Synthesis of phosphorus, sulfur and silicon-containing flame retardant via thiol-ene click reaction and its use for durable finishing of cotton fabric.

The article presents a very simple method of synthesis and application of a halogen and formaldehyde free, P, S and Si-containing flame retardant for the durable finishing of cotton fabric. The compound was obtained as a result of the thiol-ene click reaction. The compound was designed to have two functional groups: an alkoxysilyl group for cross-linking and binding to the cotton fabric, and a phosphate group to provide flame retardant properties. The flame retardant was applied to cotton fabric using the sol-gel method. According to the pyrolysis-combustion flow calorimetry (PCFC) technique, the use of the obtained silane for cotton treatment can reduce heat release rate (HRR) to almost 75% compared to the raw fabric. FT-IR analyses and SEM images indicate that impregnated cotton samples were covered with a layer of silanes. The SEM-EDS analysis confirmed successful modification of cotton fabrics. After 10 cycles of washing it was found that the created coatings are resistant to washing and retain their flame retardant properties.

Food addiction and the physical and mental health status of adults with overweight and obesity.

Background: Overweight and obesity now affect more than a third of the world's population. They are strongly associated with somatic diseases, in particular increasing the risk of many metabolic and cardiovascular diseases, but also with mental disorders. In particular, there is a strong association between obesity and depression. As a result, more attention is paid to the neurobiological, behavioural, and psychological mechanisms involved in eating. One of these is food addiction (FA). Research comparing lifestyle elements, physical and mental health problems of excess body weight and individuals with FA is limited and has focused on younger people, mainly students. There is also a lack of studies that relate actual metabolic parameters to FA. To better understand the problem of FA also in older adults, it is important to understand the specific relationships between these variables. Methods: A cross-sectional survey was conducted with 172 adults with overweight and obesity (82% female) aged 23-85 years. The mean age of all subjects was M = 59.97 years (SD = 11.93), the mean BMI was M = 32.05 kg/m2 (SD = 4.84), and the mean body fat was M = 39.12% (SD = 6.48). The following questionnaires were used: Food Frequency Questionnaire-6 (FFQ-6), Global Physical Activity Questionnaire (GPAQ), Three Factor Eating Questionnaire-R18 (TFEQ-R18), Yale Food Addiction Scale 2. 0 (YFAS 2.0), Zung Self-Rating Depression Scale (SDS). Body composition, anthropometry, fasting glucose, lipid profile, and blood pressure were measured. Results: A total of 22.7% of participants with overweight and obesity had symptoms of depression according to the SDS, and 18.6% met the criteria for FA according to YFAS 2.0. FA was statistically significantly more common among people up to 50 years. BMI, body fat mass, diastolic blood pressure and sedentary behaviour were statistically significantly higher in people with FA symptoms. Those who were sedentary for 301-450 min per day were significantly more likely to have depressive symptoms, and those who were sedentary for more than 450 min per day were significantly more likely to have FA symptoms. Conclusions: Our findings complement the current literature on FA, particularly in older adults and metabolic parameters, and suggest further research directions. Although our cross-sectional study design does not allow causal interpretations, increasing physical activity appears to be particularly important in the management of people with overweight or obesity and FA. This may be even more important than for people with depression alone, but future research is needed to explore these relationships further.

Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to ß-glucocerebrosidase deficiency and glucosylceramide accumulation. Methods: We analyzed short- and long-term dynamics of lyso-glucosylceramide (lyso-Gb1) in a large cohort of GD patients undergoing enzyme replacement therapy (ERT). Results: Eight-years analysis of lyso-Gb1 revealed statistically insignificant variability in the biomarker across the years and relatively high individual variability in patients' results. GD type 1 (GD1) patients exhibited higher variability compared to GD type 3 (GD3) patients (coefficients of variation: 34% and 23%, respectively; p-value = 0.0003). We also investigated the short-term response of the biomarker to enzyme replacement therapy (ERT), measuring lyso-Gb1 right before and 30 min after treatment administration. We tested 20 GD patients (16 GD1, 4 GD3) and observed a rapid and significant reduction in lyso-Gb1 levels (average decrease of 17%; p-value < 0.0001). This immediate response reaffirms the efficacy of ERT in reducing substrate accumulation in GD patients but, on the other hand, suggests the biomarker's instability between the infusions. Conclusions: These findings underscore lyso-Gb1's potential as a reliable biomarker for monitoring efficacy of treatment. However, individual variability and dry blood spot (DBS) testing limitations urge a further refinement in clinical application. Our study contributes valuable insights into GD patient management, emphasizing the evolving role of biomarkers in personalized medicine.

The Liver and Lysosomal Storage Diseases: From Pathophysiology to Clinical Presentation, Diagnostics, and Treatment.

The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann-Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement.

Medicinal Anti-Inflammatory Patch Loaded with Lavender Essential Oil.

Transdermal drug delivery offers a promising alternative for administering medications like ibuprofen, known for its analgesic and anti-inflammatory properties, with reduced gastrointestinal side effects compared to oral administration. This study explored the potential synergistic effects of combining ibuprofen with lavender essential oil (LEO) in transdermal patches. The composition of LEO was analyzed, revealing predominant compounds such as linalyl acetate and linalool, which are known for their analgesic and anti-inflammatory properties. The physicochemical properties of the patches were investigated, indicating improved cohesion with the addition of LEO. Additionally, thermal stability assessments demonstrated enhanced stability with LEO incorporation with an increase in onset decomposition temperature from 49.0 to 67.9 °C. The antioxidant activity of patches containing LEO was significantly higher with a free radical scavenging ability of 79.13% RSA compared to 60% RSA in patches without LEO. Release and permeation studies showed that patches with LEO exhibited an increased permeation of ibuprofen through the skin with 74.40% of the drug released from LEO-containing patches compared to 36.29% from patches without LEO after 24 h. Moreover, the permeation rate was notably faster with LEO, indicating quicker therapeutic effects. The inclusion of LEO in transdermal patches containing ibuprofen holds promise for enhancing drug delivery efficiency and therapeutic effectiveness, offering a potential strategy for improved pain management with reduced side effects.

Investigating the Anti-Inflammatory Properties and Skin Penetration Ability of Cornelian Cherry (Cornus mas L.) Extracts.

Plant extracts can be a valuable source of biologically active compounds in many cosmetic preparations. Their effect depends on the phytochemicals they contain and their ability to penetrate the skin. Therefore, in this study, the possibility of skin penetration by phenolic acids contained in dogwood extracts of different fruit colors (yellow, red, and dark ruby red) prepared using different extractants was investigated. These analyses were performed using a Franz chamber and HPLC-UV chromatography. Moreover, the antioxidant properties of the tested extracts were compared and their impact on the intracellular level of free radicals in skin cells was assessed. The cytotoxicity of these extracts towards keratinocytes and fibroblasts was also analyzed and their anti-inflammatory properties were assessed using the enzyme-linked immunosorbent assay (ELISA). The analyses showed differences in the penetration of individual phenolic acids into the skin and different biological activities of the tested extracts. None of the extracts had cytotoxic effects on skin cells in vitro, and the strongest antioxidant and anti-inflammatory properties were found in dogwood extracts with dark ruby red fruits.

Can transesophageal echocardiography be safely omitted in patients scheduled for elective ablation of atrial arrhythmias? Data based on the LATTEE registry.

BACKGROUND: According to the present guidelines, transesophageal echocardiography (TEE) before scheduled catheter ablation (CA) for atrial arrhythmias (atrial fibrillation [AF] or atrial flutter [AFL]) is not deemed obligatory for optimally anticoagulated patients. However, daily clinical practice significantly differs from the recommendations. AIMS: We aimed to identify transthoracic echocardiographic parameters that could be useful in identifying patients without left atrial thrombus (LAT), which makes it possible to avoid unnecessary TEE before scheduled CA. METHODS: This is a sub-analysis of a multicenter, prospective, observational study - the LATTEE registry. A total of 1346 patients referred for TEE before scheduled CA of AF/AFL were included. RESULTS: LAT was present in 44 patients (3.3%) and absent in the remaining 1302, who were younger, more likely to have paroxysmal AF, and displayed sinus rhythm during TEE. Additionally, they exhibited a lower incidence of heart failure, diabetes, systemic connective tissue disease, and chronic obstructive pulmonary disease. Furthermore, they had a lower CHA2DS2-VASc score and a higher prevalence of direct oral anticoagulants. Echocardiographic parameters, including left ventricular ejection fraction (LVEF) >65%, left atrial diameter (LAD) <40 mm, left atrial area (LAA) <20 cm2, left atrial volume (LAV) <113 ml, and left atrial volume index (LAVI) <51 ml/m2, demonstrated 100% sensitivity and 100% negative predictive value for the absence of LAT and were met by 417 patients. Additional echocardiographic indices: LVEF/LAD ≥1.4, LVEF/LAVI ≥1.6, and LVEF/LAA ≥2.7 identified 57 additional patients, bringing the total of predicted LAT-free patients to 474 (35%). CONCLUSIONS: Simple echocardiographic parameters could help identify individuals for whom TEE could be safely omitted before elective CA due to atrial arrhythmias.

Risk factors for thrombosis and spontaneous echocardiographic contrast with sludge in atrial fibrillation patients treated with oral anticoagulants before electrical cardioversion.

BACKGROUND: Knowledge of thrombosis (T) risk predictors and transesophageal echocardiography (TEE) are important tools in appropriate qualification of patients for safe electrical cardioversion. AIMS: We aimed to investigate predictors of T and spontaneous echocardiographic contrast (SEC) with sludge in the left atrium (LA) and appendage (LAA) in atrial fibrillation (AF) patients on oral anticoagulation. METHODS: The study included 300 patients with AF lasting >48 hours. Two hundred and nineteen patients were treated with oral anticoagulants (OACs) (study group, rivaroxaban: 104 [47.5%], apixaban: 52 [23.7%], dabigatran: 23 [11.5%], VKAs: 40 [18.3%]). Eighty-one consecutive patients with AF lasting >48 hours and not treated with OACs constituted the control group. Before electrical cardioversion, all patients underwent transthoracic echocardiography and TEE. RESULTS: TEE revealed T in the LAA in 4.7% of cases. The number of patients with T or SEC4+ with sludge in the OAC and control groups was similar, 5.9% vs. 1.2% and 16.4% vs. 16.0%, respectively. The risk of SEC4+/T in patients treated with OACs was lowest in those taking rivaroxaban (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.21-0.87; P = 0.027) and highest in those receiving VKAs (OR, 2.49; 95% CI, 1.15-5.39; P = 0.018). Multivariable analysis showed independent prognostic factors for SEC 4+/T: female sex (OR, 3.800; 95% CI, 1.592-9.072; P = 0.003), left ventricular ejection fraction (OR, 0.932; 95% CI, 0.890-0.957; P <0.001), and minimum LAA flow velocity (LAAfly min) (OR, 0.895; 95% CI, 0.841-0.954; P <0.001). CONCLUSIONS: Female sex, transthoracic echocardiography, and TEE results should be taken into account in assessing the risk of T/SEC with sludge in LA/LAA patients with AF.

Kombucha as a Potential Active Ingredient in Cosmetics-An Ex Vivo Skin Permeation Study.

Kombucha is a non-alcoholic beverage, that is increasingly used in the cosmetic industry. The available literature reports the positive effects of kombucha on the skin, in particular its antioxidant action. However, there is a lack of information on skin permeation and the accumulation of active ingredients showing such effects. Skin aging is largely dependent on oxidative stress, therefore in our study we assessed the ex vivo permeation of two types of kombucha (green and black tea) through porcine skin. The antioxidant activity (DPPH, ABTS, FRAP methods) and total polyphenol content of these extracts were determined before and after permeation testing. Moreover, the content of selected phenolic acids as well as caffeine was assessed. Skin permeation was determined using a Franz diffusion cell. The antioxidant activity of both Kombuchas was found to be high. In addition, gallic acid, chlorogenic acid, protocatechuic acid, coumaric acid, m-hydroxybenzoic acid, and caffeine were identified. A 24-h ex vivo study showed the permeation of some phenolic acids and caffeine and their accumulation in the skin. Our results confirm the importance of studying the skin permeation of what are still little known ingredients in cosmetic preparations. Evaluation of the accumulation of these ingredients can guarantee the efficacy of such preparations.

Artificial intelligence in detecting left atrial appendage thrombus by transthoracic echocardiography and clinical features: the Left Atrial Thrombus on Transoesophageal Echocardiography (LATTEE) registry.

AIMS: Transoesophageal echocardiography (TOE) is often performed before catheter ablation or cardioversion to rule out the presence of left atrial appendage thrombus (LAT) in patients on chronic oral anticoagulation (OAC), despite associated discomfort. A machine learning model [LAT-artificial intelligence (AI)] was developed to predict the presence of LAT based on clinical and transthoracic echocardiography (TTE) features. METHODS AND RESULTS: Data from a 13-site prospective registry of patients who underwent TOE before cardioversion or catheter ablation were used. LAT-AI was trained to predict LAT using data from 12 sites (n = 2827) and tested externally in patients on chronic OAC from two sites (n = 1284). Areas under the receiver operating characteristic curve (AUC) of LAT-AI were compared with that of left ventricular ejection fraction (LVEF) and CHA2DS2-VASc score. A decision threshold allowing for a 99% negative predictive value was defined in the development cohort. A protocol where TOE in patients on chronic OAC is performed depending on the LAT-AI score was validated in the external cohort. In the external testing cohort, LAT was found in 5.5% of patients. LAT-AI achieved an AUC of 0.85 [95% confidence interval (CI): 0.82-0.89], outperforming LVEF (0.81, 95% CI 0.76-0.86, P < .0001) and CHA2DS2-VASc score (0.69, 95% CI: 0.63-0.7, P < .0001) in the entire external cohort. Based on the proposed protocol, 40% of patients on chronic OAC from the external cohort would safely avoid TOE. CONCLUSION: LAT-AI allows accurate prediction of LAT. A LAT-AI-based protocol could be used to guide the decision to perform TOE despite chronic OAC.

Thiol-ene click reaction as an effective tool for the synthesis of PEG-functionalized alkoxysilanes-precursors of anti-fog coatings.

The article presents a very simple method of glass modification to obtain the anti-fog effect. Silanes containing two types of functional groups, namely a hydrophilic and polar polyether group and an alkoxysilyl group (to bond with the surface of the modified material) were synthesized in thiol-ene reactions. The hydrothiolation reactions of polyethers containing a C=C terminal bond with mercaptoalkoxysilane proceeded efficiently, yielding quantitatively appropriate products under mild reaction conditions. This method enabled the synthesis of a series of alkoxysilanes functionalized with polyethers, differing in structure. The group of obtained derivatives was characterized by 1H, 13C, 29Si NMR, and FT-IR analyses, and then used to prepare coatings on glass using the sol-gel method. The coated glass surfaces exhibited transparency, superhydrophilic or hydrophilic properties, anti-fog and anti-frost performance.

Metabolic dysfunction-associated steatotic liver disease as a cardiovascular risk factor.

In recent years, the diagnosis and understanding of nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), and its relationship with cardiovascular diseases (CVD) are gaining better understanding. As MASLD shares common risk factors with CVD, including obesity, insulin resistance, hypertension, and dyslipidemia, research increasingly identifies it as a potential independent risk factor for CVD. The exact mechanisms linking MASLD to CVD remain complex and multifaceted, involving metabolic, inflammatory, and vascular pathways. Current cardiology guidelines recognize the significant association between MASLD and CVD, advocating its integration into cardiovascular risk assessment and management. Despite the progress, gaps persist in understanding underlying molecular and cellular mechanisms and the representation of diverse populations in epidemiological studies. The review illuminates the clinical implications of the MASLD-CVD link and identifies directions for future research.

Diagnosis and Management of Mucopolysaccharidosis Type II (Hunter Syndrome) in Poland.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is a rare, inherited lysosomal storage disease. The disease is caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S) due to mutations in the IDS gene, which leads to accumulation of glycosaminoglycans (GAGs). Deficiency of I2S enzyme activity in patients with MPS II leads to progressive lysosomal storage of GAGs in the liver, spleen, heart, bones, joints, and respiratory tract. This process disturbs cellular functioning and leads to multisystemic disease manifestations. Symptoms and their time of onset differ among patients. Diagnosis of MPS II involves assessment of clinical features, biochemical parameters, and molecular characteristics. Life-long enzyme replacement therapy with idursulfase (recombinant human I2S) is the current standard of care. However, an interdisciplinary team of specialists is required to monitor and assess the patient's condition to ensure optimal care. An increasing number of patients with this rare disease reach adulthood and old age. The transition from pediatric care to the adult healthcare system should be planned and carried out according to guidelines to ensure maximum benefit for the patient.

A library of new organofunctional silanes obtained by thiol-(meth)acrylate Michael addition reaction.

A simple and efficient method for the synthesis of organofunctional silanes by the thiol-(meth)acrylate addition reaction is presented. At first, systematic studies were carried out to select an optimum initiator/catalyst of the addition reaction for the model reaction involving 3-mercaptopropyltrimethoxysilane (MPTMS) and hexyl acrylate. Photoinitiators (in the presence of UV light energy), thermal initiators (such as aza compound and peroxide) as well as catalysts (primary and tertiary amines, phosphines and Lewis acid) were studied. After selecting an effective catalytic system and optimizing the reaction conditions, reactions between the thiol group (i.e. 3-mercaptopropyltrimethoxysilane) and (meth)acrylates containing various functional groups were carried out. All derivatives obtained were characterized by 1H, 13C, 29Si NMR and FT-IR analysis. In reactions carried out at room temperature, in an air atmosphere and in the presence of dimethylphenylphosphine (DMPP) as a catalyst, quantitative conversions of both substrates were obtained within a few minutes. The library of organofunctional silanes was expanded by compounds (containing various functional groups, i.e. alkenyl, epoxy, amino, ether, alkyl, aralkyl, fluoroalkyl) which were obtained in the thiol-Michael addition of 3-mercaptopropyltrimethoxysilane to a group of organofunctional (meth)acrylic acid esters.

Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy.

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for ß-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

A 20-Year Longitudinal Study of Plasma Chitotriosidase Activity in Treated Gaucher Disease Type 1 and 3 Patients-A Qualitative and Quantitative Approach.

Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload. Gaucher disease (GD) is a recessively inherited disorder resulting in storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. It is directly caused by the deficiency of beta-glucocerebrosidase (GBA) activity. Chitotriosidase has been measured systematically each year in the same group of 49 patients with type 1 and 3 GD for over 20 years. Our analysis showed that chitotriosidase is very sensitive biomarker to enzyme replacement therapy (ERT). The response to treatment introduction is of an almost immediate nature, lowering pathologically high chitotriosidase levels by a factor of 2 in a time scale of 8 months, on average. Long term enzyme replacement therapy (ERT) brings chitotriosidase activity close to reference values. Finally, reducing the dose of ERT quickly boosts chitotriosidase activity, but restoring the initial dose of treatment brings chitotriosidase level of activity back onto the decreasing time trajectory.

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration.

Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study.

Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.

Echocardiographic predictors of thrombus in left atrial appendage-The role of novel transthoracic parameters.

Introduction: The left atrium appendage thrombus (LAAT) formation is a complex process. A CHA2DS2-VASc scale is an established tool for determining the thromboembolic risk and initiation of anticoagulation treatment in patients with atrial fibrillation or flutter (AF/AFL). We aimed to identify whether any transthoracic echocardiography (TTE) parameters could have an additional impact on LAAT detection. Methods: That is a sub-study of multicenter, prospective, observational study LATTEE (NCT03591627), which enrolled 3,109 consecutive patients with AF/AFL referred for transesophageal echocardiography (TEE) before cardioversion or ablation. Results: LAAT was diagnosed in 8.0% of patients. The univariate logistic regression analysis [based on pre-specified in the receiver operating characteristic (ROC) analysis cut-off values with AUC ≥ 0.7] identified left ventricular ejection fraction (LVEF) ≤ 48% and novel TTE parameters i.e., the ratios of LVEF and left atrial diameter (LAD) ≤ 1.1 (AUC 0.75; OR 5.64; 95% CI 4.03-7.9; p < 0.001), LVEF to left atrial area (LAA) ≤ 1.7 (AUC 0.75; OR 5.64; 95% CI 4.02-7.9; p < 0.001), and LVEF to indexed left atrial volume (LAVI) ≤ 1.1 (AUC 0.75, OR 6.77; 95% CI 4.25-10.8; p < 0.001) as significant predictors of LAAT. In a multivariate logistic regression analysis, LVEF/LAVI and LVEF/LAA maintained statistical significance. Calculating the accuracy of the abovementioned ratios according to the CHA2DS2-VASc scale values revealed their highest predictive power for LAAT in a setting with low thromboembolic risk. Conclusion: Novel TTE indices could help identify patients with increased probability of the LAAT, with particular applicability for patients at low thromboembolic risk.

Pharmacological chaperone therapy for the treatment of inborn errors of metabolism / Stosowanie farmakologicznych chaperonów w leczeniu wrodzonych chorób metabolicznych.

The article describes the mechanism of molecular and pharmacological chaperones in the treatment of inborn errors of metabolism. The literature review of the usage of ambroxol acting as a pharmacological chaperone for beta-glucocerebrosidase in Gaucher disease and Parkinson's disease associated with GBA variants has been reviewed.