Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

Effect of autologous platelet-rich plasma on the fertility and quality of cryopreserved buffalo bull semen: a comparative study using OptiXcell® and tris egg yolk extenders.

BACKGROUND: Buffalo spermatozoa have a distinct membrane structure that makes them more vulnerable to cryopreservation, resulting in lower-quality post-thawed sperm. This decreases the success rate of artificial insemination in buffaloes. Understanding and addressing these specific vulnerabilities are essential for improving reproductive techniques in buffalo populations. The properties of cryopreserved buffalo bull semen were examined in this study regarding the impact of adding autologous platelet-rich plasma (PRP) to OptiXcell® or Tris egg yolk-based extenders. Ten buffalo bulls were used to collect semen. Each bull's ejaculate was separated into two main equal amounts, each of which was then diluted with either OptiXcell® or Tris egg yolk-based extender, supplemented with various PRP concentrations (5%, 10%, and 15%), and the control (0%), before being cryopreserved according to established protocols. Following equilibration and thawing, the quality and functionality of the sperm were evaluated, along with the antioxidant enzyme activities (GSH and TAC), malondialdehyde (MDA) content, and in vivo fertilization rate of the thawed semen. RESULTS: All PRP concentrations in both extenders, particularly 10% PRP, improved the quality and functionality of the sperm in both equilibrated and frozen-thawed semen. Additionally, the antioxidant enzyme activities in both extenders were higher in the PRP-supplemented groups compared to the control group in thawed semen (P < 0.05). All post-thaw sperm quality, antioxidant enzyme activities, and functionality aside from DNA integrity were higher (P < 0.05) in the PRP-supplemented OptiXcell® than in the PRP-supplemented Tris egg yolk-based extender. The fertility of cryopreserved semen in the extenders supplemented with 10% and 15% PRP increased (P < 0.05) significantly more than that of the control extenders, with 10% PRP being the optimum concentration in OptiXcell® (80%) compared to that of Tris egg yolk-based extender (66.67%) and control of two extenders (53.33% and 46.67%, respectively). CONCLUSIONS: Even though autologous PRP-supplemented extenders have a protective impact on equilibrated and cryopreserved semen, 10% PRP-supplemented OptiXcell® extenders are more effective at preserving post-thaw semen quality, functionality, and antioxidant capacity, which increases the in vivo fertility of buffalo bulls.

Metabolic changes assessed by 1H MR spectroscopy in the corpus callosum of post-COVID patients.

OBJECTIVE: Many patients with long COVID experience neurological and psychological symptoms. Signal abnormalities on MR images in the corpus callosum have been reported. Knowledge about the metabolic profile in the splenium of the corpus callosum (CCS) may contribute to a better understanding of the pathophysiology of long COVID. MATERIALS AND METHODS: Eighty-one subjects underwent proton MR spectroscopy examination. The metabolic concentrations of total N-acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (Cr), myo-inositol (mI), and NAA/Cho in the CCS were statistically compared in the group of patients containing 58 subjects with positive IgG COVID-19 antibodies or positive SARS-CoV-2 qPCR test at least two months before the MR and the group of healthy controls containing 23 subjects with negative IgG antibodies. RESULTS: An age-dependent effect of SARS-CoV-2 on Cho concentrations in the CCS has been observed. Considering the subjective threshold of age = 40 years, older patients showed significantly increased Cho concentrations in the CCS than older healthy controls (p = 0.02). NAA, Cr, and mI were unchanged. All metabolite concentrations in the CCS of younger post-COVID-19 patients remained unaffected by SARS-CoV-2. Cho did not show any difference between symptomatic and asymptomatic patients (p = 0.91). DISCUSSION: Our results suggest that SARS-CoV-2 disproportionately increases Cho concentration in the CCS among older post-COVID-19 patients compared to younger ones. The observed changes in Cho may be related to the microstructural reorganization in the CCS also reported in diffusion measurements rather than increased membrane turnover. These changes do not seem to be related to neuropsychological problems of the post-COVID-19 patients. Further metabolic studies are recommended to confirm these observations.

Symbiotic Antidiabetic Effect of Lactobacillus casei and the Bioactive Extract of Cleome droserifolia (Forssk.) Del. on Mice with Type 2 Diabetes Induced by Alloxan.

The consumption of probiotics protects pancreatic ß-cells from oxidative damage, delaying the onset of type 2 diabetes mellitus (T2DM) and preventing microvascular and macrovascular complications. This study aimed to evaluate the antidiabetic activity of CDE fermented by Lactobacillus casei (ATCC 39539) (LC) in alloxan-induced diabetic rats. The oxidative stress identified by catalase (CAT), serum AST, ALT, ALP, creatinine, urea, and uric acid were measured. The chemical profiles of the plant extract and the fermented extract were studied using HPLC/MS. The potential of the compounds towards the binding pockets of aldose reductase and PPAR was discovered by molecular docking. A significant reduction in fasting blood glucose in alloxan-treated rats. The CAT showed a significant decrease in diabetic rats. Also, serum AST, ALT, ALP, creatinine, urea, and uric acid were significantly decreased in the mixture group. Mild histological changes of pancreatic and kidney tissues suggested that the mixture of probiotics and cleome possesses a marked anti-diabetic effect. Overall, the study suggests that the combination of Cleome droserifolia fermented by Lactobacillus casei exhibits significant antidiabetic activity (p-value=0.05), reduces oxidative stress, improves lipid profiles, and shows potential for the treatment of diabetes.

Evaluating the Effect of TeamSTEPPS on Teamwork Perceptions and Patient Safety Culture among Newly Graduated Nurses.

BACKGROUND: Quality healthcare delivery is contingent upon effective teamwork and a patient safety-focused culture. TeamSTEPPS offers an evidence-based framework that enhances these competencies. However, the impact of TeamSTEPPS on newly graduated nurses, who undergo a significant transitional phase, has yet to be comprehensively explored. Consequently, the objective of this study was to assess the influence of TeamSTEPPS on perceptions of teamwork and patient safety culture among newly graduated nurses. METHODS: This study employed a quasi-experimental pretest-posttest design with a single group, utilizing a convenience sample of 132 newly recruited nurses from a university hospital. The participants completed the hospital survey on patient safety culture and the TeamSTEPPS teamwork perceptions questionnaire at three different time points. RESULTS: The impact of the TeamSTEPPS training program was found to be significant, as indicated by the substantial improvement in the mean scores of nurses' perceptions regarding teamwork and the culture of patient safety across multiple assessments (p < 0.001). The effect size (η2p ≥ 0.14) suggests a large effect, further emphasizing the meaningful impact of the program on the measured outcomes. CONCLUSIONS: The study underscores the effectiveness of TeamSTEPPS as a valuable framework for facilitating the seamless transition of newly graduated nurses into the healthcare field. Integrating TeamSTEPPS into nursing training programs can significantly enhance nurses' perceptions of teamwork and the culture of patient safety. Therefore, it is crucial for nurse managers to implement TeamSTEPPS systematically, aiming to improve teamwork perception and cultivate a patient safety culture among nurses. Furthermore, they should establish mechanisms to ensure the consistent application of these skills over time.

Menopausal symptom management: Fezolinetant's varied doses provide effective relief for vasomotor symptoms in women - A meta-analysis of 3291 participants.

Menopause represents the physiological transition when a woman's reproductive period ends associated with a variety of symptoms, including vasomotor symptoms, such as night sweats and hot flashes. This systematic review and meta-analysis aimed to assess the effectiveness and safety of oral Fezolinetant for treating vasomotor symptoms associated with menopause. Five electronic databases were searched from their inception until May 2023. Via the Cochrane risk of bias tool, two reviewers assessed the studies' quality. The primary outcomes were a decrease in VMSs frequency and severity and safety outcomes at 4 and 12 weeks. Data were extracted and then analyzed using RevMan software. This meta-analysis included six trials with a total of 3291 women that compared Fezolinetant to a placebo in the treatment of menopausal VMSs. After 4 and 12 weeks of therapy, fezolinetant at 30 mg QD or 45 mg QD substantially decreased the frequency and severity of VMSs per 24 hours compared to placebo. Fezolinetant at 90 mg BID, 30 mg QD, or 45 mg QD did not show a significant difference in the rate of treatment-emergent adverse events (TEAEs), headache, and TEAEs leading to permanent discontinuation compared to placebo. Fezolinetant proves to be a successful and well-tolerated remedy for menopausal women suffering from VMSs. Notably, the 45 mg daily dosage over 12 weeks exhibited significant efficacy. Nonetheless, extensive future trials are necessary to ascertain its long-term safety, effectiveness, and relative potency compared to alternative VMS treatments like hormone therapy.

La ménopause représente la transition physiologique lorsque la période de reproduction d'une femme se termine, associée à divers symptômes, notamment des symptômes vasomoteurs, tels que des sueurs nocturnes et des bouffées de chaleur. Cette revue systématique et méta-analyse visaient à évaluer l'efficacité et l'innocuité du Fezolinetant oral pour traiter les symptômes vasomoteurs associés à la ménopause. Cinq bases de données électroniques ont été consultées depuis leur création jusqu'en mai 2023. Via l'outil Cochrane sur le risque de biais, deux examinateurs ont évalué la qualité des études. Les principaux critères de jugement étaient une diminution de la fréquence et de la gravité des SVM ainsi que des critères de sécurité à 4 et 12 semaines. Les données ont été extraites puis analysées à l'aide du logiciel RevMan. Cette méta-analyse comprenait six essais portant sur un total de 3 291 femmes comparant Fezolinetant à un placebo dans le traitement des SVM ménopausiques. Après 4 et 12 semaines de traitement, le fézolinetant à la dose de 30 mg une fois par jour ou de 45 mg une fois par jour a considérablement réduit la fréquence et la gravité des SMV toutes les 24 heures par rapport au placebo. Le fézolinetant à la dose de 90 mg deux fois par jour, de 30 mg une fois par jour ou de 45 mg une fois par jour n'a pas montré de différence significative dans le taux d'événements indésirables survenus pendant le traitement (TEAE), de maux de tête et de TEAE conduisant à un arrêt définitif par rapport au placebo. Le fézolinetant s'avère être un remède efficace et bien toléré pour les femmes ménopausées souffrant de VMS. Notamment, la dose quotidienne de 45 mg sur 12 semaines a montré une efficacité significative. Néanmoins, de futurs essais approfondis sont nécessaires pour vérifier son innocuité, son efficacité et sa puissance relative à long terme par rapport aux traitements alternatifs du VMS comme l'hormonothérapie.

Chemopreventive Effects of Onosma mutabilis against Azoxymethane-Induced Colon Cancer in Rats via Amendment of Bax/Bcl-2 and NF-κB Signaling Pathways.

Onosma species (Boraginaceae) are well known as medicinal plants due to their wide range of pharmaceutical potential. The present study aims to investigate the anticancer (in vitro) and chemo-protective (in vivo) efficacies of Onosma mutabilis extract (OME) in the azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats. The in vitro antiproliferative effects of OME were determined on two human tumor cell lines (Caco-2 and HT-29) via MTT assay. The in vivo chemoprotective effects of OME were investigated by performing various biochemical analyses in serum and tissue homogenates of albino rats, along with determining oxidative stress biomarkers. Inflammatory biomarkers of colon, colonic gross morphology (by methylene blue), ACF formation, and colonic histopathology (H & E stain) were determined. The immunohistochemistry of colonic tissues was also assessed by Bax and Bcl-2 protein expression. The results showed that the antitumor activity of OME against Caco-2 and HT-29 colorectal cancer cells ranged between 22.28-36.55 µg/mL. OME supplementation caused a significant drop in the ACF values and improved the immunohistochemistry of the rats shown by up-regulation of Bax and down-regulation of Bcl-2 protein expressions. These outcomes reveal that O. mutabilis may have chemoprotective efficiency against AOM-induced colon cancer represented by the attenuation of ACF formation possibly through inhibition of free radicals, inflammation, and stimulation of the colon antioxidant armory (SOD, CAT, and GPx) and positive regulation of the Nrf2-Keap1 pathway.

Maternal microbiota and gestational diabetes: impact on infant health.

Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has been associated with an increased risk of obesity and diabetes in the offspring. Pregnancy is accompanied by tightly regulated changes in the endocrine, metabolic, immune, and microbial systems, and deviations from these changes can alter the mother's metabolism resulting in adverse pregnancy outcomes and a negative impact on the health of her infant. Maternal microbiomes are significant drivers of mother and child health outcomes, and many microbial metabolites are likely to influence the host health. This review discusses the current understanding of how the microbiota and microbial metabolites may contribute to the development of GDM and how GDM-associated changes in the maternal microbiome can affect infant's health. We also describe microbiota-based interventions that aim to improve metabolic health and outline future directions for precision medicine research in this emerging field.

Structural characterization and physicochemical properties of the exopolysaccharide produced by the moderately halophilic bacterium Chromohalobacter salexigens, strain 3EQS1.

A strain, 3EQS1, was isolated from a salt sample taken from Lake Qarun (Fayoum Province, Egypt). On the basis of physiological, biochemical, and phylogenetic analyses, the strain was classified as Chromohalobacter salexigens. By 72 h of growth at 25 °C, strain 3EQS1 produced large amounts (15.1 g L-1) of exopolysaccharide (EPS) in a liquid mineral medium (initial pH 8.0) containing 10% sucrose and 10% NaCl. The EPS was precipitated from the cell-free culture medium with chilled ethanol and was purified by gel-permeation and anion-exchange chromatography. The molecular mass of the EPS was 0.9 × 106 Da. Chemical analyses, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy showed that the EPS was a linear ß-D-(2 → 6)-linked fructan (levan). In aqueous solution, the EPS tended to form supramolecular aggregates with a critical aggregation concentration of 240 µg mL-1. The EPS had high emulsifying activity (E24, %) against kerosene (31.2 ± 0.4%), sunflower oil (76.9 ± 1.3%), and crude oil (98.9 ± 0.8%), and it also had surfactant properties. A 0.1% (w/v) aqueous EPS solution reduced the surface tension of water by 11.9%. The levan of C. salexigens 3EQS1 may be useful in various biotechnological processes.

A case of hyperhemolysis syndrome in sickle cell disease and concomitant COVID-19.

BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon transfusion reaction described in several hematologic disorders, including sickle cell disease (SCD). HHS is characterized by a decline in hemoglobin (Hb) values below pre-transfusion levels following transfusion of red blood cells (RBCs), coupled with laboratory markers consistent with hemolysis. The proposed pathophysiologic mechanisms underlying HHS include increased phosphatidylserine expression, macrophage activation, and complement dysregulation. Many pathophysiologic mechanisms thought to contribute to HHS have been similarly described in cases of severe COVID-19. CASE REPORT: A 28-year-old male with a history of HbSS presented with shortness of breath, right-sided chest pain, and a two-day history of fever. Polymerase chain reaction (PCR) detected SARS-CoV-2 infection with the omicron variant. The patient required an RBC transfusion (pre-transfusion hemoglobin [Hb]5.8 g/dL) with an immediate post-transfusion Hb of 6.3 g/dL. However, Hb rapidly declined to 1.7 g/dL, and lactate dehydrogenase (LDH) rose to 8701 u/L. The absolute reticulocyte count of 538 × 109/L correspondingly fell to 29 × 109/L. Despite additional RBC transfusions and initiation of immunosuppressive therapy, he expired on Day 9(D9). CONCLUSION: Given the similarities in their proposed pathophysiology, patients with SCD and concomitant SARS-CoV-2 infection may be predisposed to developing HHS.

Identification of promising multi-targeting inhibitors of obesity from Vernonia amygdalina through computational analysis.

Vernonia amygdalina, a widely consumed West African food herb, can be a boon in the discovery of safe anti-obesity agents given the extensive reports on its anti-obesity and antidiabetic potentials. The main aim of this study was to screen 78 Vernonia-Derived Phytocompounds (VDPs) against the active site regions of Human Pancreatic Lipase (HPL), Human Pancreatic Amylase and Human Glucosidase (HG) as drug targets associated with obesity in silico. Structure-based virtual screening helped to identify Luteolin 7-O-glucuronoside and Andrographidoid D2 as hit compounds with dual targeting tendency towards the HPL and HG. Analysis of the molecular dynamic simulation trajectory files of the ligand-receptor complexes as computed from the thermodynamic parameters plots showed not only increased flexibility and greater interaction potential of the active site residues of the receptor towards the VDPs as indicated by the root mean square fluctuation but also higher stability as indicated by the root mean square deviation, radius of gyration and number of hydrogen bonds. The cluster analysis further showed that the interactions with important residues were preserved in the dynamic environment. These observations were further verified from Molecular Mechanics Generalized Born Surface Area Analysis, which also showed that residual contributions to the binding free energies were mainly from catalytic residues at the active sites of the enzymes. The hit compounds also feature desirable physicochemical properties and drug-likeness. This study provides in silico evidence for the inhibitory potential of phytochemicals from Vernonia amygdalina against two target enzymes in obesity.

Identification of potential inhibitors of cholinergic and ß-secretase enzymes from phytochemicals derived from Gongronema latifolium Benth leaf: an integrated computational analysis.

Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against hAChE, hBChE and hBACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for hAChE, hBChE and hBACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and - 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3' and flip (67-75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation.

New apoptotic anti-triple-negative breast cancer theobromine derivative inhibiting EGFRWT and EGFRT790M: in silico and in vitro evaluation.

A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural characteristics to interact with EGFR's pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (T-1-DOMPA). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of T-1-DOMPA. Then, T-1-DOMPA's anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies, T-1-DOMPA bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of T-1-DOMPA were computed before preparation, and its drug-likeness was anticipated. Therefore, T-1-DOMPA was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of T-1-DOMPA against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC50 value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly, T-1-DOMPA inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC50 values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally, T-1-DOMPA prevented effectively the MDA-MB-231cell line's healing and migration abilities. Also, T-1-DOMPA's abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally, T-1-DOMPA caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell.

Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors.

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

Machine learning prediction for COVID-19 disease severity at hospital admission.

IMPORTANCE: Early prognostication of patients hospitalized with COVID-19 who may require mechanical ventilation and have worse outcomes within 30 days of admission is useful for delivering appropriate clinical care and optimizing resource allocation. OBJECTIVE: To develop machine learning models to predict COVID-19 severity at the time of the hospital admission based on a single institution data. DESIGN, SETTING, AND PARTICIPANTS: We established a retrospective cohort of patients with COVID-19 from University of Texas Southwestern Medical Center from May 2020 to March 2022. Easily accessible objective markers including basic laboratory variables and initial respiratory status were assessed using Random Forest's feature importance score to create a predictive risk score. Twenty-five significant variables were identified to be used in classification models. The best predictive models were selected with repeated tenfold cross-validation methods. MAIN OUTCOMES AND MEASURES: Among patients with COVID-19 admitted to the hospital, severity was defined by 30-day mortality (30DM) rates and need for mechanical ventilation. RESULTS: This was a large, single institution COVID-19 cohort including total of 1795 patients. The average age was 59.7 years old with diverse heterogeneity. 236 (13%) required mechanical ventilation and 156 patients (8.6%) died within 30 days of hospitalization. Predictive accuracy of each predictive model was validated with the 10-CV method. Random Forest classifier for 30DM model had 192 sub-trees, and obtained 0.72 sensitivity and 0.78 specificity, and 0.82 AUC. The model used to predict MV has 64 sub-trees and returned obtained 0.75 sensitivity and 0.75 specificity, and 0.81 AUC. Our scoring tool can be accessed at https://faculty.tamuc.edu/mmete/covid-risk.html . CONCLUSIONS AND RELEVANCE: In this study, we developed a risk score based on objective variables of COVID-19 patients within six hours of admission to the hospital, therefore helping predict a patient's risk of developing critical illness secondary to COVID-19.

Effectiveness of simulation-based cesarean section education on improving non-physician clinician midwife's competency in performing cesarean section in Ethiopia: a quasi-experimental study.

BACKGROUND: Simulation-based education enhances fundamental and clinical knowledge, procedural abilities, teamwork, and communication skills, as well as quality of care and patient safety. Due to excessive clinical loads and a lack of physicians, even classic teaching methods like bedside instruction are constrained in low-income settings. Thus, this study aimed to ascertain if simulation-based cesarean section education successfully raises non-physician clinician midwives' competency in Ethiopia. METHODS: A quasi-experimental study design triangulated with a qualitative design was implemented. Sixty Masters Clinical Midwifery students (29 intervention and 31 control) were taken in 5 universities. Three questionnaires (knowledge, confidence levels, and skills) were used. Qualitative data was also collected from 14 participants. The data were analyzed using SPSS version 25. Descriptive and inferential analyses were conducted. P < 0.05 was used for statistical significance. A difference-in-difference with a 95% confidence level was employed to control the potential confounders for knowledge and self-confidence. Multiple linear regression was fitted to identify the independent effect of simulation-based education interventions while controlling for other variables. Thematic analysis was performed using MAXQDA 2020. RESULT: The age of the respondents varies from 24 to 34 years, with the control group's mean age being 28.8 (± 2.3) years and the intervention group's mean age being 27.2 (± 2.01) years. The intervention and control groups' pre-intervention and post-intervention knowledge scores showed a statistically significant difference. There was a substantial increase in self-confidence mean scores in both the intervention and control groups and between the pre-intervention and post-intervention periods in both the intervention and control groups. Furthermore, there was a substantial improvement in cesarean section skills in the intervention group as compared to the control group (59.6 (3.3) vs. 51.5 (4.8). The qualitative findings supported these. CONCLUSIONS: The study showed that simulation-based education improved students' procedural knowledge, self-confidence, and skills. As a result, professional care teams can create simulation-based teaching packages to help students prepare for their residency.

A novel thieno[2,3-d]pyrimidine derivative inhibiting vascular endothelial growth factor receptor-2: A story of computer-aided drug discovery.

Following the pharmacophoric features of vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, a novel thieno[2,3-d]pyrimidine derivative has been designed and its activity against VEGFR-2 has been demonstrated by molecular docking studies that showed an accurate binding mode and an excellent binding energy. Furthermore, the recorded binding was confirmed by a series of molecular dynamics simulation studies, which also revealed precise energetic, conformational, and dynamic changes. Additionally, molecular mechanics with generalized Born and surface area solvation and polymer-induced liquid precursors studies were conducted and verified the results of the MD simulations. Next, in silico absorption, distribution, metabolism, excretion, and toxicity studies have also been conducted to examine the general drug-like nature of the designed candidate. According to the previous results, the thieno[2,3-d]pyrimidine derivative was synthesized. Fascinatingly, it inhibited VEGFR-2 (IC50 = 68.13 nM) and demonstrated strong inhibitory activity toward human liver (HepG2), and prostate (PC3) cell lines with IC50 values of 6.60 and 11.25 µM, respectively. As well, it was safe and showed a high selectivity index against normal cell lines (WI-38). Finally, the thieno[2,3-d]pyrimidine derivative arrested the growth of the HepG2 cells at the G2/M phase inducing both early and late apoptosis. These results were further confirmed through the ability of the thieno[2,3-d]pyrimidine derivative to induce significant changes in the apoptotic genes levels of caspase-3, caspase-9, Bcl-2 associated X-protein, and B-cell lymphoma 2.

Computer-Aided Drug Design of Novel Derivatives of 2-Amino-7,9-dihydro-8H-purin-8-one as Potent Pan-Janus JAK3 Inhibitors.

Rheumatoid arthritis (RA) remains one of the most prevalent autoimmune diseases worldwide. Janus kinase 3 (JAK3) is an essential enzyme for treating autoimmune diseases, including RA. Molecular modeling techniques play a crucial role in the search for new drugs by reducing time delays. In this study, the 3D-QSAR approach is employed to predict new JAK3 inhibitors. Two robust models, both field-based with R2 = 0.93, R = 0.96, and Q2 = 87, and atom-based with R2 = 0.94, R = 0.97, and Q2 = 86, yielded good results by identifying groups that may readily direct their interaction. A reliable pharmacophore model, DHRRR1, was provided in this work to enable the clear characterization of chemical features, leading to the design of 13 inhibitors with their pIC50 values. The DHRRR1 model yielded a validation result with a ROC value of 0.87. Five promising inhibitors were selected for further study based on an ADMET analysis of their pharmacokinetic properties and covalent docking (CovDock). Compared to the FDA-approved drug tofacitinib, the pharmaceutical features, binding affinity and stability of the inhibitors were analyzed through CovDock, 300 ns molecular dynamics simulations, free energy binding calculations and ADMET predictions. The results show that the inhibitors have strong binding affinity, stability and favorable pharmaceutical properties. The newly predicted molecules, as JAK3 inhibitors for the treatment of RA, are promising candidates for use as drugs.

Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Computer-assisted drug discovery (CADD) of an anti-cancer derivative of the theobromine alkaloid inhibiting VEGFR-2.

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA's oral treatment didn't show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.