Estimation of inflammatory cytokines in maternal serum for assessing the outcome of threatened miscarriage.

Objectives: This study investigates the use of pro- and anti-inflammatory cytokines in predicting the outcome of pregnancy complicated by threatened miscarriage. Materials and Methods: Of the 140 eligible pregnant women recruited for the study, maternal serum levels of selected inflammatory cytokines (IL-2, IFNγ, IL-4, and IL-13) for 70 women with threatened miscarriage were analysed for this study. Serum concentrations were measured using the enzyme-linked immunosorbent assay (ELISA) kit. Inevitable miscarriage or ongoing pregnancy was used as the outcome, whereas serum levels of selected inflammatory cytokines, women's sociodemographic characteristics, gynaecologic history, and clinical history were used as the explanatory variables. The Student's t test was used to compare the cytokine profiles between women with inevitable miscarriages and women with normal ongoing pregnancy after 13 weeks of gestation. Poisson regression models were performed to investigate the factors associated with inevitable miscarriage. Results: The result revealed significantly higher pro-inflammatory cytokines, IL-2 (P < 0.001), and IFNγ (P < 0.001) in women with a pregnancy that resulted in an inevitable miscarriage than in those that resulted in an ongoing pregnancy. The incidence rate of inevitable miscarriage increased by 16% (IRR = 1.16, 95% CI: 0.58-2.32) for a unit increase in IL-2 and by 25% (IRR = 1.25, 95% CI: 1.09-1.43) when adjusted for sociodemographic characteristics, gynaecology, and clinical history. Conclusion: The IL-2 was the best biomarker for predicting the outcome of threatened pregnancy with a sensitivity of 80% and a specificity of 70% at 1.30 pg/mL cut-off point.

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance.

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of -9.1, -8.9, and -8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (-9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

Structure-based design, and development of amidinyl, amidoximyl and hydroxamic acid based organic molecules as novel antimalarial drug candidates.

Malaria remains a significant global health concern causing numerous fatalities and the emergence of antimalarial drug resistance highlights the urgent need for novel therapeutic options with innovative mechanisms of action and targets. This study aimed to design potential inhibitors of Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PfPTPS), synthesize them, and experimentally validate their efficacy as antimalarial agents. A structure-based approach was employed to design a series of novel derivatives, including amidinyl, amidoximyl and hydroxamic acid analogs (1c, 1d, 2b, and 3b), with a focus on their ability to bind to the Zn2+ present in the active site of PfPTPS. The syntheses of these compounds were accomplished through various multi-step synthetic pathways and their structural identities were confirmed using 1H and 13C NMR spectra, mass spectra, and elemental analysis. The compounds were screened for their antiplasmodial activity against the NF54 strain of P. falciparum and in vitro cytotoxicity testing was performed using L-6 cells. The in vivo acute toxicity of the compounds was evaluated in mice. Docking studies of the compounds with the 3D structure of PfPTPS revealed their strong binding affinities, with compound 3b exhibiting notable metal-acceptor interaction with the Zn2+ in the protein binding pocket thereby positioning it as a lead compound for PfPTPS inhibition. The in vitro antiplasmodial studies revealed moderate efficacies against the Pf NF54 strain, particularly compounds 1d and 3b which displayed IC50 < 0.2 µM. No significant cytotoxicity was noted on the L-6 rat cell line. Moreover, in vivo studies suggested that compound 3b exhibited both safety and efficacy in treating rodent malaria. The identified lead compound in this study represents a possible candidate for antimalarial drug development and can be further explored in the search for alternative antifolate drugs to combat the malaria menace.

Inflammatory cytokines in maternal serum between women with threatened miscarriage and normal pregnancy.

OBJECTIVE: To compare the levels of proinflammatory cytokines in women with threatened miscarriage and normal pregnancy. METHODS: This study was a longitudinal study. Consenting women with normal pregnancy and those admitted on account of threatened miscarriage at an estimated gestational age of 6-10 weeks were included in the study. The proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) and the anti-inflammatory cytokines IL-4 and IL-13 were measured at the diagnosis of threatened miscarriage (baseline) and in the 13th week of pregnancy. The χ2 test of association was used to examine the relationship between the pregnancy type and demographic characteristics; clinical history and gynecologic history. Student t test was used to compare the selected cytokine between women with threatened miscarriage and normal pregnancy. RESULTS: There was a significantly higher IL-2 (P = 0.033), IFN-γ (P < 0.001), and IL-13 (P < 0.001) in women with threatened miscarriage than in women with normal pregnancy at the baseline. At the follow up, the results revealed a significantly higher IFN-γ level (P < 0.001) and IL-4 (P = 0.019) in women with threatened miscarriage than in women with normal pregnancies. CONCLUSION: Proinflammatory cytokine profiles were associated with a higher risk of threatened miscarriage.

Predicting Pain Intensity after Mandibular Third Molar Surgery using Cold Pressor Testing: A Quasi-Experimental Study.

BACKGROUND: Patients complain differently about their experiences of post-operative pain. However, clinicians are often guided by their own viewpoints despite the highly subjective nature of pain resulting in suboptimal post-operative pain management. This impacts negatively on the quality of life of patients in the immediate post-operative period. Investigating patients' pain behavior in the pre-operative period may therefore help to predict the intensity of post-operative pain, thereby assisting in identifying patients who are at risk of greater pain after third molar surgery, and allocating extra resources for pain control. AIM: This study aims to predict the intensity of pain after third molar surgery by correlating post-operative pain perception with the sensory-discriminative dimension and affective response to a cold pressor stimulus. MATERIALS AND METHODS: This study is a quasi-experimental study that was conducted in the oral surgery clinic of (name of hospital in the title page). The procedure was undertaken in an isolated clinic cubicle with well-controlled room temperature and minimal distraction. Study participants were recruited by convenience sampling. Forty-three consenting participants, 20 years and above, who met eligibility criteria were subjected to pre-operative cold pressor testing. Subsequently, third molar surgery was done and post-operative pain intensity was recorded at specific intervals. Data analyses were completed using IBM SPSS version 25. The Kolmogorov-Smirnov (KS) test was used to test for normality of continuous variables. Ordinal regression was used to test for contributory value of pre-operative measurement while Spearman's rank correlation test was used to test their degree of relationships with post-operative pain P < 0.05. RESULT: The median pain threshold was 20 s (Interquartile Range, IQR 12.75-32.25) and the median pain tolerance was 33 s (IQR = 23.00-54.00) from the cold pressor test. The peak median pain score in this study was reached at 3-h after the last stitch. There was a statistically significant predictive effect of both variables on post-operative pain at 3-h. CONCLUSION: Sensory-discriminative dimension and affective response to cold pressor test are significant predictors of peak post-operative pain after impacted mandibular third molar surgery.

Synthesis, in silico and in vitro antimicrobial efficacy of substituted arylidene-based quinazolin-4(3H)-one motifs.

Introduction: Quinazolin-4(3H)-one derivatives have attracted considerable attention in the pharmacological profiling of therapeutic drug targets. The present article reveals the development of arylidene-based quinazolin-4(3H)-one motifs as potential antimicrobial drug candidates. Methods: The synthetic pathway was initiated through thermal cyclization of acetic anhydride on anthranilic acid to produce 2-methyl-4H-3,1-benzoxazan-4-one 1, which (upon condensation with hydrazine hydrate) gave 3-amino-2-methylquinazolin-4(3H)-one 2. The reaction of intermediate 2 at its amino side arm with various benzaldehyde derivatives furnished the final products, in the form of substituted benzylidene-based quinazolin-4(3H)-one motifs 3a-l, and with thiophene-2-carbaldehyde to afford 3 m. The purified targeted products 3a-m were effectively characterized for structural authentication using physicochemical parameters, microanalytical data, and spectroscopic methods, including IR, UV, and 1H- and 13C-NMR, as well as mass spectral data. The substituted arylidene-based quinazolin-4(3H)-one motifs 3a-m were screened for both in silico and in vitro antimicrobial properties against selected bacteria and fungi. The in silico studies carried out consisted of predicted ADMET screening, molecular docking, and molecular dynamics (MD) simulation studies. Furthermore, in vitro experimental validation was performed using the agar diffusion method, and the standard antibacterial and antifungal drugs used were gentamicin and ketoconazole, respectively. Results and discussion: Most of the compounds possessed good binding affinities according to the molecular docking studies, while MD simulation revealed their levels of structural stability in the protein-ligand complexes. 2-methyl-3-((thiophen-2-ylmethylene)amino) quinazolin-4(3H)-one 3 m emerged as both the most active antibacterial agent (with an minimum inhibitory concentration (MIC) value of 1.95 µg/mL) against Staphylococcus aureus and the most active antifungal agent (with an MIC value of 3.90 µg/mL) against Candida albicans, Aspergillus niger, and Rhizopus nigricans.

Chemistry and Pharmacological diversity of Benzothiazepine - Excellent pathway to drug discovery.

In this era of sporadic advancement in science and technology, a substantial amount of intervention is being set in motion to reduce health-related diseases. Discoveries from researchers have pinpointed the usefulness of heterocyclic compounds, amongst which benzothiazepine (BTZ) derivatives have been synthesized for their various pharmacological activities. This also contributes to their undeniable application in therapeutic medicine for the development of efficacious drugs. BTZs are compounds with a benzene ring fused with a thiazepine ring. This work contains several methods that have been used to synthesize 1,3-, 1,4-, 1,5-, and 4-1-benzothiazepine derivatives. In addition, up-to-date information about the crucial pharmacological activities of BTZ derivatives has been reviewed in this present study to appreciate their druggable potential in therapeutic medicine for drug development. Drug design and development have further been simplified with the implementation of computer aided approaches to predict biological interactions which can help in the design of several derivatives. Hence, the structural activity relationship (SAR), ADMET and the molecular docking studies of BTZ derivatives were discussed to further establish their interactions and safety in biological systems. This present work aims to expound on the reported chemistry and pharmacological propensity of BTZ moiety in relation to other relevant moieties to validate their potential as excellent pharmacophores in drug design and development.

In silico Structure Prediction, Molecular Docking, and Dynamic Simulation of Plasmodium falciparum AP2-I Transcription Factor.

Plasmodium falciparum Apicomplexan Apetala 2 Invasion (PfAP2-I) transcription factor (TF) is a protein that regulates the expression of a subset of gene families involved in P. falciparum red blood cell (RBC) invasion. Inhibiting PfAP2-I TF with small molecules represents a potential new antimalarial therapeutic target to combat drug resistance, which this study aims to achieve. The 3D model structure of PfAP2-I was predicted ab initio using ROBETTA prediction tool and was validated using Save server 6.0 and MolProbity. Computed Atlas of Surface Topography of proteins (CASTp) 3.0 was used to predict the active sites of the PfAP2-I modeled structure. Pharmacophore modeling of the control ligand and PfAP2-I modeled structure was carried out using the Pharmit server to obtain several compounds used for molecular docking analysis. Molecular docking and postdocking studies were conducted using AutoDock vina and Discovery studio. The designed ligands' toxicity predictions and in silico drug-likeness were performed using the SwissADME predictor and OSIRIS Property Explorer. The modeled protein structure from the ROBETTA showed a validation result of 96.827 for ERRAT, 90.2% of the amino acid residues in the most favored region for the Ramachandran plot, and MolProbity score of 1.30 in the 98th percentile. Five (5) best hit compounds from molecular docking analysis were selected based on their binding affinity (between -8.9 and -11.7 Kcal/mol) to the active site of PfAP2-I and were considered for postdocking studies. For the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, compound MCULE-7146940834 had the highest drug score (0.63) and drug-likeness (6.76). MCULE-7146940834 maintained a stable conformation within the flexible protein's active site during simulation. The good, estimated binding energies, drug-likeness, drug score, and molecular dynamics simulation interaction observed for MCULE-7146940834 against PfAP2-I show that MCULE-7146940834 can be considered a lead candidate for PfAP2-I inhibition. Experimental validations should be carried out to ascertain the efficacy of these predicted best hit compounds.

Anopheles gambiae Trehalase Inhibitors for Malaria Vector Control: A Molecular Docking and Molecular Dynamics Study.

Trehalase inhibitors are considered safe alternatives for insecticides and fungicides. However, there are no studies testing these compounds on Anopheles gambiae, a major vector of human malaria. This study predicted the three-dimensional structure of Anopheles gambiae trehalase (AgTre) and identified potential inhibitors using molecular docking and molecular dynamics methods. Robetta server, C-I-TASSER, and I-TASSER were used to predict the protein structure, while the structural assessment was carried out using SWISS-MODEL, ERRAT, and VERIFY3D. Molecular docking and screening of 3022 compounds was carried out using AutoDock Vina in PyRx, and MD simulation was carried out using NAMD. The Robetta model outperformed all other models and was used for docking and simulation studies. After a post-screening analysis and ADMET studies, uniflorine, 67837201, 10406567, and Compound 2 were considered the best hits with binding energies of -6.9, -8.9, -9, and -8.4 kcal/mol, respectively, better than validamycin A standard (-5.4 kcal/mol). These four compounds were predicted to have no eco-toxicity, Brenk, or PAINS alerts. Similarly, they were predicted to be non-mutagenic, carcinogenic, or hepatoxic. 67837201, 10406567, and Compound 2 showed excellent stability during simulation. The study highlights uniflorine, 67837201, 10406567, and Compound 2 as good inhibitors of AgTre and possible compounds for malaria vector control.

Characteristics, Process Metrics, and Outcomes Among Patients With ST-Elevation Myocardial Infarction in Rural vs Urban Areas in the US: A Report From the US National Cardiovascular Data Registry.

Importance: Patients with ST-segment elevation myocardial infarction (STEMI) living in rural settings often have worse clinical outcomes compared with their urban counterparts. Whether this discrepancy is due to clinical characteristics or delays in timely reperfusion with primary percutaneous coronary intervention (PPCI) or fibrinolysis is unclear. Objective: To assess process metrics and outcomes among patients with STEMI in rural and urban settings across the US. Design, Setting, and Participants: This cross-sectional multicenter study analyzed data for 70 424 adult patients with STEMI from the National Cardiovascular Data Registry Chest Pain-MI Registry in 686 participating US hospitals between January 1, 2019, and June 30, 2020. Patients without a valid zip code were excluded, and those transferred to a different hospital during the course of the study were excluded from outcome analysis. Main Outcomes and Measures: In-hospital mortality and time-to-reperfusion metrics. Results: This study included 70 424 patients with STEMI (median [IQR] age, 63 [54-73] years; 49 850 [70.8%] male and 20 574 [29.2%] female; patient self-reported race: 6753 [9.6%] Black, 60 114 [85.4%] White, and 2096 [3.0%] of another race [including American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander]; 5281 [7.5%] individuals of Hispanic or Latino ethnicity) in 686 hospitals (50 702 [72.0%] living in urban zip codes and 19 722 [28.0%] in rural zip codes). Patients from rural settings were less likely to undergo PPCI compared with patients from urban settings (14 443 [73.2%] vs 43 142 [85.1%], respectively; P < .001) and more often received fibrinolytics (2848 [19.7%] vs 937 [2.7%]; P < .001). Compared with patients from urban settings, those in rural settings undergoing PPCI had longer median (IQR) time from first medical contact to catheterization laboratory activation (30 [12-42] minutes vs 22 [15-59] minutes; P < .001) and longer median (IQR) time from first medical contact to device (99 minutes [75-131] vs 81 [66-103] minutes; P < .001), including those who arrived directly at PPCI centers (83 [66-107] minutes vs 78 [64-97] minutes; P < .001) and those who transferred to PPCI centers from another treatment center (125 [102-163] minutes vs 103 [85-135] minutes; P < .001). Among those who transferred in, median (IQR) door-in-door-out time was longer in patients from rural settings (63 [41-100] minutes vs 50 [35-80] minutes; P < .001). Out-of-hospital cardiac arrest was more common in patients from urban vs rural settings (3099 [6.1%] vs 958 [4.9%]; P < .001), and patients from urban settings were more likely to present with heart failure (4112 [8.1%] vs 1314 [6.7%]; P < .001). After multivariable adjustment, there was no significant difference in in-hospital mortality between rural and urban groups (adjusted odds ratio, 0.97; 95% CI, 0.89-1.06). Conclusions and Relevance: In this large cohort of patients with STEMI from US hospitals participating in the National Cardiovascular Data Registry Chest Pain-MI Registry, patients living in rural settings had longer times to reperfusion, were less likely to receive PPCI or meet guideline-recommended time to reperfusion, and more frequently received fibrinolytics than patients living in urban settings. However, there was no difference in adjusted in-hospital mortality between patients with STEMI from urban and rural settings.

Predicting mortality in nonsurgical patients before cannulation for veno-arterial extracorporeal life support: Development and validation of the LACT-8 score.

OBJECTIVES: We sought to derive and validate a model to predict inpatient mortality after veno-arterial extracorporeal life support (VA-ECLS) based on readily available, precannulation clinical data. BACKGROUND: Refractory cardiogenic shock supported by VA-ECLS is associated with high morbidity and mortality. METHODS: VA-ECLS cases at our institution from January 2014 through July 2019 were retrospectively reviewed. Exclusion criteria were cannulation: (1) at another institution; (2) for primary surgical indication; or (3) for extracorporeal cardiopulmonary resuscitation. Multivariable logistic regression compared those with and without inpatient mortality. Multiple imputation was performed and optimism-adjusted area under the curve (oAUC) values were computed. RESULTS: VA-ECLS cases from August 2019 through November 2020 were identified as a validation cohort. In the derivation cohort (n = 135), the final model included Lactate (mmol/L), hemoglobin (g/dl; Anemia), Coma (Glasgow Coma Scale [GCS] < 8) and resusciTATEd cardiac arrest (LACTATE score; oAUC = 0.760). In the validation cohort (n = 30, LACTATE showed similar predictability [AUC = 0.710]). A simplified (LACT-8) score was derived by dichotomizing lactate (>8) and hemoglobin (<8) and summing together the number of components for each patient. LACT-8 performed similarly (derivation, oAUC = 0.724; validation, AUC = 0.725). In the derivation cohort, both scores outperformed SAVE (oAUC = 0.568) and SOFA (oAUC = 0.699) scores. A LACT-8 ≥ 3 had a specificity for mortality of 97.9% and 92.9%, in the derivation and validation cohorts, respectively. CONCLUSIONS: The LACT-8 score can predict inpatient mortality prior to before cannulation for VA-ECLS. LACT-8 can be implemented utilizing clinical data without the need for an online calculator.

Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

BACKGROUND: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. METHODS: We queried Veterans Affairs' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. RESULTS: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70-0.74], P<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes. CONCLUSIONS: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.

Recent advances in functionalized quinoline scaffolds and hybrids-Exceptional pharmacophore in therapeutic medicine.

Quinoline is one of the most common nitrogen-containing heterocycles owing to its fascinating pharmacological properties and synthetic value in organic and pharmaceutical chemistry. Functionalization of this moiety at different positions has allowed for varying pharmacological activities of its derivative. Several publications over the last few decades have specified various methods of synthesis. This includes classical methods of synthesizing the primary quinoline derivatives and efficient methods that reduce reaction time with increased yield employing procedures that fulfill one of the twelve green chemistry principles, "safer solvent". The metal nanoparticle-catalyzed reaction also serves as a potent and effective technique for the synthesis of quinoline with excellent atom efficiency. The primary focus of this review is to highlight the routes to synthesizing functionalized quinoline derivatives, including hybrids that have moieties with predetermined activities bound to the quinoline moiety which are of interest in synthesizing drug candidates with dual modes of action, overcoming toxicity, and resistance amongst others. This was achieved using updated literature, stating the biological activities and mechanisms through which these compounds administer relief. The ADMET studies and Structure-Activity Relationship (SAR) of novel derivatives were also highlighted to explore the drug-likeness of the quinoline-hybrids and the influence of substituent characteristics and position on the biological activity of the compounds.

Structure-based pharmacophore modeling, virtual screening, and molecular dynamics simulation studies for identification of Plasmodium falciparum 5-aminolevulinate synthase inhibitors.

Plasmodium falciparum (Pf) 5-aminolevulinic acid synthase (5-ALAS) is an essential enzyme with high selectivity during liver stage development, signifying its potential as a prophylactic antimalarial drug target. The aim of this study was to identify important potential lead compounds which can serve as inhibitors of Pf 5-ALAS using pharmacophore modeling, virtual screening, qualitative structural assessment, in silico ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluation and molecular dynamics simulation. The best model of the tertiary structure of Pf 5-ALAS was obtained using MolProbity, while the following databases were explored for the pharmacophore-based virtual screening: CHEMBL, ChemDiv, ChemSpace, MCULE, MCULE-ULTIMATE, MolPort, NCI Open Chemical Repository, LabNetwork and ZINC databases. 2,621 compounds were screened against the modeled Pf 5-ALAS using AutoDock vina. The post-screening analysis was carried out using Discovery Studio while molecular dynamics simulation was performed on the best hits using NAMD-VMD and Galaxy Europe platform. Compound CSMS00081585868 was observed as the best hit with a binding affinity of -9.9 kcal/mol and predicted Ki of 52.10 nM, engaging in seven hydrogen bonds with the target's active site amino acid residues. The in silico ADMET prediction showed that all ten best hits possessed relatively good pharmacokinetic properties. The qualitative structural assessment of the best hit, CSMS00081585868, revealed that the presence of two pyridine scaffolds bearing hydroxy and fluorine groups linked by a pyrrolidine scaffold contributed significantly to its ability to have a strong binding affinity with the receptor. The best hit also showed stability in the active site of Pf 5-ALAS as confirmed from the RMSD obtained during the MD simulation.

Temporal Trends and Outcomes of Elective Thoracic Aortic Repair and Acute Aortic Syndromes in Bicuspid Aortic Valves: Insights from a National Database.

INTRODUCTION: There is paucity of data on the outcomes of hospitalization for bicuspid aortic valve (BAV)-related aortopathies. METHODS: We queried the NIS database (2012-2016) for hospitalizations for elective thoracic aortic repair or acute aortic syndrome (AAS) among those with BAV versus trileaflet aortic valve (TAV). RESULTS: Our analysis yielded 38,010 hospitalizations for elective aortic repair, of whom 34.4% had BAV, as well as 81,875 hospitalizations for thoracic AAS, of whom 1.1% had BAV. Hospitalizations for BAV were younger and had fewer comorbidities compared with their TAV counterparts. The number of hospitalizations for BAV during the observational period was unchanged. After propensity matching, elective aortic repair for BAV was associated with lower mortality (0.5% versus 1.7%, odds ratio = 0.28; 95% CI 1.5-0.50, p < 0.001), use of mechanical circulatory support, acute stroke, and shorter length of hospital stay compared with TAV. After propensity matching, AAS among those with BAV had a greater incidence of bleeding events, blood transfusion, cardiac tamponade, ventricular arrhythmias, and a longer length of hospital stay compared with TAV. Among those with BAV, predictors of lower mortality if undergoing elective aortic repair included larger hospitals and teaching hospitals. Predictors of higher mortality in patients with AAS included heart failure, chronic kidney disease, and coronary artery disease. CONCLUSION: Data from a national database showed no change in the number of hospitalizations for BAV-related aortopathy, with relatively lower incidence of AAS. Compared with TAV, elective aortic repair for BAV is associated with lower mortality, while BAV-related AAS is associated with higher in-hospital complications.

Orthopantometric Assessment of Mandibular Parameters in a Sub-Population of Yorubas: A Study of 2 Tertiary Hospitals in South-Western Nigeria.

BACKGROUND: Considerable racial, gender and age differences exist in mandibular parameters, hence anthropometric analyses have evolved to be an important scientific tool in forensic medicine and medico-legal issues. AIMS: The purpose of this study was to determine the mandibular parameters (bilateral gonial angle/ ramus height and the bigonial width) in a sub-population of adult Yorubas with normal occlusion in south western part of Nigeria. METHODS: This was a retrospective study of digital panoramic radiographs (Planmeca ProMax®) of 116 subjects that had routine panoramic radiographic investigation done between January 2015 and June 2020 at two teaching hospitals. Angular and linear measurements of the mandible were made and values obtained analyzed for gender differences. RESULTS: The gonial angle for males (118.08o ) was lower than that for females (118.87o ) but this difference was not statistically significant ( p= 0.3742) while the ramus height and bigonial width for males (61.22mm and186.63mm respectively) were higher than that for females (57.06mm and 179.23 mm) which were statistically significant (p < 0.001 and p < 0.001 respectively). CONCLUSION: Males have statistically significant longer ramus height and bigonial width when compared with females. These finding may be useful in gender determination, however, further studies are recommended. KEY MESSAGES: Males have statistically significant longer ramus height and bigonial width when compared with females in the population studied, hence ramus height and bigonial width in combination with other parameters are useful parameters in studies on gender dimorphism.

CONTEXTE RÉSUMÉ: Des différences considérables de race, de sexe et d'âge existent dans les paramètres mandibulaires, d'où l'évolution des analyses anthropométriques pour devenir un outil scientifique important dans la médecine légale et les questions médico-légales. OBJECTIFS: Le but de cette étude était de déterminer les paramètres mandibulaires (angle gonial bilatéral/hauteur de branche et largeur bigoniale) dans une sous-population de Yorubas adultes avec une occlusion normale dans la partie sud-ouest du Nigeria. MÉTHODES: Il s'agissait d'une étude rétrospective de radiographies panoramiques numériques (Planmeca ProMax®) de 116 sujets ayant subi une exploration radiographique panoramique de routine entre janvier 2015 et juin 2020 dans deux hôpitaux universitaires. Des mesures angulaires et linéaires de la mandibule ont été effectuées et les valeurs obtenues ont été analysées pour les différences entre les sexes. RÉSULTATS: L'angle gonial des mâles (118,08o ) était inférieur à celui des femelles (118,87o ) mais cette différence n'était pas statistiquement significative (p = 0,3742) tandis que la hauteur de la branche et la largeur bigoniale pour les mâles (61,22 mm et 186,63 mm respectivement) étaient plus élevés que ceux des femmes (57,06 mm et 179,23 mm) qui étaient statistiquement significatifs (p < 0,001 et p < 0,001 respectivement). CONCLUSION: Les mâles ont une hauteur de ramus et une largeur bigoniales plus longues statistiquement significatives par rapport aux femelles. Ces résultats peuvent être utiles dans la détermination du sexe, cependant, d'autres études sont recommandées. WAJM 2021 ; 38(6) : 561­565. MESSAGES CLÉS: Les mâles ont une hauteur de ramus et une largeur de bigonie statistiquement plus longues que les femelles dans la population étudiée, donc la hauteur de ramus et la largeur de bigonial en combinaison avec d'autres paramètres sont des paramètres utiles dans les études sur le dimorphisme de genre. MOTS CLÉS: Angle gonial, paramètres mandibulaires, hauteur de branche, largeur bigoniale, Yoruba.

Family physicians/GP and Internist opinions, familiarity and practice behaviour regarding clinical practice guidelines (CPGs) of common medical conditions in Nigeria.

BACKGROUND: Few studies exist on physicians' opinions, attitudes, familiarity and practice behaviour regarding clinical practice guidelines in sub-Saharan Africa. OBJECTIVES: To determine the opinions, familiarity, and practice behaviour regarding clinical practice guidelines (CPGs) and factors associated with their use among internists and family physicians/GP in Nigeria. METHODS: A semi-structured questionnaire regarding guidelines of five common medical conditions: hypertension, diabetes mellitus, tuberculosis, asthma and hepatitis B encountered in everyday medical practice were self-administered by 183 doctors across the country. RESULTS: Over 90% of respondents believed that guidelines were evidence-based, improved management outcomes, and quality of care, nevertheless, 57.4% were against using them in litigations against doctors. The majority (>70%) of the respondents were familiar with the guidelines except that of hepatitis B. Overall, guidelines were used regularly by 45.9%, used in part by 23.5% and 30.6% never used it. Approximately 50% of physicians had immediate accessibility to them at the point of care. The proportions of respondents reporting a change in practice behaviour ranged from 37.7-57.9% depending on the guideline. The factors associated with guideline-related behaviour change were familiarity with its contents, postgraduate educational training, increased helpfulness score, and practiced >5 years. CONCLUSIONS: The present study shows that most physicians have favourable opinions and are familiar with these guidelines, however, the proportions reporting changes in their patient management because of the guidelines are not satisfactory. It is important to ensure guidelines accessibility and promotes factors that encourage their implementation in medical practice.

Trends and Outcomes of Elective Thoracic Aortic Repair and Acute Thoracic Aortic Syndromes in the United States.

BACKGROUND: There is a paucity of data on the contemporary outcomes and trends of elective thoracic aortic aneurysm repair and aneurysm-associated acute aortic syndrome. METHODS: We queried the National Inpatient Sample (NIS) database years 2012-2016 to identify hospitalizations for elective thoracic aortic aneurysm repair and aneurysm-associated acute aortic syndrome. The main study outcome was in-hospital mortality. RESULTS: The analysis yielded 24,295 hospitalizations for elective thoracic aortic aneurysm repair and 8875 hospitalizations for aneurysm-associated acute aortic syndrome. The number of hospitalizations for elective aortic repair significantly increased from 4375 in 2012 to 5450 in 2016 (Ptrend = .01). The number of hospitalizations for acute aortic syndrome numerically increased from 1545 in 2012 to 2340 in 2016 (Ptrend = .10). Overall in-hospital mortality for elective aortic repair was 2.4% with no change over time. In-hospital mortality for acute aortic rupture was 39.4% and for acute aortic dissection was 6.2% with no change over time. Hospitalizations for elective aortic repair had lower incidence of complications compared with those for aneurysm-associated acute aortic syndrome, including cardiogenic shock, cardiac arrest, acute stroke, and shorter length of stay. Factors associated with higher mortality among admissions undergoing elective aortic repair included older age, heart failure, valvular disease, and chronic kidney disease. Older age, coagulopathy, and fluid/ electrolytes disorders were associated with increased mortality among those with acute aortic syndrome. CONCLUSION: Contemporary elective thoracic aortic aneurysm repair is associated with lower in-hospital mortality and morbidity when compared with a clinical presentation for an aneurysm-associated acute aortic syndrome. This should be taken into account when deciding the timing of elective aortic aneurysm repair and balancing the risks and benefits.

Outcomes of transcatheter versus surgical aortic valve replacement among solid organ transplant recipients.

BACKGROUND: There is a paucity of data regarding the outcomes of transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) among solid-organ transplant recipients. METHODS: Temporal trends in hospitalizations for aortic valve replacement among solid-organ transplant recipients were determined using the National Inpatient Sample database years 2012-2017. Propensity matching was conducted to compare admissions who underwent TAVR versus SAVR. The primary outcome was in-hospital mortality. RESULTS: The analysis included 1,730 hospitalizations for isolated AVR; 920 (53.2%) underwent TAVR and 810 (46.7%) underwent SAVR. TAVR was increasingly utilized for solid-organ transplant recipients (Ptrend = 0.01), while there was no change in the number of SAVR procedures (Ptrend = 0.20). The predictors of undergoing TAVR for solid-organ transplant recipients included older age, diabetes, and prior coronary artery bypass surgery, while TAVR was less likely utilized in small-sized hospitals. TAVR was associated with lower in-hospital mortality after matching (0.9 vs. 4.7%, odds ratio [OR] 0.19; 95% confidence interval [CI] 0.11-0.35, p < .001) and after multivariable adjustment (OR 0.07; 95% CI 0.03-0.21, p < .001). TAVR was associated with lower rate of acute kidney injury, acute stroke, postoperative bleeding, blood transfusion, vascular complications, discharge to nursing facilities, and shorter median length of hospital stay. There was no difference between both groups in the use of mechanical circulatory support, hemodialysis, arrhythmias, or pacemaker insertion. CONCLUSION: This contemporary observational nationwide analysis showed that TAVR is increasingly performed among solid-organ transplant recipients. Compared with SAVR, TAVR was associated with lower in-hospital mortality, complications, and shorter length of stay.

Annona senegalensis extract demonstrates anticancer properties in N-diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common and leading cancer around the globe. This study investigated the anticancer properties of extract of Annona senegalensis in N-diethylnitrosamine (DEN) - induced hepatocellular carcinoma in male Wistar rats. METHODS: Rats were simultaneously induced with a combination of 100 mg/kg b.wt of DEN and 0.5 mL/kg of carbon tetrachloride (CCl4) intraperitoneally once a week for three weeks in a row. Thereafter, animals were treated with 100 mg/kg and 200 mg/kg b.wt of A. senegalensis extract daily for 21days. Analysis using gas chromatography-mass spectrometry (GC-MS) was carried out to discover the phytoconstituents contained in the n-hexane extract of A. senegelensis. The levels of liver function parameters and antioxidant enzyme activities were determined via spectrophotometric analysis. Reverse transcriptase-polymerase chain reaction technique was used to assess the gene expression patterns of BCL-2, P53, P21, IL-6, FNTA, VEGF, HIF, AFP, XIAP, and EGFR mRNAs. RESULTS: Treatment of DEN-induced hepatocellular carcinoma Wistar rats with the extract caused significant (p < 0.05) decrease in the activities of ALT and AST. It also resulted in a reduction of the concentration of MDA and a significant increase (p < 0.05) in SOD and GSH activities. IL-6, BCL-2, VEGF, EGFR, XIAP, FNTA, and P21 mRNAs expressions were significantly (p < 0.05) downregulated after treatment. Histopathological analysis revealed that the extract improved the liver architecture. CONCLUSION: A. senegelensis n-hexane extract demonstrates its anticancer properties by improving the liver architecture, increasing the antioxidant defense systems, downregulating the pro-inflammatory, anti-apoptotic, angiogenic, alpha-fetoprotein and farnesyl transferase mRNAs expression and hitherto up-regulate the expression of tumor suppressor (P21 and P53) mRNAs.