Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility.

New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

Temperature-Controlled Chain Dynamics in Polyimide Doped with CoCl2 Probed Using Dynamic Mechanical Analysis.

Cobalt(II) chloride (CoCl2) being in the vicinity of polyimide chains entails modifications in terms of the molecular dynamics, which are mainly governed by the possible presence of amic acid residual groups, by the transition-metal-type characteristics of cobalt and by the CoCl2 content. Polyimide was synthesized using poly(amic acid) according to the reaction of 2,2'-bis(3,4-dicarboxylphenyl)hexafluoropropane dianhydride (6FDA) with 3,3'-dimethyl-4,4'-diaminodiphenylmethane (MMDA) in N,N-dimethylacetamide. CoCl2 was added before the thermal imidization of the poly(amic acid). An experimental approach was designed to establish the interaction between the polyimide and CoCl2 and whether the interaction depends on the quantity of the salt. Evidence for the existence of residual amic acid groups was obtained using second derivative Fourier Transform Infrared Spectroscopy (FTIR) and with the help of 2D correlation spectroscopy (2D-COS). Moreover, FTIR, along with X-ray photoelectron spectroscopy (XPS), revealed the interaction between the polymer and CoCl2, primarily in the form of Co(II)-N coordinated bonds. Nevertheless, the coordination of cobalt with suitable atoms from the amic acid groups is not precluded. The results of dynamic mechanical analysis (DMA) featured a specific relaxation assigned to the presence of CoCl2 in the polymeric film and demonstrated that its (non)reinforcing effect depends on its content in the polyimide.

Utility and Utilization of Patient-Reported Experience Measures for the Supplementary COVID-19 Protective Actions at the Ovidius Clinical Hospital in Romania.

Patient-reported experience measures (PREMs) provide assessments of patients' subjective experiences and perceptions regarding their interactions with the healthcare system and its services. We present a cross-sectional study of the patient perception and evolution of COVID-19 cases performed at Ovidius Clinical Hospital in Romania during the COVID-19 pandemic. The study objective is to explore the utility and the utilization of PREMs in monitoring patient perceptions of the supplementary protective actions. During the pandemic, the hospital implemented early supplementary protective actions, like PCR and lung CT, to all surgically admitted patients in the hospital alongside government-recommended actions. At the same time, functional PREMs were used to evaluate patient perceptions regarding these supplementary actions. The research was carried out for 19 months between June 2020 and December 2021. The findings revealed that opinions about the severity of the COVID-19 pandemic, the personal risk of infection, and the perception of protective actions in the hospital were not correlated. Conclusions: The patients' appreciation of the COVID-19 protective actions taken by the hospital is related more to the general perceptions induced by the number of cases presented in the mass media and less by perceptions of the gravity of the problem or the risk of infection. In a hospital, the primary mission of patient safety is essential, and it must be fulfilled even if the patients are not sure or fully convinced that this is for their benefit. For management decisions and monitoring, using PREMs can be essential in a situation when general evidence is not conclusive.

Zein/Polysaccharide Nanoscale Electrostatic Complexes: Preparation, Drug Encapsulation and Antibacterial Properties.

Characterization of zein aqueous solutions, as a function of the ethanol content and pH, was performed, giving information on the zein aggregation state for the construction of complexes. The aggregation state and surface charge of zein was found to depend on the mixed solvent composition and pH. Nonstoichiometric complex nanoparticles (NPECs) were prepared by electrostatically self-assembling zein, as the polycation, and sodium alginate or chondroitin sulfate, as the polyanions, at a pH of 4. A wide range of parameters were investigated: the alcohol-water content in the zein solutions, the charge molar ratios, the solution addition order and the addition rate. The resulting nanoparticles were characterized by dynamic and electrophoretic light scattering, circular dichroism and scanning electron microscopy. The smallest size for the NPECs (100 nm) was obtained when the polysaccharides acted as the titrate with an addition rate of 0.03 mL·min-1. The NPECs with the best characteristics were selected for loading with ciprofloxacin and then deposited on a cellulosic material in order to evaluate their antibacterial activity. Substantial drug encapsulation with desired drug release profiles were found together with notable antibacterial efficiency, showing the tunability of the properties for both the zein and its complexes with polysaccharides, together with their application potential in the biomedical field.

Evidence through Thermal Analysis of Retro Diels-Alder Reaction in Model Networks Based on Anthracene Modified Polyester Resins.

The present work is focused on polyester resins obtained from the diglycidyl ether of bisphenol A and anthracene modified 5-maleimidoisophthalic acid. Because the maleimide-anthracene Diels-Alder (DA) adduct is stable at high temperatures, it is considered a good option for high performance polymers. However, the information related to the retroDA reaction for this type of adduct is sometimes incoherent. A detailed thermal study (conventional TGA, HiRes TGA, MTGA, DSC, MDSC) was performed in order to establish whether the rDA reaction can be revealed for this type of anthracene modified polyester resins. The TGA method confirmed the cleavage of the anthracene-maleimide DA adduct, while the DSC demonstrated the presence of anthracene in the system. At high temperatures, unprotected maleimide homopolymerizes and/or reacts with allyl groups according to the -ene reaction. Therefore, the thermal DA reaction is not displayed anymore upon the subsequent cooling, and the glass transition region is registered at a higher temperature range during the second heating. The use of sample-controlled thermal analysis (HiRes TGA) and MTGA improved the TGA result; however, it was not possible to separate the very complex degradation processes that are interconnected.

Digital technology for health shows disparities in cancer prevention between digital health technology users and the general population in Romania.

Introduction: Digital health services and technology are rapidly developing following the COVID-19 pandemic. This study aimed to reveal the differences between users of digital health technology (DHT) and the general population with regard to cancer prevention. Materials and Methods: This was an observational study on a conventional sample of 270 DHT users with completed data, performed in September 2021. Results: A significant difference was observed in the proportion of DHT users and the general population reporting the screening test results, which was 2-6 times higher in the DHT group. Digital technologies applied to the "self-care" model were more suitable for internet-literate populations. Discussion: Including digital technologies in a self-care model may be more suitable for internet-literate individuals. Thus, in a preventative health organizational framework, DHT should be integrated and used at the primary care level in the general population to improve disparities in the preventative health domain.

Coherent terahertz laser feedback interferometry for hydration sensing in leaves.

The response of terahertz to the presence of water content makes it an ideal analytical tool for hydration monitoring in agricultural applications. This study reports on the feasibility of terahertz sensing for monitoring the hydration level of freshly harvested leaves of Celtis sinensis by employing a imaging platform based on quantum cascade lasers and laser feedback interferometry. The imaging platform produces wide angle high resolution terahertz amplitude and phase images of the leaves at high frame rates allowing monitoring of dynamic water transport and other changes across the whole leaf. The complementary information in the resulting images was fed to a machine learning model aiming to predict relative water content from a single frame. The model was used to predict the change in hydration level over time. Results of the study suggest that the technique could have substantial potential in agricultural applications.

Large-scale high-density brain-wide neural recording in nonhuman primates.

High-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmatically select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.

Near-Field Localization of the Boson Peak on Tantalum Films for Superconducting Quantum Devices.

Superconducting circuits are among the most advanced quantum computing technologies; however, their performance is limited by losses found in surface oxides and disordered materials. In this work, we demonstrate the identification and spatial localization of a near-field signature of loss centers on tantalum films using terahertz scattering-type scanning near-field optical microscopy. By utilizing terahertz nanospectroscopy, we observe a localized excess vibrational mode around 0.5 THz and identify this resonance as the boson peak, a signature of amorphous materials. Grazing-incidence wide-angle X-ray scattering reveals that oxides on freshly solvent-cleaned samples are amorphous, whereas crystalline phases emerge after aging in air. Through nanoscale localization of defect centers, our findings provide valuable insights for the optimization of fabrication procedures for new low-loss superconducting circuits.

Terahertz imaging of human skin pathologies using laser feedback interferometry with quantum cascade lasers.

Early detection of skin pathologies with current clinical diagnostic tools is challenging, particularly when there are no visible colour changes or morphological cues present on the skin. In this study, we present a terahertz (THz) imaging technology based on a narrow band quantum cascade laser (QCL) at 2.8 THz for human skin pathology detection with diffraction limited spatial resolution. THz imaging was conducted for three different groups of unstained human skin samples (benign naevus, dysplastic naevus, and melanoma) and compared to the corresponding traditional histopathologic stained images. The minimum thickness of dehydrated human skin that can provide THz contrast was determined to be 50 µm, which is approximately one half-wavelength of the THz wave used. The THz images from different types of 50 µm-thick skin samples were well correlated with the histological findings. The per-sample locations of pathology vs healthy skin can be separated from the density distribution of the corresponding pixels in the THz amplitude-phase map. The possible THz contrast mechanisms relating to the origin of image contrast in addition to water content were analyzed from these dehydrated samples. Our findings suggest that THz imaging could provide a feasible imaging modality for skin cancer detection that is beyond the visible.

CCRL2 affects the sensitivity of myelodysplastic syndrome and secondary acute myeloid leukemia cells to azacitidine.

Better understanding of the biology of resistance to DNA methyltransferase (DNMT) inhibitors is required to identify therapies that can improve their efficacy for patients with high-risk myelodysplastic syndrome (MDS). CCRL2 is an atypical chemokine receptor that is upregulated in CD34+ cells from MDS patients and induces proliferation of MDS and secondary acute myeloid leukemia (sAML) cells. In this study, we evaluated any role that CCRL2 may have in the regulation of pathways associated with poor response or resistance to DNMT inhibitors. We found that CCRL2 knockdown in TF-1 cells downregulated DNA methylation and PRC2 activity pathways and increased DNMT suppression by azacitidine in MDS/sAML cell lines (MDS92, MDS-L and TF-1). Consistently, CCRL2 deletion increased the sensitivity of these cells to azacitidine in vitro and the efficacy of azacitidine in an MDS-L xenograft model. Furthermore, CCRL2 overexpression in MDS-L and TF-1 cells decreased their sensitivity to azacitidine. Finally, CCRL2 levels were higher in CD34+ cells from MDS and MDS/myeloproliferative neoplasm patients with poor response to DNMT inhibitors. In conclusion, we demonstrated that CCRL2 modulates epigenetic regulatory pathways, particularly DNMT levels, and affects the sensitivity of MDS/sAML cells to azacitidine. These results support CCRL2 targeting as having therapeutic potential in MDS/sAML.

New chromatographic insights on drug:cyclodextrin inclusion complexes and their potential use in drug delivery.

OBJECTIVES: Cyclodextrins (CDs) play a pivotal role in the controlled release of drugs; however, their ability to gradually release drugs is here interrogated: can cyclodextrins, even those that form strong inclusion complexes, sustain a prolonged release of drugs? METHODS: An original chromatographic approach was developed and accordingly we classified and determined drugs that form the most stable inclusion complexes with cyclodextrins. ß-CD and hydroxypropyl-ß-CD (HP-ß-CD) were coupled to pullulan (Pul) microspheres and packed into a chromatographic column. Then, different drugs or model compounds were eluted, and values of the retention time (RT) were determined. In vitro release studies were performed for drugs that form the most stable inclusion complexes. RESULTS: The drugs with the longest RT value form the most stable inclusion complexes with Pul/ß-CD and Pul/HP-ß-CD microspheres. Pul/ß-CD microspheres form more stable inclusion complexes than Pul/HP-ß-CD microspheres. However, in spite of their high stability, they were not able to gradually release the included drug (15 min release time). The cross-chromatographic experiments confirmed the hypothesis that in aqueous solution, drug/cyclodextrin complexes are continuously associated and dissociated. CONCLUSIONS: If the dissociation of the guest molecule is very rapid, why is it expected that these complexes gradually release the drug?

Exploring Arylazo-3,5-Bis(trifluoromethyl)pyrazole Switches.

Arylazopyrazoles stand out among the azoheteroarene photoswitches due to their excellent properties in terms of stability of the least stable isomer and conversion between isomers, leading to their use in several interesting applications. We report herein the synthesis of arylazo-trifluoromethyl-substituted pyrazoles and their switching behavior under light irradiation. UV-vis and NMR experiments showed that arylazo-1H-3,5-bis(trifluoromethyl)pyrazoles displayed very long half-lives in DMSO (days), along with reasonable values of other parameters that characterize a photoswitch. Inclusion of naphthyl moieties as aryl counterparts of the arylazopyrazoles is beneficial only in combination with trifluoromethyl groups, while extending the conjugation by grafting the pyrazole moiety with electron-donating or -withdrawing substituents positively affects the photoswitching behavior, in terms of isomerization yield and half-lives of the least stable isomer. The experimental values were correlated with theoretical calculations indicating the valuable influence of the trifluoromethyl groups onto the photoswitching behavior.

Melimine-Modified 3D-Printed Polycaprolactone Scaffolds for the Prevention of Biofilm-Related Biomaterial Infections.

Biomaterial-associated infections are one of the major causes of implant failure. These infections result from persistent bacteria that have adhered to the biomaterial surface before, during, or after surgery and have formed a biofilm on the implant's surface. It is estimated that 4 to 10% of implant surfaces are contaminated with bacteria; however, the infection rate can be as high as 30% in intensive care units in developed countries and as high as 45% in developing countries. To date, there is no clinical solution to prevent implant infection without relying on the use of high doses of antibiotics supplied systemically and/or removal of the infected device. In this study, melimine, a chimeric cationic peptide that has been tested in Phase I and II human clinical trials, was immobilized onto the surface of 3D-printed medical-grade polycaprolactone (mPCL) scaffolds via covalent binding and adsorption. X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) spectra of melimine-treated surfaces confirmed immobilization of the peptide, as well as its homogeneous distribution throughout the scaffold surface. Amino acid analysis showed that melimine covalent and noncovalent immobilization resulted in a peptide density of ∼156 and ∼533 ng/cm2, respectively. Furthermore, we demonstrated that the immobilization of melimine on mPCL scaffolds by 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (EDC) coupling and noncovalent interactions resulted in a reduction of Staphylococcus aureus colonization by 78.7% and 76.0%, respectively, in comparison with the nonmodified control specimens. Particularly, the modified surfaces maintained their antibacterial properties for 3 days, which resulted in the inhibition of biofilm formation in vitro. This system offers a biomaterial strategy to effectively prevent biofilm-related infections on implant surfaces without relying on the use of prophylactic antibiotic treatment.

Understanding the Effect of Free Nitrous Acid on Biofilms.

Free nitrous acid (FNA, i.e., HNO2) has been recently applied to biofilm control in wastewater management. The mechanism triggering biofilm detachment upon exposure to FNA still remains largely unknown. In this work, we aim to prove that FNA induces biofilm dispersal via extracellular polymeric matrix breakdown and cell lysis. Biofilms formed by a model organism, Pseudomonas aeruginosa PAO1, were treated with FNA at concentrations ranging from 0.2 to 15 mg N/L for 24 h (conditions typically used in applications). The biofilms and suspended biomass were monitored both before and after FNA treatment using a range of methods including optical density measurements, viability assays, confocal laser scanning microscopy, and atomic force microscopy. It was revealed that FNA treatment caused substantial and concentration-dependent biofilm detachment. The addition of a reactive nitrogen species (RNS) scavenger, that is, 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, substantially reduced biofilm dispersal, suggesting that the nitrosative decomposition species of HNO2 (i.e., RNS, e.g., •NO + •NO2) were mainly responsible for the effects. The study provides insight into and support for the use of FNA for biofilm control in wastewater treatment.

Reactive nitrogen species from free nitrous acid (FNA) cause cell lysis.

Free nitrous acid (FNA, i.e. HNO2) has been demonstrated to have broad biocidal effects on a range of microorganisms, which has direct implications for wastewater management. However, the biocidal mechanisms still remain largely unknown. This study aims to test the hypothesis that FNA will induce cell lysis via cell membrane perforations, and consequently cause cell death via proteolysis, through the use of two model organisms namely Escherichia coli K12 and Pseudomonas putida KT2440. A combination of analytical techniques that included viability assays, atomic force microscopy (AFM), protein abundance assays and proteomic analysis using Quadruple-Orbitrap™ Mass spectrometry was used to evaluate the extent of cell death and possible cell lysis mechanisms. FNA treatment at 6.09 mg/L for 24 h (conditions typically applied in applications) induced 36 ± 4.2% and 91 ± 3.5% cell death/lysis of E. coli and P. putida, respectively. AFM showed that the lysis of cells was observed via perforations in the cell membrane; cells also appeared to shrink and become flat following FNA treatment. By introducing a reactive nitrogen species (RNS) scavenger to act as a treatment control, we further revealed that it was the nitrosative decomposition species of FNA, such as .NO that caused the cell lysis through the destruction of protein macromolecules found in the cell membrane (proteolysis). Subsequently, the RNS went on to cause the destruction of protein macromolecules within the cells. The death of these model organisms E. coli and P. putida following exposure to FNA treatment provides insights into the use of FNA as an antimicrobial agent in wastewater treatment.

Chitosan-Based Therapeutic Systems for Superficial Candidiasis Treatment. Synergetic Activity of Nystatin and Propolis.

The paper deals with new approaches to chitosan (CS)-based antifungal therapeutic formulations designed to fulfill the requirements of specific applications. Gel-like formulations were prepared by mixing CS dissolved in aqueous lactic acid (LA) solution with nystatin (NYS) powder and/or propolis (PRO) aqueous solution dispersed in glycerin, followed by water evaporation to yield flexible mesoporous (pore widths of 2-4 nm) films of high specific surfaces between 1 × 103 and 1.7 × 103 m2/g. Morphological evaluation of the antifungal films showed uniform dispersion and downsizing of NYS crystallites (with initial sizes up to 50 µm). Their mechanical properties were found to be close to those of soft tissues (Young's modulus values between 0.044-0.025 MPa). The films presented hydration capacities in physiological condition depending on their composition, i.e., higher for NYS-charged (628%), as compared with PRO loaded films (118-129%). All NYS charged films presented a quick release for the first 10 min followed by a progressive increase of the release efficiency at 48.6%, for the samples containing NYS alone and decreasing values with increasing amount of PRO to 45.9% and 42.8% after 5 h. By in vitro analysis, the hydrogels with acidic pH values around 3.8 were proven to be active against Candida albicans and Candida glabrata species. The time-killing assay performed during 24 h on Candida albicans in synthetic vagina-simulative medium showed that the hydrogel formulations containing both NYS and PRO presented the faster slowing down of the fungal growth, from colony-forming unit (CFU)/mL of 1.24 × 107 to CFU/mL < 10 (starting from the first 6 h).

Cu(II)/Guanidine Functionalized Disiloxane Complex of Supramolecular Structures for Visible Light-Driven Photocatalysis of Congo Red.

The present study focuses on the synthesis of a new guanidine-functionalized disiloxane used as a ligand to obtain copper(II) complexes linked through hydrogen bonding into supramolecular structures. A two-step procedure was used to prepare the guanidine functionalized disiloxane ligand. Firstly, the hydrosilylation reaction between the siloxane precursor, namely 1,1,3,3-tetramethyldisiloxane (DS), and the allyl glycidyl ether (AGE) was performed in the presence of a platinum catalyst resulting in glycidoxypropyldisiloxane (DS-PMO) intermediary compound. In the second step, DS-PMO derivative was modified with 1,1,3,3-tetramethyl guanidine (TMGu) to obtain the guanidine-functionalized disiloxane ligand (bGu-DS) that was further used for the coordination of copper(II) acetate hydrate. The structures of the ligand and of its Cu(II) complex were confirmed by spectral methods (IR, UV-Vis, NMR, XRF) and correlated with theoretical calculations using semi-empirical PM6 and DFT methods. The copper(II) complex was found to exhibit low optical band gap energy (2.9 eV) and good photocatalytic activity under visible light irradiation in the decomposition of Congo Red (CR). A dye removal efficiency higher than 97% at the catalyst and CR concentrations of 1 and, respectively, 200 mg/L was obtained.

The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia.

The identification of new pathways supporting the myelodysplastic syndrome (MDS) primitive cells growth is required to develop targeted therapies. Within myeloid malignancies, men have worse outcomes than women, suggesting male sex hormone-driven effects in malignant hematopoiesis. Androgen receptor promotes the expression of five granulocyte colony-stimulating factor receptor-regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor regulating cytokine signaling in granulocytes, but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is up-regulated in primitive cells from patients with MDS and secondary acute myeloid leukemia (sAML). CCRL2 knockdown suppressed MDS92 and MDS-L cell growth and clonogenicity in vitro and in vivo and decreased JAK2/STAT3/STAT5 phosphorylation. CCRL2 coprecipitated with JAK2 and potentiated JAK2-STAT interaction. Erythroleukemia cells expressing JAK2V617F showed less effect of CCRL2 knockdown, whereas fedratinib potentiated the CCRL2 knockdown effect. Conclusively, our results implicate CCRL2 as an MDS/sAML cell growth mediator, partially through JAK2/STAT signaling.

Burden of Chronic Heart Failure in Romania.

Chronic heart failure (CHF) affects millions of people across the world, with increasing trends in prevalence, putting ever increasing pressure on the healthcare system. The aim of this study was to assess the financial burden of CHF hospital care on the public healthcare sector in Romania by estimating the number of inpatient episodes and the associated costs. Additionally, societal costs associated with missed work and premature death of CHF patients were also estimated. The national claims database was analyzed to estimate the number of CHF patients. Cost data was extracted from a pool of nine public hospitals in Romania. In 2019, 375,037 CHF patient episodes were identified on specific wards at the national level. The average cost calculated for the selected nine hospitals was EUR 996. The calculated weighted national average cost per patient episode was EUR 1002, resulting in a total cost of EUR 376 million at the national level. The cost of workdays missed summed up to EUR 122 million, while the annual costs associated with the premature death of CHF patients was EUR 230 million. In conclusion, the prevalence of CHF in Romania is high, accounting for a large proportion of hospitalizations, which translates into large costs for the national payer.