Search

Objectives: Evaluate how different comorbidities increase 3-year risk of incident congestive heart failure (CHF) in new atrial fibrillation (AF) patients and the time from diagnosis of AF to developing incident CHF while controlling for risk factors and treating death as a competing risk event. Methods: We utilized CMS Medicare 100% inpatient and outpatient claims data between 2013 and 2017. Patients with new AF diagnosis (without concurrent CHF at AF diagnosis) in 2014 who had 1-year continuous enrollment prior to their AF diagnosis (baseline period) and no prior diagnosis of AF or CHF in the baseline period were identified. Results: With every 1-year increase in age of incident AF patients, 3-year risk of CHF increases by 2.6%, presence of coronary artery disease, COPD, diabetes mellitus, peripheral artery disease, and cardiomyopathy increases 3-year risk of CHF by 22.1%, 30.2%, 31.9%, 15.2%, 44.8%, and 6.3% respectively. Blacks with incident AF had 6.9% higher 3-year risk CHF than Whites. For the average aged female patient in our cohort (78.5years) with no comorbidities and death as a competing risk, we found the probability of CHF within the first 3 years after AF diagnosis to be 23.5%, 17.5% within the first 2 years, and 10% within the first year. Conclusion: Various comorbidities affect the risk of CHF differently in incident AF patients. Cumulative risk of incident CHF appears to increase fastest within the first few years following incident AF diagnosis.

After the release of the CDC guidelines in March 2016, the rate of opioid prescriptions decreased. How or whether pharmaceutical companies changed their opioid marketing practices post release of the CDC guidelines is unknown. Our objectives were to (1) evaluate whether the release of the guidelines was associated with changes in total monthly marketing spending received per physician, monthly marketing encounter frequency per physician, and spending per encounter during opioid marketing; and (2) evaluate whether such changes in marketing differed between specialist physicians and primary care physicians (PCPs) and between urban and rural primary care service areas (PCSAs).Retrospective observational cross-sectional study using opioid marketing spending data from the CMS Open Payments database between August 2013 and December 2017.Single-group and multiple-group interrupted time series analyses were used to evaluate differences in the immediate changes in level and trend over time in opioid marketing practices post release of the CDC guidelines.Post release of the CDC guidelines, the monthly number of marketing encounters per physician and total monthly amount received per physician decreased. However, the amount spent at each marketing encounter increased. The release of the CDC guidelines was associated with an immediate increase in level of opioid marketing spending per encounter by $0.59 (95% CI, $0.51-$0.68; P.001) and an over-time increase in rate of spending per encounter of $0.04 per month (95% CI, $0.03-$0.05; P .001). These changes differed between specialists and PCPs and between urban and rural PCSAs.It is important to continue ongoing education for physicians on changes in pharmaceutical opioid marketing practices.

This study examined the temporal pattern of tourists’ patronage at Yankari Game Reserve before and after the emergence of Boko Haram between 2000 and 2019. Data for this study were obtained from both primary and secondary sources. The primary data were gotten through the administration of structured questionnaire. The result indicated that 90.0% of the tourists alleged that bombings and suicide attack carried out respectively by the Boko Haram sect made them not to visit the reserve in about five years. In addition, 72.5.0% affirmed that stories and news feeds of massacre orchestrated by Boko Haram have reduced their rate of patronage of the tourist site. T-test was employed to test the hypothesis. Findings revealed that there is a significant difference (t = 6.010, p

Background: β-ketoacyl-ACP synthase I (KasA I) enzyme is crucial in mycolic acid synthesis via catalytic condensation reactions, hence implicated in M. tuberculosis’s virulence and drug resistance. Presently, there is no known potent KasA inhibitor; thiolactomycin lacks potency. Recently reported indazole compounds JSF-3285/tr1DG167 and 5G/tr2DG167 inhibit the KasA through binding to the substrate cavity. However, the molecular mechanism is still unclear, and the unknown resistance mechanisms raise concerns about JSF-3285's novelty. Method: This study is the first to report the flap dimer opening and closing of the KasA pocket using combined metrics to define the symmetry impact of the flap-dimer motions and investigate the underlying inhibitory mechanism of tr1DG167 and tr2DG167 using all-atom MD simulation. Results: The distance/d1 between the flap (PRO147) and dimer (LEU205) residues; TriC-α angle (θ1: PRO147-VAL83-LEU205 & θ2: PRO147-GLU199-LEU205); and the dihedral angle (ϕ) were applied to investigate the flap “twisting” and dimer shift closing due to concerted motion by adjacent glycine-rich and glutamic acid-rich loops around the active site during the binding pocket’s opening. The full flap-dimer of the unbound opens at 230 ns (d1 = 21.51 Å), corresponding to the largest TriC-α angle θ1 44.5° as θ2 is unreliable to describe the flap-dimer motion. The overall averages θ1 and θ2 for the bounds were ~23.13° and ~23.31°, respectively. Thus, the degree of KasA flap dimer opening is best investigated by distance and θ1. BFE (Kcal/mol) of -44.05 (tr1DG167) showed a higher affinity for the pocket than tr2DG167-KasA (-32.16). Both tr1DG167 and tr2DG167 formed hydrophobic interactions with LEU116, GLY117, ALA119, and tr1DG167 formed strong H-bonds with GLU199. The average RMSD of 2.80 Å (Apo) and RoG of 20.97 Å showed that KasA is less stable and less tightly packed without the inhibitors. Conclusion: These findings provide a background for a new structure-based design of novel KasA inhibitors.

This experimental research was conducted in 2018 and 2019 seasons at Federal College of Forestry demonstration farm Jos, Plateau State to determine the efficacy of phosphorus fertilizer rates on the growth and yield, and yield components of groundnut cultivars. The experimental design used was a randomized complete block design (RCBD) comprising of four treatments (0, 20, 40 and 60 kg P2O5ha-1) and four groundnut cultivars (Samnut 10, 14, 17 and 18) that were replicated three times. Data were collected on plant height, number of leaves, stem girth, number of branches and pods/plant, harvest index, shelling percentage, total yield and biomass weight and data were analyzed using analysis of variance (ANOVA) at 5% level of probability with XLSTAT 2018 statistical package. Tukey’s method was used to separate the means where significance was declared. The result showed that the application of 40 kg P2O5ha-1 produced the highest plant height (73.96 cm and 73.92 cm), number of leaves (173.42 and 175.00), stem girth (4.02 and 3.92 cm), number of branches (43.33 and 43.50), number of pods or plant (25.67 and 26.58), harvest index (24.17% and 24.92%), total yield (2516.25 and 2574.58 kg/ha) and biomass weight (3551.58 and 3524.17 kg/ha). Samnut 14 recorded the highest plant height (72.19 cm and 72.54 cm), number of leaves (168.33 and 167.17), number of branches (42.25 and 41.67), number of pods or plant (23.83 and 24.08), harvest index (21.47 and 22.22%), total yield (2297.17 and 2361.33 kg/ha) and biomass weight (3267.58 and 3295.75 kg/ha). It was concluded that application of 40 kg P ha-1 to Samnut 14 produced the highest growth, yield and yield characteristics of groundnut. It was therefore recommended that farmers in the experimental area be encouraged to apply 40 kg P ha-1 to Samnut 14 for optimum productivity of groundnut.

The World Health Organization has declared the novel coronavirus (COVID-19) outbreak a global pandemic and emerging threat to people in the 21st century. SARS-CoV-2 constitutes RNA-Dependent RNA Polymerase (RdRp) viral proteins, a critical target in the viral replication process. No FDA-approved drug is currently available, and there is a high demand for therapeutic strategies against COVID-19. In search of the anti-COVID-19 compound from traditional medicine, we evaluated the active moieties from Nilavembu Kudineer (NK), a poly-herbal Siddha formulation recommended by AYUSH against COVID-19. We conducted a preliminary docking analysis of 355 phytochemicals (retrieved from PubChem and IMPPAT databases) present in NK against RdRp viral protein (PDB ID: 7B3B) using COVID-19 Docking Server and further with AutoDockTool-1.5.6. MD simulation studies confirmed that Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) revealed better binding activity against RdRp (PDB ID: 7B3B) in comparison with Remdesivir. The study suggests a potential scaffold for developing drug candidates against COVID-19. PRACTICAL APPLICATIONS: Nilavembu Kudineer is a poly-herbal Siddha formulation effective against various diseases like cough, fever, breathing problems, etc. This study shows that different phytoconstituents identified from Nilavembu Kudineer were subjected to in silico and ADME analyses. Out of the former 355 phytochemical molecules, Orientin (L1), Vitexin (L2), and Kasuagamycin (L3) showed better binding activity against RdRp viral protein (PDB ID: 7B3B) in comparison with the synthetic repurposed drug. Our work explores the search for an anti-COVID-19 compound from traditional medicine like Nilavembu Kudineer, which can be a potential scaffold for developing drug candidates against COVID-19.

Researches have revealed that functional non-synonymous Single Nucleotide Polymorphism (nsSNPs) present in the Zinc-finger with UFM1-Specific Peptidase domain protein (ZUFSP) may be involved in genetic instability and carcinogenesis. For the first time, we employed in-silico approach using predictive tools to identify and validate potential nsSNPs that could be pathogenic. Our result revealed that 8 nsSNPs (rs 112738382, rs 140094037, rs 201652589, rs 201847265, rs 202076827, rs 373634906, rs 375114528, rs 772591104) are pathogenic after being subjected to rigorous filtering process. The structural impact of the nsSNPs on ZUFSP structure indicated that the nsSNPs affect the stability of the protein by lowering ZUFSP protein stability. Furthermore, conservation analysis showed that rs 201652589, rs 140094037, rs 201847265, and rs 772591104 were highly conserved. Interestingly, the protein–protein affinity between ZUFSP and Ubiquitin was altered rs 201652589, rs 140094037, rs 201847265, and rs 772591104 had a binding affinity of − 0.46, − 0.83, − 1.62, and − 1.12 kcal/mol respectively. Our study has been able to identify potential nsSNPs that could be used as genetic biomarkers for some diseases arising as a result of aberration in the ZUFSP structure, however, being a predictive study, the identified nsSNPs need to be experimentally investigated.

Mycobacterium tuberculosis (Mtb) encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are...

The global increase in the morbidity/mortality rate of Mycobacterial infections, predominantly renascent tuberculosis, leprosy, and Buruli ulcers have become worrisome over the years. More challenging is the incidence of resistance mediated by mutant Mycobacterium strains against front-line antitubercular drugs. Homologous to all Mycobacteria species is the GlcNAc-6-phosphate deacetylase (NagA) which catalyzes essential amino sugars synthesis required for cell wall architecture, hence, metamorphosing into an important pharmacological target for curtailing virulence and drug-resistance. This study used integrated bioinformatics methods, MD simulations, and DynaMut and PolyPhen2 to; explore unique features, monitor dynamics, and analyze the functional impact of non-synonymous single-nucleotide polymorphisms of the six NagA of most ruinous Mycobacterium species; tuberculosis (Mtb), smegmatis (MS), marinum (MM), ulcerans, africanum, and microti respectively. This approach is essential for multi-targeting and could result in the identification of potential polypharmacological antitubercular compounds. Comparative sequential analyses revealed ≤ 50% of the overall structure, including the catalytic Asp267 and reactive Cys131, remained conserved. Interestingly, MS-NagA and MM-NagA possess unique hydrophobic isoleucine (Ile) residues at their active sites in contrast to leucine (Leu) found in other variants. More so, unique to the active sites of the NagA is a 'subunit loop' that covers the active site; probably crucial in binding (entry and exit) mechanisms of targeted NagA inhibitors. Relatively, nsSNP mutations exerted a destabilizing effect on the native NagA conformation. Structural and dynamical insights provided, basically pin-pointed the "Achilles' heel" explorable for the rational drug design of target-specific 'NagA' inhibitors potent against a wide range of mycobacterial diseases.

Drug-resistant Tuberculosis (TB) has remained the top global health challenge, with a yearly estimation of 10 million infections and 1.5 million deaths in humans. Demethylmenaquinone methyltransferase (menG) catalyzes demethylmenaquinone conversion to menaquinone (MK) that is implicated in the TB pathogenesis, hence, it has become a major drug target. DG70 is a biphenyl amide compound known to be a high binding affinity inhibitor of menG. This study investigated the structural and dynamic impacts of DG70 upon binding to menG using atom-based dynamic simulation. Our findings revealed that the modeled structure of menG possesses some Rossman-like methyltransferase characteristic features including two GXG motifs, an omega-like loop (residues 210–220) called the Thompson loop, nine α-helices, five β-strands, etc. Furthermore, atom-based dynamic simulations revealed that the Thompson loop is critical in the therapeutic activity of DG70. The loop assumed an open conformation in the unliganded-menG structure. However, in the DG70-menG, it assumed a tightly closed conformation. This explains the high binding affinity (−32.48 kcal mol−1) observed in the energy calculations. Interestingly, these findings are further collaborated by the conformational perturbation in the menG protein. Conclusively, insights from this study, highlight the structural “Achilles heel” in menG protein which can be further leveraged by inhibitors tailored to specifically target them.

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (

The oral drug bioavailability (BA) problems have remained inevitable over the years, impairing drug efficacy and indirectly leading to eventual human morbidity and mortality. However, some conventional lab-based methods improve drug absorption leading to enhanced BA, and the recent experimental techniques are up-and-coming. Nevertheless, some have inherent drawbacks in improving the efficacy of poorly insoluble and low impermeable drugs. Drug BA and strategies to overcome these challenges were briefly highlighted. This review has significantly unravelled the different computational models for studying and predicting drug bioavailability. Several computational approaches provide mechanistic insights into the oral drug delivery system simulation of descriptors like solubility, permeability, transport protein-ligand interactions, and molecular structures. The in silico techniques have long been known still are just being applied to unravel drug bioavailability issues. Many publications have reported novel applications of the computational models towards achieving improved drug BA, including predicting gastrointestinal tract (GIT) drug absorption properties and passive intestinal membrane permeability, thus maximizing time and resources. Also, the classical molecular simulation models for free solvation energies of soluble-related processes such as solubilization, dissolutions, supersaturation, and precipitation have been used in virtual screening studies. A few of the tools are GastroPlus

Multidrug resistance is a significant drawback in malaria treatment, and mutations in the active sites of the many critical antimalarial drug targets have remained challenging. Therefore, this has necessitated the global search for new drugs with new mechanisms of action. Plasmodium falciparum lactate dehydrogenase (pfLHD), a glycolytic enzyme, has emerged as a potential target for developing new drugs due to the parasite reliance on glycolysis for energy. Strong substrate-binding is required in pfLDH enzymatic catalysis; however, there is a lack of information on small molecules' inhibitory mechanism bound to the substrate-binding pocket. Therefore, this study investigated a potential allosteric inhibition of pfLDH by targeting the substrate-binding site. The structural and functional behaviour of madecassic acid (MA), the most promising among the six triterpenes bound to pfLDH, were unravelled using molecular dynamic simulations at 300 ns to gain insights into its mechanism of binding and inhibition and chloroquine as a standard drug. The docking studies identified that the substrate site has the preferred position for the compounds even in the absence of a co-factor. The bound ligands showed comparably higher binding affinity at the substrate site than at the co-factor site. Mechanistically, a characteristic loop implicated in the enzyme catalytic activity was identified at the substrate site. This loop accommodates key interacting residues (LYS174, MET175, LEU177 and LYS179) pivotal in the MA binding and inhibitory action. The MA-bound pfLHD average RMSD (1.60 Å) relative to chloroquine-bound pfLHD RMSD (2.00 Å) showed higher stability for the substrate pocket, explaining the higher binding affinity (-33.40 kcal/mol) observed in the energy calculations, indicating that MA exhibited profound inhibitory activity. The significant pfLDH loop conformational changes and the allostery substrate-binding landscape suggested inhibiting the enzyme function, which provides an avenue for designing antimalarial compounds in the future studies of pfLDH protein as a target.