Ashutosh Gupta

A Bayes analysis of modified Weibull distribution via Markov chain Monte Carlo simulation

This paper presents the posterior analysis of a new family defined in the literature as modified Weibull distribution. This family is a modification of the two-parameter Weibull model in the sense that it, besides covering increasing and decreasing hazard rates, also represents bathtub-shaped behaviour. Both the Gibbs sampler and the Metropolis algorithms have been used to provide complete analysis of the concerned posterior surfaces. The paper also considers examining the issue of model validation using predictive simulation ideas and the Bayesian p-value. Finally, numerical illustration has been provided based on two real data sets.

Weibull extension model: A Bayes study using Markov chain Monte Carlo simulation

Several generalizations of the two-parameter Weibull model have been proposed to model data sets that exhibit complex non-monotone shapes of hazard rate function. The present paper focuses on one such generalization referred to as the Weibull extension model in the literature. Complete Bayesian analysis of the model has been provided using Markov chain Monte Carlo simulation. Finally, a thorough study has been conducted for checking the adequacy of the model for a given data set using some of the graphical and numerical methods based on predictive simulation ideas. A real data set is considered for illustration.

A coupled-cluster study on the noble gas binding ability of metal cyanides versus metal halides (metal = Cu, Ag, Au).

A coupled‐cluster study is carried out to investigate the efficacy of metal(I) cyanide (MCN; Mu2009=u2009Cu, Ag, Au) compounds to bind with noble gas (Ng) atoms. The Muf8ffNg bond dissociation energy, enthalpy change, and Gibbs free energy change for the dissociation processes producing Ng and MCN are computed to assess the stability of NgMCN compounds. The Ng binding ability of MCN is then compared with the experimentally detected NgMX (Xu2009=u2009F, Cl, Br) compounds. While CuCN and AgCN have larger Ng binding ability than those of MCl and MBr (Mu2009=u2009Cu, Ag), AuCN shows larger efficacy toward bond formation with Ng than that of AuBr. Natural bond orbital analysis, energy decomposition analysis in conjunction with the natural orbital for chemical valence theory, and the topological analysis of the electron density are performed to understand the nature of interaction occurring in between Ng and MCN. The Nguf8ffM bonds in NgMCN are found comprise an almost equal contribution from covalent and electrostatic types of interactions. The different electron density descriptors also reveal the partial covalent character in the concerned bonds.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

Objective: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. Methods: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPTA® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 μg, FF/UMEC 400/500 μg, UMEC/VI 500/100 μg, or FF/VI 400/100 μg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 μg or 400/250/100 μg, FF/VI 400/100 μg, or UMEC/VI 250/100 μg. PK and PD parameters and safety were assessed. Results: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. Conclusions: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

Toxicity of Halogen, Sulfur and Chlorinated Aromatic Compounds: A Quantitative-Structure-Toxicity-Relationship (QSTR)

In this paper, quantitative–structure–toxicity–relationship (QSTR) models are developed for predicting the toxicity of halogen, sulfur and chlorinated aromatic compounds. Two sets of compounds, containing mainly halogen and sulfur inorganic compounds in the first set and chlorinated aromatic compounds in the second, are investigated for their toxicity level with the aid of the conceptual Density Functional Theory (DFT) method. Both sets are tested with the conventional density functional descriptors and with a newly proposed net electrophilicity descriptor. Associated R2, R2CV and R2adj values reveal that in the first set, the proposed net electrophilicity descriptor (??±) provides the best result, whereas in the second set, electrophilicity index (?) and a newly proposed descriptor, net electrophilicity index (??±) provide a comparable performance. The potential of net electrophilicity index to act as descriptor in development of QSAR model is also discussed.

Accelerated test system strength models based on Birnbaum–Saunders distribution: a complete Bayesian analysis and comparison

Several models for studies related to tensile strength of materials are proposed in the literature where the size or length component has been taken to be an important factor for studying the specimens’ failure behaviour. An important model, developed on the basis of cumulative damage approach, is the three-parameter extension of the Birnbaum–Saunders fatigue model that incorporates size of the specimen as an additional variable. This model is a strong competitor of the commonly used Weibull model and stands better than the traditional models, which do not incorporate the size effect. The paper considers two such cumulative damage models, checks their compatibility with a real dataset, compares them with some of the recent toolkits, and finally recommends a model, which appears an appropriate one. Throughout the study is Bayesian based on Markov chain Monte Carlo simulation.

Systemic Exposures of Fluticasone Propionate and Salmeterol Following Inhalation via Metered Dose Inhaler with the Mini Spacer Compared with the Aerochamber Plus Spacer

BACKGROUNDnThe Mini Spacer has been developed for use with Ventolin(®) metered dose inhalers (MDIs) to improve accessibility to affordable spacers in developing countries. To ensure patient safety is not compromised if the Mini Spacer is used off-label with fluticasone propionate (FP) or salmeterol/FP combination (SFC) MDIs (currently not recommended), this study compared the systemic exposure of FP and salmeterol following delivery of FP and SFC MDIs with the Mini Spacer and the Aerochamber Plus(®) spacer (Aerochamber).nnnMETHODSnThis was an open-label, randomized, single dose, crossover study in healthy subjects that evaluated four treatments: i) FP 250u2009μg MDI with Mini Spacer; ii) FP 250u2009μg MDI with Aerochamber; iii) SFC 25/250u2009μg with Mini Spacer; iv) SFC 25/250u2009μg with Aerochamber. There was a minimum 7 day washout between treatments. Pharmacokinetic samples were collected over 24 hours post-dose. The co-primary endpoints were FP area under the concentration-time curve from time zero to 24u2009h [FP AUC(0-24)] and salmeterol maximum plasma concentration [Cmax].nnnRESULTSnFP systemic exposure in terms of AUC(0-24) was lower following inhalation with the Mini Spacer compared with the Aerochamber for both FP 250u2009μg (Mini Spacer/Aerochamber Ratio 0.76 [90% CI: 0.57-1.01]) and SFC 25/250u2009μg (Ratio 0.74 [90% CI: 0.56-0.99]). Salmeterol systemic exposure was also lower following SFC 25/250u2009μg with Mini Spacer compared with Aerochamber (Cmax Ratio 0.90 [90% CI 0.48-1.66]). The incidence of adverse events was low and similar with each treatment.nnnCONCLUSIONSnIn the event of use of the Mini Spacer with FP and SFC MDIs, which is not recommended, FP and salmeterol systemic exposure is unlikely to be higher than if MDIs were to be used with the Aerochamber. However, these data do not indicate that the Mini Spacer and Aerochamber are interchangeable.

Comparison of the Pharmacokinetics of Salmeterol and Fluticasone Propionate 50/100 µg Delivered in Combination as a Dry Powder Via a Capsule-Based Inhaler and a Multi-Dose Inhaler

Background and ObjectivesThe Rotacaps®/Rotahaler® system is a single unit dose inhaler being developed to deliver inhaled salmeterol/fluticasone propionate combination (SFC) as an alternative treatment option to the metered dose inhaler and the multi-dose dry powder inhaler, Diskus®. The aim of this study was to compare the systemic exposure of SFC 50/100xa0µg following delivery via the Rotacaps®/Rotahaler® and the Diskus®.MethodsThis was an open-label, randomized, cross-over, repeat-dose (3.5 days of twice-daily dosing) study comparing salmeterol and fluticasone propionate systemic exposure following inhaled SFC 50/100xa0µg delivered via the Rotacaps®/Rotahaler® and Diskus®, in healthy subjects. Pharmacokinetic sampling was conducted over 12xa0h post-dose on the last day of each treatment. Pharmacokinetic samples were analysed using solid phase extraction followed by high performance liquid chromatography/tandem mass spectrometry. Co-primary endpoints were fluticasone propionate area under the concentration-time curve over the dosing interval (AUC0–τ) and salmeterol maximum plasma concentration (Cmax) on the last day of treatment.ResultsFollowing SFC 50/100 µg Rotacaps®/Rotahaler®, fluticasone propionate and salmeterol systemic exposures were comparable with Diskus® in terms of both AUC0–τ [geometric mean ratio (GMR) with 90xa0% confidence interval (CI) of Rotahaler®/Diskus® for fluticasone propionate: 0.98 (0.91, 1.06) and salmeterol: 1.04 (0.99, 1.10)] and Cmax [GMR (90xa0% CI) for fluticasone propionate: 1.04 (0.94, 1.15) and salmeterol: 0.97 (0.87, 1.08)], meeting the pre-defined criteria for comparability (upper limit of the 90xa0% CI for the GMRs (Rotahaler®/Diskus®) ≤1.25]. SFC delivered from both inhalers was well tolerated.ConclusionsSFC 50/100 µg Rotacaps®/Rotahaler® showed comparable fluticasone propionate and salmeterol systemic exposure to Diskus® for all pharmacokinetic endpoints with GMR and both upper and lower limits of 90xa0% CIs within conventional acceptance criteria for bioequivalence (0.8, 1.25), sufficient for considering progression of the Rotacaps®/Rotahaler® product for further clinical development.

A Bayes comparison of Weibull extension and modified Weibull models for data showing bathtub hazard rate

A number of models have been proposed in the literature to model data reflecting bathtub-shaped hazard rate functions. Mixture distributions provide the obvious choice for modelling such data sets but these contain too many parameters and hamper the accuracy of the inferential procedures particularly when the data are meagre. Recently, a few distributions have been proposed which are simply generalizations of the two-parameter Weibull model and are capable of producing bathtub behaviour of the hazard rate function. The Weibull extension and the modified Weibull models are two such families. This study focuses on comparing these two distributions for data sets exhibiting bathtub shape of the hazard rate. Bayesian tools are preferred due to their wide range of applicability in various nested and non-nested model comparison problems. Real data illustrations are provided so that a particular model can be recommended based on various tools of model comparison discussed in the paper.

Modeling of 1-D Nanowires and analyzing their Hydrogen and Noble Gas Binding Ability

AbstractThe theoretical calculation at the M05-2X/6-311+G(d,p) level reveals that the B–B bond length in [N4-B2-N4]2− system (1.506 Å) is slightly smaller than that of typical B=B bond in B2H2 (1.518 Å). These systems interact with each M+ (M = Li, Na, K) ion very strongly with a binding energy of 213.5 (Li), 195.2 (Na) and 180.3 (K) kcal/mol. Additionally, the relief of the Coulomb repulsion due to the presence of counter-ion, M+, the B–B bond contracts to 1.484–1.488 Å in [N4-B2-N4]M2. We have further extended our study to [N4-B2-N4-B2-N4]4− and [N4-B2-N4-B2-N4-B2-N4]6− systems. The B–B bond length is found to be 1.496 Å in the former case, whereas the same is found to be 1.493 Å and 1.508 Å, respectively, for the two B–B bonds present in the latter one. The M + counter-ions stabilize such negatively charged systems and thus, create a possibility to design a long 1-D nanowire. Their utilities as probable hydrogen and noble gas (Ng) binding templates are explored taking [N4-B2-N4-B2-N4]Li4 system as a reference. It is found that each Li center binds with three H2 molecules with an average binding energy of 2.1 kcal/mol, whereas each Ng (Ar–Rn) atom interacts with Li center having a binding energy of 1.8–2.1 kcal/mol. The H2 molecules interact with Li centers mainly through equal contribution from orbital and electrostatic interaction, whereas the orbital interaction is found to be major term (ca. 51–58%) in Ng-Li interaction followed by dispersion (ca. 24–27%) and electrostatic interaction (ca. 17–24%).n Graphical AbstractThe B-B bonds in [N4-B2-N4]2-, [N4-B2-N4-B2-N4]4- and [N4-B2-N4-B2-N4-B2-N4]6- possess some degree of triple bond character. These anionic systems can be stabilized by combining with an adequate number of M+ (M = Li, Na, K) ions. It opens up the possibility of designing a long 1-D nanowire. The Li centers of this nanowire can bind hydrogen molecules and noble gas atoms effectively.