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Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), a highly infectious agent associated with unprecedented morbidity and mortality. A failure to stop growth of COVID‐19‐linked morbidity rates is caused by SARS‐CoV‐2 mutations and the emergence of new highly virulent SARS‐CoV‐2 strains. Several acquired SARS‐CoV‐2 mutations reflect viral adaptations to host immune defence. Mutations in the virus Spike‐protein were associated with the lowered effectiveness of current preventive therapies, including vaccines. Recent in vitro studies detected diminished neutralisation capacity of vaccine‐induced antibodies, which are targeted to bind Spike receptor‐binding and N‐terminal domains in the emerging strains. Lower than expected inhibitory activity of antibodies was reported against viruses with E484K Spike mutation, including B.1.1.7 (UK), P.1 (Brazil), B.1.351 (South African), and new Omicron variant (B.1.1.529) with E484A mutation. The vaccine effectiveness is yet to be examined against new mutant strains of SARS‐CoV‐2 originating in Europe, Nigeria, Brazil, South Africa, and India. To prevent the loss of anti‐viral protection in vivo, often defined as antibody resistance, it is required to target highly conserved viral sequences (including Spike protein) and enhance the potency of antibody cocktails. In this review, we assess the reported mutation‐acquiring potential of coronaviruses and compare efficacies of current COVID‐19 vaccines against 'parent' and 'mutant' strains of SARS‐CoV‐2 (Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529)). [ABSTRACT FROM AUTHOR]

Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT–SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT–ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD. [ABSTRACT FROM AUTHOR]

• This review examines advances in the epigenetic regulation of endocrine drug resistance and anti-resistance strategies in breast cancers. • The most influential breast cancer resistance-related mechanisms are regulated by epigenetic mechanisms. • Estrogen receptor (ER) modifications, expression, and ER-triggered genes are controlled by specific epigenetic tools. • ER promoter signalling can be modified by hypermethylation of CpG islands, increased histone deacetylase activity, and/or by miRNAs. • Blockade of histone acetyltransferases (MYST3), deacetylases (HDAC1), and/or demethylases (LSD1) can re-sensitize to anti-estrogen effects. Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs. [ABSTRACT FROM AUTHOR]

We did report that AEs were the reason for switch in 18/78 Miglustat patients and 17/33 Eliglustat patients. Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). [Extracted from the article]

The search for innovative forms and teaching methods is highly significant in the context of continuing education, since the competitiveness of modern teachers depends on the quality of the continuing education process. The purpose of the article is to analyze the experience of using innovative forms and methods in the system of advanced training and professional retraining of students. The article presents the experience of organizing the work of students using modern forms and methods of advanced training. The implementation of video conferencing allows students to learn advanced professional experience, exchange relevant information, ask leading experts questions of interest and receive recommendations. Training activities contribute to the intensification of the learning process. It is aimed both at mastering the cognitive component of the information transmitted by the teacher, and the formation of new professional models of behavior that meet modern requirements for the implementation of pedagogical activity. Mental maps are a means of logical structuring of information and are aimed at its operational development. Project activities allow students to build professional competence, find new innovative ways to solve problems, assess the feasibility and effectiveness of project ideas. [ABSTRACT FROM AUTHOR]

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form—Gaucher type 2—from the subacute or chronic form—Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative aimed to identify signs and co‐variables considered most indicative of early type 1 and type 3 GD, to help non‐specialists identify 'at‐risk' patients who may benefit from diagnostic testing. Methods: An anonymous, three‐round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5‐point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone‐related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co‐variables (family history of GD and Ashkenazi‐Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co‐variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co‐variables identified in the GED‐C initiative as potentially indicative of early GD will help to guide non‐specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD. [ABSTRACT FROM AUTHOR]

New cyclopentene-fused octahydropyridoquinolines and octahydrophenanthrolines were prepared by a stereoselective three-component cyclocondensation of benzene-1,4-diamine, cyclopenta-1,3-diene, and an aromatic aldehyde. Single-crystal X-ray diffraction data provided evidence for the formation of cyclopentene-fused octahydropyridoquinolines and octahydrophenanthrolines with a syn-planar arrangement of the cyclopentene rings. The cyclocondensation of benzene- 1,4-diamine, cyclopenta-1,3-diene, and formaldehyde gave new type of polycyclic compound containing four cyclopentene moieties oriented in a mutually antiplanar manner. [ABSTRACT FROM AUTHOR]

Study Design. Analysis of volumetric wear loss of retrieved growth guidance sliding devices LSZ-4D for treatment of early onset scoliosis and laboratory in vitro wear test for comparison of wear resistance of alloys Nitinol, Ti, and cobalt chromium (CoCr). Objective. To evaluate quantitatively the amount of wear debris from the sliding LSZ-4D device and to investigate the potential of using Nitinol for replacing Ti alloys in spinal instrumentation. To do that, wear resistance of Nitinol, Ti, and CoCr was compared. Summary of Background Data. There are little data regarding the amount of wear debris associated with growth guidance sliding devices for patients with early onset scoliosis and the wear resistance of superelastic Nitinol compared with Ti and CoCr. Methods. Volumetric wear loss was measured on LSZ-4D devices made from titanium alloy Ti6Al4V and each consisted of 2 rectangular section (6X4 mm) rods and 40 ± 8 fixture elements (20 ± 4 hooks and 20 ± 4 clips) retrieved from 3 patients (implantation period, 3.5-5.8 yr). Images of wear scars were taken on Bruker interferometer microscope and incorporated into MATLAB software. Wear resistance of Nitinol, Ti, and CoCr was studied using reciprocation pin-on-disk wear test in bovine serum at 37°C ± 1°C. Results. The volume wear rate of LSZ-4D device was found to be 12.5 mm³ per year from which 5 mm ³ per year is the wear debris of the rod and 7.5 mm ³ per year is the contribution of fixtures. Wear resistance of Nitinol is 100 times higher than that of Ti and comparable with that of CoCr. Conclusion. Application of wear-resistant coatings on Ti components in growth guidance sliding devices for the treatment of early onset scoliosis will be useful. High wear resistance of Nitinol combined with its superelastic and shape memory properties could make application of Nitinol rods for spinal instrumentation beneficial. [ABSTRACT FROM AUTHOR]

4 -Aryl-8-fluoro-3a,4,5,9b-tetrahydro-3 H-cyclopenta[ c]quinolines are synthesized by acid-catalyzed (CF3CO2H) three-component cyclocondensation of 4-fluoroaniline with aromatic aldehydes and cyclopentadiene. Stable ozonides with (1 R*,4 S*,5a R*,6 S*,11b S*)-configurations are obtained by ozonolysis of corresponding trifluoroacetyl derivatives. [ABSTRACT FROM AUTHOR]

Currently, significant attention is attracted to the problem of the development of the specific architecture and composition of the surface layer in order to control the biocompatibility of implants made of titanium and its alloys. The titanium surface properties can be tuned both by creating an inorganic sublayer with the desired morphology and by organic top coating contributing to bioactivity. In this work, we developed a composite biologically active coatings based on hybrid molecules obtained by chemical cross-linking of amino acid bisphosphonates with a linear tripeptide RGD, in combination with inorganic porous sublayer created on titanium by plasma electrolytic oxidation (PEO). After the addition of organic molecules, the PEO coated surface gets nobler, but corrosion currents increase. In vitro studies on proliferation and viability of fibroblasts, mesenchymal stem cells and osteoblast-like cells showed the significant dependence of the molecule bioactivity on the structure of bisphosphonate anchor and the linker. Several RGD-modified bisphosphonates of β-alanine, γ-aminobutyric and ε-aminocaproic acids with BMPS or SMCC linkers can be recommended as promising candidates for further in vivo research. [ABSTRACT FROM AUTHOR]

The significance of the problem under study is determined by the increasing requirements of society for the ability of a young person to respond optimally to the challenges of our time, and, as a consequence, the importance of studying hardiness as an integral personal construct that mediates a person's response to the stress of life. The purpose of the paper is to analyze the empirical data of the study of hardiness among the student youth, to identify the specific features in the manifestation of the psychological aspects of hardiness associated with attitudes, social skills, an aptitude of boys and girls for emotional and behavioral self-regulation. The leading approach to the study of student hardiness is a systematic approach as a methodological principle of modern science. The main research methods are personality questionnaires, projective techniques, the method of content analysis which make it possible to reveal the features of the manifestation of hardiness through patterns of attitudes and behavior in life situations. The main results of the study are data on the specifics of perceiving the concept of "hardiness" by university students; data on the hardiness indicators of boys and girls studying at universities; features of emotional self-regulation and cognitive attitudes of students with different indicators of hardiness. The materials of the paper can be useful for university teachers in terms of pedagogical activities to develop hardiness of the student youth through personal interaction in the process of educational and scientific activities. [ABSTRACT FROM AUTHOR]

Abstract This research follows a biomimetic approach for implant surface design, and it concerns surface functionalization for nanostructured Ti Grade 4 with a composite coating obtained by plasma electrolytic oxidation (PEO) with organic pore filler of integrin-active RGD containing peptide (Arg-Gly-Asp-Cys). It was shown that Ti nanostructuring via ECAP-C technique almost two-fold improves its mechanical strength; also, the nanostructuring depassivates the surface, both PEO coated and uncoated. The PEO coating on nano-Ti contains 2–3% more biocompatible elements, amorphous and bio-crystalline phases. The RGD peptide was linked to the surface via phosphonate groups allowing the organic pore filler deposition by dipping method; the RGD presence in the PEO coating pores was proven by the EIS. For the in vitro tests, fibroblasts were used; it was shown that PEO coating on nano-Ti gives 43% increase in the number of cells compared to CG-Ti + PEO; the combination of PEO coating and RGD peptide on nano-Ti gives 45% increase in the number of cells compared to nano-Ti, and 66% compared to CG-Ti. Therefore, this surface functionalization contributes to the development of Ti implants having high strength and providing improved cell proliferation. Highlights • Ti nanostructuring via ECAP-Conform increases strength almost twice compared to CG-Ti • PEO coating on nano-Ti contains 2–3% more amorphous and bio-crystalline phases compared to CG-Ti + PEO • PEO coating on nano-Ti increases cell proliferation by 43% compared to CG-Ti + PEO • Nano-Ti with RGD modified PEO coating increases cell proliferation by 45% compared to nano-Ti and by 66% compared to CG-Ti • Nano-Ti with PEO coating functionalized by RGD is promising for high strength implants with improved biocompatibility [ABSTRACT FROM AUTHOR]