Drug-induced pruritus triggers a desire to scratch, thereby diminishing one’s quality of life. Certain instances of this phenomenon follow complex mechanisms of action that diverge from histamine-mediated pathways, known contributors to pruritus. However, investigations into the relationship between drugs and pruritus are limited. In this study, data mining techniques were employed to comprehensively analyze the characteristics of drugs linked to pruritus, using the FDA Adverse Event Reporting System(FAERS) Data maintained in the United States. Reports linked to pruritus demonstrated noteworthy differences in gender, age, and weight when compared with non-pruritus cases. Among the leading candidates for drugs prompting pruritus were ophthalmic drugs, systemic antibacterials, contrast media, dermatological antifungals, and dermatological preparations. Principal component analysis showed that the second principal component served as an indicator for distinguishing between onsets at mucous membranes or the skin surface. Additionally, the third principal component functioned as an indicator for categorizing administration methods as either invasive or noninvasive. Furthermore, a hierarchical cluster analysis conducted on these obtained principal components revealed the potential for classifying drugs based on the site of pruritus onset and the method of drug administration. These findings contribute to the development of targeted prevention and treatment strategies for avoiding pruritus in clinical practice.

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and Pharmacovigilance (PV) has the potential to strengthen current antimicrobial stewardship (AMS) strategies. This study aimed to characterise AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre (Lareb); (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs).; (3) Results: Between 1998 and Jan 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n=89; 35%), colistin (n=30; 11,9%), ciprofloxacin (n=16; 6,35%), doxycycline (n=14; 5,5%) and aztreonam (n=12; 4,76%). The most frequently used PTs were drug ineffective (n=71; 28%), pathogen resistance (n=14; 5%) and drug resistance (n=13; 13%). A total of 119 reports (74%) suggested use-related issues. Watch antibiotics were in 54% of the reports and Reserve antibiotics were in 19%. In the Watch group, “Off label use” and “Product use in unapproved indication” were the most frequent PTs and majority of reports on Reserve antibiotics were coded as “Off label”. (4) Conclusions: Addressing AMR using the PV methods will provide an opportunity for PV expansion and could encourage further investment in both in AMS programs and PV systems.

Objectives: The aim of this study was to assess the knowledge, attitude and practice of healthcare professionals regarding adverse drug reaction [ADR] monitoring and pharmacovigilance [PV] in India. Materials and Methods: It was a questionnaire based cross sectional observational study. Data was collected with the help of data collection Google form that included the demographics and twenty two survey based questions. Data were analysed by using Microsoft Excel sheet, further analysed for results, including frequency, percentage, mean and standard deviation. Result: The questionnaire was filled by two hundred ten healthcare professionals in which 52.9 % were male and 47.10% of female. Most of the respondents were pharm d students (50.47%). Out of the total 91.4% responded to the definition of pharmacovigilance correctly. 87.6% participants said all ADR should be reported. 86.20% participants think Pharmacovigilance should be taught in detail to healthcare professionals. Most of the respondents (43.8%) always informed the patients about ADR while prescribing the medicines. Conclusion: Study revealed most of the participants have good knowledge about ADR and pharmacovigilance. Difficult to decide whether ADR occur or not and extra work load being major factors responsible for under reporting.

In this paper, we introduce a specialized, fully automated experimental arrangement designed for assessing the effectiveness of augmented and virtual reality technologies in healthcare setting and explore its design principles focusing on depth sensor characterization. The main goal of this project is to establish a robust benchtop platform for the quantitative evaluation of extended reality technologies in a controlled environment, emphasizing the practical assessment of augmented reality head-mounted devices. We outline a design concept and considerations for an experimental configuration aimed at creating a realistic testing environment. This apparatus comprises an observation platform mounted on a three-degree-of-freedom motorized system and a test phantom stage. Focusing on real-case scenarios, we utilized a range of sensors, including readily available range-sensing cameras and commercial augmented reality headsets, such as the Intel RealSense L515 LiDAR camera, mounted on the motion control system. The setup enabled automated data collection and facilitates controlled assessments and validation of various facets of augmented reality technologies, including object, hand, and head tracking, as well as static and dynamic image registration. This paper describes the system architecture, the process of automated data collection, and presents several evaluation studies conducted with this setup, providing insights into the quality and temporal noise associated with static or moving objects or observers in augmented reality applications.

Area covered: These drugs, particularly calcineurin inhibitors, have very narrow therapeutic windows, i.e., they have numerous drug-related side effects. Herein, we focus on the most frequent immunosuppressive drug-related side effects that we encounter in kidney-transplant recipients: namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). However, other therapies that are used after kidney transplantation, e.g., valcancyclovir, may also contribute to adverse events such as leukopenia. For each side-effect, we suggest how it can be prevented and how to treat it when present.

Construction safety is especially important because the construction industry is so important to a country's development. Significant research and practice have been conducted to mitigate potential risks during construction and improve worker efficiency. With the rapid advancement of cognitive neuroscience and the incorporation of medical technology in recent years, various wearable monitoring devices have been widely used in the construction field for real-time monitoring of workers' physical and mental status. Among these, the use of EEG (Electroencephalogram) in construction environment research allows researchers to gain insight into the physical and mental states of construction workers while performing construction tasks. This review introduces EEG technology and portable EEG devices, followed by an overview of their use in both monitoring workers' adverse reactions and identifying hazards on construction sites, providing an effective guide for EEG research in the construction field and on-site safety management.

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients versus non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs (including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89–816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients,95% CI 137.09–186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53–154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events.

To improve efficacy and safety of sunscreen emulsions, UV‐filter skin permeation could be kept as low as possible by reducing UV‐filter content or changing emulsion composition. In this work, different lipid phase ratio (12, 14 and 16% w/w) were assessed for their ability to affect the technological and sensory properties of O/W emulsions in which bemotrizinol (BMTZ), a broad spectrum sunscreen agent, was incorporated free or loaded into nanostructured lipid nanocarriers (NLC) to reduce its release from the vehicle and, hence, its skin permeation. The following technological properties were evaluated in vitro by suitable methodologies: spreadability, viscosity, pH, occlusion factor, BMTZ release, sun protection factor (SPF). Sensory attributes were assessed by trained panelists in three different phases: before/during pick‐up, rub‐in, after application. Raising the lipid phase ratio led to an increase of viscosity and to a corresponding drop of spreadability while the incorporation of BMTZ‐loaded NLC determined a decrease of occlusion factor and an increase of SPF. No BMTZ release was observed from all emulsions. Sensory attributes were mainly affected by lipid phase ratio. These results suggest that lipid phase ratio and BMTZ incorporation into NLC could contribute to determine technological and sensory properties of O/W emulsions.

CD44 is a type I transmembrane glycoprotein, which is associated with poor prognosis in various solid tumors. Since CD44 plays critical roles in tumor development by regulating cell adhesion, survival, proliferation, and stemness, it has been considered a target for tumor therapy. Anti-CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody-drug conjugates and chimeric antigen receptor-T cell therapy. We previously developed anti‐pan-CD44 mAbs, C₄₄Mab-5 and C₄₄Mab-46, which can recognize both CD44 standard (CD44s) and variant isoforms. In the present study, a defucosylated mouse IgG_2a version of the anti-pan-CD44 mAbs (5-mG_2a-f and C₄₄Mab-46-mG_2a-f) was generated to evaluate the antitumor activities against CD44-positive cells. Both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f recognized CD44s-overexpressed CHO-K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could activate effector cells in the presence of CHO/CD44s cells and exhibited the complement‐dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5-mG_2a-f and C₄₄Mab-46-mG_2a-f significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control defucosylated mouse IgG_2a. These results indicate that 5-mG_2a-f and C₄₄Mab-46-mG_2a-f could exert antitumor activities against CD44-positive cancers and could be a promising therapeutic regimen for tumors.

: Glaucoma is the most common cause of blindness, which significantly reduces quality of life. Most glaucoma cases are primary glaucoma; nevertheless, many patients suffer from glaucoma caused by drugs, such as corticosteroids. A comprehensive review of the risks associated with corticosteroid-induced glaucoma is limited. Therefore, we used the Japanese Adverse Drug Event Reporting Database (JADER) published by the Pharmaceuticals and Medical Devices Agency (PMDA) to analyze the risk factors associated with glaucoma and the trends and characteristics of corticosteroid-induced glaucoma. We did not find sex or age differences associated with the onset of glaucoma. Hierarchical clustering and principal component analysis revealed that triamcinolone acetonide and betamethasone sodium phosphate, which are used around the eyes in Japan, are more likely to induce intraocular pressure (IOP) elevation compared with other corticosteroids. Increased IOP is a direct cause of glaucoma. Based on these findings, it may be necessary to limit or avoid the use of these corticosteroids.

One of the G protein-coupled receptors, C-C chemokine receptor 5 (CCR5), is an important regulator for the activation of T and B lymphocytes, dendritic cells, natural killer cells, and macrophages. Upon binding to the ligands, CCR5 activates downstream signaling, which plays critical roles in the innate and adaptive immune response through the promotion of lymphocyte migration and the secretion of pro-inflammatory cytokines. Anti-CCR5 monoclonal antibodies (mAbs) have been developed and evaluated in clinical trials for tumors and inflammatory diseases. In this study, we developed novel mAbs for mouse CCR5 (mCCR5) using the N-terminal peptide immunization. Among the established anti-mCCR5 mAbs, C₅Mab-4 (rat IgG_2a, kappa) and C₅Mab-8 (rat IgG₁, kappa), recognized mCCR5-overexpressed Chinese hamster ovary-K1 (CHO/mCCR5) and an endogenously mCCR5-expressing cell line (L1210) by flow cytometry. The dissociation constant (K_D) values of C₅Mab-4 and C₅Mab-8 for CHO/mCCR5 were determined as 3.5 × 10⁻⁸ M and 7.3 × 10⁻⁹ M, respectively. Furthermore, both C₅Mab-4 and C₅Mab-8 could detect mCCR5 by western blotting. These results indicated that C₅Mab-4 and C₅Mab-8 are useful for detecting mCCR5 by flow cytometry and western blotting and provide a possibility to obtain the proof of concept in preclinical studies.

C-C motif chemokine receptor-8 (CCR8) belongs to class A of G protein-coupled receptors (GPCRs). CCR8 interacts with the specific chemokine ligand CCL1/I-309 in humans, which is produced by various cells, including tumor-associated macrophages and regulatory T cells (Treg). CCR8 is highly expressed on Treg and T-helper 2 (T_H2) cells recruited to the inflammation site and is implicated in allergy, asthma, and cancer progression. The CCR8⁺Treg has been suggested to be an important regulator in the immunosuppressive tumor microenvironment (TME); therefore, it has been desired to develop sensitive monoclonal antibodies (mAbs) for CCR8. This study developed a specific mAb for human CCR8 (hCCR8), which is useful for flow cytometry by employing the Cell-Based Immunization and Screening (CBIS) method. The established anti-hCCR8 mAb, C₈Mab-21, (mouse IgM, kappa) reacted with hCCR8-overexpressed Chinese hamster ovary-K1 (CHO/hCCR8) cells, TALL-1 (acute T lymphoblastic leukemia), CCRF-HSB2 (human T-lymphoblastic leukemia), and natural killer cells, which express endogenous hCCR8 by flow cytometry. Furthermore, C₈Mab-21 demonstrated a moderate binding affinity for CHO/hCCR8 and TALL-1 with a dissociation constant of 6.5×10^-8 M and 2.0×10^-8 M, respectively. C₈Mab-21, which was established by the CBIS method, could be a useful tool for analyzing the hCCR8-related biological response using flow cytometry.

The treatment of acute myeloid leukemia (AML) with adverse genetics remains unsatisfactory, with very low response rates to standard chemotherapy and shorter durations of remission commonly observed in these patients. The complex biology of AML with adverse genetics is continuously evolving. Herein, we discuss recent advances which have investigated the contribution of cell intrinsic mechanisms as well as of the immune system to myeloid leukemogenesis in this specific subset of AML. We focus on the biological rationales for combining targeted therapy and immunotherapy, which are currently being investigated in ongoing trials, and could hopefully ameliorate the poor outcomes for these patients

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a specific subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was safe and well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is safe and well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Hospital-based adverse drug reaction (ADR) monitoring and reporting programs intend to identify and quantify the risks associated with the use of drugs. To examine the causality, preventability and severity of ADR in a hospital setting; a prospective cohort study on spontaneous ADR reporting was conducted from December 2015 to May 2016. Incidence of ADRs, causality, type, severity and preventability were assessed using necessary assessment scales. The study included 3157 hospitalized individuals, in whom 51 ADRs were detected among 49 patients. The overall incidence of suspected ADRs was found to be 1.6%. According to the causality assessment, most of the ADRs reported were probable (n = 26, 51.0%), and type A (augmented/pharmacological) reactions (n = 39, 76%) were the most common type of ADR found. The majority of ADRs were moderate to severe (n = 35, 68.6%), of which 37.3% were found to be potentially preventable. Predictability was observed in 28 (54.9%) reported ADRs. The drugs most frequently associated with ADRs were antibiotics, antiepileptics and antihypertensives. This feasibility study was able to highlight the clinical pharmacist’s role in ADR monitoring service and create awareness about the way it could be done to promote safer drug use. Similar ADR reporting programs are necessary to educate and to improve awareness among the healthcare professionals in developing countries.

Green synthesis of silver nanoparticles (AgNPs) using raw Whey has never been reported. Silver nanoparticle formation involves a reduction reaction of silver salt solution with Whey extract. Extract and metal salt concentrations, and temperature can control this reaction. In this work, incubation period, extract, AgNO3, and NaOH concentrations were used as the independent factors using central composite design under response surface methodology. The aim was to elucidate the influence these factors have on the measured UV-Vis absorption spectra fitted with a Voigt function, and to optimize the conditions for nanoparticle formation. The fitting parameters, peak wavelength (λ0), peak area (A), and Full Width at Half Maximum (FWHM), were the responses. Silver nanoparticle formation was only possible in an alkaline environment (pH 10). The peak wavelength and the FWHM are influenced mainly by extract and AgNO3 concentrations. In contrast, the peak area is influenced by a total of 33.54 % from the interaction terms of AgNO3 and extract concentrations with NaOH. Metallic AgNPs were formed for the following parameter ranges: a) Whey (0.4 – 1.6 % v/v), b) AgNO3 (0.15 – 0.6 mM), c) NaOH (10 – 50 mM), and d) Time (20 – 60 min). Silver oxide nanoparticles were also observed.

Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles derivatives as potent FGFR inhibitors. Compound 10a was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that compound 13a is the most potent FGFR1 inhibitor in this series with the enzyme inhibitory activity about 30.2 nM of IC50 value.

In an effort to enhance the efficiency and safety of open-pit mines, this study explores the optimization of end slope road parameters and slope structures, specifically focusing on unmanned driving lanes.A significant aspect of the study is the development of a truck trajectory offset model, which considers the different reaction times between automated sensors and human drivers in adapting to environmental changes. To test these concepts, the study uses numerical simulations to confirm the stability of the proposed end slope designs. Using Victory West Mine No. 1 as a case study, the research determines the optimized width for unmanned driving lanes and the maximum angle for safe steepening of end slopes. The findings indicate that the optimized unmanned lane width for NTE240 mining dump trucks is 1743 mm, allowing for a 2-degree increase in the slope angle at the south end slope. This optimization leads to a steep mining stripping volume of 3.2735 million m³ and a coal output of 2.49628 million tons, maintaining a stripping ratio of 1.31m³/t. These results demonstrate that the unmanned driving road width optimization not only ensures slope safety but also significantly boosts the economic benefits of steep mining in open-pit mines.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavourable drugs properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use as inhalable formulations. Particulate-solid HA-VAN25 complex by spray drying from an aqueous dispersion was obtained. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern by X-ray was observed. The powder density, geometric size and morphology showed a suitable aerosolization and aerodynamic performance of the powder, indicating the capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 hours. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus, showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases’ progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop of new, disease-modifying drugs to treat AD and PD, thereby decreasing the social and economic burdens linked to these NDs.

To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, that selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure-activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations have determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324±8 µM and 550±45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen- binding site and penetrated deeper into the binding site near Trp1. Peptide 4, inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug-optimization in angiogenesis and cancer therapy.

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

This study aimed to evaluate the effects of Blazepod technology when incorporated with various training regimens on the essential elements of physical fitness in volleyball, such as agility, speed, visual response time, and vertical leap. Thirty-six participants (age :17.33±0.48 y, height: 183.78±6.34 cm, weight: 77.14±5.16 kg) were in-volved in this study. In randomized design, three equal groups with two experimental groups and one control group were involved in the study over a period of six weeks: (GE1) used Blazepod technology to workout at a low level; (GE2) used Blazepod technology to workout at a higher intensity; (CG) did not employ Blazepod technology, but it adhered to the same fundamental training curriculum. We conducted agility, speed, reaction time, and vertical jump tests before, midway and after the study to determine optimal training volume, intensity, and frequency. A significant main effect of time (P0.01), and time×group interaction (P>0.001) were found for all tests. Post hoc test showed that the two experimental groups gadget significantly improved in all performance variables (P

Cancer, characterized by abnormal cell proliferation driven by genetic mutations, remains a significant health challenge. Tailoring effective therapies depends on factors like tumor location, grade, and stage, alongside patient condition. Leveraging Nano-carrier encapsulated drugs offers a promising avenue, as they accumulate preferentially at tumor sites, enhancing therapeutic efficacy while mitigating side effects. Polymeric Nano-carriers, with their customizable properties, further optimize drug delivery efficiency and specificity. Incorporating active targeting ligands such as antibodies, carbohydrates, peptides, folates, and aptamers-onto polymeric nanoparticle surfaces through techniques like functionalization, adsorption, and conjugation plays a pivotal role in directing therapeutic agents to tumor cells. Consequently, polymeric nanoparticles emerge as the carrier of choice for delivering drugs to various tumor types, including breast, colon, lung, prostate, liver, and spleen tumors.

This post-hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visit and hospitalization in women and men. During the study period (January 2007 – December 2018), 61,855 reports of ADE leading to ED visit were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidi-ties were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing and adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.

Knowing professionals’ attitudes is the basis for the development of skills for dealing with drug dependence. These attitudes may affect patients’ clinical safety and the cost-benefit ratio of the interventions. The goal of this study was to assess emergency and mental health nurses’ attitudes and perceptions towards alcoholics. A multicenter prospective descriptive study was conducted in six hospitals with 167 emergency and mental health nurses. Nurses classified alcoholics as sick individuals, although there was a tendency to feel comfortable working with them. Results indicated that these professionals had a rejecting attitude towards moderate alcohol consumption. We found a significant association between the attitude of the nurse and gender, with the degree of rejection towards the alcoholic being higher in men than in women and with less punitive attitudes in professionals from 0 to 11 years of professional experience.

Functional genomics, a multidisciplinary subject, investigates the functions of genes and their products in biological systems to better understand diseases and find new drugs. Drug repurposing is an economically efficient approach that entails discovering novel therapeutic applications for already-available medications. Genomics enables the identification of illness and therapeutic molecular characteristics and interactions, which in turn facilitates the process of drug repurposing. Techniques like gene expression profiling and Mendelian randomization are helpful in identifying possible medication candidates. Progress in computer science allows for the investigation and modelling of gene expression networks that involve large amounts of data. The integration of data from DNA, RNA, and protein activities has resemblance to pharmacogenomics, which is of utmost importance in the development of cancer drugs. Functional genomics in drug discovery, particularly for cancer, is still not thoroughly investigated, despite the existence of a significant amount of literature on the subject. Next-generation sequencing and proteomics present highly intriguing opportunities. Publicly available databases and mining techniques facilitate the development of cancer treatments based on functional genomics. Expanding the study and application of functional genomics has great promise to advance the process of discovering and repurposing drugs, especially in the field of oncology.

Chitosan (CS) nanoparticles are under investigation for a wide range of applications in nanomedicine. The structural, molecular and physicochemical properties of chitosan nanoparticles have a direct bearing on their efficacy in drug conjugation and delivery, gene delivery, and tissue engineering. Herein we report on the structural, morphological and molecular properties of chitosan nanoparticles synthesized using the ionic gelation method with the intended purpose of being used for drug delivery. The chitosan nanoparticles (CS-NPs) were prepared in the 0.25 to 1.0% w/v concentration range, whereas separate samples of the 1.0% w/v CS-NPs were also functionalized with polyethylene oxide (PEO) alone and with a diblock copolymer of PEO and polypropylene glycol (PPG). The average size of the CS-NPs was determined from TEM imaging to be in the range of 11.3 to 14.8 nm. The XRD and TEM analyses show that the CS-NPs have semi-crystalline structure with the degree of crystallinity depending upon the nature of synthesis. Our results show that functionalizing the 1.0% w/v CS-NPs with PEO increases the degree of crystallinity whereas functionalizing with the diblock copolymer PEO - PPG results in a significant increase in their degree crystallinity. The CS/TPP concentration (CS:TPP fixed at 1:1 ratio) had no apparent effect on the degree of crystallinity of the CS-NPs. The results from the FTIR analysis confirm incorporation of TPP with CS in the CS-NPs. Additionally, FTIR analysis shows an enhancement of hydrogen bonding that is consistent with the increase in the degree of crystallinity of the CS-NPs.

Several bio-actors are involved in the occurrence of leishmaniasis, which is made too complex for prevention and control options. Currently, all forms of leishmaniasis are being treated with chemical drugs, which have limitations and adverse effects on patients. Searching the bioactive molecules from plant sources allows the development of a novel drug. The essential oil and solvent extract of the roots of E. kebericho showed antileishmanial activity. But looking for biological activities of the isolated active ingredient from tubers of E. kebericho was scant. Thus, the isolation of the leishmanicidal compound from the roots of E. kebericho through a bioassay-guided technique was an aim of this work. Dehydrocostus lactone showed doubled potent than the standard drug miltefosine on leishmanicidal activities against L. major and L. tropica. Besides, the broad-spectrum biological activities of dehydrocostus lactone could be a potential drug candidate for co-infected patients caused by an association of leishmania and another pathogen.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in fetal programming of the hypothalamus-pituitary-adrenal (HPA) axis, leading to adverse fetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on fetal HPA axis function and postnatal offspring development, hence this study. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone were measured in all dams and pups. Glucose tolerance and expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase in pups ACTH and corticosterone concentrations, impaired glucose tolerance and dysregulated MR and GR expression in the PD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Molecularly imprinted polymers (MIPs) were synthesized and applied for the selective extraction of oblongifolin C (OC) from fruit extracts of Garcinia yunnanensis Hu. A series of experiments and computational approaches were employed to improve the efficiency of screening for optimal MIP systems in the study. The molar ratio (1:4) was chosen at last based on the comparison of the binding energy of the complexes between the template (OC) and functional monomers using density functional theory (DFT) at the RI-PBE-D3-gCP/def2-TZVP level of theory. The binding characterization and the molecular recognition mechanism of MIPs were further explained using the molecular modeling method and NMR and IR spectra data. The reusability of this approach was demonstrated in over 20 batch rebinding experiments. 140.5 mg of OC (>95% purity) was obtained from the 5 g extracts with 2 g of MIPs with the best binding properties through gradient elution program from 35% to 70% methanol-water solution. At the same time, another structural analog, 46.5 mg of guttiferone K (GK) (>88% purity), was also obtained by the gradient elution procedure. Our results showed that the structural analogs could be separated from the crude extracts by the molecularly imprinted solid-phase extraction (MISPE) using a gradient elution procedure for the first time.

Separase is a key cysteine protease to separate sister chromatids through digestion of cohesion ring that inhibits chromosome segregation as trigger of metaphase–anaphase transition in eukaryotes and highly regulated its activity by binding with securin and cyclinB-CDK1 complex. Those bindings prevent proteolytic activity of separase until the onset of anaphase. Chromosome missegregation and aneuploidy are frequently observed in malignancies. However, there are some difficulties for biochemical examinations due to instability of separase in vitro and a few spatiotemporal resolution approaches monitoring live separase activity throughout mitotic processes. Here we have developed FRET-based molecular sensors including GFP variants with separase cleavable sequences as donor and covalently attached fluorescent dye as acceptor molecules applicable to conventional live cell imaging and flow cytometric analysis because of efficient live cell uptake. We investigated performance of equivalent molecular sensors localized or not localized inside nucleus under cell cycle control using flow cytometry. Synchronized cell cycle progression rendered significant separase activity detections in both molecular sensors. We obtained consistent outcomes with localized molecular sensor introduction and cell cycle control by fluorescent microscopic observations. We thus established live cell separase activity monitoring systems specifically or statistically that could lead to elucidate separase properties in detail.

The regulation of cell death is a fundamental issue in cell biology and continues to be intensely investigated worldwide. The significance of research in this field persists because understanding the determinants of cell lifespan directly impacts the maintenance of multicellular organism homeostasis and, consequently, is crucial for addressing biomedical challenges associated with various diseases. It is recognized that the initiation of cell death can be prompted by both specific signals (such as cytokines or hormones) and nonspecific stimuli, including radiation, temperature increase, or oxidants. When these factors affect a cell, numerous signaling pathways are triggered in the cell, leading to neutralization of the effects of their negative effects or, in case of irreparable damage, to cell elimination. This removal of damaged cells occurs through apoptosis or programmed cell death, a highly regulated process. Numerous signaling molecules participate in orchestrating the apoptotic process, many of which also govern other essential functions within the organism. Physiological factors capable of triggering the apoptotic program in cells include nitric oxide (NO), which serves as one of the key signaling molecules regulating the functions of the cardiovascular, nervous, and immune systems of the organism. The unique chemical nature of NO, along with its numerous intracellular targets and physiologically active redox forms, raises questions about the specific mechanisms through which NO exerts its damaging effects on cells. Utilizing pharmacological preparations- such as sources (donors) of exogenous nitric oxide- represents an approach to investigating the initiation and execution of the apoptotic program in sensitive target cells. Furthermore, this approach holds promise as a direction for discovering new selective drugs.

Plant proteins being considered to become the most important protein source of the future, they must be able to replace the animal-derived proteins currently in use as technofunctional food ingredients. This poses challenges because plant proteins are oftentimes storage proteins with a high molecular weight and low water solubility. One promising approach to overcome these limitations is the glycation of plant proteins. The covalent bonding between the proteins and different carbohydrates created via the initial stage of the Maillard reaction can improve the technofunctional characteristics of these proteins without the involvement of potentially toxic chemicals. However, compared to studies with animal-derived proteins, glycation studies on plant proteins are currently still underrepresented in literature. This review provides an overview of the existing studies on the glycation of the major groups of plant proteins with different carbohydrates using different preparation methods. Emphasis is put on the reaction conditions used for glycation as well as the modifications to physicochemical properties and technofunctionality. Different applications of these glycated plant proteins in emulsions, foams, films, and encapsulation systems are introduced. Another focus lies on the reaction chemistry of the Maillard reaction and ways to harness it for controlled glycation and to limit the formation of undesired advanced glycation products. Finally, challenges related to the controlled glycation of plant proteins to improve their properties are discussed.

Background: Although triptorelin acetate (TA) is generally considered a safe medication, severe adverse drug reactions (ADRs) to triptorelin have occurred. In this study, we present the largest retrospective analysis of ADRs related to TA during the treatment of pediatric central precocious puberty. Methods: We describe a total of 38 suspected cases of TA-induced ADRs reported to the pharma-covigilance center of Shenzhen Children’s Hospital from September 2015 to December 2022. Causality assessment was carried out using the validated Kramer’s algorithm. The severity of ADRs was evaluated using the Modified Hartwig and Siegel Scale. Results: The most common ADRs attributed to TA were damage to the cutaneous tissues (29.3%) and reactions affecting the systemic and digestive systems (20.7%). The majority (61.1%) of ADRs occurred within 2 hours of administration. Among the 12 patients with severe ADRs, the three most frequent symptoms were anaphylactic reactions, hip synovitis, and arthralgia. Additional-ly, six patients experienced ADRs due to a change in the manufacturing process. Conclusion: The majority of ADRs observed in pediatric cases were type I anaphylactic reactions, which are rare but life-threatening. It is advisable to perform skin prick tests and intradermal tests when switching pharmaceutical manufacturers.

Lead optimization in drug discovery is a crucial phase where initial hits are refined into compounds with improved pharmacological properties. While traditional methods rely on manual experimentation and modifications, AI-driven techniques have revolutionized this process by leveraging big data and predictive modeling. This review explores how AI-driven approaches accelerate lead optimization, showcasing examples like deep neural networks and reinforcement learning. Integration of multi-omic data and experimental validation further enhances AI-driven strategies. The future lies in refining these AI methods, democratizing tools, and interdisciplinary collaboration to streamline drug discovery and address medical needs efficiently.

Public restrooms are often a hub of microbial contamination, and the examination of bacterial contamination in these facilities can serve as an important indicator of the transmission of infectious diseases. This study was conducted to determine the prevalence of bacterial contamination in public restrooms based on the economic class of the building. Samples were collected from various spots in 32 restrooms found in 10 shopping malls, classifying them into two categories: upper-end restrooms and lower-end restrooms. The findings showed that the level of contamination was higher in the lower-end restrooms, with the seat being the most contaminated area. The most dominant Gram-positive bacteria were coagulase-negative staphylococci species, making up 86% of the identified Gram-positive isolates. The most dominant Gram-negative bacteria identified were Klebsiella pneumoniae and Pseudomonas aeruginosa. The antibiotic sensitivity test results revealed the presence of multi-drug resistant bacteria among the Gram-positive and negative isolates, including Staphylococcus haemolyticus, Staphylococcus kloosi, Acinetobacter baumanii, and Pseudomonas aeruginosa. In conclusion, the study underscores the significance of monitoring bacterial contamination in public restrooms and the need for measures to reduce the spread of infectious diseases. Further research is crucial to gain a complete understanding of the bacterial contamination in public restrooms and their resistance patterns, to ensure the safety and health of the public. The implementation of improved cleaning practices and hands-free designs in restrooms can help reduce the risk of cross-contamination and prevent the spread of diseases.

Noninvasive brain stimulation technique can be used for modulation of motor behaviors such as reaction time (RT). The main aim of this study was to investigate whether RT during a sequential visual isometric pinch task (SVIPT) can be affected by anodal transcranial direct current stimulation (a-tDCS) over three different stimulation sites such as dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1) or posterior parietal cortex (PPC). We also aimed to assess if stimulation of these cortical sites affect the transfer of learning during SVIPT. A total of 48 right-handed healthy participants were randomly assigned to one of the four a-tDCS groups: 1) left M1, 2) left DLPFC, 3) left PPC and 4) sham. A-tDCS was applied concurrent with SVIPT in which the participants were precisely controlled their forces to reach seven different target forces from 10 to 40% of maximum voluntary contraction (MVC) presenting on a computer screen with right dominant hand. Four test blocks were randomly performed at baseline and 15 min after the intervention including sequence and random blocks with either hand. Our results showed significant differences between a-tDCS groups on ratio RT in the sequence blocks of both the right trained (P = .041) and left untrained hands (P = .023) for target forces of 15% and 30 % of MVC, respectively. In sequence blocks, M1 showed significant elongation in ratio RT for the target force of 15% and 30 % MVC compared to PPC and Sham groups in the right hand. In sequence blocks with left hand, this negative effect were found between M1-DLPFC and M1-Sham groups. In random blocks, no significant differences were found among four groups at each target forces for the left hand while there were significant differences for 15% (P =. 04) and 40% MVC (P =. 035) in the right hand. Our findings suggest that three different stimulation sites (DLPFC, M1 or PPC) were differentially affected by a single session of a-tDCS at some target forces during SVIPT. The effects of a-tDCS on ratio RT were transferred in the left untrained hand for sequence blocks but not random blocks. Further research is needed to understand fundamental aspects of these main areas of the brain on temporal processing in a precision control task such as SVIPT.

In the dynamic landscape of drug discovery, Computer-rAided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADD's historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADD's predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. The paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

Density functional theory (DFT) calculations of hydrogen adsorption on titanium nitride had previously shown that hydrogen may adsorb on both titanium and nitrogen sites with a moderate adsorption energy. Further, the diffusion barrier was also found to be low. These findings may qualify TiN, a versatile multifunctional material with electronic conductivity, as electrode material for the hydrogen evolution reaction (HER). This was the main impetus of this work which aims to experimentally and theoretically investigate the electrocatalytic properties of TiN-layers that were processed on Ti substrate using reactive ion sputtering. The properties are discussed focusing on the role of oxygen defects introduced during the sputtering process on the HER. Based on DFT calculations, it is shown that these oxygen defects alter the electronic environment of the Ti atoms which entails a low hydrogen adsorption energy in the range of -0.1 eV; this leads to HER performances that match those of Pt-NPs in acidic media. When a few nanometr thick layer of Pd-NPs is sputtered on-top of the TiN-layer, the performance is drastically reduced. This is interpreted in terms of oxygen defects being scavenged by the Pd-NPs near the surface which is thought to reduce the hydrogen adsorption sites.

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need to redefine the drug discovery development pipeline, bringing an Artificial Intelligence (AI)-powered informational view that integrates relevant biological information and explores new ways to develop effective anticancer approaches. Here, we show SynPred, an interdisciplinary approach that leverages specifically designed ensembles of AI-algorithms, links omics and biophysical traits to predict synergistic anticancer drug synergy. SynPred exhibits state-of-the-art performance metrics: accuracy – 0.85, precision – 0.77, recall – 0.75, AUROC – 0.82, and F1-score - 0.76 in an independent test set. Moreover, data interpretability was achieved by deploying the most current and robust feature importance approaches. A simple web-based application available online at http://www.moreiralab.com/resources/synpred/ was constructed to predict synergistic anticancer drug combinations requiring only the upload of the two drug SMILES to be tested, allowing easy access by non-expert researchers.

This article delves into the intersection of generative AI and digital twins within drug discovery, exploring their synergistic potential to revolutionize pharmaceutical research and development. Through various instances and examples, we illuminate how generative AI algorithms, capable of simulating vast chemical spaces and predicting molecular properties, are increasingly integrated with digital twins of biological systems to expedite drug discovery. By harnessing the power of computational models and machine learning, researchers can design novel compounds tailored to specific targets, optimize drug candidates, and simulate their behavior within virtual biological environments. This paradigm shift offers unprecedented opportunities for accelerating drug development, reducing costs, and, ultimately, improving patient outcomes. As we navigate this rapidly evolving landscape, collaboration between interdisciplinary teams and continued innovation will be paramount in realizing the promise of generative AI and digital twins in advancing drug discovery.

This study explores the complexities involved in the extraction and purification of catechins, prominent bioactive compounds found in plant extracts and tea. It addresses challenges arising from the intricate molecular structure of catechins and their inherent variability across botanical sources. Despite these obstacles, catechins present significant potential, particularly in healthcare. Their potent antioxidant properties have been extensively investigated and associated with numerous health benefits, positioning them as promising therapeutic agents for combating chronic diseases. Furthermore, catechins have diverse applications across various industries, including food and beverage, cosmetics, agriculture, and materials science. This abstract emphasizes the importance of continued research and innovation in catechin extraction and utilization, which hold promise for advancing human health and technological progress across multiple domains.

Management of chronic inflammation and wounds has always been a key issue in the pharmaceutical and healthcare sector. Curcumin (CCM) is an active ingredient extracted from turmeric rhizomes that has antioxidant, anti-inflammatory, and antibacterial activities, thus showing significant effectiveness toward wound healing. However, its shortcomings such as poor water solubility, poor chemical stability and fast metabolic rate limit its bioavailability and long-term use. In this context, hydrogels appear to be a versatile matrix for carrying and stabilizing drugs due to the biomimetic structure, soft porous microarchitecture, and pleasant biomechanical properties. The drug loading/releasing efficiencies can also be controlled by use of highly crystalline and porous metal organic frameworks (MOFs). Here, a flexible hydrogel composed of sodium alginate (SA) matrix and CCM-loaded MOFs was constructed for long-term drug release and antibacterial activity. The morphology and physicochemical properties of composite hydrogels were analyzed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet visible spectroscopy (UV-Vis), Raman spectroscopy and mechanical property tests. The results showed that the composite hydrogel was highly twistable and bendable to mechanically comply with human skin. The as-prepared hydrogel could capture efficient CCM for slow drug release as well as effective killing of bacteria. Therefore, such composite hydrogel is expected to provide a new management system for chronic wound dressings.

Does cell clustering influence intrinsic and acquired multi-drug resistance (MDR) differently? To address this question, we studied cultured monolayers (representing individual cells) and cultured spheroids (representing clusters) formed by drug-naïve (intrinsic MDR) and drug-exposed (acquired MDR) lines of ovarian cancer A2780 cells by cytometry of reaction rate constant (CRRC). MDR efflux was characterized by accurate and robust “cell number vs. MDR efflux rate constant (kMDR)” histograms. Both drug-naïve and drug-exposed monolayer cells presented unimodal histograms; the histogram of drug-exposed cells was shifted towards higher kMDR value suggesting greater MDR activity. Spheroids of drug-naïve cells presented a bimodal histogram indicating the presence of two subpopulations with different MDR activity. In contrast, spheroids of drug-exposed cells presented a unimodal histogram qualitatively similar to that of the monolayers of drug-exposed cells but with a moderate shift towards greater MDR activity. The observed greater effect of cell clustering on intrinsic than on acquired MDR can help guide the development of new therapeutic strategies targeting clusters of circulating tumor cells.

Adverse events associated with opioid use in palliative care have been extensively studied. However, predicting the occurrence of adverse events based on the specific opioid used remains unclear. This study aimed to comprehensively analyze the adverse events caused by µ receptor stimulation of opioids approved in Japan and investigate the tendencies of adverse event occur-rence among different opioids.We utilized the FDA Adverse Event Reporting System (FAERS) database to extract reported adverse events of opioids approved in Japan. Cluster analysis was performed on reporting odds ratios (RORs) of adverse event names among opioids to visualize relationships between opioids and adverse events, facilitating a comparative study of their clas-sifications.We calculated the RORs of adverse events for the target opioids. Based on these RORs, we performed a cluster analysis, which resulted in the classification of 11 target opioids into five distinct groups. we were able to comprehensively compare and examine the relationships between opioids and adverse events. This analysis helps in understanding and managing the risks and benefits of each drug in palliative care settings. By analyzing relationships between opioids and adverse events, clinicians can make informed decisions about opioid selection, dosage, and monitoring to maximize patient safety and comfort.

Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhib-itors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines and bispecific an-tibodies are improving patients’ outcomes. However, stimulation of the immune system, benefi-cial in terms of fighting against cancer, generates the risk of harm to other cells in a patient's body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, su-perficially, are renal AEs in patients treated with ICIs. International guidelines issued by Euro-pean Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are scarce data concerning renal adverse drug reactions of other immunotherapeutic methods. This implicates the need for the collection of safety data during ongoing clinical trials and in the re-al-life world to characterize the hazard related to the use of new immunotherapies and manage-ment of irAEs.

The eutrophication of open water bodies, especially in coastal water area, has received intensive public focuses in recent years. Biological treatment of organic pollutants in industrial and domestic wastewater requires microbial flora to participate. The environmental impact of these microbes, particularly in regard to the spread of antibiotic resistance genes and pathogenicity in coastal water, remains largely unknown. We initiate studies to examine antibiotic resistance genes (ARGs) in microbial flora and study the mode of antibiotic spread in the coastal waters of Bohai Bay, North China by using high performance liquid chromatography-mass spectrum analysis and quantitative polymerase chain reaction. The metabolic features of bacteria related to the presence of ARGs in the coastal area showed the enrichment of Pseudomonadale species with triple resistance properties (ampicillin, kanamycin and gentamycin) at the estuary site locating adjacent to a coastal sewage treatment plant where both type I and type II polyketide synthase genes and b-lactam type antibiotics are detected. Pseudomonadale order is phylogenetically belonged to Proteobacteria Phylum, Gamma-proteobacteria Class and contains Pseudomonadaceae family and Pseudomonas genus. QPCR analysis suggests that the percent occupation of Pseudomonadale species to total Proteobacteria in the examined stations is close to several sampling stations close to sewage treatment plants, where consistent release of organic wastes occurred.

Artificial intelligence AI or machine learning has proven to be a potential activity in the health and biomedical sciences. Previous research it has found that AI can learn new data and transform it into the useful knowledge. In the field of pharmacology, the aim is to design more efficient and novel vaccines using this method which are also cost effective. The underlying fact is to predict the molecular mechanism and structure for increased likelihood of developing new drugs. Clinical, electronic and high resolution imaging datasets can be used as inputs to aid the drug development niche. Moreover, the use of comprehensive target activity has been performed for repurposing a drug molecule by extending target profiles of drugs which also include off targets with therapeutic potential providing a new indication.

The purpose of the present study was to investigate anti-staphylococcal activity of liposomal daptomycin, against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin resistant. Neutral and negatively charged Daptomycin-loaded liposomes were prepared by three methods thin film hydration (TFH), DRV and microfluidic mixing (MM), and characterized for drug encapsulation (EE%), size distribution, zeta-potential, vesicle stability, drug release and drug integrity. Interestingly, whilst drug loading in THF and DRV nanosized (by extrusion) vesicles was around 30-35, very low loading (~4%) was possible in MM vesicles, requiring further explanatory investigations. Liposomal encapsulation protected daptomycin from degradation and preserve its bioactivity. Quantitative microtiter plate (crystal violet, CV), methylthiazoltetrazolium (MTT), and growth curve (GC) assays evaluated antimicrobial activity of neutral and negative charge daptomycin-liposomes towards planktonic bacteria and biofilms. Neutral liposomes exhibited dramatically enhanced inhibition of bacteria growth (compared to free drug) for all species studied, while negative charged liposomes were totally inactive. Biofilm prevention and treatment studies revealed high antibiofilm activity of liposomal daptomycin. Neutral liposomes were more active for prevention and negative charge ones for treating established biofilms. Planktonic bacteria as well as matured biofilms of low daptomycin susceptible MRSE and MRSA strains were almost completely eradicated by liposomal-daptomycin indicating the need for their further exploration as antimicrobial therapeutics.

Background and Objectives: Knee osteoarthritis (KOA) is a degenerative disease that is targeting continuously people of different ages, but especially the elderly population, the number of which tends to increase continuously at the global level. Apart from age, excess weight can influence the evolution of the disease, with obesity being associated with a weak inflammation stage, and an imbalance between pro-inflammatory and anti-inflammatory cytokines. The present work aimed to identify specific biomarkers alike ACRP-30, IL-10, TNF-α, and IL-6 in synovial fluid and correlate them with patients’ clinical data. Materials and Methods: 24 subjects with KOA and over 50 years of age are involved in the present study. All patients performed a supine X-ray at the target knee. Ultrasound was performed using an ESAOTE MyLab Omega (ESAOTE Spa, Italy) ultrasound device and a 6-19 MHz linear array transducer. Results: The obtained results highlighted a significant correlation between age and adiponectin level (p=0.0451, r=-0.412). Also, the IL-10 values are lower in cases where the intensity of the pain is more pronounced (p=0.0405, r=-0.421). In addition, analyzing the data by gender, it was observed that in the case of males, stiffness is more related to age (p=0.0079, r=0.7993), compared to women (p=0.0203, r=0.6223). In the case of women, the progression of the disease tends to increase more intensively total WOMAC score’s values (p=0.00031, r=0.8342), compared with men (p=0.0289, r=7013). Regarding interleukins and BMI, significant correlations were observed only in the case of men. Conclusions: A significant correlation between age and adiponectin, and adiponectin and IL-6, suggests that advanced age may contribute to adiponectin reduction. Comparing men with women, it was observed that men's age is more related to rigidity, and IL-6 and IL-10 are directly correlated to BMI and women seem to be more sensitive to pain and stiffness.

Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disor-ders, even nearly a century after its discovery, due to the elusive nature of its causes. The develop-ment of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system's role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, open-ing new possibilities for treatment. Despite these advancements, conventional treatments for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, under-scoring the need for innovative solutions. This necessity has led to the incorporating of advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions.

Tuberculosis (TB) remains a global health threat, necessitating innovative strategies for control and prevention. This comprehensive review explores the Mycobacterium tuberculosis Lysine Exporter (LysE) gene, unveiling its multifaceted roles and potential uses in controlling and preventing tuberculosis (TB). As a pivotal player in eliminating excess L-lysine and L-arginine, LysE contributes to the survival and virulence of M. tuberculosis. This review synthesizes findings from different electronic databases and includes 13 studies focused on the LysE of M. tuberculosis. The research unveils that LysE can be a potential drug target, a diagnostic marker for TB, and a promising candidate for vaccine development. The absence of LysE in the widely used BCG vaccine underscores its uniqueness and positions it as a novel area for TB prevention. In conclusion, this review underscores the significance of LysE in TB pathogenesis and its potential as a drug target, diagnostic marker, and vaccine candidate. The multifaceted nature of LysE positions it at the forefront of innovative approaches to combat TB, calling for sustained research efforts to harness its full potential in the global fight against this infectious disease.

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing the clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus with very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo to drug-drug interactions (DDI) with other concomitant therapies. Although only few clinical evidence are available, it is possible to predict clinical relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDI of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

Establishment of diagnostic methods with low detection limits plays a critical role in the maintenance of early diagnosis, prevention of serious neurological complications, and control of the spread of ZIKA. In this study, we established the micro-droplet digital polymerase chain reaction (ddPCR) and real-time fluorescent quantification PCR (qPCR) protocols for the detection of Zika virus based on the NS5 gene. For the Zika standard plasmid, the standard curve of R² was 0.999, and the amplification efficiency was 92.203%, as determined by qPCR. Both ddPCR and qPCR were positive for cell culture of Zika nucleic acid.The minimum detection limit of ddPCR is 1–2 times lower than qPCR. Moreover, all tests of Dengue virus (1–4 serotypes) were negative in cell culture. Overall, these results suggested than ddPCR may have a lower limit of detection than qPCR.

Nonmedical prescription stimulant use (NPSU) is an ongoing public health crisis in the United States. There exists, however, a dearth of research investigating specific childhood risk factors that may contribute to this illicit use. Adverse childhood experi-ences (ACEs) may be a significant risk factor to address in the prevention and treatment of NPSU, as research has provided evi-dence for increased substance use, potentially including prescription stimulant misuse, among individuals who have experienced trauma. A systematic review of the literature was conducted to gather and synthesize research articles specifically examining the relationship between nonmedical prescription stimulant use in adults and the experience of adverse childhood experiences (ACEs). Four studies met all inclusion criteria and were included in the review. The results demonstrated that nonmedical use of prescription stimulants in adults is significantly associated with ACEs, with a higher numerical count of ACEs associated with a greater likelihood of nonmedical prescription stimulant use. Gaps in the literature were identified, specifically noting a lack of information available regarding the relationship between ACEs and NPSU within gender- and racially-diverse populations. The findings have implications for informing interventions related to ACEs and the misuse of prescription stimulant medication in adults.

(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in woman and is a high cause of mortality of them in reason to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy and inhibit distant metastases so potentially acts on tumor micro-environment; (2) Methods: Ferroptosis/Extracellular matrix remodeling literature text-mining results were integrated in breast cancer transcriptome cohort according their distant relapse free survival (DRFS) under adjuvant therapy (anthracyclin+taxanes) and also in MDA-MB-231 transcriptome functional experiments with ferroptosis activations (GSE173905); (3) Results: Ferroptosis/Extracellular matrix remodeling text-mining identified 910 associated genes in at list 10 articles. Univariate Cox analyses censored on breast cancer (GSE25066) selected 252 individual significant genes and 171 of them found with an adverse expression. Functional enrichment of these 171 adverse genes predicted basal breast cancer signatures. By text-mining some ferroptosis significant adverse selected genes shared citations in domain of ECM remodeling such as: TNF, IL6, SET, CDKN2A, EGFR, HMGB1, KRAS, MET, LCN2, HIF1A, TLR4. A molecular score based on expression the eleven genes was found predictive of worst prognosis breast cancer at univariate level: basal subtype, short DRFS, high grade values 3 and 4, estrogen and progesterone receptors negative and nodal stages 2 and 3. This eleven gene signature was validated as regulated by ferroptosis inductors (erastin and RSL3) in triple negative breast cancer cellular model MDA-MB-231.; (4) Conclusions: Crosstalk between ECM remodeling-Ferroptosis functionalities allowed to define a molecular score which have been characterized as an independent adverse parameter in prognosis of breast cancer patients. Gene signature of this molecular score have been validated to be regulated by erastin/RSL3 ferroptosis activators. This molecular score could be promising to evaluate ECM impact of ferroptosis target therapies in breast cancer.

Endoscopic retrograde cholangiopancreatography (ERCP) is a routinely used therapeutic procedure for the biliary and pancreatic diseases. Population aging may increase the typical indications of ERCP and come with more complexity and difficulties, especially in cannulation. This study aimed to evaluate the incidence, causes, and management of difficult biliary cannulation during ERCP in super-aged patients and the role of difficult cannulation as a risk factor for adverse events. A total of 614 patients, underwent ERCP, were prospectively studied as a cohort and divided into two groups based on their age. There were 146 patients aged 80 years or older in group A and 468 patients aged less than 80 years in group B. The primary outcome measures were the difficulty grade of papilla cannulation, clinical outcomes, and ERCP-related complications in the two groups. The adverse events were analyzed using logistic regression for patient age, co-morbidities, indications, and cannulation difficulty grade variables. There was no difference in the incidence of difficult cannulation between the two groups (32.9% vs. 34.4%, p=0.765) though, as expected, super-aged Group A had a higher prevalence of periampullary diverticulum (29.5% vs. 16.7%, p=0.001). The technical cannulation success rate was (96.6% vs. 96.8%, p= 0.54). All used cannulation techniques in the elderly group were efficient and safe. Logistic regression showed that age ≥80 was not associated with increased adverse events; however, difficult cannulation (adjusted odds ratio [AOR]=3.478; 95% confidence interval [CI]=1.877, 6.442; p<0.001) and CCI ≥2 (AOR=1.824; 95% CI=0.993, 3.349; p=0.045) were more likely to have adverse events. Age ≤65 (AOR=3.460; 95% CI=1.511, 7.922; p=0.003), female gender (AOR=2.362; 95% CI=1.089, 5.124; p=0.030), difficult cannulation (AOR=4.527; 95% CI=2.078, 9.860; p<0.001), and patients with cholangitis (AOR=3.261; 95% CI=1.204, 8.832; p=0.020) were strongly associated with increasing Post-ERCP Pancreatitis (PEP). Advanced age has not proved to be a risk factor of difficult cannulation, and secondary cannulation techniques can be safely and efficaciously utilized for this group. CCI ≥2 and difficult cannulation are associated with increased overall adverse events rate while age ≥80 factor is not.

We present a formalism to assess the safety of the COVID19 vaccines and infer a causal relation between vaccine administration and adverse effects, in particular death. We use data on adverse effects from VAERS covering the time interval [01-10-2020, 31-12-2021] (downloaded on 1 Feb 2022). We measure a vaccine fatality rate of order 0.01 for all vaccine manufacturers and identify a strong heterogeneity in the vaccine toxicity across vaccine lots, spanning up to four orders of magnitude. We compute the correlation between vaccination dates and death dates, and produce an estimate of the time lag that maximises the correlation, finding that the onset of adverse effects happened statistically (i.e. 32-41 percentiles) within one day after the vaccine administration and that death happened statistically (i.e. 22-50 percentiles) within about two weeks after the vaccine administration. These results provide data-based insights that can guide public health measures and health insurance policies.

We tested the possibility of using “adverse events count” (AEC) as a drug-risk indicator and side-effect severity indicator. Data from 3938 adverse event (AE) reports for COVID-19 vaccines (Comirnaty, Moderna, Vaxzevria, and Janssen) and 6869 AE reports for other medicines were collected from the Bulgarian Drug Agency database (01.01.2018–31.03.2022). AEC was modeled with zero-adjusted negative binomial (ZANBI) and zero-adjusted Poisson inverse Gaussian (ZAPIG) regression models, which account for zero absence and overdispersion. The models’ fit was checked with residual diagnostic plots and parametric correspondence to normality. Explanatory variables were: age, sex, sequence number (order of submission), severity of AE, and vaccine type. Average AEC was higher in severe vs. non-severe AE, and in females vs. males; it decreased with age and was lower in Comirnaty than other vaccines. Variability of AEC for COVID-19 data decreased with sequence number in severe AE and increased in non-severe AE. Full ZANBI models had greater sensitivity than parametric ZANBI or ZAPIG models. Results showed correlation between AEC and AE severity, suggesting AEC as a simple and reliable measure of drug-risk and side-effect severity for clinicians and regulators, especially for COVID-19 vaccines.

Polysaccharides such as alginate and gellan gum are biocompatible and easily accessible biopolymers with excellent properties to produce microparticles as drug delivery systems. However, the production methods often fail in reproducibility, compromising the translational potential of such systems. In this work, microparticles made from gellan gum and alginate were optimized using the coaxial air flow method, and an inexpensive and reproducible production method. A Design of Experiments was used to identify the main parameters that affect the microparticle’s production and optimization, focusing on the diameter and dispersibility. Airflow was the most significant factor for both parameters. Pump flow affected the diameter, whilst the gellan gum/alginate ratio affected dispersibility. After optimization, microparticle swelling, drug entrapment and release profile were analyzed at two pH, 7.4 and 6.5. Using methylene blue as a model drug, higher encapsulation and swelling indexes were obtained at pH 7.4, whilst a more pronounced release occurred at pH 6.5. The microparticle release profiles were studied by resorting to well-known models, showing a Fickian type release. The developed microparticles show promising results as drug-delivery vehicles for biomedical applications.

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective antileishmanial through pointing to new drug targets in less time having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

Novel Coronavirus (2019-nCOV) causes inflammatory response with worsening symptoms. Classification of potential anti-viral and anti-inflammatory drugs in managing the symptoms of the COVID-19 and reducing morbidity is important. The objective of this study is to identify a group of drugs, best suited for COVID-19 treatment based on recent developments in clinical trials, FDA drug evaluation, directions and developments and from drug therapies globally. Online literature search was done on Medline, PubMed and google scholar databases for studies on various treatments and drug therapies for COVID-19 and relevant studies were identified and the identified drugs are described in detail as per their Pharmacological, pharmaceutical properties of the drugs, mechanism of action, current COVID-19 drug therapy, contraindications and drug-drug interactions Certain drugs can inhibit action against viral infection and protect lungs from severe inflammatory response. This article summarizes several drugs like Hydroxychloroquine, Chloroquine, Remdesivir, Favipiravir, Lopinavir, Ritonavir, Dexamethasone, Ivermectin, Baricitinib, Casirivimab / imdevimab, Bamlanivimab along with auxiliary treatment like convalescent plasma transfusion. Remdesivir is first drug approved by FDA. Hydroxychloroquine, dexamethasone and remdesivir are showing results against COVID-19 but it is important to test the efficacy and safety of such drugs though some drugs have shown remarkable results.

A sustainable green one pot procedure for the synthesis of dihydropyrimidinones (DHPMs) derivatives by a three-component reaction of β-ketoester derivatives, aldehyde and urea or thiourea over the alkali-treated H-ZSM-5 zeolite under ball-milling has been developed. The product was isolated by simple washing of the crude reaction residue with ethyl acetate followed by evaporation of solvent. The hierachical zeolite catalyst (MFI27_6) showed high yield (86–96%) of dihydropyrimidinones (DHPMs), in very short time (10-30 min). The catalyst is recycled for subsequent reactions in four runs without appreciable loss of activity and high yields of products provide efficient protocol for Biginelli reactions.

Background: Circulating rare cells participate in breast cancer evolution as systemic components of the disease and thus, are a source of theranostic information. Exploration of cancer-associated rare cells is in its infancy. We determined the validity of a rare-cell detection platform and demonstrated the usefulness of a certain rare cell subset as a novel approach to characterize the breast cancer system. Methods: Linearity of the Rarmax® platform was established using a spike-in approach. The platform includes red blood cell lysis, leukocyte depletion and high-resolution fluorescence image recording. Rare cell analysis was conducted on 28 samples (before and after surgery) from 14 patients with breast cancer, 20 healthy volunteers and 9 non-cancer control volunteers. In-depth identification of rare cells, including circulating tumor cells, endothelial-like cells, erythroblasts and inflammation-associated cells, was performed using a phenotype and morphology-based classification system. Results: The platform performed linearly over a range of 5-950 spiked cells, with an average recovery of 84.6%. Circulating epithelial and endothelial-like cell subsets have been demonstrated to be associated with or independent of cancer with tumor presence. Furthermore, certain cell patterns may be associated with treatment-related adverse effects. The sensitivity in detecting tumor-presence and cancer-associated abnormality before surgery was 50% and 85.7%, respectively and the specificity was 100% and 96.6%, respectively. Conclusion: The present study supports the idea of a cancer-associated rare cell abnormality to represent tumor entities as well as systemic cancer. The latter is independent of the apparent clinical cancer.

For autonomous driving, perception is a primary and essential element that fundamentally deals with the insight into the ego vehicle’s environment through sensors. Perception is a challenging task suffering from dynamic objects and continuous environmental changes. The issue gets worse due to interrupting the quality of perception by adverse weather like snow, rain, fog, night light, sand storm, strong daylight, etc. In this work, we have tried to improve camera-based perception accuracy, such as autonomous driving-related object detection in adverse weather. We proposed the improvement of YOLOv8-based object detection in adverse weather through transfer learning using merged data from various harsh weather datasets. Two prosperous open-source datasets (ACDC and DAWN) and their merged dataset were used to detect primary objects on the road in harsh weather. A set of training weights were collected from training on the individual datasets, their merged version, and several subsets of those datasets according to their characteristics. A comparison between the training weights also occurred by evaluating the detection performance on the above-mentioned datasets and their subsets. The evaluation revealed that using custom datasets for training significantly improves the detection performance compared to the YOLOv8 base weights. And using more images through the feature-related data merging technique steadily increases the object detection performance.

Catalyst material plays a pivotal role in the pharmaceutical industry process. Among them, Friedel-Craft acylation reaction is a well-known reaction to synthesis acetophenone derivatives. However, Friedel-Craft acylation mostly used acetyl chloride as starting material with Lewis acid as homogeneous catalyst, which is nonenvironmental friendly process. In this work, a simple and efficient Friedel-Craft acylation reaction is reported by using the palladium oxide doped on activated bentonite (PdOAB) as the heterogeneous catalyst. The PdOAB catalyst material was characterized with scanning electron microscopy-energy dispersive X-ray (SEM-EDX), nitrogen isotherm adsorption, Fourier transform infrared (FTIR), X-ray powder diffraction (XRD), and thermogravimetric-differential thermal analysis (TG-DTA). The acetophenone derivatives with R = -H, -Cl, -CH₃, -OCH₃, -OH and -NH₂ at para position were successfully synthesized from its corresponding aromatic compounds with glacial acetic acid in 86.6, 7.9, 91.7, 86.6, 82.7, and 78.9% yield, respectively. Therefore, a green method was established because the byproduct is water and the catalyst material can be recovered. Furthermore, the substituent (σ) constants were obtained by using Hammet equation, and the catalysis mechanism has been proposed.

Developing sustainable and renewable energy sources is critical as higher and higher global energy and environmental challenges arise. Hydrogen has the highest mass/energy density of any fuel and is considered one of the best sources of clean energy. Water splitting is regarded as one of the most promising solutions for hydrogen production on a large scale. Highly efficient, durable and cost-effective catalysts for hydrogen evolution reaction (HER) are critical in the realization of this goal. Among many materials proposed, graphene-based materials offer some unique properties for HER catalysis. In this review, we present recent progress on development of graphene-based electrocatalysts toward HER throughout the past few years.

This work demonstrates that a plasmid can function as an efficient biocatalyst in mediating the nitroaldol (Henry) reaction at high temperatures in ultrapure water. Compared with ssDNA, the plasmid displayed a remarkable catalytic efficiency (97% yield within 20 min). Aromatic aldehydes which bear strong or moderate electron-withdrawing groups reacted satisfactorily with nitromethane, which afforded the corresponding β-nitroalcohols in good yields within 2 h (up to 98%). By contrast, aliphatic and aromatic aldehydes with electron-donating groups did not react. Moreover, the yield significantly dropped when the size of the carbanion increased, and the yield was only 10% when nitropropane was used as the donor.

Abstract: Background: With the growing trends in recreational marijuana use, our study aims at analyzing the association between Acute coronary syndromes (ACS) and Ventricular Fibrillation (Vfib) and cannabis use disorder in young adults (18 – 45) Methods: National In-patient Sample was used for population analysis. Probit logistic regression was used for analyzing the associations between diagnosis of ACS/ Vfib and documented cannabis use disorder. Propensity Score matched samples were made from the ACS/Vfib admissions with Cannabis use disorder to analyze the in-hospital outcomes. Results: Statistically significant association was found between admission diagnosis of ACS/ vfib, and documented cannabis use disorder in the study population. The association remained sig-nificant after accounting for potential confounders. Documented race as black, documented di-agnosis of uncontrolled hypertension and diabetes were found to have significant association with admissions for ACS among the population with documented Cannabis use disorder. No difference in mortality were found between ACS admissions with and without documented cannabis use disorder in the propensity matched cohorts. Conclusions: Documented diagnosis of Cannabis use disorder has statistically significant associ-ation with admission diagnosis of ACS/Vfib even after accounting for confounders. Documented race as black, and co existing diagnosis of uncontrolled hypertension and diabetes had significant association with admission diagnosis of ACS in population with documented cannabis use dis-order. Keywords: Cannabis use disorder; ACS; Ventricular fibrillation

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, and can impact quality of life significantly. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, 3-period, drug-drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), and a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron reduced by approximately 17%, when administered along with tamsulosin. No clinically significant changes in safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug-drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination therapy could be a promising treatment option for patients with OAB.

The cytokine-producing nucleotide-binding domain leucine-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome is generally recognized to play a central role in the immune response to vaccination and NLRP3 activity is known to be increased by both aluminum adjuvants and by oxidative stress. Thus, the presence of oxidative stress may place individuals at higher risk for exaggerated or prolonged inflammatory responses and related side effects from vaccination. We here examine the relationship between oxidative stress and NLRP3 inflammasome activity, particularly in the context of aluminum-adjuvanted vaccines, and its implications for subpopulations of individuals with restricted antioxidant capacity.

The clinical application of Phentolamine Mesylate (PM) as an anaesthetic reversal agent has been documented in paediatric patients and in conservative dentistry, but no studies have been found in implant surgery. A prospective randomised study was conducted in 60 patients eligible for mandibular implant treatment, randomly divided between the Control Group (CG) and Experimental Group (EG), who were administered PM. Haemodynamic changes, adverse effects and patient satisfaction were assessed. No statistically significant differences in haemodynamic changes and postoperative pain were found between CG and EG (p&lt;0.05), except for Systolic Blood Pressure (SBP) which increased slightly in EG, without posing a risk to the patient. There were no differences in the presence of adverse effects between the two groups, except in the CG which presented greater difficulty in chewing and biting (p&lt;0.05) and the EG with greater pain in the injection area (p=0.043). 83.3% of the EG patients would request PM again for future dental treatment. The use of PM offers an alternative in implant surgery, without increasing the risks and increasing the patient's quality of life.

Findings from studies of prenatal exposure to pesticides and adverse birth outcomes have been equivocal so far. We examined prenatal exposure to agricultural pesticides in relation to preterm birth and term low birthweight, respectively, in children born between 1998 and 2010 randomly selected from California birth records. We estimated residential exposures to agriculturally applied pesticides within 2 km of residential addresses at birth by pregnancy trimester for 17 individual pesticides and 3 chemical classes (organophosphates, pyrethroids, and carbamates). Among maternal addresses located within 2 km of any agricultural pesticide application, we identified 24,693 preterm and 220,297 term births, and 4,412 term low birthweight and 194,732 term normal birthweight infants. First or second trimester exposures to individual pesticides (e.g., glyphosates, paraquat, imidacloprid) or exposures to 2+ pesticides in the three chemical classes were associated with small increases (3-7%) in risk for preterm birth; associations were stronger for female offspring. We did not find associations between term low birthweight and exposures to pesticides other than for myclobutanil (OR: 1.11; 95% CI: 1.04-1.20) and possibly pyrethroids as a class. Our improved exposure assessment revealed that first and second trimester exposures to pesticides were associated with preterm delivery but few affected term low birthweight.

It is unclear whether military shoes (combat boots and sports shoes) attenuate loading rate or affect force transfer during walking. Therefore, this study compared ground reaction forces (GRF) related to impact and force transfer between combat boots, military sports shoes and running shoes. Ten army recruits walked over a walkway with two force plates embedded. GRF were measured when walking barefoot (for data normalization) and with combat boots, military sports shoes and running shoes. Loading rate, first and second peak forces and push-off rate of force were computed along with temporal analysis of waveforms. Reduced loading rate was observed for the running shoe compared to the combat boot (p = 0.02 and d = 0.98) and to the military sports shoe (p = 0.04 and d = 0.92). The running shoe elicited a smaller second peak force than the combat boot (p < 0.01 and d = 0.83). Walking with military shoes and combat boots led to larger force transfer then running shoes potentially due to harder material used in midsole composition (i.e. styrene-butadiene rubber). These results could lead to a potentially larger risk of injuries while long duration walking in military shoes and boots compared to traditional running shoes.

Drugs-drugs interactions(DDI) are entities composed of different chemical substructures (functional groups). In existing methods that predict drug–drug interactions based on the usage of substructures, each node is considered the center of a substructure, and adjacent nodes eventually become centers of similar substructures, resulting in redundancy. Furthermore, the significant differ- ences in structure and properties among compounds can lead to unrelated pairings, making it difficult to integrate information. This heterogeneity negatively affects the prediction results. To address these issues, we propose a drug–drug interaction prediction method based on substructure signature learning (DDI-SSL). This method extracts useful information from local subgraphs surrounding drugs and effectively utilizes substructures to assist in predicting drug side effects. Additionally, a deep clustering algorithm is used to aggregate similar substructures, allowing any individual subgraph to be reconstructed using this set of global signatures. Furthermore, we developed a layer-independent collaborative attention mechanism to model the mutual influence between drugs, generating signal strength scores for each class of drugs to mitigate noise caused by heterogeneity. Finally, we evaluated DDI-SSL on a comprehensive dataset and demonstrated improved performance in DDI prediction compared to state-of-the-art methods.

Heavy load carrying of water, firewood, and sand/stones is a ubiquitous activity for women living in developing countries. Although the intra-abdominal pressure associated with heavy load carrying is hypothesized to increase the risk of pelvic organ prolapse (POP) among women, relevant epidemiologic data are lacking. We conducted a comparative study involving two exploratory cross-sectional studies among convenience samples of women carrying heavy loads, with different characteristics: (1) as part of their activities for daily living, in Shinyanga region, Tanzania; and (2) working as sand miners in Pokhara, Nepal. Women were categorized has having “low” or “high” load-carrying exposures based on the measured weights of the loads being carried at the time of the survey, as well as on self-reported duration and frequency of load carrying. A summary score for lower abdominal discomfort suggestive of POP was generated using questions from the Pelvic Organ Prolapse Distress Inventory (POPDI-6). Women with higher load carrying exposures had on average higher discomfort scores in both Tanzania (adjusted prevalence difference (PDa)=3.7; 95% CI: -3.8-11.3; p=0.33) and Nepal (PDa=9.3; 95% CI: -4.9-23.6; p=0.18). We identified trends suggestive of an association between increasing heavy load carrying exposures and symptoms of lower abdominal discomfort. Our findings underscore the need for larger epidemiologic studies of the potential adverse reproductive health effects of heavy load carrying activities on women in developing countries.

Numerous study reports on chitosan hydrogels in different forms such as films, porous structures, nanoparticles, and microspheres for biomedical applications, however, this study concentrates on their modifications with different crosslinking agents and observing their effects on drug loading and releasing capacities. Linear chitosan along with crosslinked by two major cross-linkers, i.e., genipin and disulfide have been used to formulate three different hydrogel systems. The cross-linking process is heavily impacted by the temperature and the pH conditions. Three different drugs, i.e., thymoquinone, gefitinib, and erlotinib are loaded in phosphate buffer solutions and infused with three different hydrogel systems, thus, a total of nine combinations are studied and analyzed for drug loading and releasing capabilities with Ultraviolet–visible (UV-Vis) spectroscopy. This study finds thymoquinone shows the lowest loading efficacy compared to two other drugs in all three systems. Gefitinib shows stable loading and releasing regardless of crosslinking systems and genipin crosslinked system shows stable loading and releasing with all three drug molecules. These experimental results agree well with the findings of our previously published results conducted with molecular dynamics simulations.

Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.

The study aimed to identify clinical pharmacology patterns of prescribed and taken medications in older cardiovascular patients using electronic health records (EHRs) (n = 704) (2019–2022). Medscape Drug Interaction Checker was used to identify pairwise drug-drug interactions (DDIs). Prevalence rates of DDIs were 73.5% and 68.5% among taken and prescribed drugs, respectively. However, total number of DDIs was significantly higher among prescribed medications compared with the list of taken drugs (p < 0.05). Serious DDIs comprised 16% and 7% of all DDIs among prescribed and taken medications, correspondingly (p < 0.05). Median DDI numbers between prescribed versus taken medications were Me = 2, IQR 0-7 and Me = 3, IQR 0-7 per record, respectively. Prevalence of polypharmacy was significantly higher among prescribed medications compared with taken medications (p < 0.05). Women were taking significantly more drugs and had higher rates of polypharmacy and DDIs (p < 0.05). No sex-related differences were observed in the list of prescribed medications. ICD code U07.1 (COVID-19, virus identified) was associated with the highest median DDI number per record. Further research is warranted to improve EHR structure, patient engagement in reporting adverse drug reactions, and genetic profiling of patients to avoid potentially serious DDIs.

Increasing global concern over COVID-19 has recently brought greater attention to studies due to the ease of person-to-person transmission and the current lack of effective antiviral therapy. Here, we proposed the application of the adverse outcome pathway (AOP) framework to support re-search on the pathogenesis of viral disease. We first constructed adverse outcome pathways (AOPs) applicable to COVID-19 management to understand whether the infection causes severe acute respiratory distress. Based on the AOP framework where mechanistic elucidation of the pathway from the interaction of chemicals (or viruses) to apical endpoints is represented, our COVID-19 AOP indicated that the molecular initiating event (MIE) was angiotensin-converting enzyme 2 (ACE2) interaction, and the key events (KEs) were the increased pro-inflammatory cytokines in immune cells, with increased mortality as an apical adverse outcome (AO). However, there is still limited information on the toxicity mechanisms of AOPs in COVID-19; therefore, detailed KEs and AOs on toxicity mechanisms will be required to fill these gaps in the data. This study demonstrated that the COVID-19 AOP framework is a suitable tool to design new drugs and to integrate crowded-sourced information for the battle against the COVID-19 pandemic.

: Oscillation synchronization through diffusion-based communication of active materials can lead to emergence of diverse patterns and collective behaviors. A detailed general description of the formation process of synchronization or resynchronization dynamics is a challenging task. We employ a photosensitive Belousov-Zhabotinsky reaction-diffusion model (within a gel media) to investigate the recovery process of oscillation synchronization between a pair of gel patches. The recovery time for oscillation resynchronization can be modulated by patch-distance, species of signaling molecules, intensity and duration of illumination. Analysis reveals that the “switch effect” of the gel-distance and the “promotion effect” from illumination on the oscillation resynchronization originate from the competition between processes of photo-promotion of oscillation, diffusion of signaling molecules (HBrO2 and Br-) and disproportionation of HBrO2. These results will benefit studies on bio-inspired active materials and soft motors.

The increase in carbon dioxide emissions has a significant impact on human society and the global environment. As the most abundant and cheap C1 resource, the conversion and utilization of carbon dioxide has received extensive attention from researchers. In many methods of carbon dioxide conversion and utilization, the reverse water gas conversion reaction is considered to be one of the most effective ways. In this paper, the research progress of reverse water gas conversion reaction in recent years is introduced.

MoS2 has long been considered as a promising catalyst for hydrogen production. At present, there are many strategies to further improve its catalytic performance, such as edge engineering, defect engineering, phase engineering and so on. However, at present, there is still a great deal of controversy about the mechanism of MoS2 catalytic hydrogen production. For example, it is generally believed that the base plane of MoS2 is inert, but it has been reported that the inert base plane can undergo a transient phase transition in the catalytic process to play the catalytic role, which is contrary to the common understanding that the catalytic activity is only at the edge. Therefore, it is necessary to further understand the mechanism of MoS2 catalytic hydrogen production. In this article, we summarized the latest research progress on the catalytic hydrogen production of MoS2, which is of great significance for revisited the mechanism of MoS2 catalytic hydrogen production.

Dynamics of human populations can be affected by various socio-economic factors through their influence on the natality and mortality rates, and on the migration intensity and directions. In this work we study an economic-demographic model which takes into account the dependence of the wealth production rate on the available resources. In the case of nonlocal consumption of resources the homogeneous in space wealth-population distribution is replaced by a periodic in space distribution for which the total wealth increases. For the global consumption of resources, if the wealth redistribution is small enough, then the homogeneous distribution is replaced by a heterogeneous one with a single wealth accumulation center. Thus, economic and demographic characteristics of nonlocal and global economies can be quite different in comparison with the local economy.

Temperature influences the life of many organisms in various ways. A great number of them live under conditions, where their ability to adapt to changes in temperature can be vital and largely determine their fitness. Understanding the mechanisms and principles underlying this ability to adapt can be of great advantage, for example, to improve growth conditions for crops and increase their yield. In times of imminent, increasing climate change, this becomes even more important, in order to find strategies and help crops cope with these fundamental changes. There is intense research in the field of acclimation, that comprises fluctuations of various environmental conditions, but most acclimation research focuses on regulatory effects and the observation of gene expression changes within the examined organism. As thermodynamic effects are a direct consequence of temperature changes, these should necessarily be considered in this field of research, but are often neglected. Also, compensated effects might be missed, even though they are equally important for the organism, since they do not cause observable changes, but rather counteract them. In this work, using a systems biology approach, we demonstrate that even simple network motifs can exhibit temperature dependent functional features, resulting from the interplay of network structure and the distribution of activation energies over the involved reactions. The demonstrated functional features are (i) the reversal of fluxes within a linear pathway, (ii) a thermo-selective branched pathway with different flux modes and (iii) the increased flux towards carbohydrates in a minimal calvin cycle that was designed to demonstrate temperature compensation within reaction networks. By this, we expand the scope of thermodynamic modelling of biochemical processes by addressing further possibilities and effects, following established mathematical descriptions of biophysical properties.

The tsscds method, recently developed in our group, discovers chemical reaction mechanisms with minimal human intervention. It employs accelerated molecular dynamics, spectral graph theory, statistical rate theory and stochastic simulations to uncover chemical reaction paths and to solve the kinetics at the experimental conditions. In the present review, its application to solve mechanistic/kinetics problems in different research areas will be presented. Examples will be given of reactions involved in photodissociation dynamics, mass spectrometry, combustion chemistry and organometallic catalysis. Some planned improvements will also be described.

Zinc (Zn) is the second most abundant metal in the human body, and is essential for the function of 10% of all proteins. As metals cannot be synthesized or degraded, they must be assimilated from diet by specialized transport proteins, which unfortunately also provide an entry route for the toxic metal pollutant cadmium (Cd). The intestinal absorption of Zn depends on the composition of food that is consumed, firstly the amount of Zn itself, and then the quantity of other food constituents such as phytate, protein and calcium (Ca). In cells, Zn is involved in regulation of intermediary metabolism, gene expression, cell growth, differentiation, apoptosis, and antioxidant defense mechanisms. Cellular influx, efflux, subcellular compartmentalization, and trafficking of Zn are coordinated by transporter proteins, the Solute-Linked Carrier 30A and 39A (SLC30A and SLC39A), known as the ZnT and the Zrt-/Irt-like protein (ZIP). Because of its chemical similarity with Zn and Ca, Cd disrupts the physiological functions of both. The concurrent induction of a Zn efflux transporter ZnT1 (SLC30A1) and metallothionein by Cd disrupts the homeostasis and reduces the bioavailability of Zn. The present review highlights the increased mortality and the severity of various diseases, including those induced by COVID-19 infections, among Cd-exposed persons and the roles of Zn and other transport proteins in the manifestation of Cd cytotoxicity. Special emphasis is given to the potential protective effects of Zn against bone, lung and heart diseases associated with Cd exposure. The difficult challenge of determining a permissible intake level of Cd is discussed in relation to the recommended dietary Zn intake levels.

Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. In particular, the modRNA-based COVID-19 vaccines have proven that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options. MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and improves cardiac dysfunction. However, it remains elusive whether the early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. To obtain acute CCN5 expression, we used modRNA-mediated gene transfer in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: 1) preventive intervention and 2) therapeutic intervention. Cardiac function and structural changes were measured by echocardiography and magnetic resonance imaging. Finally, fibrosis and the underlying molecular pathway were analyzed by western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The modRNA-CCN5 gene transfer successfully ameliorated CF and enhanced cardiac function in both preventive and therapeutic interventions without LV rupture or any adverse cardiac remodeling. Conclusively, early intervention in CF by modRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure without adverse structural remodeling.

Allergic reactions are the most frequent adverse effects of blood transfusion, and anaphylactic shock, although less frequent, is systemic and serious. The causes of allergic reactions to blood transfusions are largely unknown, but deficiencies in serum proteins such as haptoglobin (Hp) can lead to anaphylactic shock. A complete deletion of the haptoglobin gene (HPdel) was first identified in families with anomalous inheritance and then verified as a genetic variant that can cause anaphylactic shock because homozygotes of HPdel have an Hp deficiency. Thereby, they may produce antibodies against Hp from blood transfusions. HPdel is found in East and Southeast Asian populations, but not in other populations, with a frequency of approximately 0.9% to 4%. Diagnosis of Hp deficiency due to HPdel prior to transfusion is desirable because severe adverse reactions can be prevented by washing the red blood cells and/or platelets with saline or by administrating plasma products obtained from an Hp deficient donor pool. This review outlines the background of the identification of HPdel and several genetic and immunological methods developed for diagnosing Hp deficiency caused by HPdel.

Objective: To evaluate the existing meta-analytic evidence of associations between exposure to ultra-processed foods, as defined by the Nova food classification system, and adverse health outcomes. Design: Systematic umbrella review of existing meta-analyses. Data Sources: MEDLINE, PsycINFO, Embase, and the Cochrane Database of Systematic Reviews, as well as manually searching reference lists from 2009 to June 2023. Inclusion Criteria: Systematic reviews and meta-analyses of cohort, case-control, and/or cross-sectional study designs that evaluated the associations between exposure to ultra-processed foods and adverse health outcomes in humans across the lifespan. Results: The search identified 45 unique pooled analyses, including 13 dose-response and 32 non-dose-response associations (n=9,888,373). Overall, direct associations were found between exposure to ultra-processed foods and 32 (71%) health outcome domains spanning cardiometabolic, gastrointestinal, and respiratory conditions, cancer, mental health, and mortality. Based on a pre-specified evidence classification criteria, convincing evidence (Class I) supported direct associations between greater ultra-processed food exposure and higher risks of incident cardiovascular disease-related mortality (RR: 1.50; 95%CIs: 1.37 to 1.63), type two diabetes (dose-response RR: 1.12; 95%CIs: 1.11 to 1.13), and depressive outcomes (HR: 1.21; 95%CIs: 1.16 to 1.28), as well as higher risks of prevalent anxiety outcomes (OR: 1.48; 95%CIs: 1.37 to 1.59) and combined common mental disorder outcomes (OR: 1.53; 95%CIs: 1.43 to 1.63). Highly suggestive (Class II) evidence indicated that greater exposure to ultra-processed foods was directly associated with higher risks of incident all-cause mortality (RR: 1.21; 95%CIs: 1.15 to 1.27), heart disease-related mortality (dose-response HR: 1.66; 95%CIs: 1.51 to 1.84), and type two diabetes (OR: 1.40; 95%CIs: 1.23 to 1.59), together with higher risks of prevalent obesity (OR: 1.55; 95%CIs: 1.36 to 1.77), adverse sleep-related outcomes (OR: 1.41; 95%CIs: 1.24 to 1.60), and wheezing (RR: 1.40; 95%CIs: 1.27 to 1.55). Out of the remaining 34 pooled analyses, 21 were graded as suggestive or weak strength (Class III-IV) and 13 were graded as no evidence (Class V). Using the GRADE framework, 22 pooled analyses were rated as "Low" quality, with 19 rated as "Very Low” and four rated as "Moderate" quality. Conclusions: Higher exposure to ultra-processed food was associated with a greater risk of adverse health outcomes, especially cardiometabolic, common mental disorder, and mortality outcomes. These findings provide a rationale to evaluate the effectiveness of using population-based measures to target and reduce dietary exposure to ultra-processed foods for improved human health. Systematic Review Registration: PROSPERO CRD42023412732.

Background: Few studies examined the contributions of childhood adversities, intimate partner violence and social support to antenatal depression (AD). This study aims to 1) evaluate association of these psychosocial factors with AD symptoms in early pregnancy; and 2) examine the mediating effect of social support on the relationship between psychosocial stressors and AD symptoms.Methods: Participants were 120 pregnant women aged from 18 to 49 in less than 16 gestational weeks and attending at Antenatal Care Center at Khon Kaen hospital, Thailand. AD symptoms were assessed by the Edinburgh Postnatal Depression Scale (EPDS). Childhood adversities, intimate partner violence and social support were measured using the Adverse Childhood Experiences Questionnaire (ACE questionnaire), Abuse Assessment Screen (AAS), and Multidimensional Scale of Perceived Social Support (MSPSS). Results: We found that the EPDS score was significantly and positively associated with adverse childhood experiences (ACEs) and negatively with social support. Partial Least Square analysis showed that 49.1% of the variance in the depressive subdomain of the EPDS score was predicted by ACEs, namely psychological and physical abuse and neglect, emotional or physical abuse by the partner, unplanned pregnancy, and no satisfaction with their relationship. The effects of adverse childhood experience due to neglect on the EDPS score was mediated by social support by friends. Limitations: ACEs were assessed retrospectively and, therefore, may be susceptible to recall bias.Conclusion: Prenatal depression scores are to a large extent predicted by psychological distress as indicated by early lifetime trauma, abuse by partner, relation satisfaction, and implications of unintended pregnancy.

In this paper, the computational fluid dynamics (CFD) method has been used to simulate the gas flow and the catalytic hydrogenation process of the C-2 hydrogenation adiabatic reactor in a practical ethylene production unit of a chemical plant. The laminar finite-rate model was used for the chemical reaction model. The standard two-equation model was used for the turbulence model. The exponent-function kinetic model was used for the reaction dynamics model. The simulation results were in good agreement with the actual industrial data obtained from the C-2 hydrogenation reactor, and the distributions of reaction parameters such as temperature and component concentrations in the reactor were further analyzed. Based on the validated CFD models, the structure and operating conditions of the reactor, as well as hydrogen load distribution ratios, are simulated for comparing the comprehensive performance metrics of ethylene selectivity and acetylene conversion rate; as a result, we can obtain the optimal temperature of 312 K, the optimal hydrogen/acetylene ratio of 0.10 as well as the optimal hydrogen load distribution ratio of 4:4:2, and the diameter/height ratio exerts a marginal effect on the selectivity, conversion rate and harmonic mean of the reactor.

The primary purpose of this study was to determine the prevalence of drug-drug interaction (DDI) and duplicate therapy in chronic patients in a completely random study population engaged in digital health apps. In this cross-sectional study, polypharmacy checks for 100 completely anonymous patients were analyzed for the occurrence of DDIs and duplicate therapy. Logistic regression models were used to identify factors associated with DDIs and duplicate therapy. DDIs and duplicate therapy prevalence were 34% and 33%, respectively. Chi-Square test discovered a significant association between the DDIs and duplicate therapy variables. Logistic regression models showed a strong association between the number of medications taken and higher odds of DDIs occurring in our population only. In conclusion, our study shows that polypharmacy is a determining factor for the occurrence of unwanted DDIs, and the prevalence of duplicate therapy and DDIs is around 33%, increasing an issue regarding patient safety and its burden to the healthcare system.

Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It has been early on recognized that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical composition has recently been used as a means to enhance their targeting or absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.

A systematic study has been conducted on barbiturate complexes of all five alkali metals Li–Cs prepared from the metal carbonates or hydroxide in aqueous solution without other potential ligands present, varying the stoichiometric ratio of metal ion to barbituric acid (BAH). Eight polymeric compounds (two each for Na, K, and Rb and one each for Li and Cs) have been characterised by single-crystal X-ray diffraction. All contain some combination of barbiturate anion BA− (necessarily in a 1:1 ratio with the metal cation M+), barbituric acid, and water. All organic species and water molecules are coordinated to the metal centres via oxygen atoms as either terminal or bridging ligands. Coordination numbers range from 4 (for the Li complex) to 8 (for the Cs complex). Extensive hydrogen bonding plays a significant role in all the crystal structures, almost all of which include pairs of N–H…O hydrogen bonds linking BA− and/or BAH components into ribbons extending in one dimension. Factors influencing the structure adopted by each compound include cation size and reaction stoichiometry as well as hydrogen bonding.