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The nature of H-bonding interactions is still far from being understood despite intense experimental and theoretical studies on this subject carried out by the leading research centers. In this paper, by a combination of unique high-pressure infrared, dielectric and volumetric data, the intramolecular dynamics of hydroxyl moieties (which provides direct information about H-bonds) was studied along various isolines, i.e., isotherms, isobars, isochrones, and isochores, in a simple monohydroxy alcohol (2-ethyl-1-hexanol). This allowed us to discover that the temperature controls the intermolecular hydrogen bonds, which then affect the intramolecular dynamics of OH units. Although the role of density fluctuations gets stronger as temperature rises. We also demonstrated a clear connection between the intra- and intermolecular dynamics of the associating liquid at high pressure. The data reported herein open a new perspective to explore this important aspect of the glass transition phenomenon and understand H-bonding interactions at varying thermodynamic conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

In recent years, the importance of the gut microbiome in human health and disease has increased. Growing evidence suggests that gut dysbiosis might be a crucial risk factor for coronary artery disease (CAD). Therefore, we conducted a systematic review and meta-analysis to determine whether or not CAD is associated with specific changes in the gut microbiome. The V3-V4 regions of the 16S rDNA from fecal samples were analyzed to compare the gut microbiome composition between CAD patients and controls. Our search yielded 1181 articles, of which 21 met inclusion criteria for systematic review and 7 for meta-analysis. The alpha-diversity, including observed OTUs, Shannon and Simpson indices, was significantly decreased in CAD, indicating the reduced richness of the gut microbiome. The most consistent results in a systematic review and meta-analysis pointed out the reduced abundance of Bacteroidetes and Lachnospiraceae in CAD patients. Moreover, Enterobacteriaceae , Lactobacillus , and Streptococcus taxa demonstrated an increased trend in CAD patients. The alterations in the gut microbiota composition are associated with qualitative and quantitative changes in bacterial metabolites, many of which have pro-atherogenic effects on endothelial cells, increasing the risk of developing and progressing CAD., Competing Interests: The authors have no conflicts of interest to declare. All co-authors have seen and agree with the manuscript’s contents, and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. The authors have no competing interests to declare.

In this paper, efficient MMA photo O -ATRP protocols conducted inside nanoreactors varying in nanostructured interfaces are reported for the first time. We showed that the microstructure of recovered polymers could be easily tuned just by implementing a given type of nanochannel ( d = 10, 19-28, 35, 160 nm).

We built a high-speed TDS setup with the use of electronically controlled optical sampling (ECOPS), which can measure up to 1600 terahertz pulses per second. The movement of the sample was provided by two fast-speed motorized linear stages constituting the gantry. We developed a flat-bar-based metal marker approach for the synchronization of continuous line-by-line scans. We carefully compared the performance of the terahertz reflection time-domain spectroscopy (TDS) scanner operating in a slow point-by-point and a one-hundred-times faster line-by-line imaging scheme. We analyzed images obtained for both schemes for a uniform metallic breadboard with holes, as well as a glass composite sample with defects. Although the measurement time was reduced by 100 times in terms of the line-by-line scheme, the overall performance in both schemes was almost identical in terms of the defects' sizes, shapes and locations. The results proved that the proposed ECOPS TDS system can provide uniform and extremely fast scanning without any deterioration in image quality.

Herein, the annealing of highly polar ( S )-(-)-4-methoxymethyl-1,3-dioxolan-2-one ( S -methoxy-PC) within alumina and silica porous membranes characterized by different pore diameters was studied by means of dielectric spectroscopy. We found a significant slowing down of the structural dynamics of confined S -methoxy-PC with annealing time below and, surprisingly, also above the glass transition temperatures of the interfacial layer, T g,interfacial . Furthermore, unexpectedly, a change in the slope of temperature dependencies of the characteristic time scale of this process τ anneal , at T g,interfacial for all confined samples, was reported. By modeling τ anneal ( T ), we noted that the observed enormous variation of τ anneal results from a decrease of the pore radius due to the vitrification of the interfacial molecules. This indicates that the enhanced dynamics of confined materials upon cooling is mainly controlled by the interfacial molecules.

New chemical structures with antifungal properties are highly desirable from the point of view of modern pharmaceutical science, especially due to the increasingly widespread instances of drug resistance in the case of these diseases. One way to solve this problem is to use polymeric drugs, widely described as biocidal, positively charged macromolecules. In this work, we present the synthesis of new cationic β-glucan derivatives that show selective antifungal activity and at the same time low toxicity toward animal and human cells. Two β-glucans isolated from oats and barley and modified using glycidyltrimethylammonium chloride were obtained and evaluated for biocidal properties on the cells of mammals and pathogenic fungi and bacteria. These compounds were found to be nontoxic to fibroblast and bacterial cells but showed selective toxicity to certain species of filamentous fungi ( Scopulariopsis brevicaulis ) and yeasts ( Cryptococcus neoformans ). The most important aspect of this work is the attempt to explain the mechanisms of action of these compounds by studying their interaction with biological membranes. This was achieved by examining the interactions with model biological membranes representative of given families of microorganisms using Langmuir monolayers. The data obtained partly show correlations between the results for model systems and biological experiments and allow indicating that the selective antifungal activity of cationic β-glucans is related to their interaction with fungal biological membranes and partly lack of such interaction toward cells of other organisms. In addition, the obtained macromolecules were characterized by spectral methods (Fourier transform infrared (FTIR) and 1 H nuclear magnetic resonance (NMR) spectroscopies) to confirm that the desired structure was obtained, and their degree of modification and molecular weights were determined., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

( R )-7 [ ( R )-AS-1 ] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. ( R )-7 [ ( R )-AS-1 ] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, ( R )-7 [ ( R )-AS-1 ] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.

Background: Cytokines soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 6 (IL-6) are involved in immune response, proliferation, apoptosis, and cardiovascular pathologies. We have previously confirmed that changes of their platelet or plasma contents are associated with pulmonary arterial hypertension (PAH). The positron emission tomography/magnetic resonance imaging (PET/MRI) hybrid imaging provides detailed insight into right ventricle (RV) hemodynamic and metabolic function., Objectives: To evaluate the relationship between RV parameters obtained using PET/MRI and concentrations of plasma and platelet sTWEAK and IL-6 in stable PAH patients., Material and Methods: Eighteen stable PAH patients (48.44 ±16.7 years) had simultaneous PET/MRI scans with 18F-fluorodeoxyglucose (18F-FDG) performed. Its uptake was presented as a standardized uptake value (SUV) for RV and left ventricle (LV). Cytokines concentrations were measured in platelet-poor plasma and platelet lysate. Follow-up time of this study was 58 months; the combined endpoint (CEP) was defined as death or clinical deterioration., Results: We observed significant correlations between platelet sTWEAK levels, plasma IL-6 and PET parameter SUVRV/LV (r = -0.57, p = 0.011; r = 0.50, p = 0.032, respectively). In logistic regression, platelet sTWEAK and IL-6 were both prognostic factors for unfavorable ratio of SUVRV/LV higher than 1 (hazard ratio (HR) = 0.44, 95% confidence interval (95% CI): [0.23; 0.84], p = 0.017; and HR = 3.62, 95% CI: [1.21; 10.17], p = 0.011, respectively). Furthermore, their concentrations were related with prognostically important higher late gadolinium enhancement mass index (LGEMI) and RV global longitudinal strain/systolic pulmonary artery pressure (RV GLS/sPAP) values. Patients who had CEP in follow-up (n = 13) had significantly lower platelet sTWEAK content and higher plasma IL-6 at baseline than stable patients. Lower platelet sTWEAK was related to a worse prognosis in log-rank test (p = 0.006). Platelet sTWEAK and plasma IL-6 together with RV GLS/sPAP, RV ejection fraction (RVEF), mean pulmonary arterial pressure (mPAP), and SUVRV/LV were significantly associated with time to CEP in univariate Cox analysis., Conclusions: The sTWEAK and IL-6 concentrations in PAH patients are linked with metabolic and functional changes of RV visualized in PET/MRI, and both sTWEAK and IL-6 predict clinical deterioration.

Competing Interests: The authors declare no conflict of interest.

Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-β-CD) with various molecular weights (M w ) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-β-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-β-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (E cr ) in ASDs with the oligosaccharide having a greater M w (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs' core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-β-CD. Therefore, this modified saccharide is a better stabilizer of the examined API., (Copyright © 2022. Published by Elsevier B.V.)

In this paper, thermal properties, atomic-scale structure, and molecular dynamics (at ambient and high pressure) of native melatonin (MLT) and its partially-deuterated derivative (MLT-d 2 ) have been investigated. Based on infrared spectroscopy, it was shown that treating MLT with D 2 O causes the replacement of hydrogen atoms attached to the nitrogen by deuterium. The degree of such substitution was very high (> 99%) and the deuterated sample remained stable after exposure to the air as well as during the melting and vitrification processes. Further calorimetric studies revealed the appearance of a peculiar thermal event before the melting of crystalline MLT-d 2 , which was assigned by the X-ray diffraction to a local negative thermal expansion of the unit cell. Finally, the high-pressure dielectric experiments indicated a few interesting findings, including the variation in the shape of the structural relaxation peak during compression, the difference in the pressure evolution of the glass transition temperature, and the temperature dependence of activation volume for both MLT species. The variations in these parameters manifest a different impact of the compression/densification on the dynamics of hydrogen and deuterium bonds in the native and partially-deuterated MLT, respectively., (© 2022. The Author(s).)

Introduction: Clinically overt depression is associated with an increased risk for insulin resistance. Data regarding the impact of subclinical depressive symptoms on the risk of diabetes are limited., Objectives: The study aimed to assess the relationship of subclinical depressive symptoms with body fat distribution and diabetes risk in women., Patients and Methods: The analysis included 250 women, 68 with subclinical depressive symptoms and 182 controls. A clinical examination, oral glucose tolerance test, and lipid and liver enzyme level assessments were performed. Body composition was estimated by dual‑energy X‑ray absorptiometry. The participants completed the Beck Depression Inventory (BDI) questionnaire., Results: The women with subclinical depressive symptoms had higher visceral adipose tissue (VAT) mass than the control group. The groups did not differ in the body mass index, waist circumference, total fat, fat‑free, android, and gynoid fat mass. Homeostatic Model Assessment for Insulin Resistance (HOMA‑IR) and alanine aminotransferase (ALT) activity were higher in the women with subclinical depressive symptoms than in the control group. In the women with subclinical depressive symptoms, we observed a positive correlation between the severity of somatic‑vegetative symptoms reported in the BDI and VAT mass, HOMA‑IR, and gamma glutamyltransferase (GGT) activity. Dysglycemia occurred more frequently in the women with subclinical depressive symptoms. In a subgroup analysis of postmenopausal women, the individuals with subclinical depressive symptoms had higher HOMA‑IR, GGT, ALT, and triglyceride / high‑density lipoprotein cholesterol ratios than the control group., Conclusions: Subclinical depressive symptoms in women might predispose to dysglycemia.

In this study, several experimental techniques were applied to probe thermal properties, molecular dynamics, crystallization kinetics and intermolecular interactions in binary mixtures (BMs) composed of flutamide (FL) and various poly( N -vinylpyrrolidone) (PVP) polymers, including a commercial product and, importantly, samples obtained from high-pressure syntheses, which differ in microstructure (defined by the tacticity of the macromolecule) from the commercial PVP. Differential Scanning Calorimetry (DSC) studies revealed a particularly large difference between the glass transition temperature ( T g ) of FL+PVPsynth. mixtures with 10 and 30 wt% of the excipient. In the case of the FL+PVPcomm. system, this effect was significantly lower. Such unexpected findings for the former mixtures were strictly connected to the variation of the microstructure of the polymer. Moreover, combined DSC and dielectric measurements showed that the onset of FL crystallization is significantly suppressed in the BM composed of the synthesized polymers. Further non-isothermal DSC investigations carried out on various FL+10 wt% PVP mixtures revealed a slowing down of FL crystallization in all FL-based systems (the best inhibitor of this process was PVP M n = 190 kg/mol). Our research indicated a significant contribution of the microstructure of the polymer on the physical stability of the pharmaceutical-an issue completely overlooked in the literature.

We study the molecular origin of a prepeak (PP) observed at low q values in the structure factors of three oligomers in a bulk (poly(mercaptopropyl)methylsiloxane, PMMS, poly(methylmercaptopropyl)- grafted -hexylmethacrylate, PMMS- g -HMA, and poly(methylphenyl)siloxane, PMPS) in order to understand the lowering of the PP intensity detected for oligomers confined in cylindrical pores with low diameter. For this purpose, we use a combination of X-ray diffraction measurements and coarse-grained bead-spring molecular dynamics simulations. Our molecular modelling demonstrated that the planarity of the pendant groups triggers the self-association of oligomers into nanoaggregates. However, the formation of oligomeric nanodomains is not sufficient for building-up the PP. The latter requires spatial disturbance in the arrangement of the side groups of oligomers within clusters. Importantly, our numerical analysis revealed that the increasing degree of the confinement of oligomers limits their aggregation and consequently lowers the amplitude of the PP observed in the experimental data.

Atherosclerosis remains the leading cause of cardiovascular diseases and represents a primary public health challenge. This chronic state may lead to a number of life-threatening conditions, such as myocardial infarction and stroke. Lipid metabolism alterations and inflammation remain at the forefront of the pathogenesis of atherosclerotic cardiovascular disease, but the overall mechanism is not yet fully understood. Recently, significant effects of trained immunity on atherosclerotic plaque formation and development have been reported. An increased reaction to restimulation with the same stimulator is a hallmark of the trained innate immune response. The impact of trained immunity is a prominent factor in both acute and chronic coronary syndrome, which we outline in this review.

In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, KA-104 , that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds 53 and 60 displayed the following pharmacological profile: ED 50 = 89.7 mg/kg (MES), ED 50 = 29.9 mg/kg (6 Hz, 32 mA), ED 50 = 68.0 mg/kg (6 Hz, 44 mA), and ED 50 = 73.6 mg/kg (MES), ED 50 = 24.6 mg/kg (6 Hz, 32 mA), and ED 50 = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, 53 and 60 were effective in the iv PTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for 53 and 60 . These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for 53 and 60 (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, 53 and 60 seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel.

The aim of our study was to evaluate the importance of insulin-like growth-factor-binding protein 7 (IGFBP-7) as a potential marker of symptomatic peripheral artery disease (PAD) occurrence. The study group consisted of 145 patients with diagnosed PAD, who qualified for the invasive treatment. The control group consisted of 67 individuals representing the local population and an ischemic heart disease (IHD) group of 88 patients after myocardial infarction or percutaneous coronary intervention. Patients with PAD had significantly higher IGFBP-7 concentrations than control group (1.80 ± 1.62 vs. 1.41 ± 0.45 ng/mL, p = 0.04). No significant differences between PAD patients and IHD patients were found (1.80 ± 1.62 vs. 1.76 ± 1.04 ng/mL, p = 0.783). Patients with multilevel PAD presented significantly higher IGFBP-7 concentrations than patients with aortoiliac PAD-median 1.18 (IQR 0.48-2.23) vs. 1.42 ng/mL (0.71-2.63), p = 0.035. In the group of patients who died or had a major adverse cardiovascular event (MACE) during six months of follow-up, a statistically significant higher IGFBP-7 concentration was found (median 2.66 (IQR 1.80-4.93) vs. 1.36 ng/mL (IQR 0.65-2.34), p = 0.004). It seems that IGFBP-7 is elevated in patients with atherosclerotic lesions-regardless of their locations. Further research should be conducted to verify IGFBP-7 usefulness as a predictor of MACE or death.

We show the remarkable effect of using static (DC) and alternating (AC) electric fields to control the free-radical polymerization of methyl methacrylate (MMA). The magnitude and/or frequency of the applied electric field (up to 154 kV cm -1 ) were found to control the molecular weight, dispersity, and stereochemistry of the produced polymers.

Our goal was to assess the anti-SARS-CoV-2 antibodies presence in COVID-19 convalescents and assess the differences in anti-SARS-CoV-2 antibodies production regarding the disease severity, sex, vaccination, and assess the correlation between anti-SARS-CoV-2 antibodies production and inflammatory parameters. Three hundred twenty-two COVID-19 patients (282 hospitalized and 40 patients with oligosymptomatic COVID-19 isolated at homes) were included in the study. Blood was taken at 4 time points: during hospitalization, 1 month, 3 months, and 6 months. Detection of SARS-CoV-2 antibodies was performed with LIAISON SARS-CoV-2 S1/S2 IgG tests (DiaSorin, Italy). Clinical and laboratory parameters were compared. Significant differences between higher anti-SARS-CoV-2 antibodies titer in symptomatic patients 3 months after infection (III sample) and significantly higher ratio II/I in symptomatic patients were observed. Subgroup analysis based on sex showed differences only in laboratory tests, not in serological. Analysis of the results of serological tests showed significant differences in ratio IV/I and a significant increase in antibodies level after vaccination. The most significant rise was observed between the 3rd and 6th month when the patients received a vaccination. Immunological response after COVID-19 infection lasted over 6 months in all patients, although antibodies titers were significantly higher in patients with a history of severe COVID-19 and vaccinated patients. Immunological response after COVID-19 infection did not depend on sex. There was a significant correlation between anti-SARS-CoV-2 antibodies production and the degree of inflammation in the acute phase of the disease (inflammatory parameters in blood and severity of lung affection in CT). IMPORTANCE The results of our study confirm the knowledge on immune response in the Polish population and add new information regarding correlations with the severity of the disease. The data in the literature concerning the correlation between antibodies response and sex are ambiguous, and we did not observe differences between antibodies production and gender, which also adds new information.

Background: Insulin resistance is a risk factor for cardiovascular disease. Recently, we have developed a novel index, FLAIS (Fasting Laboratory Assessment of Insulin Sensitivity), which accurately reflects insulin sensitivity, measured with hyperinsulinemic-euglycemic clamp, in different groups of subjects. The aim of the present study was to assess the relationship of FLAIS with cardiovascular risk factors in a population-based study., Methods: The study group comprised 339 individuals from the ongoing Białystok Plus study, without previously known diabetes. Clinical examination, oral glucose tolerance test and the measurement of blood laboratory parameters were performed., Results: Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) was diagnosed in 165 individuals whereas type 2 diabetes was diagnosed in 19 subjects. FLAIS was lower in individuals with prediabetes and diabetes in comparison with individuals with normal glucose tolerance. FLAIS was significantly related to waist circumference, systolic and diastolic blood pressure, triglycerides, HDL-cholesterol and LDL-cholesterol in the entire study group and in the subgroups with normal glucose tolerance and with prediabetes/diabetes. HOMA-IR, QUICKI and Matsuda index were not related to blood pressure and LDL-cholesterol in individuals with normal glucose tolerance. Majority of the adjusted models with FLAIS were characterized by better fit with the data in comparison with other indices for all cardiovascular risk factors except waist circumference., Conclusions: FLAIS represents useful index to assess the cluster of insulin resistance-associated cardiovascular risk factors in general population., (© 2022. The Author(s).)

The routine monitoring of direct oral anticoagulants (DOACs) may be considered in patients with renal impairment, patients who are heavily obese, or patients requiring elective surgery. Using the heparin-binding copolymer (HBC) and polybrene, we aimed to develop a solution for monitoring the anticoagulant activity of DOACs in human plasma in the interfering presence of unfractionated heparin (UFH) and enoxaparin. The thrombin time (TT) and anti-factor Xa activity were monitored in pooled plasma from healthy volunteers. In these tests, plasma with dabigatran or rivaroxaban was mixed with UFH or enoxaparin and then incubated with HBC or polybrene, respectively. HBC and polybrene neutralized heparins and enabled monitoring of anticoagulant activity of dabigatran in the TT test. Both agents allowed for accurate measurement of anti-factor Xa activity in the plasma containing rivaroxaban and heparins in the concentration range reached in patients' blood. Here, we present diagnostic tools that may improve the control of anticoagulation by eliminating the contamination of blood samples with heparins and enabling the monitoring of DOACs' activity.

Antiseizure drugs (ASDs) are commonly used to treat a wide range of nonepileptic conditions, including pain. In this context, the analgesic effect of four pyrrolidine-2,5-dione derivatives (compounds 3 , 4 , 6 , and 9 ), with previously confirmed anticonvulsant and preliminary antinociceptive activity, was assessed in established pain models. Consequently, antinociceptive activity was examined in a mouse model of tonic pain (the formalin test). In turn, antiallodynic and antihyperalgesic activity were examined in the oxaliplatin-induced model of peripheral neuropathy as well as in the streptozotocin-induced model of painful diabetic neuropathy in mice. In order to assess potential sedative properties (drug safety evaluation), the influence on locomotor activity was also investigated. As a result, three compounds, namely 3 , 6 , and 9 , demonstrated a significant antinociceptive effect in the formalin-induced model of tonic pain. Furthermore, these substances also revealed antiallodynic properties in the model of oxaliplatin-induced peripheral neuropathy, while compound 3 attenuated tactile allodynia in the model of diabetic streptozotocin-induced peripheral neuropathy. Apart from favorable analgesic properties, the most active compound 3 did not induce any sedative effects at the active dose of 30 mg/kg after intraperitoneal ( i.p. ) injection.

Introduction: Adherence to health‑promoting behaviors intended to mitigate modifiable risk factors plays an important role in secondary cardiovascular prevention., Objectives: We aimed to evaluate sex differences in the prevalence and control of risk factors in patients with coronary heart disease (CHD)., Patients and Methods: The study included 1236 patients who experienced acute coronary syndrome or coronary revascularization within the last 6 to 24 months. Definitions of risk factors and treatment goals were based on the 2016 European Society of Cardiology guidelines on cardiovascular prevention., Results: The prevalence of modifiable risk factors in both sexes was high, and their control inadequate. Women were older (P <0.001) and had a higher accumulation of multiple cardiovascular risk factors than men (P = 0.036). They more frequently had central obesity (P <0.001) and reduced values of glomerular filtration rate (P <0.001). Women more often experienced anxiety (P <0.001), reported lower levels of education (P <0.001) and lower income (P = 0.001), and those in the youngest age group were more likely to be exposed to second‑hand smoking (P = 0.01). A large fraction of the study patients, men and women alike, did not meet the recommended therapeutic goals. For both sexes, participation in cardiac rehabilitation programs was associated with more frequent attainment of the recommended level of physical activity (P = 0.046) and smoking cessation (P = 0.01)., Conclusions: The prevalence of cardiovascular risk factors in patients with CHD is high, especially in women. Therapeutic goals are met infrequently in both sexes. This situation calls for widening the access to educational programs and paying greater attention to their proper implementation.

Mucopolysaccharidosis, type IIIB (MPS IIIB) is a rare disease caused by mutations in the N-alpha-acetylglucosaminidase ( NAGLU ) gene resulting in decreased or absent enzyme activity. On the cellular level, the disorder is characterized by the massive lysosomal storage of heparan sulfate (HS)-one species of glycosaminoglycans. HS is a sulfur-rich macromolecule, and its accumulation should affect the turnover of total sulfur in cells; according to the studies presented here, it, indeed, does. The lysosomal degradation of HS in cells produces monosaccharides and inorganic sulfate (SO 4 2- ). Sulfate is a product of L-cysteine metabolism, and any disruption of its levels affects the entire L-cysteine catabolism pathway, which was first reported in 2019. It is known that L-cysteine level is elevated in cells with the Naglu -/- gene mutation and in selected tissues of individuals with MPS IIIB. The level of glutathione and the Naglu -/- cells' antioxidant potential are significantly reduced, as well as the activity of 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2) and the level of sulfane sulfur-containing compounds. The direct reason is not yet known. This paper attempts to identify some of cause-and-effect correlations that may lead to this condition and identifies research directions that should be explored.

Background: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed., Methods: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others., Results: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive., Limitations: . Cross-sectional survey, preponderance of non-representative participants., Conclusions: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics., (Copyright © 2021. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial., Methods: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life., Results: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries., Limitations: Cross-sectional and anonymous design., Conclusions: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The objective of this study was to determine the associations between insulin-like growth-factor-binding protein 7(IGFBP7) concentrations and concentrations of troponin T(TnT), N-terminal pro-B-type natriuretic peptide(NT-proBNP) and the parameters of kidney function in patients with stable ischemic heart disease(IHD). The IHD group consisted of 88 patients, and the population group comprised 66 subjects without a history of IHD. IGFBP7, TnT and NTproBNP concentrations were measured. The IGFBP7 value was considerably higher in the IHD group (1.76 ± 1 ng/mL vs. 1.43 ± 0.44 ng/mL, respectively, p = 0.019). Additionally, IHD subjects had a significantly higher concentration of TnT and NTproBNP. In both groups there was a significant correlation between IGFBP7 and serum parameters of kidney function (creatinine concentration: population gr. r = 0.45, p < 0.001, IHD gr. r = 0.86, p < 0.0001; urea concentration: population gr. r = 0.51, p < 0.0001, IHD gr. r = 0.71, p < 0.00001). No correlation between IGFBP7 and microalbuminuria or the albumin to creatinine ratio in urine was found. Moreover, there was a significant correlation between IGFBP7 concentration and markers of heart injury/overload-TnT and NT-BNP(r = 0.76, p < 0.001 and r = 0.72, p < 0.001, respectively). Multivariate regression analysis in joint both revealed that the IGFBP7 concentration is independently associated with urea, creatinine and TnT concentrations (R 2 for the model 0.76). IHD patients presented significantly higher IGFBP7 concentrations than the population group. Elevated IGFBP7 levels are associated predominantly with markers of kidney function and myocardial damage or overload.

A series of anionic homopolymers, poly(sodium 2-(acrylamido)-2-methyl-1-propanesulfonate) (PAMPS) and amphiphilic copolymers of AMPS and sodium 11-(acrylamido)undecanoate (AaU), both block (PAMPS 75 -b-PAaU n ), and random (P(AMPS m -co-AaU n )), were synthesized and their antiviral activity against Zika virus (ZIKV) was evaluated. Interestingly, while the homopolymers showed limited antiviral activity, the copolymers are very efficient antivirals. This observation was explained considering that under the conditions relevant to the biological experiments (pH 7.4 PBS buffer) the macromolecules of these copolymers exist as negatively charged (zeta potential about -25 mV) nanoparticles (4-12 nm) due to their self-organization. They inhibit the ZIKV replication cycle by binding to the cell surface and thereby blocking virus attachment to host cells. Considering good solubility in aqueous media, low toxicity, and high selectivity index (SI) of the PAMPS-b-PAaU copolymers, they can be considered promising agents against ZIKV infections.

The Rossmann fold enzymes are involved in essential biochemical pathways such as nucleotide and amino acid metabolism. Their functioning relies on interaction with cofactors, small nucleoside-based compounds specifically recognized by a conserved βαβ motif shared by all Rossmann fold proteins. While Rossmann methyltransferases recognize only a single cofactor type, the S-adenosylmethionine, the oxidoreductases, depending on the family, bind nicotinamide (nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate) or flavin-based (flavin adenine dinucleotide) cofactors. In this study, we showed that despite its short length, the βαβ motif unambiguously defines the specificity towards the cofactor. Following this observation, we trained two complementary deep learning models for the prediction of the cofactor specificity based on the sequence and structural features of the βαβ motif. A benchmark on two independent test sets, one containing βαβ motifs bearing no resemblance to those of the training set, and the other comprising 38 experimentally confirmed cases of rational design of the cofactor specificity, revealed the nearly perfect performance of the two methods. The Rossmann-toolbox protocols can be accessed via the webserver at https://lbs.cent.uw.edu.pl/rossmann-toolbox and are available as a Python package at https://github.com/labstructbioinf/rossmann-toolbox., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature ( T g ), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism (APE). Both pharmacological and invasive treatments for CTEPH are available in Poland, and awareness of the disease among physicians is growing. It has been suggested that the COVID-19 pandemic may increase the incidence of CTEPH and facilitate disease detection during more advanced stages of the illness. Thus, the Polish Cardiac Society's Working Group on Pulmonary Circulation, in cooperation with independent experts in this field, launched the updated statement on the algorithm to guide a CTEPH diagnosis in patients with previous APE. CTEPH should be suspected in individuals after APE with dyspnea, despite at least 3 months of effective anticoagulation, particularly when specific risk factors are present. Echocardiography is the main screening tool for CTEPH. A diagnostic workup of patients with significant clinical suspicion of CTEPH and right ventricular overload evident on echocardiography should be performed in reference centers. Pulmonary scintigraphy is a safe and highly sensitive screening test for CTEPH. Computed tomography pulmonary angiography with precise detection of thromboembolic residues in the pulmonary circulation is important for the planning of a pulmonary thromboendarterectomy. Right heart catheterization definitively confirms the presence of pulmonary hypertension and direct pulmonary angiography allows for the identification of lesions suitable for thromboendarterectomy or balloon pulmonary angioplasty. In this document, we propose a diagnostic algorithm for patients with suspected CTEPH. With an individualized and sequential diagnostic strategy, each patient can be provided with suitable and tailored therapy provided by a dedicated CTEPH Heart Team.

Melanoma is the most aggressive skin cancer, with a growing number of incidents worldwide and with no effective cure in a metastatic stage so far. There are several pathways and processes engaged in melanoma pathogenesis that have been extensively explored in recent years. The emerging evidence suggests that oxidative stress (OS) is highly involved in melanin synthesis and melanoma formation. Melanoma is particularly susceptible to OS due to the involvement of melanin synthesis and UV radiation in the generation of reactive oxygen species. Oxidative stress influences melanoma immunity, the metastatic potential of melanoma cells and their resistance to therapy. In malignant melanocytes, the process of melanogenesis is frequently upregulated, suggesting possible therapeutic targets. This review describes the role of OS in melanin synthesis in melanocytes and explains how it affects melanoma cells. Better knowledge about the mechanisms involved in cancer progression may result in the development of better treatment strategies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Termedia.)

We report herein a series of water-soluble analogues of previously described anticonvulsants and their detailed in vivo and in vitro characterization. The majority of these compounds demonstrated broad-spectrum anticonvulsant properties in animal seizure models, including the maximal electroshock (MES) test, the pentylenetetrazole-induced seizure model ( sc PTZ), and the psychomotor 6 Hz (32 mA) seizure model in mice. Compound 14 showed the most robust anticonvulsant activity (ED 50 MES = 49.6 mg/kg, ED 50 6 Hz (32 mA) = 31.3 mg/kg, ED 50 sc PTZ = 67.4 mg/kg). Notably, it was also effective in the 6 Hz (44 mA) model of drug-resistant epilepsy (ED 50 = 63.2 mg/kg). Apart from favorable anticonvulsant properties, compound 14 revealed a high efficacy against pain responses in the formalin-induced tonic pain, the capsaicin-induced neurogenic pain, as well as in the oxaliplatin-induced neuropathic pain in mice. Moreover, compound 14 showed distinct anti-inflammatory activity in the model of carrageenan-induced aseptic inflammation. The mechanism of action of compound 14 is likely complex and may result from the inhibition of peripheral and central sodium and calcium currents, as well as the TRPV1 receptor antagonism as observed in the in vitro studies. This lead compound also revealed beneficial in vitro ADME-Tox properties and an in vivo pharmacokinetic profile, making it a potential candidate for future preclinical development. Interestingly, the in vitro studies also showed a favorable induction effect of compound 14 on the viability of neuroblastoma SH-SY5Y cells.

In this study, we report the acid-catalyzed and high pressure assisted ring-opening polymerization (ROP) of γ-butyrolactone (GBL). The use of a dually-catalyzed approach combining an external physical factor and internal catalyst (trifluoromethanesulfonic acid (TfOH) or p -toluenesulfonic acid (PTSA)) enforced ROP of GBL, which is considered as hardly polymerizable monomer still remaining a challenge for the modern polymer chemistry. The experiments performed at various thermodynamic conditions ( T = 278-323 K and p = 700-1500 MPa) clearly showed that the high pressure supported polymerization process led to obtaining well-defined macromolecules of better parameters ( M n = 2200-9700 g mol -1 ; Đ = 1.05-1.46) than those previously reported. Furthermore, the parabolic-like dependence of both the molecular weight ( M W ) and the yield of obtained polymers on variation in temperature and pressure at either isobaric or isothermal conditions was also noticed, allowing the determination of optimal conditions for the polymerization process. However, most importantly, this strategy allowed to significantly reduce the reaction time (just 3 h at room temperature) and increase the yield of obtained polymers (up to 0.62 g PGBL /g GBL ). Moreover, despite using a strongly acidic catalyst, synthesized polymers remained non-toxic and biocompatible, as proven by the cytotoxicity test we performed in further analysis. Additional investigation (including MALDI-TOF measurements) showed that the catalyst selection affected not only M W and yield but also the linear/cyclic form content in obtained macromolecules. These findings show the way to tune the properties of PGBL and obtain polymer suitable for application in the biomedical industry., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)

Novel multifunctional biomimetic injectable hybrid systems were synthesized. The physicochemical as well as biological in vitro and in vivo tests demonstrated that they are promising candidates for bone tissue regeneration. The hybrids are composed of a biopolymeric collagen/chitosan/hyaluronic acid matrix and amine group-functionalized silica particles decorated with apatite to which the alendronate molecules were coordinated. The components of these systems were integrated and stabilized by cross-linking with genipin, a compound of natural origin. They can be precisely injected into the diseased tissue in the form of a viscous sol or a partially cross-linked hydrogel, where they can serve as scaffolds for locally controlled bone tissue regeneration/remodeling by supporting the osteoblast formation/proliferation and maintaining the optimal osteoclast level. These materials lack systemic toxicity. They can be particularly useful for the repair of small osteoporotic bone defects.

In this paper, the molecular dynamics as well as inter- and intramolecular interactions in the homogenous solid dispersions (SDs) of active pharmaceutical ingredient - probucol (PRO) with acetylated glucose (acGLU), acetylated sucrose (acSUC), and sucrose acetoisobutyrate (aibSUC), prepared in 5:1 molar ratio, have been investigated using broadband dielectric (BD) and Fourier transform infrared (FTIR) spectroscopy. Importantly, high pressure dielectric measurements revealed that as for neat PRO, a breakdown of the isochronal structural (α) and JG-β exact superpositioning, due to increasing separation between both processes under compression, can also be detected in its mixtures with acetylated saccharides (acSACCHs). Furthermore, the analysis of temperature dependences of JG-β-relaxation times for PRO and PRO-acSACCH SDs at selected isobaric conditions indicated the increase in the cooperativity of the secondary process (reflected in the value of the activation entropy, ΔS β ) at elevated pressure in all systems. The mere addition of the small amount of excipient to neat PRO (p = 0.1 MPa) resulted in a greater value of ΔS β (it was the most noticeable in the case of aibSUC). Further FTIR studies carried out on the pressure densified glasses of PRO, and binary mixtures suggested that the observed changes in the cooperativity of the JG-β-process, as well as the failure of the exact isochronal superpositioning of α- and JG-β relaxation times, are due to varying H-bond pattern in the examined single- and two-component systems at high compression/in the presence of saccharide., (Copyright © 2021. Published by Elsevier B.V.)

Lipid-lowering in patients with coronary artery disease (CAD) is related to a lower risk of cardiovascular events. We evaluated factors related to the management of hypercholesterolemia in patients with established CAD. Patients were interviewed 6-18 months after hospitalization for an acute coronary syndrome (ACS) or a myocardial revascularization procedure. Statins were prescribed at discharge to 94.4% of patients, while 68.1% of the patients hospitalized for an ACS were prescribed a high-dose statin. Hospitalization in a teaching hospital, percutaneous coronary intervention, cholesterol measurement during hospitalization and the male sex were related to prescription of statins at discharge. The intensity of lipid-lowering therapy in the post-discharge period increased in 17.3%, decreased in 11.7%, and did not change in 71.0% of the patients. The prescription of a lipid-lowering drug (LLD) at discharge (odds ratio 5.88 [95% confidence intervals 3.05-11.34]) and a consultation with a cardiologist (2.48 [1.51-4.08]) were related to the use of LLDs, while age (1.32 [1.10-1.59] per 10 years), loneliness (0.42 [0.19-0.94]), professional activity (1.56 [1.13-2.16]), and diabetes (1.66 [1.27-2.16]) were related to achieving an LDL cholesterol goal 6-18 months after discharge. In conclusion, health-system-related factors are associated with the LLD utilization, whereas mainly patient-related factors are related to the control of hypercholesterolemia following hospitalization for CAD.

Since the declaration of the SARS-CoV-2 pandemic confirmed by World Health Organization, work on the development of vaccines has been stimulated. When vaccines are commonly available, a major problem is persistent vaccine hesitancy in many European countries. The main goal of our study was to understand the multidimensional factors inducing this phenomenon in Poland. Our study was carried out at the third wave's peak of the pandemic, with record rates of daily cases and deaths associated with COVID-19. The results indicate that vaccine hesitancy/acceptability should always be considered in an interdisciplinary manner and according to identified factors where most negative attitudes could be altered. Our analyses included the assessment of a representative quota sample of adult Poles ( N = 1000). The vaccine hesitancy in the studied group reached 49.2%. We performed stepwise logistic regression modeling to analyze variables set into six trajectories (groups) predicting the willingness to vaccinate. Apart from typical, socio-demographic and economic determinants, we identified the fear of vaccines' side effects, beliefs in conspiracy theories and physical fitness. We were also able to establish the order of importance of factors used in a full model of all impact trajectories.

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM ( p < 0.001) and VPA ( p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED 50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber's rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are garlic oil compounds exhibiting beneficial healthy properties including anticancer action. However, these compounds are sparingly water-soluble with a limited stability that may imply damage to blood vessels or cells after administration. Thus, their encapsulation in the oil-core nanocapsules based on a derivative of hyaluronic acid was investigated here as a way of protecting against oxidation and undesired interactions with blood and digestive track components. The nuclear magnetic resonance ( 1 H NMR) technique was used to follow the oxidation processes. It was proved that the shell of the capsule acts as a barrier limiting the sulfur oxidation, enhancing the stability of C=C bonds in DADS and DATS. Moreover, it was shown that the encapsulation inhibited the lysis of the red blood cell membrane (mainly for DADS) and interactions with serum or digestive track components. Importantly, the biological functions and anticancer activity of DADS and DATS were preserved after encapsulation. Additionally, the nanocapsule formulations affected the migration of neoplastic cells-a desirable preliminary observation concerning the inhibition of migration. The proposed route of administration of these garlic extract components would enable reaching their higher concentrations in blood, longer circulation in a bloodstream, and thus, imply a better therapeutic effect.

The aim of this study was to design and synthesize two new series of pyrrolidine-2,5-dione-acetamides with a benzhydryl or sec-butyl group at position 3 as potential anticonvulsants. Their anticonvulsant activity was evaluated in standard animal models of epilepsy: the maximal electroshock (MES), the 6 Hz, and the subcutaneous pentylenetetrazole (scPTZ) tests. The in vivo studies revealed the most potent anticonvulsant activity for 15 (3-(sec-butyl)-1-(2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione), with ED 50 values of 80.38 mg/kg (MES) and 108.80 mg/kg (6 Hz). The plausible mechanism of action was assessed in in vitro binding assays, in which 15 interacted effectively with voltage-gated sodium (site 2) and L-type calcium channels at a concentration of 100 μM. Subsequently, the antinociceptive activity of compounds 7 and 15 was observed in the hot plate test of acute pain. Moreover, compounds 7, 11 and 15 demonstrated an analgesic effect in the formalin test of tonic pain. The hepatotoxic properties of the most effective compounds (7, 11 and 15) in HepG2 cells were also investigated., (© 2021 Wiley-VCH GmbH.)

Dysglycemia is a public health challenge for the coming decades, especially in patients with chronic coronary syndromes (CCS). We want to assess the prevalence of undiagnosed diabetes mellitus (DM) and prediabetes, as well as identify factors associated with the development of dysglycaemia in patients with CCS. In total, 1233 study participants (mean age 69 ± 9 years), who, between 6 and 18 months earlier were hospitalized for acute coronary syndrome or elective revascularization, were examined (71.4% men). The diagnosis of DM, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) have been made according to World Health Organization (WHO) criteria. Based on the oral glucose tolerance test (OGTT) results, DM has been newly diagnosed in 28 (5.1%, mean age 69.9 ± 8.4 years) patients, 75% were male ( n = 21). Prediabetes has been observed in 395 (72.3%) cases. IFG was found in 234 (42.9%) subjects, 161 (29.5%) individuals had IGT. According to multinomial logistic regression, body mass index (BMI) and high-density lipoprotein cholesterol (HDL-C) should be considered when assessing risk of development of dysglycaemia after discharge from the hospital. Among people with previously diagnosed DM, a significantly higher percentage were willing to change their lifestyles after the index event compared to other patients. Patients with chronic coronary syndromes suffer a very high frequency of dysglycaemia. Most patients with chronic coronary syndromes, especially those with high BMI or low HDL-C, should be considered for screening for dysglycemia using OGTT within the first year after hospitalization. A higher percentage of patients who were aware of their diabetic status changed their lifestyles, which added the benefit of timely diagnosis and treatment of diabetes.

Background: Smoking cessation in patients with coronary artery disease (CAD) is related to decreased risk of cardiovascular events., Aims: To evaluate factors related to persistent smoking in patients with established coronary artery disease., Methods: Patients aged 80 years or younger and hospitalized for acute coronary syndrome or a myocardial revascularization procedure were interviewed 6 to 18 months after the recruiting event. Medical history, smoking behavior, and exposure to environmental smoke were assessed during the interview. Self--reported smoking status was validated by carbon monoxide in exhaled air measurement. Persistent smoking was defined as smoking at the time of interview among those who smoked during the month prior to the recruiting event., Results: We analyzed the data of 1034 patients, including 764 (73.9%) who reported smoking at any time in the past and 296 (28.6%) who smoked within 1 month before the recruiting hospitalization. At the time of the interview, the overall smoking rate was 17.2%, whereas 54.7% of patients were persistent smokers. Secondhand smoke exposure and duration of smoking were associated with lower likelihood whereas older age, high socioeconomic status, cardiac rehabilitation following a cardiovascular event, and consultation with a cardiologist were associated with higher likelihood of smoking cessation., Conclusions: Over half of all smokers hospitalized for CAD are still smoking 6 to 18 months after discharge. Older age, secondhand smoking, low socioeconomic status, lack of consultation with a cardiologist, and cardiac rehabilitation following hospitalization were related to persistent smoking. Our findings may help develop strategies aimed at assisting smoking cessation in patients with CAD.

In the current studies we carried out an optimized multistep asymmetric synthesis of R-enantiomers (eutomers) for a previously identified series of racemic hybrid anticonvulsants. The spatial structure of selected enantiomers was solved by the use of crystallographic methods. The compound (R)-16 was identified as a lead, which revealed broad-spectrum protective activity in a range of epilepsy models with the following ED 50 values: the maximal electroshock (MES) test (36.0 mg/kg), the 6 Hz (32 mA) seizure model (39.2 mg/kg), and the pentylenetetrazole-induced seizure model (scPTZ) (54.8 mg/kg). Furthermore, (R)-16 displayed a low potency for the induction of motor impairment in the rotarod test (TD 50  = 468.5 mg/kg), resulting in potentially very beneficial therapeutic window. Finally, (R)-16 showed satisfying ADME-Tox properties in the in vitro assays. Therefore, the data obtained in the current studies justify the further preclinical development of (R)-16 as candidate for potentially broad-spectrum and safe anticonvulsant., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Significant achievements in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) have provided effective therapeutic options for most patients. However, the true impact of the changed landscape of CTEPH therapies on patients' management and outcomes is poorly known. We aimed to characterize the incidence, clinical characteristics, and outcomes of CTEPH patients in the modern era of CTEPH therapies., Methods: We analyzed the data of CTEPH adults enrolled in the prospective multicenter registry., Results: We enrolled 516 patients aged 63.8 ± 15.4 years. The incidence rate of CTEPH was 3.96 per million adults per year. The group was burdened with several comorbidities. New oral anticoagulants ( n  = 301; 58.3%) were preferred over vitamin K antagonists ( n  = 159; 30.8%). Pulmonary endarterectomy (PEA) was performed in 120 (23.3%) patients and balloon pulmonary angioplasty (BPA) in 258 (50%) patients. PEA was pretreated with targeted pharmacotherapy in 19 (15.8%) patients, and BPA in 124 (48.1%) patients. Persistent CTEPH was present in 46% of PEA patients and in 65% of patients after completion of BPA. Persistent CTEPH after PEA was treated with targeted pharmacotherapy in 72% and with BPA in 27.7% of patients. At a mean time period of 14.3 ± 5.8 months, 26 patients had died. The use of PEA or BPA was associated with better survival than the use of solely medical treatment., Conclusions: The modern population of CTEPH patients comprises mostly elderly people significantly burdened with comorbid conditions. This calls for treatment decisions that are tailored individually for every patient. The combination of two or three methods is currently a frequent approach in the treatment of CTEPH., Clinical Trial Registration: clinicaltrials.gov/ct2/show/NCT03959748., Competing Interests: Conflict of interest statement: Grzegorz Kopeć reports grants and personal fees from Actelion Pharma, personal fees from Janssen-Cilag Polska, personal fees from AOP Orphan, personal fees from MSD. Olga Dzikowska-Diduch has nothing to declare. Ewa Mroczek has nothing to declare. Tatiana Mularek-Kubzdela reports fees for lectures from MSD, Bayer, Jansen, AOP Orphan, Beringher, Pfizer, grants from MSD, Bayer, Jansen, AOP Orphan, Beringher. Łukasz Chrzanowski reports fees for lectures from MSD, non-financial support from MSD. Ilona Skoczylas has nothing to declare. Michał Tomaszewski has nothing to declare. Małgorzata Peregud-Pogorzelska has nothing to declare. Danuta Karasek has nothing to declare. Ewa Lewicka reports fees for lectures from Bayer, MSD, AOP Orphan, Janssen-Cilag, Pfizer and Boehringer-Ingelheim. Wojciech Jacheć has nothing to declare. Zbigniew Gąsior has nothing to declare. Piotr Błaszczak has nothing to declare. Katarzyna Ptaszyńska-Kopczyńska has nothing to declare. Katarzyna Mizia-Stec has nothing to declare. Andrzej Biederman has nothing to declare. Dariusz Zieliński has nothing to declare. Roman Przybylski has nothing to declare. Piotr Kędzierski has nothing to declare. Marcin Waligóra has nothing to declare. Marek Roik has nothing to declare. Marek Grabka has nothing to declare. Joanna Orłowska has nothing to declare. Aleksander Araszkiewicz has nothing to declare. Marta Banaszkiewicz has nothing to declare. Sylwia Sławek-Szmyt has nothing to declare. Szymon Darocha reports grants and personal fees from Janssen-Cilag, MSD, Bayer, and AOP Orphan. Wojciech Magoń has nothing to declare. Alicja Dąbrowska-Kugacka reports fees for lectures from MSD, Actelion, AOP Orphan and Bayer. Jakub Stępniewski has nothing to declare. Kamil Jonas has nothing to declare. Karol Kamiński has nothing to declare. Jarosław D. Kasprzak reports fees for lectures from Janssen/Actelion, AOP Orphan. Piotr Podolec reports personal fees from Actelion, personal fees from Jansen, personal fees from AOP ORPHAN, personal fees from Bayer. Piotr Pruszczyk reports fees for lectures from Merck. Adam Torbicki reports grants and personal fees from Actelion Pharma, personal fees from Janssen-Cilag Polska, personal fees from AOP Orphan, personal fees from MSD, grants and personal fees from Bayer Healthcare and the Chairperson of the Foundation on Pulmonary Hypertension. The foundation receives donations including those from industry. The chairmanship is an honorary function and is unrelated to financial or other benefits. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. Marcin Kurzyna reports fees for lectures from MSD, AOP Orphan and Janssen-Cilag., (© The Author(s), 2021.)

The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole ( sc PTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione ( 6 ) showed more beneficial ED 50 and protective index values than the reference drug-valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds-namely, 6 and 19 -was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABA A and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.

Herein, we examined the effect of finite size and wettability on the structural dynamics and the molecular arrangement of the propylene carbonate derivative, (S)-(-)-4-methoxymethyl-1,3-dioxolan-2-one (assigned as s-methoxy-PC), incorporated into alumina and silica porous templates of pore diameters d = 4 nm-10 nm using Raman and broadband dielectric spectroscopy, differential scanning calorimetry, and x-ray diffraction. It was demonstrated that only subtle changes in the molecular organization and short-range order of confined s-methoxy-PC molecules were detected. Yet, a significant deviation of the structural dynamics and depression of the glass transition temperatures, T g , was found for all confined samples with respect to the bulk material. Interestingly, these changes correlate with neither the finite size effects nor the interfacial energy but seem to vary with wettability, generally. Nevertheless, for s-methoxy-PC infiltrated into native (more hydrophilic) and modified (more hydrophobic) silica templates of the same nanochannel size (d = 4 nm), a change in the dynamics and T g was negligible despite a significant variation in wettability. These results indicated that although wettability might be a suitable variable to predict alteration of the structural dynamics and depression of the glass transition temperature, other factors, i.e., surface roughness and the density packing, might also have a strong contribution to the observed confinement effects.

The impact of the chain length or dispersity of polymers in controlling the crystallization of amorphous active pharmaceutical ingredients (APIs) has been discussed for a long time. However, because of the weak control of these parameters in the majority of macromolecules used in pharmaceutical formulations, the abovementioned topic is poorly understood. Herein, four acetylated oligosaccharides, maltose (acMAL), raffinose (acRAF), stachyose (acSTA), and α-cyclodextrin (ac-α-CD) of growing chain lengths and different topologies (linear vs cyclic), mimicking the growing backbone of the polymer, were selected to probe the influence of these structural factors on the crystallization of naproxen (NAP)-an API that does not vitrify regardless of the cooling rate applied in our experiment. It was found that in equimolar systems composed of NAP and linear acetylated oligosaccharides, the progress and activation barrier for crystallization are dependent on the molecular weight of the excipient despite the fact that results of Fourier transform infrared studies indicated that there is no difference in the interaction pattern between measured samples. On the other hand, complementary dielectric, calorimetric, and X-ray diffraction data clearly demonstrated that NAP mixed with ac-α-CD (cyclic saccharide) does not tend to crystallize even in the system with a much higher content of APIs. To explain this interesting finding, we have carried out further density functional theory computations, which revealed that incorporation of NAP into the cavity of ac-α-CD is hardly possible because this state is of much higher energy (up to 80 kJ/mol) with respect to the one where the API is located outside of the saccharide torus. Hence, although at the moment, it is very difficult to explain the much stronger impact of the cyclic saccharide on the suppression of crystallization and enhanced stability of NAP with respect to the linear carbohydrates, our studies clearly showed that the chain length and the topology of the excipient play a significant role in controlling the crystallization of this API.

A focused library of new 3-(3-methyl-2,5-dioxo-3-phenylpyrrolidin-1-yl)propanamides and their nonimide analogs were synthesized and tested for anticonvulsant activity. These compounds were obtained through the coupling reaction of the starting carboxylic acids with appropriate amines. The initial anticonvulsant screening was performed in mice (intraperitoneal administration) using the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models. The most promising compound 6 showed more potent protection in the MES and scPTZ tests than valproic acid, which is still recognized as one of the most relevant first-line anticonvulsants. The structure-activity relationship analysis revealed that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable to retain anticonvulsant activity. Additionally, compound 6 showed potent antinociceptive properties in the oxaliplatin-induced neuropathic pain model in mice. The most plausible mechanism of action for compound 6 may result from its influence on the neuronal sodium channel (Site 2) and the high-voltage-activated L-type calcium channel., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

Dielectric studies under various temperature ( T ) and pressure ( p ) conditions on five active pharmaceutical ingredients (APIs) with antifungal properties-itraconazole (ITZ), posaconazole (POS), terconazole (TER), ketoconazole (KET), and fluconazole (FLU)-were carried out. We have thoroughly studied the connection between the pressure coefficient of the glass transition temperature (d T g /d p ) and the activation volume of both relaxation modes (Δ V α , Δ V δ/α' ) with respect to the molecular weight ( M w ) or molar volume ( V m ) in these systems. Besides, high pressure data revealed that the time scale separation between α- and δ- or α'-processes increases with pressure in ITZ and TER. What is more, the activation entropy, which is a measure of cooperativity, calculated from the Eyring model for the secondary (β)-relaxation in ITZ and POS, increased and decreased, respectively, in the compressed samples. To understand these peculiar results, we have carried out X-ray diffraction (XRD) measurements on the pressure-densified glasses and found that pressure may induce frustration in molecular organization and destroy the medium-range order while enhancing the short-range correlations between molecules. This finding allowed us to conclude that varying molecular spatial arrangement is responsible for the extraordinary dynamical behavior of ITZ, POS, and TER at high pressure.