winter, with a median duration of 10-21 weeks. Not all epidemics fit this pattern in a consistent manner, with some occurring later or in an irregular manner. More variation in timing was observed in (sub)tropical countries, and we found substantial differences in seasonality at a subnational level. No association was found between the timing of the epidemic and the dominant RSV subtype. Conclusions: Our findings suggest that geographical location or climatic characteristics cannot be used as a definitive predictor for the timing of RSV epidemics and highlight the need for (sub)national data collection and analysis. This study was funded by Sanofi/AstraZeneca. Sí

Background: Dance is a complex activity combining physical exercise with cognitive, social, and artistic stimulation.Objectives: We aimed to assess the effects of dance intervention (DI) on intra and inter-network resting-state functional connectivity (rs-FC) and its association to cognitive changes in a group of non-demented elderly participants.Methods: Participants were randomly assigned into two groups: DI and life as usual (LAU). Six-month-long DI consisted of supervised 60 min lessons three times per week. Resting-state fMRI data were processed using independent component analysis to evaluate the intra and inter-network connectivity of large-scale brain networks. Interaction between group (DI, LAU) and visit (baseline, follow-up) was assessed using ANOVA, and DI-induced changes in rs-FC were correlated with cognitive outcomes.Results: Data were analyzed in 68 participants (DI; n = 36 and LAU; n = 32). A significant behavioral effect was found in the attention domain, with Z scores increasing in the DI group and decreasing in the LAU group (p = 0.017). The DI as compared to LAU led to a significant rs-FC increase of the default mode network (DMN) and specific inter-network pairings, including insulo-opercular and right frontoparietal/frontoparietal control networks (p = 0.019 and p = 0.023), visual and language/DMN networks (p = 0.012 and p = 0.015), and cerebellar and visual/language networks (p = 0.015 and p = 0.003). The crosstalk of the insulo-opercular and right frontoparietal networks were associated with attention/executive domain Z-scores (R = 0.401, p = 0.015, and R = 0.412, p = 0.012).Conclusion: The DI led to intervention-specific complex brain plasticity changes that were of cognitive relevance.

BackgroundThe emergence of a novel SARS-CoV-2 variant of concern called B.1.1.7 lineage sparked global alarm due to evidence of increased transmissibility, mortality, and uncertainty about vaccine efficacy, thus accelerating efforts to detect and track the variant. Current approaches to detect lineage B.1.1.7 include sequencing and RT-qPCR tests containing a target assay that fails or results in reduced sensitivity towards the B.1.1.7 variant.AimSince many countries lack robust genomic surveillance programs and failed assays detect multiple unrelated variants containing similar mutations as B.1.1.7, we sought to develop an RT-qPCR test that can accurately and rapidly differentiate the B.1.1.7 variant from other SARS-CoV-2 variants.MethodsWe used bioinformatics, allele-specific PCR, and judicious placement of LNA-modified nucleotides to develop a test that differentiates B.1.1.7 from other SARS-CoV-2 variants. We validated the test on 106 clinical samples with lineage status confirmed by sequencing and conducted a surveillance study of B.1.1.7 lineage prevalence in Slovakia.ResultsOur multiplexed RT-qPCR test showed 97% clinical sensitivity at detecting lineage B.1.1.7. The assay was used in a country-wide surveillance of B.1.1.7 lineage spread in Slovakia. Retesting nearly 7,000 SARS-CoV-2 positive samples obtained during three campaigns performed within a one month period, revealed pervasive spread of B.1.1.7 with an average prevalence of 82%.ConclusionLabs can easily implement this test to rapidly scale B.1.1.7 surveillance efforts and it is particularly useful in countries with high prevalence of variants possessing only the ΔH69/ΔV70 deletion because current strategies using target failure assays incorrectly identify these as putative B.1.1.7 variants.

Aims. Curative sphincter sparing radiotherapy is a treatment option for early rectal cancer. There are many methods developed for fertility preservation in young patients treated with pelvic radiotherapy. Pregnancy rates after radiotherapy are dependent on the radiation dose to ovaries and uterus. Data on outcomes of total body irradiation suggest a pregnancy is possible following 12-14 Gy TBI, despite elevated rates of preterm deliveries and other complications. Methods. We report a case of full-term delivery of twins after curative chemoradiotherapy for anorectal adenocarcinoma T2 N0 M0 with the total dose 58.6 Gy. The patient underwent laparoscopic laterocranial ovarian transposition before radiotherapy. Results. Long term complete remission was achieved after treatment. Although a spontaneous conception was not successful, the patient underwent an in vitro fertilisation procedure with donor eggs and conceived twins 10 years after the radiotherapy treatment. The mean dose to the uterus was 16 Gy and to the uterine cervix 35 Gy. She reached a full-term pregnancy and delivered two healthy babies by caesarean section at a gestational age of 38 weeks, weighing 2420 g and 2220 g. Conclusion. This is the first case report of the successful pregnancy following sphincter sparing curative pelvic radiotherapy for rectal cancer. Furthermore it allows us to propose an increased limit dose to the uterus enabling fertility sparing beyond the limits achieved from total body irradiation series with 12-14 Gy and accept 16 Gy as uterine body (35 Gy for uterine cervix) limit for IMRT treatment planning in young patients asking for maintaining fertility potential.